Purpose
To investigate the efficacy and safety of intravitreal ranibizumab for the treatment of nonproliferative macular telangiectasia (MacTel) type 2.
Design
Prospective, open-label, uncontrolled, nonrandomized interventional clinical trial.
Methods
One eye (disease stage 2 or 3) of each patient (n = 10) with nonproliferative MacTel type 2 was injected with 0.5 mg ranibizumab at monthly intervals for one year. Visual acuity, angiographic findings, and retinal thickness were assessed at each visit. The primary endpoint was the change in best-corrected distance visual acuity after one year compared to baseline.
Results
Mean visual acuity showed a transient increase in the study eye. However, after 12 months of treatment there was no significant change of visual acuity compared to baseline or compared to the fellow eye. Fluorescein angiography revealed a decrease of telangiectatic-appearing capillaries and of late-phase leakage, which was accompanied by a topographically related significant reduction in macular thickness. Three to 5 months after the last treatment, angiographic appearance and retinal thickness were similar to baseline. In one patient, the last intravitreal injection was not performed because of safety concerns after a transitory ischemic attack. Otherwise, no serious adverse events were observed.
Conclusions
The angiographic and tomographic effects after intravitreal inhibition of vascular endothelial growth factor (VEGF) using ranibizumab implicate a pathophysiological role of the VEGF pathway in nonproliferative MacTel type 2. As the morphologic response was not associated with a clear functional benefit, and because of the transient nature of the treatment effect, monthly intravitreal ranibizumab is not recommended for the nonproliferative disease stage of MacTel type 2.
Macular telangiectasia (MacTel) type 2 is a bilateral retinal disease that is usually diagnosed between the fifth and seventh decade of life. Symptoms include metamorphopsia, decreased visual acuity, and an impaired reading ability. Typical but often subtle macular findings on ophthalmoscopy predominantly affect the temporal parafoveolar region and include a peculiar retinal graying, blunted venules, superficial crystalline deposits, and intraretinal pigment migration. Fluorescein angiography (FA) and optical coherence tomography (OCT) facilitate the diagnosis. In the early angiographic phase there may be characteristic ectatic-appearing parafoveolar capillaries that show low-grade leakage in later phases. Despite this leakage, there is typically no retinal thickening on OCT imaging because of coexistent atrophic neurosensory alterations. Using various techniques to assess macular pigment, a characteristic abnormal distribution with a central loss of lutein and zeaxanthin has recently been described as an additional phenotypic hallmark of the disease. In a subset of patients, neovascular membranes or macular holes may occur. Notably, based only on grading from stereoscopic fundus photographs, the disease prevalence in the population-based Beaver Dam study was 0.1% and, thus, much higher than previously assumed. Advanced imaging technologies such as spectral-domain (SD) OCT and fundus autofluorescence might further increase this number by detecting asymptomatic disease carriers. A large body of the recent knowledge gain on MacTel type 2 derived from investigations as part of the MacTel Study ( www.mactelresearch.org ), which aims at investigating the natural history, pathophysiology, and potential treatment strategies.
An increased intravitreal level of vascular endothelial growth factor (VEGF) may lead to vascular ectasia and leakage and is involved in the pathogenesis of neovascularization at the ocular fundus. This has previously led to the hypothesis that VEGF plays a role in the pathophysiology of MacTel type 2. Indeed, even in the absence of neovascularizations, intravitreal application of bevacizumab, a full-length humanized monoclonal antibody against VEGF, resulted in reduced capillary leakage on FA. Some studies also reported an accompanying reduction of retinal thickness and a normalization of the appearance of macular capillaries in the early angiographic phase. A subset of patients experienced an improvement in visual acuity. The treatment effects usually disappeared within 3 to 4 months.
Ranibizumab—a 48-kDa antigen-binding fragment (Fab) of a recombinant, humanized monoclonal antibody developed for intraocular administration that binds to all human VEGF-A isoforms—was recently approved by the US Food and Drug Administration and in other countries for the treatment of all angiographic subtypes of neovascular age-related macular degeneration (AMD). Based on its effectiveness in neovascular AMD and preliminary data on efficacy of bevacizumab in MacTel type 2, we performed a prospective clinical study to evaluate the efficacy and safety of fixed monthly intravitreal ranibizumab in non-neovascular MacTel type 2.
Methods
Study Design and Treatment
In a prospective, uncontrolled, nonrandomized study, 10 patients with MacTel type 2 were enrolled at the Department of Ophthalmology, University of Bonn, Germany, between December 21, 2007 and July 10, 2008. One eye was treated in each patient. Twelve intravitreal injections of 0.5 mg ranibizumab (Lucentis; Novartis Opthalmics, Nürnberg, Germany) were performed in monthly intervals (mean: 31.3 days; SD, 3.7 days; range 21 to 43 days) in accordance with previously published guidelines. The primary endpoint was the best-corrected distance visual acuity (VA) one month after the last treatment (visit 13) compared to baseline (visit 1).
