Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

endothelial growth factor (VEGF) inhibitors represents a treatment option that targets the disease at the causal molecular level. Increased VEGF levels were measured in patients with vein occlusion, and correlated with the extent of macular edema [179, 180]. Preliminary studies using anti-VEGF drugs such as pegaptanib and bevacizumab show a promising effect on macular edema of vascular origin, especially venous occlusive disorders [121, 125, 203]. Both substances are potent anti-edematous agents, possibly specifically reducing the permeability of retinal capillaries or even downregulating VEGF, but they do not eliminate the cause of the disease. The exact duration of therapeutic effect is as yet unknown and seems to decrease within a few weeks. The need for repeat injections has been reported after 4 weeks. No information exists about the long term outcome and possible negative influences on the development of collateral vessel formation or normal retinal vasculature. Controlled studies are mandatory to evaluate the role of this off-label therapy.

21.3.8.2.10 Surgical Treatment

None of the aforementioned therapies is able to restore blood flow in BRVO. It is believed that the therapeutic goal must be directed to solving the obstructive process in the vascular lumen. The unique opportunity to visualize and reach the retinal vessels during vitreous surgery is leading to surgical approaches to either decompress or cannulate the affected vein. The surgical options of arteriovenous adventitial sheathotomy, vitrectomy and vessel cannulation are discussed below.

21.3.8.2.11Arteriovenous Adventitial Sheathotomy

Pars plana vitrectomy with surgical separation of the retinal artery from the underlying vein at the site of the presumed pathologic AV crossing has been advocated as a potential treatment for BRVO. The separation addresses a theoretical pathogenic mechanism of BRVO and should effect reperfusion of the retina, rather than treating the BRVO sequelae. It is hypothesized that dissection of a common adventitia surrounding the artery and vein mitigates the obstruction. Mechanical relief of the retinal vessels may generate higher intraluminal pressure, resulting in better venous blood flow and improvement of visual function (Fig. 21.3.24).

Osterloh and Charles first described successful surgical decompression by dissection of the common adventitial sheath at the crossing site in one patient with BRVO [184]. Eleven years later, this therapeutic strategy was resurrected by Opremczak

Fig. 21.3.24. Schematic drawing of surgical arteriovenous decompression with dissection of the common adventitial sheath at the occlusion site using a bent microvitreoretinal blade

and Bruce. They published favorable results with sheathotomy in 15 eyes with BRVO [182]. After 3 months, the vision of 67 % of patients improved by an average of four lines. Recently, successful arteriovenous adventitial sheathotomy (AAS) was reported using the 25 gauge vitrectomy technique [82, 150]. Kube et al. measured that AAS led to a significant decrease of AV passage time and can ameliorate retinal perfusion in the affected branch [142]. Yamaji et al. reported a reduced filling delay after AAS [258]. Fluorescein videoangiography with computerassisted image analysis has shown improved retinal circulation [220]. Meanwhile, AAS has been reported in more than 250 patients. Preand postoperative images of a patient are shown in Figs. 21.3.31 and 21.3.32. There are studies claiming a favorable outcome [35, 85, 157, 158, 168, 172, 173, 215, 259] while others deny a treatment benefit [17, 32, 75, 83, 102]. In a long term follow-up (mean 6.5 years) of five patients with a poor visual prognosis, Shah et al. reported substantial visual improvement after AAS on a long term basis [215]. Mester and Dillinger reported significantly improved results in a larger series but in several patients the internal limiting membrane was also removed [172]. The aforementioned authors observed intraoperative restoration of the downstream blood flow in the occluded vein immediately after decompression. FLA revealed improved capillary perfusion in 93 % of patients 6 weeks after surgery. Functional improvement has been reported in patients with ischemic BRVO as well [157]. Following AAS a transient improvement of retinal blood flow was measured [116]. The addition of a thrombolytic over the crossing after its dissection may be helpful. Garcia-Arumi et al. performed additional fluid-air exchange and injected 25 μg of recombinant tissue plasminogen activator

(rTPA) in the affected area [85]. Using a bimanual technique they achieved successful unroofing of the vein in all 35 patients. In 28.6 % they observed thrombus release, an immediate restoration of downstream blood flow in FLA and in 74.3 % proximal venous widening. In most of these patients improvement of VA was four lines or more. Except-

ing the general risks of a vitrectomy, potential com- III 21 plications of the procedure include laceration of the

vein or artery with consecutive hemorrhage, or arcuate scotoma due to incision on the nerve fiber layer [85, 182]. Different techniques and instruments such as vitreoretinal scissors, bent microvitreoretinal blades, ring forceps and microscissors have been suggested for separating the crossing and cutting the glial tag at the occlusion site [71, 73, 85, 182]. Despite these developments, in a considerable number of patients surgical separation of the vessels cannot be achieved [17, 72, 73]. In a clinicopathological correlation, Feltgen et al. showed surgically induced nerve fiber damage. Han et al. modified their approach to a more limited dissection [102] without separation of the retinal vessels. Interestingly, incomplete dissection or even iatrogenic perforation of the vein resulted in better visual results [52, 73, 102]. This supports the possibility that freeing the vessels from their retinal bed alone might be effective [73].

