- Email: [email protected]
Findings in Fluorescein Angiography and Optical Coherence Tomography after Intravitreal Bevacizumab in Type 2 Idiopathic Macular Telangiectasia
Findings in Fluorescein Angiography and Optical Coherence Tomography after Intravitreal Bevacizumab in Type 2 Idiopathic Macular Telangiectasia Peter Charbel Issa, MD, Frank G. Holz, MD, Hendrik P. N. Scholl, MD, MA Purpose: To report the short-term effects of intravitreal bevacizumab in patients with type 2 idiopathic macular telangiectasia (IMT). Design: Noncomparative, interventional, retrospective case series. Participants: Seven eyes of 6 patients with type 2 IMT were studied. Methods: Patients received 2 doses of intravitreal bevacizumab (1.5 mg) at 4-week intervals. Serial examinations included standardized Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA), fluorescein angiography, and optical coherence tomography (OCT). Main Outcome Measures: Assessments of OCT retinal thickness, angiographic characteristics, and VA were performed at baseline and at 4 and 8 weeks after the initial treatment. Results: A mean increase in VA of 8 ETDRS letters at 8 weeks was found (P⬍0.05). Visual acuity improved by more than 15 letters in 1 patient and by 10 to 15 letters in 2 patients and remained stable (⫺1 to ⫹10 letters) in another 4 patients compared with baseline. All patients showed a reduction in extension and intensity of late-stage parafoveal hyperfluorescence on fluorescein angiography. In OCT imaging, mean retinal thickness showed a reduction in the foveal and in the parafoveal zones (P⬍0.01). The most pronounced effect (mean decrease, 22m) was in the parafoveal temporal zone. No significant ocular or systemic side effects were observed. Conclusions: Short-term results indicate that inhibition of vascular endothelial growth factor by intravitreal bevacizumab is associated with a decrease in retinal thickness and a reduction in angiographic leakage in type 2 IMT. Furthermore, intravitreal bevacizumab may improve VA in affected patients. Ophthalmology 2007;114: 1736 –1742 © 2007 by the American Academy of Ophthalmology.
Type 2 idiopathic macular telangiectasia (IMT) is characterized by a slow decrease in visual acuity, reading difficulties, metamorphopsia, or a combination thereof starting in the fifth to seventh decade.1–3 Typical findings in fluorescein angiography are parafoveal ectatic capillaries and a late-stage diffuse leakage, mainly temporal to the fovea. Both atrophy and secondary choroidal neovascularization may occur with disease progression.1–3 Imaging with optical coherence tomography (OCT) typically shows intraretinal hyporeflective spaces in the foveal area.4,5 So far, no therapy has been proven to benefit type 2 IMT. Originally received: December 18, 2006. Final revision: March 19, 2007. Accepted: March 20, 2007. Manuscript no. 2006-1456. From the Department of Ophthalmology, University of Bonn, Bonn, Germany. Supported by the Macular Telangiectasia Project; Deutsche Forschungsgemeinschaft (Bonn, Germany) Heisenberg (fellowship no. SCHO 734/21); and European Commission (Brussels, Belgium) FP6, Integrated Project “EVI-GENORET” (grant no. LSHG-CT-2005-512036). No author has any financial interest to disclose. Correspondence to Hendrik P. N. Scholl, MD, Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, D-53127 Bonn, Germany. E-mail: [email protected].
1736
© 2007 by the American Academy of Ophthalmology Published by Elsevier Inc.
Vascular endothelial growth factor (VEGF) plays an integral part in the formation of abnormal blood vessels and increasing vascular permeability in many pathologic conditions.6,7 Intravitreal inhibition of VEGF was shown to be effective for a variety of ocular diseases with destabilized blood–retina barrier or pathologic growth of new vessels.8 –13 Recently, it has been hypothesized that VEGF also may play an essential role in the pathogenesis of macular telangiectasia.14,15 In type 2 IMT, it is unknown if anti-VEGF therapy has the potential to reduce leakage in fluorescein angiography and to reduce retinal thickness in OCT imaging. In fact, the authors showed recently for the first time in a case report that intravitreal application of bevacizumab, a humanized monoclonal antibody to VEGF, may have beneficial effects in type 2 IMT.15 Further pursuing this notion, the authors systematically evaluated the effect of intravitreal bevacizumab on the characteristics in angiography and OCT imaging in a larger case series of patients with type 2 IMT.
Patients and Methods Seven eyes of 6 patients with type 2 IMT were included in the study and were staged according to the system of Gass and Blodi.2 ISSN 0161-6420/07/$–see front matter doi:10.1016/j.ophtha.2007.03.079
Charbel Issa et al 䡠 Findings after Intravitreal Bevacizumab in Type 2 IMT
Figure 1. Late-stage fluorescein angiography results at approximately 10 minutes at baseline, 4 weeks after the first injection, and 4 weeks after the second intravitreal injection of bevacizumab. Each row represents one eye. Visual acuity (Snellen equivalent; no. of letters read on the Early Treatment Diabetic Retinopathy Study [ETDRS] chart) is given in the left upper corner of each angiographic image. A marked decrease of fluorescein leakage is seen at 4 weeks after the initial injection. This decrease remained stable or is even slightly enforced at 4 weeks after the second injection. Fourth column, Average interpolated retinal thickness (micrometers) within the 9 ETDRS-type regions in optical coherence tomography imaging. Numbers have a gray background if the interpolated thickness in the respective area was greater and have a black background if it was lesser than the normative value ⫾ 2 standard deviations. Fifth column, Change in retinal thickness 4 weeks after the second intravitreal injection of bevacizumab. The background again codes the retinal thickness in relation to the normative values—in this case, 4 weeks after the second injection.
