Visual improvement in central retinal vein occlusion
following intravitreal anti-VEGF therapy

Peep V. Algvere

Department of Ophthalmology,
Karolinska Institutet, St. Eriks Eye Hospital
Stockholm, Sweden

Correspondence to:
Professor PV Algvere,

St. Eriks Eye Hospital,
Polhemsgatan 50,
S-112 82 Stockholm, Sweden;

peep.algvere@sankterik.se

In central retinal vein occlusion (CRVO) macular edema with cystoid macular degeneration is a common feature and histopathological examinations reveal that macular edema is present in approximately 90% of cases. High-resolution optical coherence tomography (OCT), also, demonstrates diffuse retinal edema and intraretinal vacuoles in the macular area in most cases of CRVO with moderate or severe visual loss.

Vascular endothelial growth factor (VEGF) plays a pivotal role in complications associated with retinal vein occlusions. It is most likely that an upregulation of VEGF is induced by hypoxia. VEGF increases vascular permeability leading to edematous changes in the retina and particularly in the development of macular edema. In addition, VEGF stimulates vascular endothelial growth promoting neovascularization.

Experimental research has indicated that levels of VEGF₁₂₁ and VEGF₁₆₅ isoforms are increased in monkeys after laser-induced retinal vein occlusion. In human retinal vein occlusion, also, increased concentraton of VEGF is present in the vitreous and aqueous and  being higher in CRVO than in branch retinal vein occlusion.

In order to inhibit the excess of VEGF in the vitreous and aqueous, intravitreal injections of anti-VEGF agents such as ranibizumab (Lucentis®) and bevacizumab (Avastin®) have been used. Bevacizumab is a recombinant, humanized, monoclonal IgG1 antibody to VEGF (molecular weight148 kD) and ranibizumab is a Fab-fragment of the antibody (molecular weight 48 kD).

A number of clinical studies show that in response to repeated injections of anti-VEGF agents, visual acuity can be significantly improved and macular edema reduced.

Diagnostic and therapeutic methods

Well-defined routine methods for preoperative diagnosis have emerged and been used  when assessing anti-VEGF therapy. The clinical examination includes best corrected visual acuity (preferably using the ETDRS chart), intraocular pressure, gonioscopy, biomicroscopy of the anterior and posterior segment of the eye. Optical coherence tomography (OCT) is most valuable for depicting the retinal morphology and thickness. The OCT ‘macular map’ measures and calculates the foveal average thickness in the central circle of the fovea  indicating the numerical value (µm). Digital fluorescein angiography is performed at baseline, and usually at 6 months and12 months, or whenever necessary for evaluating the retinal status. Patients undergo clinical ophthalmological examination at baseline and every 4 or 6 weeks during the first 6 months, and after that with intervals of 6 to 8 weeks according to the physician’s assessment.

Bevacizumab (Avastin®) is a commercially available recombinant humanized, monoclonal IgG1 antibody to VEGF (148 kD) (Roche AG, Basel, Switzerland). Ranibizumab (Lucentis®) is a Fab-antibody (48 kD) with high affinity for VEGF (Novartis, Basel, Switzerland). Intravitreal injections of these agents are instituted following dilatation of the pupil, prophylactic administration of anti-bacterial agents ( e.g. Fucithalmic; Leo Pharma, Malmö, Sweden), periocular skin cleaning with chlorohexidine solution (5.0%), and irrigation of the conjunctiva with chlorohexidine solution (0.5%). The intravitreal injections should be performed under an operating microscope and aseptic conditions using a 30-gauge needle through pars plana 3.5 – 4.0 mm posterior to the limbus under microscopic control. The doses generally injected are Avastin® 1.25 mg or Lucentis® 0.3 mg  given at baseline, and at 4 or 6 weeks intervals during the first 3 months, and after that  according to the discretion of the attending physician. The criteria for reinjection are decline of visual acuity (5 ETDRS letters or more), increase of foveal thickness on OCT (100 µm or more), persisting or increasing intraretinal edema. Patients should be followed with 4 to 6 weeks intervals for at least 6 months, in many cases much longer.            

General results

Reports on the treatment of CRVO with intravitreal anti-VEGF agents have shown that, generally, a substantial visual improvement can be achieved parallel with a decrease of macular edema as measured by the foveal thickness on OCT. The results following injections of Lucentis® and Avastin® seem to be fairly similar and, so far, no essential differences have emerged.

However, published case series differ considerably as to the severity and duration of the disease, the number of injections, and the period of follow-up. It was reported that during 6 months following intravitreal injections of Avastin®, visual acuity improved from 20/320 (0.06) to 20/100 (0.2) in one study and from 20/250 (0.08) to 20/80 (0.25) in another investigation. In two other studies with 12-month follow-up, visual acuity increased from 20/428 (0.05) to 20/53 (0.4) and from 20/100 (0.2) to 20/50 (0.4), respectively, in response to intravitreal  Avastin®. It became obvious that the beneficial effect of Avastin® is of limited duration, requiring repeated injections over a long period of time.

