The vitreous body adheres tightly to the peripheral retina, the optic disc, and the central macula. During aging, these adhesions progressively diminish and lead to a separation of the vitreous body from the posterior retina and optic nerve, a process known as posterior vitreous detachment (PVD).1 If a partial PVD leaves an attached area of perifoveal cortical vitreous, it is known as vitreomacular adhesion (VMA).2 This adhesion may cause traction on the retina due to anteroposterior or tangential forces, and this vitreomacular traction (VMT) may be associated with symptoms of metamorphopsia and loss of visual acuity.2 In addition to VMT, abnormalities of the vitreoretinal interface may contribute to a number of disorders, including full-thickness macular hole (FTMH), cystoid macular edema, epiretinal membrane (ERM), vitreoschisis, and diabetic macular edema.2,3
Previous treatment of these conditions has relied on observation for mild cases or surgical intervention with pars plana vitrectomy for more severe or progressive conditions. Pharmacologic vitreolysis has been investigated over a number of years as a potential nonsurgical option for treating VMT and its associated complications. Enzymes such as collagenase, chondroitinase, dispase, and hyaluronidase have been evaluated but discounted due to ocular toxicity, lack of efficacy, or a combination of both.5,6 Plasmin, a nonspecific serine protease that contributes to fibrinolysis, is a well-studied vitreolytic agent that has shown clinical efficacy without significant toxicity; however, plasmin breaks down quickly, limiting its clinical usefulness.5 Plasmin is not commercially available, and autologous plasmin is expensive and time-consuming to produce. Ocriplasmin (previously microplasmin) is a stable, recombinant, truncated form of human plasmin that enzymatically cleaves proteins at the vitreoretinal interface, including collagen, laminin, and fibronectin.5 Key phase 3 clinical trials conducted by the MIVI-TRUST study group demonstrated VMA resolution in 27% of ocriplasmin-treated eyes compared to 10% in placebo-treated eyes at day 28.7 Based on these critical clinical trials, ocriplasmin (Jetrea; ThromboGenics, Iselin, NJ) became the first commercially available pharmacologic treatment for symptomatic VMA.
In the phase 3 clinical trials, 72% of ocriplasmin-treated patients who experienced successful release of VMA did so by day 7.8 As this was the first scheduled follow-up visit, it is unclear what occurred at the vitreomacular interface during that first week. To observe the evolution of changes in the vitreomacular interface early after treatment with ocriplasmin, patients were brought back for frequent follow-up visits within the first 2 weeks after treatment. Analysis of the clinical trials data identified baseline characteristics including FTMH presence, ERM absence, phakic lens status, and age less than 65 years as being associated with higher rates of VMA resolution.7 These identified associations have helped clinicians select eyes for treatment with ocriplasmin that have a better prognosis for successful VMA release. Further identification of additional characteristics associated with improved outcomes may benefit real-world clinical practice. In this study, we report on our clinical experience with intravitreal ocriplasmin injection, describing a novel association between baseline visual acuity and higher rates of VMA resolution, and report on the early evolution of the vitreomacular interface in the first days and weeks after treatment.
Patients and Methods
This research was conducted as an institutional review board–approved multicenter, retrospective case series. All patients treated with intravitreal ocriplasmin for symptomatic VMA by the contributing authors between February 1 and June 30, 2013, with at least 28 days of follow-up and at least three follow-up visits in the 2 weeks after treatment were included in the study. Patient demographics, safety, and clinical findings were collected at baseline and at all follow-up visits. Spectral-domain optical coherence tomography (SD-OCT) was performed at each visit using either Spectralis (Heidelberg Engineering, Heidelberg, Germany) or Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). The exported series of OCT data was interpreted by trained readers at the Boston Image Reading Center. Visual acuity data were converted to logMAR form for analysis.
