Ординатура / Офтальмология / Английские материалы / Current Aspects of Pathogenesis and Treatment in Diabetic Retinopathy_Kroll_2007

Fig. 3. Tractional retinal detachment nasally to the fovea. The membranes were atrophic after scatter laser treatment and the traction did not threaten the fovea. Vision was 20/25 and no further therapy was performed.

fibrovascular membranes require retinal photocoagulation. Laser treatment induces fibrotic transformation of the neovascularizations and possibly contraction of the membranes, which may eventually lead to progression of the tractional detachment [27]. Before vitreous surgery was available, these eyes had a very poor prognosis and laser treatment was considered to be dangerous in these eyes. Now that we can surgically treat these tractional membranes, scatter laser treatment is recommended if active neovascularizations are present, but a close followup is mandatory. Vitrectomy is recommended if the detachment progresses and threatens the fovea or if significant vitreous hemorrhage develops.

Tractional Rhegmatogenous Retinal Detachment

Traction by diabetic fibrovascular membranes may create retinal tears and a rhegmatogenous retinal detachment may develop (fig. 4). This combined tractional and rhegmatogenous retinal detachment is relatively rare and shows both features of a tractional detachment with membranes tightly adhering to the retina and a retinal tear. The retinal tear itself may be difficult to identify, but the shape of the retinal detachment is quite different. A pure tractional detachment is usually concave, tent-like shaped and the retina is not mobile. The appearance of rhegmatogenous detachment is convex, bullous and mobile. While a tractional detachment progresses slowly and does not require emergency surgery, a tractional-rhegmatogenous detachment usually progresses rapidly and has to be operated without delay. The prognosis of tractional rhegmatogenous retinal detachment is less favorable than for pure tractional detachments. Intraoperatively it is more difficult to separate the membranes from a mobile retina than from a fixed and relatively stable retina. Perfluorcarbon should not be used until the membranes are removed from the posterior pole. Intraoperative complications are relatively common in this type of surgery [28]. In addition, we occasionally observe reproliferations in the postoperative course which represent a combination of diabetic fibrovascular membranes and the typical proliferative vitreoretinopathy. These proliferations are surgically very difficult to manage.

Fig. 4. Tractional rhegmatogenous retinal detachment, visual acuity hand movement. The retinal tear is marked with an arrow.

Tractive Macular Edema

In some cases traction on the fovea may cause tractive macular edema, even if the fovea itself is not detached. Traction of diabetic fibrovascular membranes may cause an ophthalmoscopic appearance with typical hard exudates (fig. 5). Atrophic fibrovascular membranes may

also create a picture similar to macular pucker with distortion of the central retina. The best therapy for tractional edema is to remove the traction. Tractional membranes may often be easily visible, but in other cases biomicroscopy only shows minimal changes. In some instances ocular coherence tomography can clearly demonstrate the fine membranous structures exerting tractional forces and creating swelling of the macula [29]. Thus, ocular coherence tomography imaging should be included in the diagnostic workup of diabetic macular edema. In cases without traction, laser treatment is a valuable approach; focal laser treatment is not recommended if mechanical traction is the cause for macular edema. Visual recovery after surgery is mainly dependent on the degree of macular ischemia; therefore preoperative fluorescein angiography is helpful to give a picture of the status of macular microcirculation.

Diffuse Macular Edema

Several recent reports have described an improvement of diffuse diabetic macular edema without visible traction after vitrectomy in eyes with attached vitreous [30]. The pathophysiological basis for this attempt was to improve access of oxygen and nutrients from the vitreous to

the retina, and vice versa, to facilitate diffusion of cytokines from the retinal tissue into the vitreous, avoiding accumulation of factors triggering macular edema within the macular tissue. Despite significant anatomical improvement of the edema after removal of the vitreous, recovery of vision was rather unsatisfactory in many cases. It is still controversial whether this approach with or without removal of the inner limiting membrane significantly improves the long-term course of the disease in eyes with diffuse diabetic macular edema without traction [31, 32].