To be included in the study, patients had to be at least 18 years old and present with characteristic findings for MacTel type 2 on ophthalmoscopy and fluorescein angiography according to Gass and Blodi. Moreover, findings on OCT and macular pigment assessment had to be in line with previously published phenotypic characteristics. Only eyes without a neovascular membrane and without intraretinal pigmentation were considered for treatment, and visual acuity had to be between 20/200 and 20/32.
Eyes with any ocular comorbidity that would interfere with the study procedures or outcome measures were not eligible for the study. Therefore, exclusion criteria encompassed other retinal vascular diseases, ocular surgery less than 3 months before enrollment, intravitreal anti-VEGF therapy less than 6 months before enrollment, uncontrolled glaucoma, ocular inflammation, or subfoveal fibrosis. Further exclusion criteria were any systemic disease that would not allow the application of the study treatment.
Assessment of Function and Morphology
A complete ophthalmic examination was performed at each visit, including assessment of VA, stereoscopic funduscopy, fundus photography (Zeiss FF450; Zeiss, Oberkochen, Germany), FA, and SD OCT. Best-corrected distance VA in each eye was measured at 4 meters with standard Early Treatment Diabetic Retinopathy Study (ETDRS) protocols using a testing chart transilluminator (Lighthouse International, New York, New York, USA). Visual acuity was scored as the total number of letters read correctly.
Standardized FA with a confocal scanning laser ophthalmoscope (cSLO) and SD-OCT were recorded with a combined instrument (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany). Early angiographic frames were acquired in the study eye and at 1, 2, 5, and 10 minutes in both eyes. As described previously, the combined system allows to record averaged OCT scans in an exact anatomic correlation with the cSLO image. Single SD-OCT scans were positioned on topographic cSLO images by the examiner, and always included a horizontal scan through the foveal center. A sequence of horizontal scans recorded in the high-speed mode (768 A-scans/30 degrees) and covering an area of 30 degrees (horizontal) × 25 degrees (vertical) with a distance of ∼120 μm between individual scans was recorded to assess changes in macular thickness. On follow-up examinations, the imaging processing software allowed reevaluation at exactly the same location. The automated alignment of the outer and inner retinal border was reviewed and, where necessary, manually corrected. For thickness analysis, a grid with 9 ETDRS-type regions was centered on the foveola. The central region encompassed an area with a radius of 0.5 mm; the inner and outer rings were segmented into 4 quadrants, with radii of 1.5 and 3 mm, respectively. Thickness measurements of the inner (inner retina including the outer plexiform layer) and outer (outer retina including the outer nuclear layer) neurosensory layers allowed assessing their relative contribution to changes in retinal thickness. These measurements were performed manually at 750 μm temporal to the foveal center, where changes were marked and where pathology of the retinal architecture did not preclude delineation of the different retinal layers.
Results
The baseline characteristics of the 10 patients enrolled into the study are shown in the Table . Nine patients completed all study visits and scheduled treatments. One patient did not receive the last treatment (see subsection Adverse Events) and therefore completed the study visits one month earlier (ie, after the 11th injection). All patients were reviewed additionally 3 to 5 months (mean 109 days ± 19 days; range 85-140 days) after the last treatment. In eyes previously treated with bevacizumab there was an overall similar therapeutic effect of ranibizumab.
| Patient | Sex | Age | Study Eye | Visual Acuity a | Disease Stage b | Ocular History | |||
|---|---|---|---|---|---|---|---|---|---|
| Study Eye | Fellow Eye | Study Eye | Fellow Eye | Study Eye | Fellow Eye | ||||
| 1 | F | 72 | R | 20/100 | 20/32 | 3 | 3 | IOL | IOL, IVB |
| 2 | F | 54 | L | 20/40 | 20/50 | 3 | 3 | — | — |
| 3 | F | 53 | R | 20/63 | 20/63 | 3 | 3 | IVB | IVB |
| 4 | M | 69 | R | 20/63 | 20/25 | 3 | 1 | IVB | — |
| 5 | F | 66 | R | 20/50 | 20/25 | 3 | 2 | IVB | — |
| 6 | F | 59 | L | 20/32 | 20/32 | 3 | 3 | — | — |
| 7 | M | 64 | R | 20/40 | 20/25 | 2 | 4 | — | — |
| 8 | F | 61 | R | 20/32 | 20/40 | 3 | 3 | — | — |
| 9 | M | 59 | R | 20/125 | 20/100 | 3 | 3 | — | FLC |
| 10 | F | 72 | R | 20/32 | 20/63 | 3 | 3 | IOL | IOL (decentered) |
| Mean | 62.9 | 20/50 | 20/40 | ||||||
a Visual acuity is converted to the Snellen equivalent from ETDRS visual acuity scores. Mean visual acuity was calculated after transformation to logMAR values.