1737
Ophthalmology Volume 114, Number 9, September 2007 The off-label use of the drug and its potential risks and benefits were discussed with all patients. The study adhered to the tenets of the Declaration of Helsinki and informed consent was obtained from every patient. Intravitreal injection of 1.5 mg (0.06 ml) of bevacizumab (Avastin, Roche, Grenzach, Germany) was performed twice in each eye with an interval of 4 weeks. Best-corrected distance visual acuity (VA) in each eye was measured at 4 m with standard Early Treatment of Diabetic Retinopathy Study (ETDRS) protocols with a distance chart transilluminated with a chart illuminator (Lighthouse International, New York, NY). Visual acuity was scored as the total number of letters read correctly and was converted to the Snellen equivalent. All patients underwent a complete ophthalmic examination, including standardized fluorescein angiography (by digital photography: Zeiss FF450; Zeiss, Oberkochen, Germany; or by confocal scanning laser ophthalmoscope: cSLO, HRA2; Heidelberg Engineering, Heidelberg, Germany) and OCT imaging (Stratus OCT; Carl Zeiss Meditec, Oberkochen, Germany) at baseline and at 4 and 8 weeks after the initial injection. Optical coherence tomography is a high-resolution technique that permits cross-sectional visualization of the retinal structure with 10-m longitudinal resolution from the time delay of reflected light using low-coherence interferometry, as described previously in detail.16 –18 The macular thickness map scan protocol on the OCT was used to obtain 6 consecutive macular scans 6 mm in length, centered on the fovea at equally spaced angular orientations. The cross-sectional images were analyzed using OCT mapping software that uses an edge detection technique to locate the inner and outer retinal borders. The former is represented by the vitreoretinal interface, and the line that presumably represents the border of the outer and inner segments of the photoreceptors is recognized as the outer retinal border. Retinal thickness was measured as the distance between these 2 interfaces at each measurement point along the scan’s x-axis. The retinal map analysis protocol on the OCT was selected to reconstruct a surface map displayed with numeric averages of the measurements for each of the 9 map zones that have been called ETDRS-type regions because of their similarity to zones of analysis of photographs by ETDRS graders.19,20 The inner and outer rings were segmented into 4 quadrants, with radii of 1.5 and 3 mm, respectively. Foveal thickness was defined as the average thickness in the central 1000-m diameter of the ETDRS layout. Central foveal thickness was defined as the mean thickness at the point of intersection of the 6 radial scans. Two standard deviations (according to Chan et al21) were used to define the cutoffs for the upper and lower levels of normal retinal thickness. The individual OCT scans were reviewed to assess qualitative changes. Statistical calculations were performed using a commercially available software program (Statistical Package for the Social Sciences, version 14.0; SPSS, Inc., Chicago, IL). For statistical analysis of OCT thickness, only the nonproliferative cases were included. Power and Precision version 2.0 (Biostat, Inc., New York, NY) was used for the power analysis.
Results The mean age of the patients was 60 years (standard deviation [SD], 7.6 years; range, 51–70 years), and all eyes except 1 (patient 3, stage 5) were classified as stage 2 or 3 according to the system of Gass and Blodi.2 Of the 6 patients, 4 were female and 2 were male. At baseline, all patients showed ectatic parafoveal capillaries and a late-stage diffuse parafoveal hyperfluorescence (Fig 1) on fluorescein angiography. One patient had a secondary vascular membrane at presentation (patient 3). Optical coherence tomography imaging revealed foveal intraretinal hyporeflective spaces.
1738
Table 1. Effect of 2 Doses of Intravitreal Bevacizumab (1.5 mg) at 4-Week Intervals in Eyes with Type 2 Idiopathic Macular Telangiectasia Visual Acuity (ETDRS Letters)
Thickness of Foveal Zone (m)
Eye
Baseline
Final
Change
Baseline
Final
Change
I II III IV V VI VII
20/100 (51) 20/50 (65) 20/200 (35) 20/80 (54) 20/80 (58) 20/63 (59) 20/80 (56)
20/50 (63) 20/32 (75) 20/200 (37) 20/80 (57) 20/63 (60) 20/50 (62) 20/25 (79)
⫹12 ⫹10 ⫹2 ⫹3 ⫹2 ⫹3 ⫹23
221 194 240 200 210 203 208
194 179 186 172 179 179 188
⫺27 ⫺15 ⫺54 ⫺28 ⫺31 ⫺24 ⫺20
ETDRS ⫽ Early Treatment Diabetic Retinopathy Study. Visual acuity and foveal thickness (defined as the average thickness in the central 1000-m diameter determined by optical coherence tomography) at baseline and at 8 wks after the initial treatment.