Surgery for Neovascular Glaucoma

The cause for neovascularizations of the iris and chamber angle is believed to be the ischemic retina, which produces vasoproliferative growth factors. These cytokines may diffuse to the anterior segment of the eye, triggering anterior segment neovascularizations. In aphacic and vitrectomized eyes there is no diffusion barrier between the anterior and posterior segment of the eye. Therefore these eyes are particularly at risk for the development of neovascular glaucoma. Therapy has to be primarily directed to the cause of the neovascular stimulus, the ischemic retina. The most important element of treatment is there-

fore retinal ablation by laser or cryotreatment [33]. Since this treatment can induce fibrotic regression but not complete dissolution of the membranes in the chamber angle, retinal ablation is often not sufficient to regulate intraocular pressure. Therefore additional treatment to lower intraocular pressure is usually necessary. Filtering surgery has a poor prognosis, since the high levels of cytokines in the aqueous humor stimulate fibrosis which is obstructing the fistula. Antimetabolites or glaucoma drainage devices [34] may be used to improve success rates but have an increased risk for complications. Transscleral cryotherapy [35] or transscleral laser treatment to the ciliary body is an alternative to reduce aqueous humor production but has a relatively narrow therapeutic window; overtreatment may induce phthisis of the globe. If other diabetic complications are present, requiring vitreoretinal surgery, direct endolaser treatment to the ciliary processes can be applied to reduce aqueous humor production [36]. In severe cases instillation of liquid silicone can form a diffusion barrier between the retina and the anterior segment of the eye and may contribute to a stabilization of anterior segment neovascularization [37].

Cataract Surgery

Second to age, diabetes is the main epidemiological risk factor for the development of cataracts. Cataract surgery in eyes with diabetic retinopathy is performed to improve vision for the patient, but it also allows a clear view to the fundus for diagnosis and treatment of the retinopathy. However, cataract surgery may worsen retinopathy [38]. Neovascularizations and macular edema may be stimulated to grow after cataract surgery [39, 40]. Nevertheless, conventional cataract surgery with phacoemulsification and implantation of an intraocular lens can be safely performed in most eyes with diabetic retinopathy [41, 42]. Intracapsular surgery is associated with an increased risk for neovascular glaucoma [43] and should be avoided in diabetic eyes. Several other aspects should be taken into account. Whenever possible retinopathy should be treated and stabilized before surgery using adequate laser photocoagulation. Especially eyes with iris neovascularizations require intense preoperative laser coagulation or transscleral cryotreatment of the retina. If this is not possible before surgery or not sufficient, a combined procedure with cataract and vitreous surgery including endolaser treatment of the retina should be considered. Fibrinous reaction after cataract surgery alone may render postoperative laser treatment in eyes with iris rubeosis difficult.

If macular edema is present, preoperative focal laser treatment should be used. If it is not possible to have a completely dry macula at the time of cataract surgery, there is a high risk for worsening of macular edema and visual loss. If cataract surgery has to be performed in the presence of diabetic macular edema, it may be recommended to combine cataract surgery with an intravitreal injection of triamcinolone [44–46]. Intravitreal triamcinolone has been shown to successfully improve vision and retinal thickening in diabetic macular edema [47].

Other specific aspects for cataract surgery in eyes with diabetic retinopathy include a large capsulorhexis and an intraocular lens with large optics to facilitate possible subsequent diagnosis and laser treatment of the retina. Silicone intraocular lenses should be avoided because they interact with liquid silicone which possibly has to be used for endotamponade in the later course of diabetic eye disease. Diabetic eyes have an increased risk for postoperative fibrin exudation and formation of synechiae between the lens capsule and the iris due to an impaired blood retinal barrier [48–50].

Complications of Surgery for Diabetic Retinopathy

Cataract

Opacification of the lens is a mandatory consequence of vitrectomy independently of the cause for vitrectomy. Generally, development of cataracts appears to occur faster in diabetic eyes after vitrectomy than after vitrectomy in nondiabetic eyes. Silicone tamponade leads to an acceleration of cataract formation. Gas tamponade induces an immediate posterior subcapsular opacification occurring a few hours after surgery, which is mostly reversible. Later nuclear sclerosis develops, which does not appear to be much faster after gas tamponade than after vitrectomy with Ringer’s solution [48]. In young patients cataract formation occurs more slowly, and the lens may remain clear for many years or decades before surgery becomes necessary [51]. In older patients significant cataracts may form within a few months after vitrectomy.

The rapid development of cataract after vitrectomy especially in older diabetics has led some surgeons to perform combined viteoretinal and cataract surgery even for eyes with primarily clear lenses. This approach has been shown to be successful and saves the patient a second surgery [52, 53]. Combined surgery however appears to be associated with a higher rate of inflammatory responses with fibrin in the anterior chamber and the formation of synechiae compared to a 2-step procedure [50]. It may

Helbig

therefore be safer to operate on the lens in a second surgery if possible. Combined cataract and vitreoretinal procedure may only be performed if lens opacities are disturbing intraoperative visualization of the posterior segment.

