The vast majority of retina physicians in the world now treat age related macular degeneration (AMD), retinal vein occlusion (RVO), and diabetic macular edema (DME) with anti-vascular endothelial growth factor (anti-VEGF) agents. However, despite the fact that most of these patients respond to treatment, there is still a proportion of patients who are considered nonresponders or who become resistant to this class of medicine. How do we care for these patients and what other options are available to us? The 2 cases below illustrate such patients and offer a potential alternative.

Patient #1: Recalcitrant Wet AMD

A man aged 65 years presented with a history of retinal detachment and no light perception in his right eye and wet AMD in his left eye. We administered monthly injections of ranibizumab (Lucentis, Genentech) after which his visual acuity improved, vacillating between 20/20 and 20/50, and the retinal thickness on optical coherence tomography (OCT) improved over the course of the first 6 injections, although there was still swelling despite vision being 20/25 (Figure 1).

During months 7 through 9, we continued to inject ranibizumab monthly and we observed some drying of the edema at months 7 and 8 (Figure 2), but the swelling came back at month 9.

We continued monthly ranibizumab injections through month 12, but the patient's vision and retinal thickness began to fluctuate more widely (Figure 3).

Would you: (1) change from ranibizumab to bevacizumab; (2) increase the dose of ranibizumab; (3) decrease the duration between injections; or (4) add intravitreal triamcinolone?

In the second 12 months, we chose to first alternate between ranibizumab and bevacizumab, but we were unable to maintain 20/20 vision or dry OCTs (Figure 4). We then began to decrease the duration between ranibizumab and bevacizumab injections, and although the vision increases with the injections, we were still not able to maintain 20/20 vision or a dry OCT (Figure 5).

In months 27 through 33, the patient received intravitreal triamcinolone acetonide and, although he developed pseudo-endophthalmitis, his vision improved to 20/20 at month 28 and OCT shows his eye to almost dry at 304 µm (Figure 6). However, within 6 weeks his vision decreased the retina began to re-swell, despite switching back to ranibizumab only and decreasing the time between injections to every 3 weeks. The vision, however, is good, varying between 20/20 and 20/30 (Figure 7). What would you do now?

Because frequent injections seem necessary with just anti-VEGF agents, at month 37 (Figure 8), we decided to use a combination approach with injecting the dexamethasone intravitreal implant 2 weeks later. After injection with the dexamethasone implant, the cysts that were present in Figure 8 began to resolve, retinal thickness was reduced to 327 µm in spectral domain OCT and vision began to improve to 20/20 (Figure 9). The patient remained dry through month 40 (Figure 11), enjoying a drug holiday at 20/20 for 3 months.

In this case of AMD that was recalcitrant to ranibizumab in regard to mainlining visual acuity improvement and dryness on OCT, combination therapy with ranibizumab and the dexamethasone intravitreal implant worked best.

Patient #2: Proliferative Diabetic Retinopathy

A man aged 44 years presented with proliferative diabetic retinopathy and previous vitrectomy in both eyes. He had multiple fluid-air exchanges postoperatively for recurrent vitreous hemorrhages. When his vitreous hemorrhages did clear, it was revealed that he had bilateral diabetic macular edema (DME) and received monthly bevacizumab injections to control both the DME and to decrease the incidence of rebleeding and prevent rubeosis.

We gave the patient numerous intravitreal bevacizumab injections, but even after 5 injections, retinal thickness was 886 µm and visual acuity was 20/150 (Figure 12). We then tried adding intravitreal triamcinolone acetonide to prolong the effect. However, because the patient had had vitrectomy, the injected medications had a short duration of effect. In fact, at month 16 and the 12th injection of bevacizumab, the patient's visual acuity was 20/60 and the retinal thickness was 699 µm (Figure 13).

What would you do? Our choices included: (1) continuing bevacizumab injections; (2) administer a sub-Tenon triamcinolone injection; or (3) applying combination therapy with bevacizumab and the dexamethasone intravitreal implant. We chose combination therapy with bevacizumab and the dexamethasone intravitreal implant because in our experience, we have found that this approach produces an increased duration of effect in regard to normalization of OCT contour, increased vision, and decreased need for reinjections.

At month 17, the patient's visual acuity was 20/40 and the retinal thickness was 540 µm (Figure 14) and we injected the dexamethasone intravitreal implant. After we injected the dexamethasone implant, the patient's OCT showed a significant improvement in retinal thickness, which thinned to 251 µm and visual acuity improved to 20/30. The reduced retinal thickness and improved visual acuity was sustained through month 20.

In this patient , in whom drug clearance was more rapid due to previous vitrectomy, a significant benefit was obtained by using combination therapy with an anti- VEGF agent and a sustained drug delivery system.

Summary

Macular edema due to AMD, RVO, and DME is due to a cascade of many factors, 2 of which are ischemia and inflammation. By using combination therapy in selected cases, the physician is able to attack the disease with a “one-two punch&rdquo and create a drug holiday by minimizing retinal edema and maximizing visual potential.