Retinal thickness at baseline is depicted in Figure 1 for each eye. Mean central foveal thickness was 159 m (SD, 15.7m) at baseline (patient 3 excluded), and only 1 patient showed a central foveal thickness different from the normative value (182 m) ⫾2 SDs (patient 2, 130m). At 4 and 8 weeks after the initial injection, visual acuity had improved compared with baseline by 15 letters or more in 1 eye and by 10 to 15 letters in 2 eyes and remained stable (⫺1 to ⫹10 letters) in another 4 eyes (Table 1). There was a mean increase in VA of 8 letters at 4 weeks (SD, 6.0) as well as at 8 weeks (SD, 7.8) after initial treatment compared with baseline. This difference was statistically significant for both visits (P⬍0.05, paired t test). Early-stage fluorescein angiography showed a reduction in ectatic capillaries (Fig 2). Late-stage fluorescein angiography showed a marked reduction in size and intensity of the parafoveal hyperfluorescent area at 4 and 8 weeks after initial treatment (Fig 1). In OCT imaging, mean retinal thickness showed a marked reduction in the foveal zone (P⬍0.01, paired t test, patient 3 excluded; Table 1) and in the inner annular band (all 4 zones, P⬍0.01, paired t test, patient 3 excluded). The most pronounced effect (mean decrease, ⫺22 m) was in the inner temporal zone. Retinal thickness in the outer ring substantially decreased only in the patient with the neovascular membrane (patient 3) and did not show statistically significant changes in the other patients. Overall, the hyporeflective foveal spaces within the inner neurosensory retina decreased in size and number, and some even disappeared (Fig 3A–C). In contrast, deep cystic spaces within the photoreceptor layer seemed to persist (Fig 3E). Overall, at 4 weeks after the second injection, angiographic appearance and visual function remained stable compared with the effect 4 weeks after the initial treatment.
Discussion In the only histopathological study to date, Green et al22 described thickening of the wall of retinal capillaries resulting from proliferation of basement membrane and narrowing of the capillary lumen in an eye with type 2 IMT. Furthermore, they observed degeneration of pericytes and occasional areas of degenerated endothelial cells. The authors hypothesize that these structural capillary changes
Charbel Issa et al 䡠 Findings after Intravitreal Bevacizumab in Type 2 IMT
Figure 2. Early-phase angiography results from (A) patient 2 and (B) patient 5 at baseline and 4 weeks after initial intravitreal injection of bevacizumab. A decrease of ectatic parafoveal ectatic capillaries is demonstrated.
could lead to a disturbed exchange of oxygen and substrates between the vascular lumen and neurosensory retina. This may lead to a hypoxia-induced increased VEGF release by retinal cells. The loss of pericytes may render the capillaries more susceptible to effects mediated by VEGF.6 The observed morphologic effects in fluorescein angiography and OCT imaging were associated with an improvement in VA in some but not all eyes. Histopathologic examination22 as well as OCT imaging4,5 revealed microcystic degenerations within the neurosensory retina. Such previously existing atrophic neurosensory changes within the fovea may be responsible for a lack of improvement in VA.
Vascular leakage and neovascularization are major effects of VEGF.6,7,23 Leakage is the consequence of a breakdown of the blood–retina barrier.24 The VEGF-induced increase in permeability requires the tonic presence of VEGF.7 Because type 2 IMT is assumed to be a chronic disease, stimulation by VEGF may be long-standing. An intravitreally administered single dose of bevacizumab (1.25 mg) was shown to have an intravitreal half-life of approximately 3 days with still complete VEGF blockade after 4 weeks, but decreasing thereafter.25 The time courses of other diseases that are currently treated with intravitreal VEGF antagonists, such as neovascular age-related macular degeneration, are distinguished by their time-limited active
1739
Ophthalmology Volume 114, Number 9, September 2007
Figure 3. Optical coherence tomography (OCT) scans centered on the fovea (left) before and (right) after treatment with intravitreal bevacizumab. Orientation of the 2 scans is always equal and is specified in the left upper corner. A, B, Patient 6 (VI in Fig 1): after treatment, thickness of the neurosensory retina was reduced parafoveally and the hyporeflective foveal spaces show a reduction in size. C, Patient 4 (IV in Fig 1): the foveal cysts disappeared after treatment. D, Patient 3 (III in Fig 1): intraretinal fluid and retinal thickening decreased in the patient with the secondary neovascular membrane. E, Patient 1 (I in Fig 1): the foveal hyporeflective spaces in the superficial neurosensory layer disappeared after treatment, whereas the deep spaces remained.
disease process. Other anti-VEGF agents (ranibizumab, pegaptanib) were tested extensively and were found to be safe in patients with age-related macular degeneration for application periods of up to 2 years, with a 4- or 6-week treatment interval.12,26 However, long-term safety (i.e., several years) for intravitreal application has not been shown for any of the available anti-VEGF drugs. Therefore, the longterm applicability of currently available anti-VEGF drugs in type 2 IMT remains uncertain. Moreover, it has been suggested that VEGF plays a role in photoreceptor differentiation, may contribute to photore-
1740
ceptor survival, and may serve a role in maintaining retinal vascular homeostasis.27–29 Therefore, it can not be ruled out that blocking VEGF may cause an increased rate of apoptosis among ganglion cells and photoreceptors. Granted that neurosensory degeneration is a pathologic event in type 2 IMT,22 it remains to be seen whether VEGF antagonists will accelerate these processes in the long run. Vascular endothelial growth factor also triggers the production of metalloproteinases, which are enzymes that are required for the breakdown of basement membrane.6 Therefore, there is the possibility that the pathologic thickening of basement