Retinal Detachment

Rhegmatogenous retinal detachment is a typical complication of vitrectomy [54]. Retinal holes may be created intraoperatively when traction to the vitreous base is exerted. The most common location of iatrogenic holes is close to the sclerotomies where intraocular instruments are introduced into the eye. The more instruments are exchanged during surgery, the higher the risk for creating holes. The risk can be reduced by carefully removing the anterior vitreous next to the sclerotomies with the cutter before instruments like scissors are introduced. In righthanded surgeons the most common location is temporal superior in the right eye and nasal superior in the left eye. Careful inspection of the peripheral retina out to the ora serrata at the end of the surgery under indentation using a wide angle viewing system may identify such retinal tears [55]. Adequate treatment can reduce the risk for postoperative retinal detachment. If postvitrectomy rhegmatogenous retinal detachment occurs, pneumatic retinopexy as a minimum invasive procedure is often the treatment of choice. The tears are anteriorly located and can be reached with transscleral cryotherapy without opening the conjunctiva. The holes are mostly located in the superior quadrants and gas injection in a vitrectomized eye is not associated with a high risk of creating new holes.

Another possible cause for postoperative retinal detachment after vitrectomy for diabetic retinopathy are retinal holes located more posteriorly. These holes may be created during the preparation of membranes tightly adhering to the thin and atrophic retina mostly being located close to the major vascular arcades. If such holes are recognized intraoperatively, all traction surrounding the hole has to be released, the hole should be encircled with laser spots and an adequate internal tamponade, often liquid silicone, should be used.

Tractive redetachment may occur if severe reproliferations develop. The traction of reproliferation may also tear off laser scars and create a combined tractional rhegmatogenous retinal detachment.

Reproliferations

Reproliferation of diabetic fibrovascular membranes is a severe complication after vitrectomy for diabetic ret-

inopathy. Since the ischemic retina is believed to secrete the proliferative stimuli, the ischemic retina has to be adequately treated with laser. Especially in eyes with silicone tamponade growth factors may concentrate in the shallow interface between silicone and retina and provide an intense stimulus for reproliferations [56, 57]. Complete removal of all fibrovascular tissue using various techniques (‘segmentation’ technique [58], ‘delamination’ [59] or ‘en bloc’ [60] technique) eliminates the starting point and the substrate for reproliferations. In rare cases fibrovascular membranes may also develop along the anterior vitreous remnants creating anterior hyaloid fibrovascular membranes. Neovascularizations at the internal side of the sclerotomies may be the source for recurrent hemorrhage, if no neovascularizations are present in the posterior pole. In advanced cases it may be difficult to differentiate between diabetic reproliferations and proliferative vitreoretinopathy reactions, which we also occasionally see after surgery for rhegmatogenous retinal detachment in nondiabetic eyes.

Hemorrhage

Small amounts of blood are found in most eyes after vitreous surgery for diabetic retinopathy and significant rebleeding is not exceptionally rare. Diabetic neovascularizations are cut or torn off during surgery creating opening of the vessel lumen and a potential source for a vitreous hemorrhage. Bleeding vessels may be identified intraoperatively by lowering the intraocular pressure and should be coagulated intraoperatively using endodiathermia. If the source of hemorrhage is a large vessel or the optic disk, this may not be possible. The bleeding often stops spontaneously or after increasing the infusion pressure, but it may cause hemorrhages in the early postoperative phase when the blood pressure increases. Very dense hemorrhages after vitrectomy may be removed by revitrectomy or by fluid-air exchange [61].

Iris Rubeosis and Neovascular Glaucoma

Neovascularizations of the iris and chamber angle may occur if growth factors from the ischemic retina reach the anterior segment of the eye. Obstruction of the trabecular meshwork by fibrovascular membranes and increased intraocular pressure is a severe complication of diabetic retinopathy. Two aspects of vitreous surgery may contribute to the development of postoperative iris rubeosis. First, the removal of preretinal neovascularizations may worsen retinal ischemia and further stimulate the production of growth factors. Second, after removal of the vitreous these cytokines can more easily diffuse to

the anterior segment of the eye. Especially after additional intracapsular cataract surgery there is no diffusion barrier left between iris and retina. To reduce the stimulus for neovascularizations, endolaser treatment should be applied at the end of vitreous surgery whenever possible.