Although some authors speculate that early surgical decompression may reduce retinal hemorrhages and ischemia [85, 172, 182], it is questionable whether the procedure is worth the risks [52, 72]. Resolution of the stigmata of retinal venous insufficiency does not uniformly occur. The mechanism by which intraretinal hemorrhage may clear faster may be related to improved blood flow or to easier dissipation of blood into the vitreous cavity.

The role of AV dissection itself and the mechanisms by which AAS improves VA have not yet been clarified. The different results may depend on different inclusion criteria, surgical techniques and the time lapse between onset of the BRVO and surgery. Other confounding factors may also affect the outcome. Vitrectomy with AAS consists of several components, the relative contributions of which toward improvement of retinal venous blood flow (if any) remain undetermined. Other procedural factors include the vitrectomy method itself, stripping of the posterior hyaloid and the delamination of the internal limiting membrane (ILM). These components may play a decisive role as well and are discussed later [205, 224, 225]. Also the adjunctive use of triamcinolone at the end of vitrectomy for BRVO was reported [241].

Lakhanpal et al. proposed transvitreal limited arteriovenous crossing manipulation (LAM) without vitrectomy as a minimally invasive way to achieve clot dislodgement and reperfusion and to avoid the

typical complications of vitrectomy such as cataract formation [149, 150].

In one trial comparing AAS and macular grid LC, no difference of the functional outcome could be detected [154], whereas another comparative study found significantly improved visual results following AAS [168]. However, both sample sizes were small,

21 III no randomization was performed or no Early Treatment Diabetic Retinopathy Study (ETDRS) VA was obtained. In a recent prospective case series a favorable functional outcome of AAS irrespective of successful dissection against isovolemic hemodilution was reported [73]. Irreversible fibrotic alterations of the vascular structure are probably due to the duration of vein occlusion [41, 50, 196] and as in most macular disorders a better functional outcome after AV decompression is reported after shorter duration of BRVO [172]. Also, youth had a beneficial influence on the functional results. Han et al. observed worse visual recovery in patients with unsuccessful preexisting macular grid LC [102]. Positive treatment results even after long-standing BRVO may be explained by the presence of a minimal rest-perfu- sion of the occluded vessel on FLA. Since eyes without rest-perfusion did not benefit from surgical decompression [172], this may serve as a predictive factor.

Unfortunately, the inclusion criteria and the postoperative results of all published studies are very heterogenous and hardly comparable. To date, it cannot be concluded that surgical AAS is more beneficial than other therapies for BRVO or even the natural course of the disease. To evaluate the effectiveness of this new treatment approach, several prospective randomized trials are currently underway.

21.3.8.2.12 Vitrectomy

Pars plana vitrectomy and posterior hyaloid peeling alone have been associated with visual and morphological improvement in eyes with BRVO [145, 147, 205, 212, 227]. Recent studies support the premise that vitrectomy improves macular edema and visual acuity whether or not AAS is performed [17, 38, 75, 83, 259]. In a small study, pars plana vitrectomy with posterior hyaloid removal and intraocular gas tamponade resulted in a reduction of macular edema and restoration of the normal foveal contour in 10 of 19 eyes with BRVO [205]. A recent study reported improved VA and new collateral vessel growth into previously nonperfused areas after vitrectomy in 75 % of eyes with BRVO and ischemic macular edema [5].

Interestingly, eyes with BRVO and spontaneous posterior vitreous detachment have a significantly lower rate of macular edema [12, 228]. Eyes with

vitreomacular separation, however, may still have macular edema [228], but vitrectomy may allow access of oxygenated aqueous to the inner retina, thereby improving macular edema and VA. Stefansson et al. demonstrated that inducing a BRVO in nonvitrectomized feline eyes resulted in retinal hypoxia, while inducing a BRVO in vitrectomized eyes produced no change in the retinal oxygen tension [224]. In seven eyes with BRVO and no PVD, Kurimoto et al. reported that vitrectomy and posterior hyaloid removal improved VA and decreased macular edema [147].