Charbel Issa et al 䡠 Findings after Intravitreal Bevacizumab in Type 2 IMT membrane described in type 2 IMT22 is enforced by antagonizing VEGF. Survival of vascular endothelial cells has been shown to be dependent on VEGF as long as there is no pericyte coverage, and pericytes were shown to be diminished in type 2 IMT.22 Further studies will have to clarify if the macular capillaries in type 2 IMT remain intact after anti-VEGF treatment. Green et al22 postulated that the angiographic telangiectatic appearance is the result of focal endothelial defects. They concluded that these may be sites at which fluorescein diffused into capillary walls that were thickened by edema and excess basement membrane accumulation and eventually leaked out of the capillary wall into the surrounding retina. Breakdown of intercellular tight junctions is a known effect of VEGF.7,23 Antagonization may result in stabilization of the endothelial lining, and this effect could be a rationale for the reduction of ectatic-appearing capillaries in early-phase fluorescein angiography. It was a surprising finding that retinal thickness significantly decreased in the foveal zone and the inner ring, although the initial retinal thickness was in the range of normal values. Only 1 eye (patient 1) showed a slight retinal thickening that was present in all quadrants of the inner ring except the nasal quadrant. After application of intravitreal bevacizumab, retinal thickness decreased in all eyes and was even lower than normal in 3 eyes in at least 1 quadrant (patients 2, 5, and 6). This may point to a low-grade intraretinal edema that is superposed on a rather atrophic neurosensory retina. In 2 eyes (patients 2 and 5), the effect had the same magnitude temporally and nasally to the fovea. In 1 eye (patient 6), the effect was even stronger in the nasal quadrant, although angiography suggested a more active disease process temporal to the fovea. It may be speculated that, in this particular case, more advanced atrophic changes in the temporal quadrant hinder the respective retinal area from a more pronounced thickening. Limitations must be considered regarding the quantification of retinal thickness in type 2 IMT by third-generation OCT imaging, which may be erroneous in some cases because of specific findings associated with this disease. The retinal thickness analysis protocol of the third-generation OCT software automatically delineates the neural retina by considering marked changes in reflectivity as the inner and outer boundaries, respectively. The inner boundary is represented by the retinal surface. In type 2 IMT, the foveal superficial hyporeflective spaces often are covered only by a thin drapelike structure4,5 that may not be detected by the automatic delineation as the inner boundary. This results in a thinner measurement of the central foveal thickness. When this error was detected in one of the retinal thickness analyses, central foveal thickness was measured manually. However, foveal thickness (defined as the average thickness in the central 1000-m diameter) that is calculated by the software could not be influenced. Because the cystic spaces were most notable before treatment, the treatment effect on foveal thickness would rather be underestimated. Furthermore, it is an inherent characteristic of type 2 IMT that the outer boundary is altered in parts or that it is disrupted by deep neurosensory hyporeflective spaces. In the normal eye, there are 2 highly reflective layers at the outer neural retina.
The inner layer is supposed to represent the border between outer segments and inner segments of the photoreceptors and is recognized by the software as the outer delineation of the neurosensory retina. In type 2 IMT, often a disruption in the photoreceptor layer occurs, and therefore, the software instead uses the outer highly reflective layer, which delineates the retinal pigment epithelium for thickness analysis. This systematic error should not have consequences on the analysis of treatment effects in this study because the error would be the same before and after therapy (if there was no new formation of such defects). In summary, this report confirms an initial single observation15 and supports the concept that intravitreally administered bevacizumab has a biologic effect in type 2 IMT. The authors conclude that VEGF may play a pathophysiologic role in the disease. For validation of these short-term results and to study the long-term effects, the authors propose a prospective confirmatory study with equivalent antiVEGF drugs such as ranibizumab, administered in 4-week intervals over 12 months. Assuming an effect size of ⑀ ⫽ 1 (based on the effect 8 weeks after the initial injection), a 2-sided 1-sample t test at a level of 0.05 would require a sample size of 10 patients to reach a power of 80%.
References 1. Gass JD, Oyakawa RT. Idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol 1982;100:769 – 80. 2. Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis: update of classification and follow-up study. Ophthalmology 1993;100:1536 – 46. 3. Yannuzzi LA, Bardal AM, Freund KB, et al. Idiopathic macular telangiectasia. Arch Ophthalmol 2006;124:450 – 60. 4. Gaudric A, Ducos de Lahitte G, Cohen SY, et al. Optical coherence tomography in group 2A idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol 2006;124:1410 –9. 5. Paunescu LA, Ko TH, Duker JS, et al. Idiopathic juxtafoveal retinal telangiectasis. New findings by ultrahigh-resolution optical coherence tomography. Ophthalmology 2006;113: 48 –57. 6. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581– 611. 7. Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina 2005;25: 111– 8. 8. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695–705. 9. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–72. 10. Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113:23– 8. 11. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–16. 12. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419 –31. 13. Qaum T, Xu Q, Joussen AM, et al. VEGF-initiated blood-
1741
Ophthalmology Volume 114, Number 9, September 2007
14.
15.
16.
17.
18.
19.
20.
21.
22.
retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci 2001;42:2408 –13. Chew EY. Parafoveal telangiectasis. In: Ryan SJ, Hinton DR, Schachat AP, Wilkinson CP, eds. Retina. 4th ed. Vol. 2. St. Louis: Mosby; 2006:1409 –15. Charbel Issa P, Scholl HP, Holz FG. Intravitreal bevacizumab for the treatment of type 2 idiopathic macular telangiectasis. Retin Cases Brief Rep. In press. Hee MR, Izatt JA, Swanson EA, et al. Optical coherence tomography of the human retina. Arch Ophthalmol 1995;113: 325–32. Hee MR, Puliafito CA, Wong C, et al. Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol 1995;113:1019 –29. Puliafito CA, Hee MR, Lin CP, et al. Imaging of macular diseases with optical coherence tomography. Ophthalmology 1995;102:217–29. Hee MR, Puliafito CA, Duker JS, et al. Topography of diabetic macular edema with optical coherence tomography. Ophthalmology 1998;105:360 –70. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study findings. Ophthalmology 1978;85:82–106. Chan A, Duker JS, Ko TH, et al. Normal macular thickness measurements in healthy eyes using Stratus optical coherence tomography. Arch Ophthalmol 2006;124:193– 8. Green WR, Quigley HA, De la Cruz Z, Cohen B. Parafoveal
1742
23.