Iris rubeosis is associated with retinal detachment in diabetic eyes. Sudden appearance of rubeosis in the postoperative course should alert the ophthalmologist to carefully inspect the peripheral retina [62].

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Table 1. Level of evidence (modified from Centre for EvidenceBased Medicine [4], 2004)

Table 2. Grade of recommendation (modified from Centre for Evidence-Based Medicine [4], 2004)

4case series (and poor quality cohort and case

control studies)

5consensus conference and expert opinion

The implementation of EBM principles into the treatment regimen of diabetic retinopathy seems to be immensely important, since diabetic retinopathy continues to be the most frequent cause of blindness among working age adults in industrialized countries [29] despite various treatment approaches such as laser photocoagulation, cryocoagulation, pars plana vitrectomy, intravitreal triamcinolone and others. In Germany about 1,500–2,000 diabetics become legally blind each year. The risk of blindness is thus increased by a factor of 29 compared to nondiabetics. Economic costs of about EUR 100 million arise per year in welfare payments to the blind [18, 20, 29].

Material and Methods

Sackett et al. [44] generated ‘levels of evidence’ for ranking the validity of evidence and tied them as ‘grades of recommendations’ to the advice given in a certain report. These levels, which were first brought up as a basis for recommendations about the use of antithrombotic agents [44], have grown increasingly sophisticated [4]. They evolved over time and are now widely used in various fields of medicine (tables 1, 2).

In ophthalmo-diabetology EBM has been applied for many years. Laser coagulation has proven effective by randomized, controlled, clinical trials with an evidence level of 1, as well as pars plana vitrectomy for more advanced proliferative stages of diabetic retinopathy. Intravitreal triamcinolone injection and pars plana vitrectomy for treatment of diabetic macular edema so far have only lower levels of evidence.

The most important studies which are the basis for today’s treatment of diabetic retinopathy and maculopathy are described below. Tables 3 and 4 show classification systems for nonproliferative/proliferative diabetic retinopathy and for diabetic maculopathy and they also show which stages were treated in different studies.

Grade of recommendation

Aconsistent level 1 studies

Bconsistent level 2 or 3 studies or extrapolations from level 1 studies

Clevel 4 studies or extrapolations from level 2 or 3 studies

Dlevel 5 evidence or troublingly inconsistent or inconclusive studies of any level

Results

Diabetic Retinopathy Study

The Diabetic Retinopathy Study (DRS) was carried out between 1971 and 1975. It tried to determine whether photocoagulation could prevent severe vision loss due to proliferative diabetic retinopathy. Furthermore, efficacy and safety of argon laser coagulation and xenon photocoagulation were compared. It was the first randomized, controlled, clinical trial dealing with laser treatment of proliferative diabetic retinopathy involving 11,700 patients enrolled at 15 medical centers [23, 49–53]. The study has an evidence level of 1b.

In order to be eligible for the study, patients had to have a visual acuity of at least 20/100 in each eye. In addition, proliferative diabetic retinopathy had to be present in at least 1 eye or severe nonproliferative retinopathy in both eyes.

The patients included had 1 eye randomized to a treatment group receiving immediate photocoagulation. The other eye remained untreated and served as control. The treated eye was again randomized to either argon laser coagulation or xenon photocoagulation.

The Diabetic Retinopathy Study could show that both types of coagulation could reduce the risk of suffering a severe vision loss by 150%. It was concluded, therefore, that argon laser coagulation and xenon photocoagulation were beneficial over no treatment and that there was only a moderate risk of coagulation induced visual acuity or visual field loss. High-risk proliferative diabetic retinopathy was determined as the stage of retinopathy where benefits of coagulation treatment outweigh its risks. Because of its clear results, the study was terminated early [52].

The upper part of the table shows 3 classification systems of diabetic retinopathy. The lower part lists important studies dealing with various stages of diabetic retinopathy. All studies have an evidence level of 1b. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) deal with mild and moderate cases of nonproliferative diabetic retinopathy (NPDR), the Diabetic Retinopathy

Study (DRS) with severe NPDR to high-risk proliferative diabetic retinopathy (PDR). The Early Treatment Diabetic Retinopathy Study (ETDRS) in turn covers cases of mild, moderate and severe NPDR and cases of early PDR. Finally the Diabetic Retinopathy Vitrectomy Study (DRVS; modified from Aiello [1], 2003) was performed on patients with high-risk and severe PDR. PDVR = Proliferative diabetic vitreoretinopathy; DM = diabetes mellitus.