Yamamoto et al. reported a reduction in macular edema associated with BRVO after vitrectomy with and without AAS [259]. They found no difference between the treatment groups but the entry criteria were different, and in a considerable number of patients combined cataract surgery was performed. It is surprising that vitrectomy with posterior hyaloid removal alone could improve macular edema, because macular traction is rare in eyes with BRVO. It is possible that removal of the posterior hyaloid by vitrectomy improves oxygenation of the retina [224, 225]. Alternatively, vitrectomy may improve diffusion of harmful cytokines that promote increased vascular permeability, such as VEGF, leading them away from the retina, thereby influencing the oncotic pressure outside and the hydrostatic pressure within the vein. It is unknown whether vitrectomy also has a beneficial effect in eyes with preexisting posterior vitreous detachments.

Mandelcorn found a beneficial effect of ILM removal in BRVO patients with macular edema [166] as was seen in patients with diabetic macular edema. Different possible pathomechanisms are discussed including the removal of a diffusion barrier. Currently it is unknown whether an additional ILM removal during vitrectomy is advantageous.

21.3.8.2.13 Vessel Cannulation

Successful cannulations of branch retinal arterioles and branch retinal venules were described in porcine eyes [3, 240] and in a human cadaver eye model [233]. 10-0 monofilament nylon sutures were placed in the vessel lumen through an arteriotomy or phlebotomy opening [233]. Surgical penetration of retinal vessels was also accomplished in an allantois membrane model [156], and micro- manipulator-assisted cannulation of retinal vessels could be achieved successfully in cat eyes [93]. Other researchers maximized the view of the cannulation site using a high resolution gradient index of refraction (GRIN) lens endoscope [117] allowing hand cannulation of canine retinal veins in vivo.

Retinal vein cannulation with prolonged intravascular injection of rTPA was found to be feasible and safe in an experimental BRVO in canine eyes [231]. Weiss et al. first described retinal endovascular surgery (REVL) injecting rTPA in a clinical setting [251] with favorable results. The method is difficult and has not gained general acceptance but may offer new future treatment options.

21.3.8.2.14 Fibrinolytic Therapy

Fibrinolytic agents such as streptokinase or rt-PA have been used in an attempt to cause dissolution of the venous obstruction. rt-PA has been applied as either an intravitreal injection [148, 252], as intravenous therapy [104], or directly injected into the obstructed vein [251]. Hattenbach reported encouraging results of systemic thrombolysis with low dose rt-PA (50 mg) in patients with hemorrhagic retinopathy in CRVO and BRVO [104]. However, the risk of life threatening hemorrhages is a major problem with intravenous fibrinolysis. Garcia-Arumi used rtPA in BRVO in a combined approach with AAS. Recently, it was demonstrated that rt-PA administered intravitreally penetrates into the retinal vasculature in a porcine model of vascular occlusion [164]. A similar effect might be expected in humans. Thus, the fibrinolytic activity of rt-PA would help to restore venous flow.

21.3.8.3Treatment of Neovascular Related Complications

Essentials

Patients with areas of capillary nonperfusion exceeding five disk areas in fluorescein angiography should be closely followed for the development of neovascularization

Only when preretinal neovascularization is present should scatter LC in the affected quadrant be performed

Patients should be seen 4 – 6 weeks after scatter LC. If regression of neovascularizations is noted, further close observation is necessary

If no regression is observed 4 – 6 weeks after treatments, additional scatter LC must be applied; after regression 6 – 12 months fol- low-up is sufficient

The main indications for vitrectomy include nonclearing vitreous hemorrhage, tractional retinal detachment involving the macula, and epiretinal membrane formation

a

Fig. 21.3.25. a Major BRVO affecting the superotemporal quadrant of the right eye with lipid exudates, sheathed venules, partially regressed hemorrhages, a few laser burns and neovascularization of the disk (NVD) (arrow)

* *

Fig. 21.3.26. d Large cystoid spaces (asterisks) in the corresponding OCT image can be seen (scan, see a)

Fig. 21.3.27. Schematic drawing of scatter LC pattern covering the involved segment, sparing the area within two disk diameters of the fovea

field can be disabling for driving and navigating [109].

For scatter LC medium white burns with a size of 200 – 500 μm in diameter spaced one burn width apart and covering the entire involved segment sparing the area within two disk diameters of the fovea is recommended [29] (Fig. 21.3.27).