24.
25. 26.
27. 28. 29.
retinal telangiectasis: light and electron microscopy studies. Trans Ophthalmol Soc U K 1980;100:162–70. Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1: a potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 1999;274:23463–7. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996;103:1820 – 8. Beer PM, Wong SJ, Hammad AM, et al. Vitreous levels of unbound bevacizumab and unbound vascular endothelial growth factor in two patients. Retina 2006;26:871– 6. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology 2006;113:1508 –25. van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA 2005;293:1509 –13. Kim I, Ryan AM, Rohan R, et al. Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 1999;40:2115–21. Yourey PA, Gohari S, Su JL, Alderson RF. Vascular endothelial cell growth factors promote the in vitro development of rat photoreceptor cells. J Neurosci 2000;20:6781– 8.
Type 2 idiopathic macular telangiectasia (IMT) is characterized by a slow decrease in visual acuity, reading difficulties, metamorphopsia, or a combination thereof starting in the fifth to seventh decade.1–3 Typical findings in fluorescein angiography are parafoveal ectatic capillaries and a late-stage diffuse leakage, mainly temporal to the fovea. Both atrophy and secondary choroidal neovascularization may occur with disease progression.1–3 Imaging with optical coherence tomography (OCT) typically shows intraretinal hyporeflective spaces in the foveal area.4,5 So far, no therapy has been proven to benefit type 2 IMT. Originally received: December 18, 2006. Final revision: March 19, 2007. Accepted: March 20, 2007. Manuscript no. 2006-1456. From the Department of Ophthalmology, University of Bonn, Bonn, Germany. Supported by the Macular Telangiectasia Project; Deutsche Forschungsgemeinschaft (Bonn, Germany) Heisenberg (fellowship no. SCHO 734/21); and European Commission (Brussels, Belgium) FP6, Integrated Project “EVI-GENORET” (grant no. LSHG-CT-2005-512036). No author has any financial interest to disclose. Correspondence to Hendrik P. N. Scholl, MD, Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, D-53127 Bonn, Germany. E-mail: [email protected].
1736
© 2007 by the American Academy of Ophthalmology Published by Elsevier Inc.
Vascular endothelial growth factor (VEGF) plays an integral part in the formation of abnormal blood vessels and increasing vascular permeability in many pathologic conditions.6,7 Intravitreal inhibition of VEGF was shown to be effective for a variety of ocular diseases with destabilized blood–retina barrier or pathologic growth of new vessels.8 –13 Recently, it has been hypothesized that VEGF also may play an essential role in the pathogenesis of macular telangiectasia.14,15 In type 2 IMT, it is unknown if anti-VEGF therapy has the potential to reduce leakage in fluorescein angiography and to reduce retinal thickness in OCT imaging. In fact, the authors showed recently for the first time in a case report that intravitreal application of bevacizumab, a humanized monoclonal antibody to VEGF, may have beneficial effects in type 2 IMT.15 Further pursuing this notion, the authors systematically evaluated the effect of intravitreal bevacizumab on the characteristics in angiography and OCT imaging in a larger case series of patients with type 2 IMT.
Patients and Methods Seven eyes of 6 patients with type 2 IMT were included in the study and were staged according to the system of Gass and Blodi.2 ISSN 0161-6420/07/$–see front matter doi:10.1016/j.ophtha.2007.03.079
Charbel Issa et al 䡠 Findings after Intravitreal Bevacizumab in Type 2 IMT
Figure 1. Late-stage fluorescein angiography results at approximately 10 minutes at baseline, 4 weeks after the first injection, and 4 weeks after the second intravitreal injection of bevacizumab. Each row represents one eye. Visual acuity (Snellen equivalent; no. of letters read on the Early Treatment Diabetic Retinopathy Study [ETDRS] chart) is given in the left upper corner of each angiographic image. A marked decrease of fluorescein leakage is seen at 4 weeks after the initial injection. This decrease remained stable or is even slightly enforced at 4 weeks after the second injection. Fourth column, Average interpolated retinal thickness (micrometers) within the 9 ETDRS-type regions in optical coherence tomography imaging. Numbers have a gray background if the interpolated thickness in the respective area was greater and have a black background if it was lesser than the normative value ⫾ 2 standard deviations. Fifth column, Change in retinal thickness 4 weeks after the second intravitreal injection of bevacizumab. The background again codes the retinal thickness in relation to the normative values—in this case, 4 weeks after the second injection.