A total of 22 patients with symptomatic VMA were treated with intravitreal ocriplasmin by nine different retina specialists. Key baseline characteristics are summarized in Table 1. The majority of patients were female, and ages ranged from 58 to 91 years, with a mean of 74. Four of the 22 patients had ERM, and 3 had a FTMH present at the time of treatment. Follow-up time ranged from 28 to 175 days, with a mean of 75 days (Table 2).
Summary of Study Population Baseline Characteristics
Baseline and Follow-up Characteristics of Study Population
Overall, 14 of 22 patients treated with ocriplasmin (64%) had VMA resolution, and one of three patients with FTMH at baseline had hole closure over the follow-up period. Of the 14 patients who had successful release of VMA, six (43%) released by day 7, 10 (71%) released by day 14, and 12 (86%) released by day 28 after treatment (Figure 1). As shown in Figure 2, of the 18 patients without ERM at time of treatment, 13 (72%) had resolution of VMA over the follow-up period; only one of four (25%) patients with ERM present at baseline achieved VMA resolution. Of the 13 phakic patients, nine (69%) had resolution of VMA compared to five of nine (56%) pseudophakic patients. VMA resolution occurred in three of four (75%) patients who were younger than 65 years, compared to 11 of 18 (61%) patients who were 65 years of age or older. Regarding gender, four of the eight (50%) male patients had release of VMA over the follow-up period compared to 10 of the 14 (71%) female patients. There were three patients with FTMH at baseline, and all three patients in this subgroup had release of VMA over the follow up-period; however, only one of the three (33%) patients had successful closure of the macular hole. Patients with poorer visual acuity prior to treatment showed a higher VMA success rate, with three of eight (38%) patients with 20/40 or better initial visual acuity achieving VMA release compared to 11 of 14 (79%) with vision worse than 20/40 (Figure 2).
Proportion of patients achieving vitreomacular adhesion resolution by days after injection.
Vitreomacular adhesion resolution rates by baseline characteristics.
The mean visual acuity for all patients at baseline was 20/63 (0.51 logMAR), and 20/50 (0.43 logMAR) at the final follow-up. Eight patients (36%) showed significant improvement in visual acuity of at least two Snellen lines, and three patients (14%) had a drop in visual acuity of at least two Snellen lines that persisted for the duration of the follow-up (Figure 3). Two of these patients had persistent and enlarged macular holes following treatment, while the third developed a macular hole that was not present prior to treatment. Of the 14 patients who had successful VMA release following treatment, mean visual acuity improved from 20/80 (0.58 logMAR) to 20/40 (0.45 logMAR), with six patients (43%) gaining at least two Snellen lines.
Change in visual acuity from baseline.
Six patients in this study had subretinal fluid (SRF) after treatment that was not present at baseline as determined by the image reading center. All but one of these cases showed complete resolution of the fluid by the final follow-up (Figures 4, 7, and 10). One patient experienced a significant loss in visual acuity related to serous macular detachment after treatment. Over time, this fluid greatly reduced, but a small layer of fluid persisted 5 months after treatment (Figure 10). This patient’s visual acuity dropped from 20/100 before treatment to a nadir of 5/200 before gradually improving to 20/70 at her most recent visit with ongoing follow-up. All of these patients showed focal disruption of the inner segment/outer segment junction/ellipsoid zone (IS/OS/E) in the area of SRF but did not show more generalized disruption.
Patient 3. Sixty-four-year-old pseudophakic woman with focal vitreomacular traction and inner-retinal cyst (top left). Sub-macular fluid is present at 3 days after treatment with continued vitreomacular traction (top right). Submacular fluid is decreased at 2 weeks (bottom left) and resolved by 6 weeks (bottom right), but vitreomacular traction is still present.
Patient 9. Sixty-seven-year-old pseudophakic woman with focal vitreomacular traction and impending macular hole (top left). The photoreceptor ellipsoid layer is centrally disrupted in association with the impending macular hole but otherwise preserved throughout the scan (arrow). Vitreomacular traction is released at day 1 after treatment with a small area of subretinal fluid present (top right). The ellipsoid layer appears diffusely disrupted throughout the scan, beyond the central area involved by the subretinal fluid (arrow). The subretinal fluid appears broader at week 1 (bottom left) but is resolved at week 3 (bottom right). The ellipsoid layer remains altered in these subsequent visits.
