- Email: [email protected]
Assessment of Retinal Alterations after Intravitreal Ocriplasmin with Spectral-Domain Optical Coherence Tomography
Ophthalmology Volume 121, Number 12, December 2014
Assessment of Retinal Alterations after Intravitreal Ocriplasmin with Spectral-Domain Optical Coherence Tomography Ocriplasmin (Jetrea, Thrombogenics, Leuven, Belgium) was recently approved by the United States Food and Drug Administration for the treatment of symptomatic vitreomacular traction (VMT). The MIVITRUST phase III randomized, controlled trials revealed that intravitreal ocriplasmin had superior efficacy for VMT resolution compared with placebo vehicle injection.1 Qualitative identification of outer retinal changes after ocriplasmin injection that were not previously recognized in the MIVI-TRUST trials have recently been described.2e4 In those reports, the outer segment ellipsoid zone (EZ), also referred to as inner segment/outer segment junction, seemed to be most impacted. Another
retinal alteration that has been described after ocriplasmin injection is increased subretinal fluid (SRF).2 The purpose of this study was to quantitatively evaluate retinal structural changes with spectral domain optical coherence tomography (SD-OCT) after ocriplasmin therapy. This was an institutional review board-approved, retrospective, consecutive case series and adhered to the tenets of the Declaration of Helsinki. Inclusion criteria were eyes that received intravitreal ocriplasmin and SD-OCT imaging at baseline and 1 week after injection. Exclusion criteria included poor quality SD-OCT and concurrent macular disease that could affect visual acuity and/or retinal architecture. All eyes received intravitreal ocriplasmin (125 mg). The SD-OCT examinations were performed with a Cirrus HDOCT (Cirrus V.6.1 software, Carl Zeiss Meditec, Dublin, CA) at baseline and at post-injection time points. Inner, middle, and outer retinal thicknesses 1.2 mm nasal, temporal, superior, and inferior to the fovea were calculated as previously
Figure 1. (A) Features identified on optical coherence tomography (OCT) 1 week after intravitreal ocriplasmin, including vitreomacular traction release, ellipsoid zone (EZ) loss and subretinal fluid (SRF) accumulation. (B) Bar graph comparing value of EZeretinal pigment epithelium (RPE) height reduction and SRF accumulation revealing that the EZ-RPE reduction was significantly larger when compared with the cases without SRF accumulation (P ¼ 0.00024). (C) Longitudinal retinal layer thickness prior to and after intravitreal ocriplasmin. A significant reduction is seen in outer retinal thickness at 1 week and in the EZeRPE height at all time points. *P < 0.01 versus baseline (Mann-Whitney U test). Error bars indicate the standard deviation. (D) Scatter plot shows the relationship between the EZeRPE height loss and SRF volume.
2506
Reports described.5 Additionally, the distance between the EZ and the retinal pigment epithelium (RPE; EZeRPE height) was quantified. All measurements were performed in a masked fashion. For SRF volumetric analysis, a custom OCT software analysis program was utilized to manually segment the SRF volume. To compare the 2 groups, Mann-Whitney U tests were used with nonparametric distribution data. Multivariate analysis was used to investigate the relationships between retinal architectural alterations and visual acuity. Spearman’s rank correlation was also performed, as appropriate. P < 0.05 was considered significant. Nineteen eyes of 19 patients were identified that met the inclusion/ exclusion criteria for this study. Mean age was 69.6 years (range, 59e85) with 5 men (26%) and 14 women (74%). Twelve eyes (63%) were phakic and 7 (37%) were pseudophakic. The mean visual acuity was 20/40 at baseline, 20/43 at 1 week postinjection, 20/38 at 1 month, and 20/32 at 3 months. Three months after injection, VMT release after ocriplasmin injection was observed in 9 of 19 eyes (47%). On SD-OCT analysis, 10 of 19 eyes (53%) exhibited transient EZ loss (Fig 1; Fig 2 is available at www.aaojournal.org). Inner and middle retinal thicknesses were unchanged after ocriplasmin therapy. Mean outer retinal thickness significantly decreased at 1 week (P ¼ 0.00029), but gradually recovered at 1 (P ¼ 0.09) and 3 months (P ¼ 0.91) after injection. The mean EZeRPE height at baseline was significantly reduced at 1 week, 1 month, and 3 months (P ¼ 0.0001, P < 0.0001, and P ¼ 