Visual Acuity
One month after the last treatment (ie, at visit 13 in Patients 1 through 9 and at visit 12 in Patient 10), mean visual acuity was not significantly different compared to baseline (study eyes: +3.5 letters, SD ±5.4, P = .07; fellow eyes: +3.7 letters, SD ±5.9, P = .08; 2-tailed paired t test).
Figure 1 shows the mean change of visual acuity in each assessment (visit 13 without Patient 10). There was an initial but transitory significant improvement in the study eyes (visits 3-10). In the fellow eyes, there was a slight gain in mean visual acuity, which was mainly driven by the marked improvement in Patient 9 ( Figure 2 ). To compensate for day-to-day changes (eg, Patient 9 may have had a poor performance at baseline) and potential learning effects, the dashed line in Figure 1 shows the visual performance of the study eyes relative to the fellow eyes. A similar change of visual acuity in both eyes results in a value around zero (ie, no change in the study eyes relative to the fellow eyes) and gain or loss in visual acuity relative to the fellow eyes results in positive or negative values, respectively. Accordingly, a slight and only transient improvement in the study eyes was observed during the 1-year review period.
To illustrate individual treatment effects, the changes in visual acuity compared to baseline in each eye at every visit are plotted in Figure 2 . As in Figure 1 , a positive difference between the 2 eyes ( Figure 2 , Bottom) means a favorable evolution of visual acuity in the study eye relative to the fellow eye and vice versa. Thus, at the end of the study, visual acuity in the treated eye relative to the fellow eye had increased in 2 patients (Patients 1 and 3), decreased in 2 patients (Patients 6 and 9), and showed no clear change in the remaining 6 study participants.
Fluorescein Angiography
The characteristic leakage on late-phase FA showed a marked reduction in all study eyes ( Figure 3 ). This treatment effect was most pronounced after the first injection and remained stable overall during the course of the study. Only one eye showed a further decrease of leakage with subsequent injections (Patient 3) and in some, the leakage slightly increased again toward the end of the treatment period (eg, Patient 5). In 7 eyes a certain degree of leakage persisted, while complete resolution was observed in 3 eyes (Patients 3, 8, and 9). The minor hyperfluorescence present in the latter was also observed in early angiographic frames without subsequent increase in size or intensity and was, therefore, interpreted as a window defect attributable to the absence of macular pigment. At visit 14, 3 to 5 months after the last treatment, late-phase leakage on FA was similar to baseline and the rebound appeared more pronounced in some eyes (Patients 7, 8, 9). Except for a minor increased leakage in Patient 5, no obvious changes in late-phase FA occurred in the fellow eye during the study period.
Early FA revealed a reduction of ectatic-appearing macular capillaries and, if present, a reduction of the caliber of blunted venules. However, a subset of altered capillaries persisted, exhibiting some residual leakage ( Figure 4 ).
Optical Coherence Tomography
In the study eyes, mean macular thickness decreased significantly in all sectors of the ETDRS grid ( Figure 5 ). The effect was most pronounced after the first treatment. An additional smaller effect was measured after the subsequent 2 injections, and thereafter macular thickness remained largely stable over the study period until 1 month after the last treatment. Figure 6 (Top) illustrates this longitudinal observation for the inner temporal sector. At visit 14 (ie, 3 to 5 months after the last treatment), mean retinal thickness measurements were similar to those at baseline. Within the observation period, the fellow eye showed a gradual minor but significant decrease in retinal thickness, which was not reversed after cessation of the therapy ( Figure 5 ).
Relative to thickness measurements at baseline, the most pronounced retinal thinning was observed in the central (n = 4) and inner temporal (n = 3) sectors, or showed a similar extent in those 2 areas (n = 3). This relative change in retinal thickness (in %) is illustrated in Figure 6 (Bottom) for the inner temporal sector in each treated eye over the study period. This graph also shows that a further but smaller decrease after the first 3 injections occurred in one eye (Patient 10) and a gradual loss of the initial effect on retinal thickness was observed in 2 eyes (Patients 7 and 8; Figure 6 ). Overall, changes in retinal thickness showed the same direction in all ETDRS sectors of the same eye.
The reduction in retinal thickness was largely confined to the area of leakage at baseline ( Figure 7 ). Analysis of the relative contribution to retinal thinning assessed at visit 4 revealed that the inner retinal layers contributed 79% to the mean reduction in retinal thickness, measured 750 μm temporal to the foveal center. At this eccentricity, the mean decrease of total retinal thickness was 16% (-53 μm; SD, ±26.8 μm) from a baseline average of 333 μm (SD; ±39.2 μm). The mean thinning within the outer retinal layers was 7% (-11 μm; SD, ±10.9 μm) from a baseline average of 137 μm (SD, ±33.3 μm), and 21% (-42 μm; SD, ±20.6 μm) within the inner retinal layers from a baseline average of 196 μm (SD, ±26.6 μm). Figure 7 shows an example of the predominant thinning within the inner retina in a patient with marked macular thinning after intravitreal VEGF inhibition. Sometimes, a minor retinal thinning was also observed in areas adjacent to or separate from areas of leakage.