Patient 20. Fifty-eight-year-old phakic woman with intraretinal cysts and impending macular hole (top left). Continued vitreomacular traction with serous macular detachment 4 days after treatment (top right). Vitreomacular traction persisted at day 7 (middle left) but had released by day 14 (middle right). Thin subretinal fluid persisted 8 weeks after treatment (bottom left). After 5 months, the central macula has reattached but paracentral subretinal fluid persists (bottom right).
Three patients in this study were found to have diffuse changes in the IS/OS/E layer after treatment, as determined by the image reading center. All three of these patients had successful VMA release. Two of these patients developed a large FTMH following treatment with associated poor visual acuity prior to surgical intervention (Figure 5). The third patient had an impending macular hole with focal disruption of the IS/OS/E layer in the central macula at baseline and developed more generalized disruption following treatment, although visual acuity actually improved from 20/60 to 20/30 (Figure 7). All three of these patients showed partial recovery of the IS/OS/E layer over time but still had significant irregularities observed at the final follow-up.
Patient 5. Sixty-four-year-old phakic man with vitreomacular traction and macular hole. At baseline (top left), the images show intact photoreceptor inner segment/outer segment/ellipsoid layer (red arrows). One week after treatment (top right), OCT highlights marked changes in the inner segment/outer segment/ellipsoid layer, showing complete disruption throughout the scan (red arrows). Note that the vitreomacular traction has released (white arrow). Two weeks after treatment (bottom left), the changes in that layer were still evident (red arrows). Five weeks after treatment (bottom right), OCT shows some recovery of the inner segment/outer segment/ellipsoid layer, although it still presents marked irregularity (red arrows).
Additionally, no cases of retinal tear, retinal detachment, or lens destabilization were found in this study. Three patients self-reported transient photopsias in the first few days after treatment, and one patient experienced post-injection discomfort with an anterior chamber inflammatory reaction that resolved with topical steroid drops.
The recent introduction of ocriplasmin is an important milestone in the treatment of patients with symptomatic VMA. As there are limited data on patient outcomes outside of phase 3 studies, we present the first case series looking at real-world outcomes utilizing reading center interpretation of high-definition SD-OCT images.
Rates of VMA resolution were higher in this study when compared to rates from phase 3 studies, possibly due to improved patient selection focusing on baseline characteristics that are associated with higher rates of successful outcomes, such as absence of ERM.7 The small sample size may also be a factor. In the phase 3 studies, the overall rate of VMA resolution in ocriplasmin-treated patients was 27%, compared to 64% in this case series. Most patients who had VMA release in this series did so relatively soon after treatment, with 43% occurring by day 7, 71% by day 14, and 86% by day 28. Similar to the phase 3 studies, higher rates of successful VMA release were associated with absence of ERM, phakic lens status, female gender, and age less than 65 years (Figure 2). Only three patients with FTMH were included in this study, but the hole closure rate of 33% was similar to the 41% observed in the phase 3 studies. Mean visual acuity improved over the follow-up period compared to baseline, and most patients either gained vision or remained stable (Figure 3). Of 22 patients, three had a decrease of two or more lines of Snellen visual acuity at final follow-up compared to before treatment. Two of these cases were related to an enlarged FTMH after release of VMA. The third case did not achieve VMA release and progressed to develop a FTMH.
An interesting and novel finding in this study is that patients with poorer initial visual acuity had a higher rate of successful VMA release, with a 38% (three of eight) release rate in patients with 20/40 or better initial visual acuity compared to 79% (11 of 14) for patients with visual acuity worse than 20/40. Although clinically important, the difference is not statistically significant (P = .3777), likely because of the small sample size. Despite this, the absolute difference in rates is important to note, as no association between successful release of VMA and initial visual acuity has been reported in previous studies. It is possible that relatively poor visual acuity prior to treatment may be associated with higher degrees of anteroposterior traction at the vitreomacular interface, with separation more likely to occur after this adhesion is weakened by ocriplasmin compared to cases with less tractional forces. This variable will need to be investigated in future studies to confirm this finding.