0.00099, respectively) after injection (Fig 1). Retinal thickness assessments based on VMT release and SRF accumulation were also performed. One week after injection, EZeRPE height was reduced in eyes with VMT release (14.99.1 mm compared with baseline) and without VMT release (8.913.2 mm). One week after injection, the EZeRPE height was reduced in eyes with increased SRF (21.94.5 mm) but not in eyes without increased SRF (0.522.0 mm) and this was significantly different (P ¼ 0.00024; Fig 1; Table 1, available at www.aaojournal.org). The amount of decreased EZeRPE height was strongly correlated with the accumulation of SRF (P ¼ 0.00021; correlation coefficient ¼ 0.88; Fig 1). As with any retrospective analysis, there are limitations to this study. The follow-up period is relatively short and the sample size small. Because of the retrospective nature, standardized follow-up could not be achieved. This study was also not controlled and did not have a comparison group, such as surgery, placebo injection, or pneumatic vitreolysis. Functional analysis within this study did not include potential important diagnostic testing, including electroretinogram and microperimetry. Recent case reports after ocriplasmin treatment suggest similar acute panretinal dysfunction in rare cases. Outer retinal changes on SD-OCT and significant reduction in electroretinogram amplitudes were present.3,4 One report suggests that these changes may reflect degradation of laminin resulting in panretinal dysfunction secondary to ocriplasmin.4 In our study, 10 of 19 eyes showed decreased length between the EZ and RPE (EZeRPE height) 1 week after ocriplasmin injection. All of these cases also exhibited increased SRF. This EZeRPE height loss gradually recovered with time. Three months after injection, outer retinal thickness recovered to baseline. The origin of the increased SRF remains unclear. Potential hypotheses include alterations from vitreoretinal traction, transient breakdown of the outer blooderetinal barrier, inherent RPE dysfunction, and accumulation of photoreceptor outer segments. All cases that showed reduction in EZeRPE height also showed an
increase in volume of the SRF compared with baseline. There was a strong correlation in the change in EZeRPE height and increase in SRF. This may support that the SRF origin is related to the degradation of photoreceptor outer segments. Although the hyporeflective nature of the SRF seen in our cases does not correspond with the typical OCT reflectivity of outer segments, in the presence of potential enzymatic changes it is unclear what characteristics outer segments would have on OCT. In addition, the loss of standard directional orientation of the outer segments would change the OCT appearance. It is important to recognize that, although the EZ band seems to rapidly reappear on the OCT qualitatively within a few weeks, it takes significantly longer for the baseline EZeRPE height to be restored to preinjection levels. This may reflect the slow reaccumulation of the outer segments. Based on our review of the literature, we believe this represents the first quantitative assessment of the retinal alterations associated with ocriplasmin therapy. Our study suggests that the outer retinal changes and SRF accumulation seem to be common findings after intravitreal ocriplasmin injection and potentially interrelated. Retinal alterations seem to nearly normalize by 3 months, but the long-term implications of these findings need further prospective research.
YUJI ITOH, MD, PHD PETER K. KAISER, MD RISHI P. SINGH, MD SUNIL K. SRIVASTAVA, MD JUSTIS P. EHLERS, MD Ophthalmic Imaging Center, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio Financial Disclosure(s): The authors have made the following disclosures: P.K.K.: Consultant e Thrombogenics, Alcon, Novartis, Allegro. R.P.S.: Consultant e Thrombogenics, Alcon. S.K.S.: Consultant e Bausch and Lomb, Leica, Allergan; Intellectual Property e Bioptigen, Synergetics. J.P.E.: Intellectual Property e Bioptigen, Synergetics; Consultant e Leica, Zeiss; Consultant, Financial Supports e Thrombogenics. Supported by National Institutes of Health/National Eye Institute K23EY022947-01A1 (J.P.E.); Ohio Department of Development TECH-13059 (J.P.E., S.K.S.); Research to Prevent Blindness (P.K.K.). Correspondence: Justis P. Ehlers, MD, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, i32, Cleveland, OH 44195. E-mail: [email protected].
