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Relation between changes in foveal choroidal thickness and 1-year results of ranibizumab therapy for polypoidal choroidal vasculopathy
  1. Taiichi Hikichi,
  2. Hirokuni Kitamei,
  3. Shoko Shioya,
  4. Makoto Higuchi,
  5. Takuro Matsushita,
  6. Shoko Kosaka,
  7. Reiko Matsushita,
  8. Kimitaka Takami,
  9. Hideo Ohtsuka
  1. Department of Ophthalmology, Ohtsuka Eye Hospital, Sapporo, Japan
  1. Correspondence to Dr Taiichi Hikichi, Ohtsuka Eye Hospital, Kita-16 Nishi-4, Kita-ku, Sapporo 001-0016, Japan; taiichi-hikichi{at}hokkaido.med.or.jp

Abstract

Aim To determine a correlation between changes in the subfoveal choroidal thickness and outcomes 1 year after ranibizumab therapy for polypoidal choroidal vasculopathy (PCV).

Methods We prospectively studied 89 consecutive eyes with treatment-naïve symptomatic PCV and 1 year of follow-up after treatment. The choroidal thickness was measured monthly by optical coherence tomography using enhanced-depth imaging and the correlation between the changes in the choroidal thickness and outcomes 1 year after treatment was analysed.

Results 86 eyes followed for 1 year were ultimately analysed. The mean logarithm of the minimum angle of resolution visual acuity (0.33±0.35) 1 year after the first injection significantly (p=0.001) improved compared to baseline (0.42±0.37). The mean choroidal and foveal retinal thicknesses decreased significantly (p=0.001 for both comparisons) from 271 and 347 μm to 212 and 203 μm, respectively. The amplitude of the change in the subfoveal choroidal thickness during the 1-year follow-up in eyes in which the polypoidal lesions resolved 1 year after the first injection (89±94 μm) was significantly (p=0.022) greater than in eyes in which the polypoidal lesions remained (45±109 μm).

Conclusions The subfoveal choroidal thickness decreased during ranibizumab therapy, which was associated with resolved polypoidal lesions and foveal retinal thickness, and may be associated with PCV activity.

  • Choroidal Thickness
  • Ranibizumab
  • Polypoidal Choroidal Vasculopathy

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Polypoidal choroidal vasculopathy (PCV), a distinct exudative macular disorder that is clinically relevant, is characterised by a network of vessels with two distinct components: a complex of branching vessels, and multiple, terminal, reddish-orange polypoidal lesions.1 Nakashizuka et al2 observed the submacular tissue surgically extracted from an eye with PCV that included sub-retinal pigment epithelium (RPE) and intra-Bruch's fibrovascular membrane that contained several dilated thin-walled vessels. Although the choroidal status seems to play an important role in the pathophysiology of PCV, indocyanine green (ICG) angiography (ICGA) was used frequently to evaluate the choroid3 before Spaide et al4 introduced optical coherence tomography (OCT) with enhanced-depth imaging (EDI) in 2008. Recently, several groups have reported that the subfoveal choroid is thicker in eyes with PCV than in eyes with typical age-related macular degeneration (AMD),5–7 and that the subfoveal choroid is thicker in eyes with PCV with choroidal vascular hyperpermeability, suggesting different pathogenic mechanisms in typical AMD and PCV.8

Although the choroidal thickness has been reported to decrease after anti-vascular endothelial growth factor (anti-VEGF) therapy and photodynamic therapy (PDT) in eyes with PCV,8–10 little is known about the effect of anti-VEGF therapy on the choroid or the relationship between the changes in choroidal thickness and therapeutic outcome in eyes with PCV. Koizumi et al8 reported that eyes with PCV and choroidal vascular hyperpermeability on ICGA had greater subfoveal choroidal thickness than those without choroidal vascular hyperpermeability. Furthermore, PCV with choroidal vascular hyperpermeability was significantly associated with persistent retinal fluid after three monthly intravitreal injections of ranibizumab. Since PCV lesions are present in the choroid, we speculated that changes in the choroidal thickness during treatment such as ranibizumab therapy for PCV must be meaningful in the treatment course. Based on this speculation, we conducted the current prospective investigation.