We conducted a prospective study on 13 patients with CRVO who were followed for 18 months. In response to intravitreal injections of Avastin® every 6 weeks, average visual acuity  improved by 13 ETDRS letters at 6 weeks, and by 20 letters from baseline at 18 weeks. Both at 6 months and at 24 months, the mean increase was 24 ETDRS letters (from 0.13 at baseline to 0.4), and at the last follow-up 18 ETDRS letters. The acuity increase from baseline was statistically significant (p<0.05) at each time-point. Eight of 13 patients (62%) had gained >15  ETDRS letters at 12 months and 7 of 13 patients (54%) had improved >15 ETDRS letters at 18 months.

There was a marked reduction of macular (foveal) edema from 596 µm at baseline to 294 µm at 18 months as demonstrated by OCT. The resorption of intraretinal edema was quite rapid, showing a considerable decrease during the first 3 months (Fig 1). The resolution of macular edema, displaying intraretinal vacuoles of fluid, was difficult to predict. It was rapid in some cases occurring after only one injection. A conspicuous resorption of subretinal fluid also occurred  and was in some cases associated with a remarkable recovery of visual acuity (Fig 2). Intraretinal vacuoles and subretinal fluid generally showed a continuous resorption over time but remained for 12 months or more in some instances.  

We gave totally 96 intravitreal injections of Avastin® during 18 months, an average of 7.4 injections per patient. During the first 6 months, 50 injections were given at 6 weeks intervals (mean 3.8 injections/patient). After that, the number of injections was reduced and delivered according to the preset reinjection criteria. From month 6 to 12 only 2.3 injections/patient were delivered, and from month 12 to 18 no more than 1.4 injections/patient.

Discussion

It was observed that the number of injections required and the appropriate intervals between injections are often difficult to predict. Regular clinical examinations are required, probably every 4 or 6 weeks, in order to prevent relapses of macular edema and visual loss. Depending on the activity of the disease, there are considerable inter individual variations. The optimal treatment regimen remains to be determined.

Our experience so far indicates that during the active stage of the disease, the treatment effect following one injection of bevacizumab appears to be limited to about 2 months for most patients. The duration of the therapeutic effect of ranibizumab may be even shorter. Bevacizumab(148 kD) is a larger molecule than ranibizumab(48 kD), and the duration of the anti-VEGF effect within the eye is presumably longer for bevacizumab.^.

It is reasonable to assume that for several cases the sequelae of CRVO may be long-lasting and difficult to predict. The duration of anti-VEGF treatment has to be determined from the clinical status, including OCT findings and fluorescein angiography. Notwithstanding, the recurrence of retinal oedema is difficult to predict, but it seems most likely that there is a considerable risk for relapses during the first 12 months.

The results following intravitreal injections of Avastin® are, by and large, comparable to those achieved in response to Lucentis®. It was reported that a visual increase of 16 ETDRS letters was achieved in response to 3 intravitreal injections of Lucentis® during the first 3 months but the initial visual improvement was lost during the following 3 to 6 months; the total number of injections being 4.5 (mean) during 9 months.

In one study, there was a visual gain of 17.5 letters ETDRS letters from baseline at 12 months follow-up, in response to an average of 7.5 injections per patient of Lucentis®. In another study, a visual gain of 18.5 ETDRS letters was achieved following a mean of 8.5 injections of Lucentis® during a period of 12 months.

Conclusion

Treatment of CRVO with anti-VEGF agents has shown that visual acuity can be significantly  improved and macular edema reduced. To maintain visual gain, regular ophthalmologic examinations and repeated injections of anti-VEGF agents are necessary as long as the disease is active. In addition to fluorescein angiography, optical coherence tomography (OCT) is a reliable tool to demonstrate the presence of macular edema and/or subretinal fluid. It is most likely that the effect of one intravitreal injection declines after 4 to 8 weeks. We are currently conducting a randomized clinical trial to evaluate the efficacy and safety of this treatment modality.

fig 1

fig 2

Legends to figures

Fig. 1.  Optical coherence tomography(OCT) showing extensive macular edema and visual decline (0.16) at baseline. Following 2 intravitreal injections of Avastin, visual acuity had improved (1.0) at 3 months.

Fig 2. OCT displays macular edema and large amount of subretinal fluid (visual acuity 0.1). Following 2 intravitreal injections of Avastin, subretinal fluid is resorbed and acuity improved (0.4) at 3 months.