A number of patients in the MIVI-TRUST study group developed transient SRF after treatment with ocriplasmin.8 In this study, six patients had SRF after treatment that was not present at baseline, and all but one resolved by final follow-up. This one patient developed a serous macular detachment after treatment with an associated drop in visual acuity. Both the fluid and visual acuity improved significantly over the follow-up period, but a small amount of SRF fluid persisted 5 months after treatment (Figure 10).
There have been several recent reports of disruption of IS/OS/E layer seen on SD-OCT in some patients after treatment with ocriplasmin, which may have been missed in the phase 3 trials because time-domain OCT was used rather than SD-OCT. Freund et al reported the case of a patient with a macular hole involving all but the innermost retinal layers who had disruption of the IS/OS/E layer after treatment with ocriplasmin that improved over time.9 Tibbetts et al reported a patient who showed disruption of the IS/OS/E layer on SD-OCT and reduced electroretinogram (ERG) amplitudes after injection of ocriplasmin for VMT.10 The patient’s visual acuity dropped initially but recovered after 4 months, although the OCT and ERG changes persisted. Fahim et al reported another case of outer retinal changes on SD-OCT and reduced ERG response, along with persistent loss of visual acuity and visual field constriction, 9 days after treatment with ocriplasmin for VMA with a small macular hole.11 Singh et al reported on a larger case series, in which seven of eight patients with successful VMA resolution showed IS/OS/E zone changes along with SRF and transiently decreased visual acuity following treatment. The IS/OS/E zone changes and SRF resolved in all patients in this series over time, and none showed persistent loss of visual acuity.12
In our study, the image reading center found three patients with diffuse changes in the IS/OS/E layer after treatment, all of whom had successful VMA release. All three of these patients showed partial recovery of the IS/OS/E layer over time but still had significant irregularity at the final follow-up. The basis of these findings is unknown, but it is possible that the drug disrupts the photoreceptor outer segments in certain patients, and that the disruption is at least partially reversible. This disruption may also lead to the accumulation of SRF. Alternatively, SRF accumulation may be caused directly by tractional forces on the retina due to ocriplasmin-induced changes in the vitreomacular interface. Larger clinical studies utilizing SD-OCT will be needed to further investigate these findings.
No serious adverse events such as retinal tear, retinal detachment, or lens destabilization were encountered in this study. Several patients did have mild adverse events associated with treatment, including three patients with transient photopsias, and one patient who experienced post-injection discomfort with an anterior chamber inflammatory reaction that resolved with topical steroid drops.
The data in this study are broadly consistent with both the published phase 3 data from the MIVI-TRUST study group as well as recent real-world studies in terms of ocriplasmin effectiveness, although the finding of baseline visual acuity influencing ocriplasmin responsiveness has not been previously reported.7,13,14 Observations regarding the efficacy and safety of ocriplasmin, as presented in this study, add important information on the expected outcomes after treatment with ocriplasmin and highlight additional patient characteristics that may be associated with improved clinical outcomes.