Patients and methods

After 13 March 2009, all patients with PCV at the Ohtsuka Eye Hospital were treated with a 0.5-mg intravitreal injection of ranibizumab (Lucentis, Genentech, South San Francisco, California, USA) for 3 months followed by a reinjection schedule based on need. After 1 August 2011, when EDI-OCT became available in our hospital, all patients who received ranibizumab therapy underwent EDI-OCT to examine the choroidal thickness at every visit. This prospective study included 89 consecutive eyes of 89 patients with treatment-naïve symptomatic PCV who underwent a baseline examination after 1 August 2011, received ranibizumab therapy, and were followed for 1 year. During the period in which the patients were enrolled in the current study, three monthly 0.5-mg ranibizumab injections followed by a reinjection schedule based on need was the only treatment strategy for treatment-naïve symptomatic PCV in our institute. In cases with bilateral disease, the eye treated first with ranibizumab was included in the study. There were no exclusion criteria regarding the baseline visual acuity (VA) or lesion size. PCV was defined as the presence of one or multiple focal areas of hyperfluorescence arising from the choroidal circulation within the first 6 min after injection of ICG, with or without an associated branching vascular network. The polypoidal lesions could have been solitary (arbitrarily defined as one or two polyps) or multiple. If multiple, the polypoidal lesions could have been in a ring or cluster.11 Since all subjects in our previous study,12 which reported the outcome of ranibizumab monotherapy for PCV, underwent a baseline examination before 1 August 2011, and EDI-OCT was not performed at every visit from baseline to 1 year after the first injection, no eyes from that study12 were included in the current study. The current research followed the tenets of the Declaration of Helsinki and all patients provided informed consent after explanation of the study protocol. The institutional Review Board at Ohtsuka Eye Hospital approved this prospective study.

During the visit at which the first injection of ranibizumab was administered, a complete ophthalmic examination was performed that included VA measurements using a Landolt ring chart, digital simultaneous fluorescein angiography (FA) and ICGA using confocal scanning laser ophthalmoscopy (Heidelberg Retina Angiograph II, Heidelberg Engineering, Heidelberg, Germany), and spectral-domain (SD)-OCT (Spectralis, software V.5.3; Heidelberg Engineering) using EDI, which was performed by placing the SD-OCT instrument sufficiently close to the eye to obtain an inverted image. Briefly, this OCT protocol uses an 870-nm wavelength superluminescent diode and can obtain 40 000 A scans/second with an axial resolution of 7 μ and transversal resolution of 14 μ. A horizontal section and a single vertical section were obtained within a 5×30° area at the fovea, in which 100 scans were averaged for each section. All images were obtained using an eye-tracking system, and 100 scans were averaged automatically to improve the signal-to-noise ratio. The B-scan was about 9 mm long. The choroidal thickness was measured manually using the Heidelberg Eye Explorer software (V.1.5.12.0).

Six radial line scans through the centre of the foveal lesions were used to identify macular fluid. The foveal thickness was determined based on the average foveal thickness on the vertical and horizontal scans. The foveal thickness on the vertical and horizontal scans was measured manually from the inner retinal surface to the pigment epithelial line.12 The foveal thickness in eyes with a subfoveal pigment epithelium detachment (PED) was defined as the length of the line from the inner foveal surface to the point at a right angle to the line between the edges of the elevated RPE. Thus, in this case, the height of the PED was included in the foveal thickness. The subfoveal choroidal thickness, defined as the vertical distance between the hyperreflective line of Bruch's membrane and the chorioscleral interface, was measured using the horizontal and vertical line scans through the centre of the fovea. Two examiners (HK, SS), who were masked to the information about treatment outcomes, independently performed the measurements. The mean values measured by the two examiners were used. Measurements from the two examiners were compared to assess inter-examiner reproducibility. In addition, one examiner (HK) repeated all measurements on a different day to determine the intra-examiner variations. Choroidal vascular hyperpermeability was evaluated in late-phase ICGA images about 10–15 min after dye injection. Guyer et al13 reported that choroidal vascular hyperpermeability is defined as multifocal areas of hyperfluorescence with blurred choroidal margins.

Measurements of the VA and OCT were performed monthly. FA and ICGA were performed 3, 6 and 12 months after the first ranibizumab injection. Resolution of the polypoidal lesions was determined based on the ICGA findings 12 months after the first injection. If no apparent polypoidal lesions were observed, they were considered to have resolved.

After intravitreal injection of ranibizumab monthly for 3 months, additional injections were administered if any of the following occurred14: any qualitative change in the appearance of the OCT images that suggested recurrent fluid in the macula including enlargement of a PED; new macular haemorrhages; or persistent fluid seen on OCT 1 month after the previous injection. All criteria were based on comparisons with the previous month's examination. If any criterion for reinjection was met, an intravitreal injection was administered. One clinician (TH) examined all patients and determined the need for reinjection during the follow-up period. All injections of intravitreal ranibizumab were administrated on the same day when the injections were determined to be needed.

The differences in the VA, foveal thicknesses and subfoveal choroidal thickness at baseline and 12 months after the first injection were analysed using the paired Student t test. The VA results were converted to the logarithm of the minimum angle of resolution (logMAR) for analysis. For inter- and intra-examiner reliability, the intraclass correlation (ICC) was calculated. Statistical analysis was performed using SPSS for Windows V.11.5.1 . All data are expressed as mean±SD.