References 1. Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367:606–15. 2. Singh RP, Li A, Bedi R, Srivastava S, et al. Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome. Br J Ophthalmol 2014;98:356–60. 3. Freund KB, Shah SA, Shah VP. Correlation of transient vision loss with outer retinal disruption following intravitreal ocriplasmin. Eye (Lond) 2013;27:773–4. 4. Fahim AT, Khan NW, Johnson MW. Acute panretinal structural and functional abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol 2014;132:484–6. 5. Hibi N, Ueno S, Ito Y, et al. Relationship between retinal layer thickness and focal macular electroretinogram components after epiretinal membrane surgery. Invest Ophthalmol Vis Sci 2013;54:7207–14.
2507
Reports
Figure 2. (A) Case example 1 reveals vitreomacular traction (VMT) release without appreciable changes to the ellipsoid zone (EZ) or increased subretinal fluid (SRF). Posterior hyaloid is noted with yellow arrow. (B) Case example 2 reveals persistent VMT (yellow arrow) and no appreciable architectural alterations, including in the EZ and subretinal space. (C) Case example 3 shows persistent VMT (yellow arrow) and significant loss of the EZ (white arrowhead) and large amount of SRF accumulation (red arrow). (D) Case example 4 exemplifies VMT release (yellow arrow highlights posterior hyaloid) with accompanying significant attenuation of the EZ (and reduction in EZ to retinal pigment epithelium distance, white arrowhead) and concurrent accumulation of SRF (red arrow).
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Ophthalmology Volume 121, Number 12, December 2014 Table 1. Longitudinal retinal layer thickness analysis following intravitreal ocriplasmin VMT Release Inner Retinal thickness (mm) Baseline 1 week 1 month 3 months Middle retinal thickness (mm) Baseline 1 week 1 month 3 months Outer retinal thickness (mm) Baseline 1 week 1 month 3 months EZ-RPE Height (mm) Baseline 1 week 1 month 3 months
SRF Accumulation
Overall
Yes
No
25.48.3 26.59.0 24.57.6 25.18.5
26.18.3 25.58.3 25.38.2 27.58.5
24.88.2 27.59.6 23.66.8 20.76.0
25.77.8 27.18.7 26.27.7 26.28.6
25.08.6 25.89.2 22.66.9 23.07.6
160.423.5 163.519.8 159.722.2 154.421.6
163.418.8 160.517.8 160.517.3 162.114.1
157.926.6 166.421.2 158.726.8 141.525.3
161.616.1 163.717.8 161.619.0 160.515.7
159.128.8 163.121.5 157.524.9 144.224.9
127.618.5 116.1±21.1* 123.019.0 127.313.2
126.718.0 112.4±16.9* 118.6±14.0* 126.513.8
128.418.9 119.623.9 128.122.4 128.711.4
127.315.6 106.216.6*,y 116.314.2*,y 127.512.4
127.920.7 128.119.1y 130.720.5y 127.014.0
30.22.4 18.3±11.6* 21.9±7.5* 28.5±2.9*
29.32.0 14.49.2* 19.06.8*,y 28.12.5
30.42.4 8.34.5*,y 15.64.5*,y 28.02.5*
30.02.4 30.32.8y 28.62.5y 29.23.3
31.02.4 22.112.5*,y 24.96.9*,y 29.1±3.4*
Yes
No
VMT ¼ vitreomacular traction; SRF ¼ subretinal fluid; mm ¼ micrometer; EZ ¼ outer segment ellipsoid zone; RPE ¼ Retinal pigment epithelium. *P < 0.05 compared to baseline (bold). y P < 0.05 between comparison groups at same period (italics).