1737
Ophthalmology Volume 114, Number 9, September 2007 The off-label use of the drug and its potential risks and benefits were discussed with all patients. The study adhered to the tenets of the Declaration of Helsinki and informed consent was obtained from every patient. Intravitreal injection of 1.5 mg (0.06 ml) of bevacizumab (Avastin, Roche, Grenzach, Germany) was performed twice in each eye with an interval of 4 weeks. Best-corrected distance visual acuity (VA) in each eye was measured at 4 m with standard Early Treatment of Diabetic Retinopathy Study (ETDRS) protocols with a distance chart transilluminated with a chart illuminator (Lighthouse International, New York, NY). Visual acuity was scored as the total number of letters read correctly and was converted to the Snellen equivalent. All patients underwent a complete ophthalmic examination, including standardized fluorescein angiography (by digital photography: Zeiss FF450; Zeiss, Oberkochen, Germany; or by confocal scanning laser ophthalmoscope: cSLO, HRA2; Heidelberg Engineering, Heidelberg, Germany) and OCT imaging (Stratus OCT; Carl Zeiss Meditec, Oberkochen, Germany) at baseline and at 4 and 8 weeks after the initial injection. Optical coherence tomography is a high-resolution technique that permits cross-sectional visualization of the retinal structure with 10-m longitudinal resolution from the time delay of reflected light using low-coherence interferometry, as described previously in detail.16 –18 The macular thickness map scan protocol on the OCT was used to obtain 6 consecutive macular scans 6 mm in length, centered on the fovea at equally spaced angular orientations. The cross-sectional images were analyzed using OCT mapping software that uses an edge detection technique to locate the inner and outer retinal borders. The former is represented by the vitreoretinal interface, and the line that presumably represents the border of the outer and inner segments of the photoreceptors is recognized as the outer retinal border. Retinal thickness was measured as the distance between these 2 interfaces at each measurement point along the scan’s x-axis. The retinal map analysis protocol on the OCT was selected to reconstruct a surface map displayed with numeric averages of the measurements for each of the 9 map zones that have been called ETDRS-type regions because of their similarity to zones of analysis of photographs by ETDRS graders.19,20 The inner and outer rings were segmented into 4 quadrants, with radii of 1.5 and 3 mm, respectively. Foveal thickness was defined as the average thickness in the central 1000-m diameter of the ETDRS layout. Central foveal thickness was defined as the mean thickness at the point of intersection of the 6 radial scans. Two standard deviations (according to Chan et al21) were used to define the cutoffs for the upper and lower levels of normal retinal thickness. The individual OCT scans were reviewed to assess qualitative changes. Statistical calculations were performed using a commercially available software program (Statistical Package for the Social Sciences, version 14.0; SPSS, Inc., Chicago, IL). For statistical analysis of OCT thickness, only the nonproliferative cases were included. Power and Precision version 2.0 (Biostat, Inc., New York, NY) was used for the power analysis.
Results The mean age of the patients was 60 years (standard deviation [SD], 7.6 years; range, 51–70 years), and all eyes except 1 (patient 3, stage 5) were classified as stage 2 or 3 according to the system of Gass and Blodi.2 Of the 6 patients, 4 were female and 2 were male. At baseline, all patients showed ectatic parafoveal capillaries and a late-stage diffuse parafoveal hyperfluorescence (Fig 1) on fluorescein angiography. One patient had a secondary vascular membrane at presentation (patient 3). Optical coherence tomography imaging revealed foveal intraretinal hyporeflective spaces.
1738
Table 1. Effect of 2 Doses of Intravitreal Bevacizumab (1.5 mg) at 4-Week Intervals in Eyes with Type 2 Idiopathic Macular Telangiectasia Visual Acuity (ETDRS Letters)
Thickness of Foveal Zone (m)
Eye
Baseline
Final
Change
Baseline
Final
Change
I II III IV V VI VII
20/100 (51) 20/50 (65) 20/200 (35) 20/80 (54) 20/80 (58) 20/63 (59) 20/80 (56)
20/50 (63) 20/32 (75) 20/200 (37) 20/80 (57) 20/63 (60) 20/50 (62) 20/25 (79)
⫹12 ⫹10 ⫹2 ⫹3 ⫹2 ⫹3 ⫹23
221 194 240 200 210 203 208
194 179 186 172 179 179 188
⫺27 ⫺15 ⫺54 ⫺28 ⫺31 ⫺24 ⫺20
ETDRS ⫽ Early Treatment Diabetic Retinopathy Study. Visual acuity and foveal thickness (defined as the average thickness in the central 1000-m diameter determined by optical coherence tomography) at baseline and at 8 wks after the initial treatment.
Retinal thickness at baseline is depicted in Figure 1 for each eye. Mean central foveal thickness was 159 m (SD, 15.7m) at baseline (patient 3 excluded), and only 1 patient showed a central foveal thickness different from the normative value (182 m) ⫾2 SDs (patient 2, 130m). At 4 and 8 weeks after the initial injection, visual acuity had improved compared with baseline by 15 letters or more in 1 eye and by 10 to 15 letters in 2 eyes and remained stable (⫺1 to ⫹10 letters) in another 4 eyes (Table 1). There was a mean increase in VA of 8 letters at 4 weeks (SD, 6.0) as well as at 8 weeks (SD, 7.8) after initial treatment compared with baseline. This difference was statistically significant for both visits (P⬍0.05, paired t test). Early-stage fluorescein angiography showed a reduction in ectatic capillaries (Fig 2). Late-stage fluorescein angiography showed a marked reduction in size and intensity of the parafoveal hyperfluorescent area at 4 and 8 weeks after initial treatment (Fig 1). In OCT imaging, mean retinal thickness showed a marked reduction in the foveal zone (P⬍0.01, paired t test, patient 3 excluded; Table 1) and in the inner annular band (all 4 zones, P⬍0.01, paired t test, patient 3 excluded). The most pronounced effect (mean decrease, ⫺22 m) was in the inner temporal zone. Retinal thickness in the outer ring substantially decreased only in the patient with the neovascular membrane (patient 3) and did not show statistically significant changes in the other patients. Overall, the hyporeflective foveal spaces within the inner neurosensory retina decreased in size and number, and some even disappeared (Fig 3A–C). In contrast, deep cystic spaces within the photoreceptor layer seemed to persist (Fig 3E). Overall, at 4 weeks after the second injection, angiographic appearance and visual function remained stable compared with the effect 4 weeks after the initial treatment.