Results

Of 89 consecutive eyes with PCV, three (3%) eyes were lost to follow-up because the patients missed some follow-up examinations. Thus, 86 eyes of 86 patients (men, 62 eyes, 72%; women, 24 eyes, 28%) were analysed in this study. The mean patient age was 77±8 years (range 57–93 years) and the mean number of injections administered including the three monthly injections was 4.3±1.2.

The changes in the mean logMAR VA during the 1-year follow-up period after the first ranibizumab injection were similar to those reported previously.13 The VA progressively improved during the loading phase, and improved significantly (p=0.004, by the paired t test) 1 month after the third intravitreal injection (0.34±0.36) compared to baseline (0.42±0.37); the improved VA was maintained (0.33±0.35, 1 year after the first injection, p=0.001, by the paired t test).

The mean foveal thickness 1 month after the third intravitreal injection (200±68 μm) significantly (p=0.001, by the paired t test) decreased compared to the mean foveal thickness at baseline (347±162 μm) and was maintained thereafter (203±68 μm at 1 year after the first injection, p=0.001, by the paired t test) (figure 1). The mean subfoveal choroidal thickness 1 month after the third intravitreal injection (232±96 μm) also decreased significantly (p=0.001, by the paired t test) compared to the baseline (271±102 μm) and was maintained thereafter (212±90 μm 1 year after the first injection, p=0.001, by the paired t test).

Figure 1

Changes in the mean subfoveal choroidal thickness and foveal thickness for all patients (86 eyes) during the 1-year follow-up period after the first ranibizumab injection to treat polypoidal choroidal vasculopathy. The vertical bars indicate one standard error of the mean.

The correlation between the change in subfoveal choroidal thickness during the 1-year follow-up period and the change in foveal thickness during the 1-year follow-up period was low but significant (correlation coefficient (r)=0.286, p=0.042, by Pearson's correlation test). The change in subfoveal choroidal thickness during the 1-year follow-up period was not correlated with the change in logMAR VA during the 1-year follow-up period or the numbers of injections during the 1-year follow-up period (by Pearson's correlation test).

The baseline ICGA images showed choroidal vascular hyperpermeability in 20 (23%) of 86 eyes. The baseline subfoveal choroidal thickness (342±113 μm) in eyes with choroidal vascular hyperpermeability was significantly (p=0.001, by the unpaired t test) larger than that (227±96 μm) in eyes without choroidal vascular hyperpermeability. The amplitude of the change in subfoveal choroidal thickness during the 1-year follow-up period was significantly (p=0.042, by the unpaired t test) greater in eyes with choroidal hyperpermeability at baseline (109±116 μm) than in eyes without choroidal hyperpermeability (55±97 μm). However, the baseline choroidal vascular hyperpermeability was not correlated with the number of injections during the 1-year follow-up period, the amplitude of change in the foveal thickness during the 1-year follow-up period, or the amplitude of change in logMAR VA during the 1-year follow-up period (by the unpaired t test). The baseline ICGA images showed polypoidal lesions in all eyes, which resolved in 32 (37%) eyes 1 year after the first injection. The amplitude of change in foveal thickness and subfoveal choroidal thickness during the 1-year follow-up period in eyes in which the polypoidal lesions resolved 1 year after the first injection (183±180 μm and 89±94 μm, respectively) was significantly (p=0.048 and p=0.022, respectively, by the unpaired t test) greater than in eyes in which the polypoidal lesions did not resolve (103±129 μm and 45±109 μm, respectively).

There was good agreement between examiners (ICC, 0.96). The difference in the subfoveal choroidal thickness measurements between examiners was 4.5±13.6 μm, with a maximal difference of 24 μm. The correlation efficient (r) between the two examiners was 0.999 (p<0.0001, R2=0.998). The intra-examiner agreement was also good (ICC, 0.98). The correlation efficient (r) between the two measurements was 0.999 (p<0.0001, R2=0.998). The mean intra-examiner variation (ie, the difference in subfoveal choroidal thickness between the two measurements by the same examiner/mean subfoveal choroidal thickness of the two values) was 0.032±0.013.

Discussion

The current results showed that subchoroidal thickness in eyes with PCV decreased with three monthly intravitreal injections of ranibizumab followed by an as-needed reinjection schedule; the course of the changes was similar to those of the improving VA and foveal thickness. Yamazaki et al9 reported that the mean subfoveal choroidal thickness in 16 eyes with PCV (some of which had been treated previously), treated with ranibizumab injections decreased during treatment with three monthly injections and was maintained until 12 months. The current results confirmed their observation and showed that subfoveal choroidal thickness responded to ranibizumab injections in a larger series of consecutive treatment-naïve eyes with PCV. The current results also showed a correlation between the changes in foveal thickness and subfoveal choroidal thickness, and that subfoveal choroidal thickness may be associated with PCV activity. In the current study, changes in subfoveal choroidal thickness were associated with resolution of the polypoidal lesions and baseline hyperpermeability.