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Assessment of Retinal Alterations after Intravitreal Ocriplasmin with Spectral-Domain Optical Coherence Tomography Ocriplasmin (Jetrea, Thrombogenics, Leuven, Belgium) was recently approved by the United States Food and Drug Administration for the treatment of symptomatic vitreomacular traction (VMT). The MIVITRUST phase III randomized, controlled trials revealed that intravitreal ocriplasmin had superior efficacy for VMT resolution compared with placebo vehicle injection.1 Qualitative identification of outer retinal changes after ocriplasmin injection that were not previously recognized in the MIVI-TRUST trials have recently been described.2e4 In those reports, the outer segment ellipsoid zone (EZ), also referred to as inner segment/outer segment junction, seemed to be most impacted. Another
retinal alteration that has been described after ocriplasmin injection is increased subretinal fluid (SRF).2 The purpose of this study was to quantitatively evaluate retinal structural changes with spectral domain optical coherence tomography (SD-OCT) after ocriplasmin therapy. This was an institutional review board-approved, retrospective, consecutive case series and adhered to the tenets of the Declaration of Helsinki. Inclusion criteria were eyes that received intravitreal ocriplasmin and SD-OCT imaging at baseline and 1 week after injection. Exclusion criteria included poor quality SD-OCT and concurrent macular disease that could affect visual acuity and/or retinal architecture. All eyes received intravitreal ocriplasmin (125 mg). The SD-OCT examinations were performed with a Cirrus HDOCT (Cirrus V.6.1 software, Carl Zeiss Meditec, Dublin, CA) at baseline and at post-injection time points. Inner, middle, and outer retinal thicknesses 1.2 mm nasal, temporal, superior, and inferior to the fovea were calculated as previously
Figure 1. (A) Features identified on optical coherence tomography (OCT) 1 week after intravitreal ocriplasmin, including vitreomacular traction release, ellipsoid zone (EZ) loss and subretinal fluid (SRF) accumulation. (B) Bar graph comparing value of EZeretinal pigment epithelium (RPE) height reduction and SRF accumulation revealing that the EZ-RPE reduction was significantly larger when compared with the cases without SRF accumulation (P ¼ 0.00024). (C) Longitudinal retinal layer thickness prior to and after intravitreal ocriplasmin. A significant reduction is seen in outer retinal thickness at 1 week and in the EZeRPE height at all time points. *P < 0.01 versus baseline (Mann-Whitney U test). Error bars indicate the standard deviation. (D) Scatter plot shows the relationship between the EZeRPE height loss and SRF volume.
2506
Reports described.5 Additionally, the distance between the EZ and the retinal pigment epithelium (RPE; EZeRPE height) was quantified. All measurements were performed in a masked fashion. For SRF volumetric analysis, a custom OCT software analysis program was utilized to manually segment the SRF volume. To compare the 2 groups, Mann-Whitney U tests were used with nonparametric distribution data. Multivariate analysis was used to investigate the relationships between retinal architectural alterations and visual acuity. Spearman’s rank correlation was also performed, as appropriate. P < 0.05 was considered significant. Nineteen eyes of 19 patients were identified that met the inclusion/ exclusion criteria for this study. Mean age was 69.6 years (range, 59e85) with 5 men (26%) and 14 women (74%). Twelve eyes (63%) were phakic and 7 (37%) were pseudophakic. The mean visual acuity was 20/40 at baseline, 20/43 at 1 week postinjection, 20/38 at 1 month, and 20/32 at 3 months. Three months after injection, VMT release after ocriplasmin injection was observed in 9 of 19 eyes (47%). On SD-OCT analysis, 10 of 19 eyes (53%) exhibited transient EZ loss (Fig 1; Fig 2 is available at www.aaojournal.org). Inner and middle retinal thicknesses were unchanged after ocriplasmin therapy. Mean outer retinal thickness significantly decreased at 1 week (P ¼ 0.00029), but gradually recovered at 1 (P ¼ 0.09) and 3 months (P ¼ 0.91) after injection. The mean EZeRPE height at baseline was significantly reduced at 1 week, 1 month, and 3 months (P ¼ 0.0001, P < 0.0001, and P ¼ 0.00099, respectively) after injection (Fig 1). Retinal thickness assessments