Early Treatment Diabetic Retinopathy Study

Between 1979 and 1991, the Early Treatment Diabetic Retinopathy Study, a multicenter, randomized clinical trial, tried to evaluate the effectiveness of both argon laser coagulation and aspirin therapy in delaying or preventing progression of early diabetic retinopathy to severer stages. Moreover, it tried to determine the best time to start laser coagulation therapy. For that purpose, a total of 13,700 patients with nonproliferative or early proliferative diabetic retinopathy were recruited and followed for at least 4 years [7–15, 23]. The study has an evidence level of 1b.

The patients were divided into different groups depending on the degree of macular involvement and on the stage of diabetic retinopathy. One eye was randomized into a treatment group and treated immediately by laser coagulation, the other eye served as a control and was not treated until high-risk proliferative retinopathy developed. The eyes randomized into the treatment group were again randomized into 4 different treatment

patterns, starting with a focal laser treatment followed by a mild or complete scatter laser coagulation, or starting with a mild or complete scatter laser coagulation followed by a focal laser treatment in the macular area (fig. 1).

For focal laser treatment, the Early Treatment Diabetic Retinopathy Study (ETDRS) could show a reduced risk of moderate vision loss, especially in eyes where the fovea was threatened or affected by macular edema. In eyes treated focally even a moderate vision gain could be observed.

In eyes with a mild to moderate nonproliferative diabetic retinopathy a scatter treatment turned out not to be necessary. However, eyes with a severe nonproliferative or an early proliferative diabetic retinopathy should be considered for scatter treatment. Finally, eyes with highrisk proliferative diabetic retinopathy should be treated to avoid disease progression. This was found to be true especially for patients with non-insulin-dependent diabetes mellitus. Patients with advanced active proliferative

The only large, randomized, controlled, clinical trial dealing with diabetic maculopathy is the Early Treatment of Diabetic Retinopathy Study. Its level of evidence is 1b. For other therapeutic methods such as vitrectomy with or without peeling of the in-

ternal limiting membrane and for intravitreal triamcinolone injections only level 4 studies exist. ILM = Internal limiting membrane.

diabetic retinopathy should be considered for early vitrectomy. All patients with diabetic retinopathy should be monitored closely and followed up carefully.

With regard to the use of aspirin, the study could show that aspirin did not affect the progression of retinopathy to the high-risk proliferative stage. It did not even increase the risk of vitreous hemorrhage or affect visual acuity. However, since aspirin was associated with a lower risk of cardiovascular disease, the study concluded that there were no ocular contraindications against aspirin use in cardiovascular or other diseases [7–15, 23].

Diabetic Retinopathy Vitrectomy Study

Between 1979 and 1990, the Diabetic Retinopathy Vitrectomy Study, which consisted of 2 randomized clinical trials, compared early vitrectomy with conventional management of diabetes induced severe vitreous hemorrhage [23, 54–58]. The study has an evidence level of 1b.

For the first trial 1600 patients with recent severe vitreous hemorrhage, a visual acuity of at least 5/200 and an attached macula in at least 1 eye were recruited. They were randomized into either an early vitrectomy group,

treated by vitrectomy immediately, or a conventional treatment group, treated by vitrectomy if vitreous hemorrhage persisted for 11 year or if retinal detachment involving the macula occurred.

For the second trial 381 patients with severe proliferative diabetic retinopathy and a visual acuity 60.2 in at least 1 eye were recruited. Again patients were randomized into either an early vitrectomy group, treated by vitrectomy immediately, or a conventional treatment group, consisting of laser coagulation when indicated and vitrectomy if severe vitreous hemorrhage did not clear after 6–12 months or if retinal detachment involving the macula occurred

In the first trial, 25% of patients vitrectomized early regained a good visual acuity of 60.5 compared with 15% treated conventionally. There was, however, a higher treatment risk. Complications such as loss of light perception occurred in 25% of cases in the early vitrectomy group versus 19% in the conventional treatment group. In the second trial, there was also a higher probability of postoperative visual acuity 10.5 in the early vitrectomy group.