Fig. 21.3.26. a Same patient as in Fig. 25 after first scatter LC treatment, with persisting NVD (arrow), and collateral vessels in the horizontal raphe. FLA shows b laser burns in the ischemic area and partial regression of the peripheral neovascularization (arrow) but c marked increase of cystoid macular edema can be seen (arrow).

21.3Branch Retinal Vein Occlusion

21.3.8.3.1Scatter Laser Photocoagulation in BRVO – Technique

Essentials

Medium white burns 200 – 500 μm in diameter should be applied one burn width apart covering the entire involved ischemic segment and sparing the area within two disk diameters of the fovea

The power should be increased in 50 mW increments starting at 200 mW until the desired burn intensity is achieved

Duration may be variable from 0.1 s near the center to > 0.2 s in the periphery

A Goldmann – or wide angle – contact lens may be used

The adjacent unaffected retina should not be treated

Topical anesthesia is mostly sufficient; retrobulbar anesthesia is rare Neovascularizations and areas of vitreoretinal traction should be spared and not photocoagulated directly

In cases of reduced funduscopic view caused by corneal edema, progressed cataract or vitreous hemorrhage, sometimes LC is not possible. In these instances, peripheral retinal transscleral cryotherapy can be performed, but visual control of cryocoagulation effects is warranted to avoid overfreezing. Also an early vitrectomy can be considered, since usually transscleral cryotherapy provides no access to the avascular areas, which are mostly located posterior to the equator in BRVO.

Regular funduscopic checks should be performed in patients especially with the ischemic type of BRVO since neovascularization and vitreous hemorrhage may also develop years after the occlusion.

Also, in the presence of iris neovascularization scatter LC is essential to treat avascular zones as the underlying cause of the rubeosis iridis. If a neovascular glaucoma is present, cryoor laser photocoagulation can be combined with cyclodestructive treatments such as cyclophotocoagulation (CPC) or cyclocryocoagulation. The main indications for vitrectomy include nonclearing vitreous hemorrhage, tractional retinal detachment involving the macula, and epiretinal membrane formation [4, 119].

497

III 21

removal alone showed similar results. In recent years, pharmatherapeutic approaches with intravitreal injection of steroids or anti-VEGF compounds appear promising. Unfortunately, the therapeutic effect is transient and the natural course of macular edema in BRVO is considerably longer. In fact, many of the patients within the published reports did have recurrent edema soon after the studies ended. Clearly, longer-term treatments are needed.

Currently, a substantial proportion of publications on BRVO belong to the class of case reports. They often do not differentiate between the different types of BRVO or between patients having a BRVO of short duration or a longer standing BRVO. This differentiation is urgently required, for the evaluation of new upcoming treatment strategies have to be evaluated. Further limitations of the available data including the small number of patients treated, the short duration of follow-up, and the lack of concurrent control patients preclude the drawing of definitive conclusions concerning the risk-benefit ratio compared with standard care. The treatment effect should not be judged only by analyzing retinal thickness but also by tortuosity and diameter of the affected vein.

There is significant lack of controlled treatment trials. BRVOs occur at high frequency allowing future prospective randomized controlled studies to be conducted to evaluate different therapies singly or in combination. But, until the results of such studies are available, what should be recommended to patients with vision loss due to BRVO? Although well-controlled clinical trials are not available to date, physicians are obliged to sort through the available evidence and make their best judgement to provide the best possible treatment for their patients. Given the relative perceived safety of steroids and anti-VEGF drugs weighed against the documented unfavorable natural history in patients with persistent macular edema with progressive visual loss and the limited benefit from macular grid LC, an argument for a low-risk intervention could be made. For eyes at higher levels of VA it would not seem prudent, in the absence of data to the contrary, to recommend initial treatment with unproven treatment modalities which may not be effective or safe in the longterm. However, the evidence-based, preferred method of therapy in eyes with poor visual prognosis remains unclear. In the absence of clear guidelines the ultimate decision as to whether to treat or not and the type of therapy to be used, is principally a decision made between the patient and his/her physician after thorough discussion of the known risks and benefits.

At the heart of it all, improved understanding of the pathophysiology of BRVO and its associated

medical conditions may offer implications for completely new treatment strategies.

Acknowledgements. The author is grateful to PD Dr. L.-O. Hattenbach, the Eye Clinic Ludwigshafen, for proof reading of “associated risk factors” and “fibrinolytic therapy”, Mrs. P. Hammermeister for typing and Mrs. A. McKenzie for translation assistance.

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