based on VMT release and SRF accumulation were also performed. One week after injection, EZeRPE height was reduced in eyes with VMT release (14.99.1 mm compared with baseline) and without VMT release (8.913.2 mm). One week after injection, the EZeRPE height was reduced in eyes with increased SRF (21.94.5 mm) but not in eyes without increased SRF (0.522.0 mm) and this was significantly different (P ¼ 0.00024; Fig 1; Table 1, available at www.aaojournal.org). The amount of decreased EZeRPE height was strongly correlated with the accumulation of SRF (P ¼ 0.00021; correlation coefficient ¼ 0.88; Fig 1). As with any retrospective analysis, there are limitations to this study. The follow-up period is relatively short and the sample size small. Because of the retrospective nature, standardized follow-up could not be achieved. This study was also not controlled and did not have a comparison group, such as surgery, placebo injection, or pneumatic vitreolysis. Functional analysis within this study did not include potential important diagnostic testing, including electroretinogram and microperimetry. Recent case reports after ocriplasmin treatment suggest similar acute panretinal dysfunction in rare cases. Outer retinal changes on SD-OCT and significant reduction in electroretinogram amplitudes were present.3,4 One report suggests that these changes may reflect degradation of laminin resulting in panretinal dysfunction secondary to ocriplasmin.4 In our study, 10 of 19 eyes showed decreased length between the EZ and RPE (EZeRPE height) 1 week after ocriplasmin injection. All of these cases also exhibited increased SRF. This EZeRPE height loss gradually recovered with time. Three months after injection, outer retinal thickness recovered to baseline. The origin of the increased SRF remains unclear. Potential hypotheses include alterations from vitreoretinal traction, transient breakdown of the outer blooderetinal barrier, inherent RPE dysfunction, and accumulation of photoreceptor outer segments. All cases that showed reduction in EZeRPE height also showed an
increase in volume of the SRF compared with baseline. There was a strong correlation in the change in EZeRPE height and increase in SRF. This may support that the SRF origin is related to the degradation of photoreceptor outer segments. Although the hyporeflective nature of the SRF seen in our cases does not correspond with the typical OCT reflectivity of outer segments, in the presence of potential enzymatic changes it is unclear what characteristics outer segments would have on OCT. In addition, the loss of standard directional orientation of the outer segments would change the OCT appearance. It is important to recognize that, although the EZ band seems to rapidly reappear on the OCT qualitatively within a few weeks, it takes significantly longer for the baseline EZeRPE height to be restored to preinjection levels. This may reflect the slow reaccumulation of the outer segments. Based on our review of the literature, we believe this represents the first quantitative assessment of the retinal alterations associated with ocriplasmin therapy. Our study suggests that the outer retinal changes and SRF accumulation seem to be common findings after intravitreal ocriplasmin injection and potentially interrelated. Retinal alterations seem to nearly normalize by 3 months, but the long-term implications of these findings need further prospective research.
YUJI ITOH, MD, PHD PETER K. KAISER, MD RISHI P. SINGH, MD SUNIL K. SRIVASTAVA, MD JUSTIS P. EHLERS, MD Ophthalmic Imaging Center, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio Financial Disclosure(s): The authors have made the following disclosures: P.K.K.: Consultant e Thrombogenics, Alcon, Novartis, Allegro. R.P.S.: Consultant e Thrombogenics, Alcon. S.K.S.: Consultant e Bausch and Lomb, Leica, Allergan; Intellectual Property e Bioptigen, Synergetics. J.P.E.: Intellectual Property e Bioptigen, Synergetics; Consultant e Leica, Zeiss; Consultant, Financial Supports e Thrombogenics. Supported by National Institutes of Health/National Eye Institute K23EY022947-01A1 (J.P.E.); Ohio Department of Development TECH-13059 (J.P.E., S.K.S.); Research to Prevent Blindness (P.K.K.). Correspondence: Justis P. Ehlers, MD, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, i32, Cleveland, OH 44195. E-mail: [email protected].