Discussion In the only histopathological study to date, Green et al22 described thickening of the wall of retinal capillaries resulting from proliferation of basement membrane and narrowing of the capillary lumen in an eye with type 2 IMT. Furthermore, they observed degeneration of pericytes and occasional areas of degenerated endothelial cells. The authors hypothesize that these structural capillary changes
Charbel Issa et al 䡠 Findings after Intravitreal Bevacizumab in Type 2 IMT
Figure 2. Early-phase angiography results from (A) patient 2 and (B) patient 5 at baseline and 4 weeks after initial intravitreal injection of bevacizumab. A decrease of ectatic parafoveal ectatic capillaries is demonstrated.
could lead to a disturbed exchange of oxygen and substrates between the vascular lumen and neurosensory retina. This may lead to a hypoxia-induced increased VEGF release by retinal cells. The loss of pericytes may render the capillaries more susceptible to effects mediated by VEGF.6 The observed morphologic effects in fluorescein angiography and OCT imaging were associated with an improvement in VA in some but not all eyes. Histopathologic examination22 as well as OCT imaging4,5 revealed microcystic degenerations within the neurosensory retina. Such previously existing atrophic neurosensory changes within the fovea may be responsible for a lack of improvement in VA.
Vascular leakage and neovascularization are major effects of VEGF.6,7,23 Leakage is the consequence of a breakdown of the blood–retina barrier.24 The VEGF-induced increase in permeability requires the tonic presence of VEGF.7 Because type 2 IMT is assumed to be a chronic disease, stimulation by VEGF may be long-standing. An intravitreally administered single dose of bevacizumab (1.25 mg) was shown to have an intravitreal half-life of approximately 3 days with still complete VEGF blockade after 4 weeks, but decreasing thereafter.25 The time courses of other diseases that are currently treated with intravitreal VEGF antagonists, such as neovascular age-related macular degeneration, are distinguished by their time-limited active
1739
Ophthalmology Volume 114, Number 9, September 2007
Figure 3. Optical coherence tomography (OCT) scans centered on the fovea (left) before and (right) after treatment with intravitreal bevacizumab. Orientation of the 2 scans is always equal and is specified in the left upper corner. A, B, Patient 6 (VI in Fig 1): after treatment, thickness of the neurosensory retina was reduced parafoveally and the hyporeflective foveal spaces show a reduction in size. C, Patient 4 (IV in Fig 1): the foveal cysts disappeared after treatment. D, Patient 3 (III in Fig 1): intraretinal fluid and retinal thickening decreased in the patient with the secondary neovascular membrane. E, Patient 1 (I in Fig 1): the foveal hyporeflective spaces in the superficial neurosensory layer disappeared after treatment, whereas the deep spaces remained.
disease process. Other anti-VEGF agents (ranibizumab, pegaptanib) were tested extensively and were found to be safe in patients with age-related macular degeneration for application periods of up to 2 years, with a 4- or 6-week treatment interval.12,26 However, long-term safety (i.e., several years) for intravitreal application has not been shown for any of the available anti-VEGF drugs. Therefore, the longterm applicability of currently available anti-VEGF drugs in type 2 IMT remains uncertain. Moreover, it has been suggested that VEGF plays a role in photoreceptor differentiation, may contribute to photore-
1740
ceptor survival, and may serve a role in maintaining retinal vascular homeostasis.27–29 Therefore, it can not be ruled out that blocking VEGF may cause an increased rate of apoptosis among ganglion cells and photoreceptors. Granted that neurosensory degeneration is a pathologic event in type 2 IMT,22 it remains to be seen whether VEGF antagonists will accelerate these processes in the long run. Vascular endothelial growth factor also triggers the production of metalloproteinases, which are enzymes that are required for the breakdown of basement membrane.6 Therefore, there is the possibility that the pathologic thickening of basement
Charbel Issa et al 䡠 Findings after Intravitreal Bevacizumab in Type 2 IMT membrane described in type 2 IMT22 is enforced by antagonizing VEGF. Survival of vascular endothelial cells has been shown to be dependent on VEGF as long as there is no pericyte coverage, and pericytes were shown to be diminished in type 2 IMT.22 Further studies will have to clarify if the macular capillaries in type 2 IMT remain intact after anti-VEGF treatment. Green et al22 postulated that the angiographic telangiectatic appearance is the result of focal endothelial defects. They concluded that these may be sites at which fluorescein diffused into capillary walls that were thickened by edema and excess basement membrane accumulation and eventually leaked out of the capillary wall into the surrounding retina. Breakdown of intercellular tight junctions is a known effect of VEGF.7,23 Antagonization may result in stabilization of the endothelial lining, and this effect could be a rationale for the reduction of ectatic-appearing capillaries in early-phase fluorescein angiography. It was a surprising finding that retinal thickness significantly decreased in the foveal zone and the inner ring, although the initial retinal thickness was in the range of normal values. Only 1 eye (patient 1) showed a slight retinal thickening that was present in all quadrants of the inner ring except the nasal quadrant. After application of intravitreal bevacizumab, retinal thickness decreased in all eyes and was even lower than normal in 3 eyes in at least 1 quadrant (patients 2, 5, and 6). This may point to a low-grade intraretinal edema that is superposed on a rather atrophic neurosensory retina. In 2 eyes (patients 2 and 5), the effect had the same magnitude temporally and nasally to the fovea. In 1 eye (patient 6), the effect was even stronger in the nasal quadrant, although angiography suggested a more active disease process temporal to the fovea. It may be speculated that, in this particular case, more advanced atrophic changes in the temporal quadrant hinder the respective retinal area from a more pronounced thickening. Limitations must be considered regarding the quantification of retinal thickness in type 2 IMT by third-generation OCT imaging, which may be erroneous in some cases because of specific findings associated with this disease. The retinal thickness analysis protocol of the third-generation OCT software automatically delineates the neural retina by considering marked changes in reflectivity as the inner and outer boundaries, respectively. The inner boundary is represented by the retinal surface. In type 2 IMT, the foveal superficial hyporeflective spaces often are covered only by a thin drapelike structure4,5 that may not be detected by the automatic delineation as the inner boundary. This results in a thinner measurement of the central foveal thickness. When this error was detected in one of the retinal thickness analyses, central foveal thickness was measured manually. However, foveal thickness (defined as the average thickness in the central 1000-m diameter) that is calculated by the software could not be influenced. Because the cystic spaces were most notable before treatment, the treatment effect on foveal thickness would rather be underestimated. Furthermore, it is an inherent characteristic of type 2 IMT that the outer boundary is altered in parts or that it is disrupted by deep neurosensory hyporeflective spaces. In the normal eye, there are 2 highly reflective layers at the outer neural retina.