- Sebag J. Anatomy and pathology of the vitreoretinal interface. Eye (Lond). 1992;6(6):541–552. doi:10.1038/eye.1992.119 [CrossRef]
- Johnson MW. Posterior vitreous detachment: evolution and complications of its early stages. Am J Ophthalmol. 2010;149(3):371–382.e1. doi:10.1016/j.ajo.2009.11.022 [CrossRef]
- Sebag J. Anomalous posterior vitreous detachment: a unifying concept in vitreoretinal disease. Graefes Arch Clin Exp Ophthalmol. 2004;242(8):690–698. doi:10.1007/s00417-004-0980-1 [CrossRef]
- Sebag J. Pharmacologic vitreolysis - premise and promise of the first decade. Retina. 2009;29(7):871–874. doi:10.1097/IAE.0b013e3181ac7b3c [CrossRef]
- Schneider EW, Johnson MW. Emerging nonsurgical methods for the treatment of vitreomacular adhesion: a review. Clin Ophthalmol. 2011;5:1151–1165. doi:10.2147/OPTH.S14840 [CrossRef]
- Girach A, Pakola S. Vitreomacular interface diseases: pathophysiology, diagnosis and future treatment options. Expert Rev Ophthalmol. 2012;7(4):311–323. doi:10.1586/eop.12.34 [CrossRef]
- Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. 2012;367(7):606–615. doi:10.1056/NEJMoa1110823 [CrossRef]
- Jetrea [package insert]. Iselin, NJ: ThromboGenics Inc; 2012.
- Freund KB, Shah SA, Shah VP. Correlation of transient vision loss with outer retinal disruption following intravitreal ocriplasmin. Eye (Lond). 2013;27(6):773–774. doi:10.1038/eye.2013.94 [CrossRef]
- Tibbetts MD, Reichel E, Witkin AJ. Vision loss after intravitreal ocriplasmin: Correlation of spectral-domain optical coherence tomography and electroretinography. JAMA Ophthalmol. 2014;132(4):487–490. doi:10.1001/jamaophthalmol.2013.8258 [CrossRef]
- Fahim AT, Khan NW, Johnson MW. Acute panretinal structural and functional abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol. 2014;132(4):484–486. doi:10.1001/jamaophthalmol.2013.8142 [CrossRef]
- Singh RP, Li A, Bedi R, et al. Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome. Br J Ophthalmol. 2014;98(3):356–60. doi:10.1136/bjoph-thalmol-2013-304219 [CrossRef].
- Knudsen V.M., Kozak I. A retrospective study of a single practice use of ocriplasmin in the treatment of vitreomacular traction. Saudi J Ophthalmol. 2014; http://dx.doi.org/10.1016/j.sjopt.2014.02.002. doi:10.1016/j.sjopt.2014.02.002 [CrossRef]
Summary of Study Population Baseline Characteristics
|Baseline Characteristics||n = 22|
|Mean age, y (range)||74 (58 – 91)|
|Female, n (%)||14 (64)|
|Phakic, n (%)||13 (59)|
|FTMH present, n (%)||3 (14)|
|ERM present, n (%)||4 (18)|
|Mean visual acuity||20/63 (0.51 logMAR)|
Baseline and Follow-up Characteristics of Study Population
|Patient No.||Lens Status||Baseline VA||Final VA||Initial FTMH Size||Final FTMH Size||ERM||VMA Release||Days to Release||Follow-up Time (days)|
Patient 7. Eighty-one-year-old pseudophakic woman with focal vitreo-macular traction and inner-retinal cysts (top left). Area of vitreomacular traction narrowed and cysts decreased at day 3 (top right) and day 7 (bottom left). One month after treatment, vitreomacular traction remains with intraretinal cysts resolved and visual acuity unchanged (bottom right).
Patient 10. Seventy-two-year-old pseudophakic woman with broad vitreomacular traction, epiretinal membrane, and subfoveal fluid (top left). OCT appearance is essentially unchanged at 3 days (top right) and 2 weeks (bottom left) after treatment. Vitreomacular traction is released and subretinal fluid resolved at 4-week follow-up visit (bottom right).
Patient 11. Seventy-one-year-old phakic man with taut vitreomacular traction and impending macular hole (top left). Following treatment, vitreomacular traction progressively narrowed at 1 day (top right). At 4 weeks, narrow vitreomacular traction was persistent, but impending macular hole had improved and visual acuity improved from 20/400 to 20/30 (bottom left). At 6 weeks, vitreomacular traction released with development of full-thickness macular hole and decreased acuity to 20/400 (bottom right).