References 1. Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367:606–15. 2. Singh RP, Li A, Bedi R, Srivastava S, et al. Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome. Br J Ophthalmol 2014;98:356–60. 3. Freund KB, Shah SA, Shah VP. Correlation of transient vision loss with outer retinal disruption following intravitreal ocriplasmin. Eye (Lond) 2013;27:773–4. 4. Fahim AT, Khan NW, Johnson MW. Acute panretinal structural and functional abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol 2014;132:484–6. 5. Hibi N, Ueno S, Ito Y, et al. Relationship between retinal layer thickness and focal macular electroretinogram components after epiretinal membrane surgery. Invest Ophthalmol Vis Sci 2013;54:7207–14.
2507
Reports
Figure 2. (A) Case example 1 reveals vitreomacular traction (VMT) release without appreciable changes to the ellipsoid zone (EZ) or increased subretinal fluid (SRF). Posterior hyaloid is noted with yellow arrow. (B) Case example 2 reveals persistent VMT (yellow arrow) and no appreciable architectural alterations, including in the EZ and subretinal space. (C) Case example 3 shows persistent VMT (yellow arrow) and significant loss of the EZ (white arrowhead) and large amount of SRF accumulation (red arrow). (D) Case example 4 exemplifies VMT release (yellow arrow highlights posterior hyaloid) with accompanying significant attenuation of the EZ (and reduction in EZ to retinal pigment epithelium distance, white arrowhead) and concurrent accumulation of SRF (red arrow).
2507.e1
Ophthalmology Volume 121, Number 12, December 2014 Table 1. Longitudinal retinal layer thickness analysis following intravitreal ocriplasmin VMT Release Inner Retinal thickness (mm) Baseline 1 week 1 month 3 months Middle retinal thickness (mm) Baseline 1 week 1 month 3 months Outer retinal thickness (mm) Baseline 1 week 1 month 3 months EZ-RPE Height (mm) Baseline 1 week 1 month 3 months
SRF Accumulation
Overall
Yes
No
25.48.3 26.59.0 24.57.6 25.18.5
26.18.3 25.58.3 25.38.2 27.58.5
24.88.2 27.59.6 23.66.8 20.76.0
25.77.8 27.18.7 26.27.7 26.28.6
25.08.6 25.89.2 22.66.9 23.07.6
160.423.5 163.519.8 159.722.2 154.421.6
163.418.8 160.517.8 160.517.3 162.114.1
157.926.6 166.421.2 158.726.8 141.525.3
161.616.1 163.717.8 161.619.0 160.515.7
159.128.8 163.121.5 157.524.9 144.224.9
127.618.5 116.1±21.1* 123.019.0 127.313.2
126.718.0 112.4±16.9* 118.6±14.0* 126.513.8
128.418.9 119.623.9 128.122.4 128.711.4
127.315.6 106.216.6*,y 116.314.2*,y 127.512.4
127.920.7 128.119.1y 130.720.5y 127.014.0
30.22.4 18.3±11.6* 21.9±7.5* 28.5±2.9*
29.32.0 14.49.2* 19.06.8*,y 28.12.5
30.42.4 8.34.5*,y 15.64.5*,y 28.02.5*
30.02.4 30.32.8y 28.62.5y 29.23.3
31.02.4 22.112.5*,y 24.96.9*,y 29.1±3.4*
Yes
No
VMT ¼ vitreomacular traction; SRF ¼ subretinal fluid; mm ¼ micrometer; EZ ¼ outer segment ellipsoid zone; RPE ¼ Retinal pigment epithelium. *P < 0.05 compared to baseline (bold). y P < 0.05 between comparison groups at same period (italics).
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