The inner layer is supposed to represent the border between outer segments and inner segments of the photoreceptors and is recognized by the software as the outer delineation of the neurosensory retina. In type 2 IMT, often a disruption in the photoreceptor layer occurs, and therefore, the software instead uses the outer highly reflective layer, which delineates the retinal pigment epithelium for thickness analysis. This systematic error should not have consequences on the analysis of treatment effects in this study because the error would be the same before and after therapy (if there was no new formation of such defects). In summary, this report confirms an initial single observation15 and supports the concept that intravitreally administered bevacizumab has a biologic effect in type 2 IMT. The authors conclude that VEGF may play a pathophysiologic role in the disease. For validation of these short-term results and to study the long-term effects, the authors propose a prospective confirmatory study with equivalent antiVEGF drugs such as ranibizumab, administered in 4-week intervals over 12 months. Assuming an effect size of ⑀ ⫽ 1 (based on the effect 8 weeks after the initial injection), a 2-sided 1-sample t test at a level of 0.05 would require a sample size of 10 patients to reach a power of 80%.
References 1. Gass JD, Oyakawa RT. Idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol 1982;100:769 – 80. 2. Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis: update of classification and follow-up study. Ophthalmology 1993;100:1536 – 46. 3. Yannuzzi LA, Bardal AM, Freund KB, et al. Idiopathic macular telangiectasia. Arch Ophthalmol 2006;124:450 – 60. 4. Gaudric A, Ducos de Lahitte G, Cohen SY, et al. Optical coherence tomography in group 2A idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol 2006;124:1410 –9. 5. Paunescu LA, Ko TH, Duker JS, et al. Idiopathic juxtafoveal retinal telangiectasis. New findings by ultrahigh-resolution optical coherence tomography. Ophthalmology 2006;113: 48 –57. 6. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581– 611. 7. Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina 2005;25: 111– 8. 8. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695–705. 9. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–72. 10. Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113:23– 8. 11. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–16. 12. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419 –31. 13. Qaum T, Xu Q, Joussen AM, et al. VEGF-initiated blood-
1741
Ophthalmology Volume 114, Number 9, September 2007
14.
15.
16.
17.
18.
19.
20.
21.
22.
retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci 2001;42:2408 –13. Chew EY. Parafoveal telangiectasis. In: Ryan SJ, Hinton DR, Schachat AP, Wilkinson CP, eds. Retina. 4th ed. Vol. 2. St. Louis: Mosby; 2006:1409 –15. Charbel Issa P, Scholl HP, Holz FG. Intravitreal bevacizumab for the treatment of type 2 idiopathic macular telangiectasis. Retin Cases Brief Rep. In press. Hee MR, Izatt JA, Swanson EA, et al. Optical coherence tomography of the human retina. Arch Ophthalmol 1995;113: 325–32. Hee MR, Puliafito CA, Wong C, et al. Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol 1995;113:1019 –29. Puliafito CA, Hee MR, Lin CP, et al. Imaging of macular diseases with optical coherence tomography. Ophthalmology 1995;102:217–29. Hee MR, Puliafito CA, Duker JS, et al. Topography of diabetic macular edema with optical coherence tomography. Ophthalmology 1998;105:360 –70. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study findings. Ophthalmology 1978;85:82–106. Chan A, Duker JS, Ko TH, et al. Normal macular thickness measurements in healthy eyes using Stratus optical coherence tomography. Arch Ophthalmol 2006;124:193– 8. Green WR, Quigley HA, De la Cruz Z, Cohen B. Parafoveal
1742
23.
24.
25. 26.
27. 28. 29.
retinal telangiectasis: light and electron microscopy studies. Trans Ophthalmol Soc U K 1980;100:162–70. Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1: a potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 1999;274:23463–7. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996;103:1820 – 8. Beer PM, Wong SJ, Hammad AM, et al. Vitreous levels of unbound bevacizumab and unbound vascular endothelial growth factor in two patients. Retina 2006;26:871– 6. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology 2006;113:1508 –25. van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA 2005;293:1509 –13. Kim I, Ryan AM, Rohan R, et al. Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 1999;40:2115–21. Yourey PA, Gohari S, Su JL, Alderson RF. Vascular endothelial cell growth factors promote the in vitro development of rat photoreceptor cells. J Neurosci 2000;20:6781– 8.