The decreased choroidal thickness was thought to be related to reduced choroidal vascular permeability in eyes with PCV. In the current study, the baseline subfoveal choroid was thicker and the amplitude of the change in subfoveal choroidal thickness 1 year after the first injection was greater in eyes with choroidal hyperpermeability. Ranibizumab may inhibit or reduce the abnormal hyperpermeability of the choroidal vessels. Dilated vessels in PCV lesions may be associated with thickened choroid in eyes with PCV.15 VEGF promotes production of nitric oxide, which has a vasodilating effect.16 Thus, ranibizumab, an anti-VEGF drug, may reduce the diameter of the dilated choroidal vessels, resulting in choroidal thinning. Although it is unclear if ranibizumab has a vasoconstrictive effect on the choroidal vasculature, Nakashizuka et al2 reported that vascular endothelial cells were not positive for VEGF, but macrophages, fibroblast-like cells and RPE cells in surgically excised PCV tissues were. Another possible mechanism for the decreased subfoveal choroidal thickness during ranibizumab treatment is decreased leakage from the PCV lesions. In the current study, resolution of the polypoidal lesions seen on ICGA images after ranibizumab therapy was associated with a decrease in subfoveal choroidal thickness. Maruko et al10 and Koizumi et al8 also reported that eyes with choroidal vascular hyperpermeability on ICGA had a significantly thicker subfoveal choroid than eyes without choroidal vascular hyperpermeability, suggesting that leakage from PCV lesions may be associated with choroidal thickness.

Choroidal thickness varies with age, refractive status and time of day.17–20 The subfoveal choroidal thickness in elderly Chinese subjects was reported to decrease by 4 μm for every 1-year increase in age and by 15 μm for every 1-diopter (D) increase in myopia.18 Since the mean subfoveal choroidal thickness decreased about 60 μm from baseline to 1 year after the first injection in the current study, the amplitude of this decreased subfoveal choroidal thickness exceeded the aging change. The spherical equivalent was less than −1 D in 64 (74%) of 86 eyes and less than −3 D in all eyes in the current study; thus, the effect of myopia on subfoveal choroidal thickness seemed small. Previous studies19–21 have reported significant diurnal variations in choroidal thickness (average 33–59.5 μm). In the current study, almost all OCTs were obtained between 9:00 and 12.30. Thus, the effect of diurnal variation on the choroidal thickness on the current results should be minimal.

Although several studies22 ,23 have reported good reproducibility of EDI-OCT when measuring choroidal thickness, light scattering by the RPE and choroid affects visualisation of the outer border of the choroid, especially in eyes with a very thick choroid, and may make obtaining measurements more difficult.23 Although vessel dilatation and exudative changes are present in the choroid in eyes with PCV, the amplitude of the change in subfoveal choroidal thickness during the 1-year follow-up period was more than 10 times larger than the intra-examiner variation in the measurement of subfoveal choroidal thickness. Thus, the decrease in subfoveal choroidal thickness resulting from ranibizumab therapy in eyes with PCV is not a measurement error but an exact phenomenon. Another limitation of the current study was that the Early Treatment of Diabetic Retinopathy Study chart was not used to measure the VA. The current results showed that subfoveal choroidal thickness decreased during ranibizumab therapy, which was associated with resolution of polypoidal lesions and foveal retinal thickness, and may be associated with PCV activity. Further advances in instrumentation that can facilitate detailed investigations of the choroid will increase the importance of monitoring the choroid during treatment of PCV.

References

Footnotes

  • Contributors TH: conception, design, acquisition of data, analysis, drafting and revising the article, and final approval of all the versions. HK: interpretation of data and final approval of all the versions. SS: interpretation of data and final approval of all the versions. MH: conception, design, and final approval of all the versions. TM: conception, design, and final approval of all the versions. SK: conception, design, and final approval of all the versions. RM: conception, design, and final approval of all the versions. KT: conception, design, and final approval of all the versions. HO: conception, design, and final approval of all the versions.

  • Competing interests TH received lecture fees from Novartis Pharma Japan, Bayer. Japan, Santen, and Alcon Japan. HK received lecture fee from Novartis Pharma Japan. SS received lecture fees from Novartis Pharma Japan and Bayer. Japan.

  • Patient consent Obtained.

  • Ethics approval The institutional Review Board at Ohtsuka Eye Hospital prospectively approved the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.