Intravitreal ocriplasmin was approved by the U.S. Food and Drug Administration for the treatment of symptomatic vitreomacular adhesion (VMA) in 2012. The MIVI-TRUST study evaluated ocriplasmin treatment of vitreomacular traction (VMT), both isolated and associated with full-thickness macular holes (FTMH), and found that 40.6% of FTMH less than 400 µm in aperture size closed after ocriplasmin compared to 10.6% in the placebo group (P < .001).1 Subgroup analysis revealed that small FTMH (defined as aperture size less than 250 µm) had a higher likelihood of closure (58.3%) than medium-sized (250 to 400 µm) FTMH (24.6%) after intravitreal ocriplasmin. Large (greater than 400 µm) FTMHs were excluded from the trial.
Eyes with FTMH that do not close after ocriplasmin may ultimately require surgical intervention for repair. The visual and anatomic outcomes after pars plana vitrectomy (PPV) following unsuccessful FTMH closure with ocriplasmin have not been previously reported. This retrospective case series evaluates the results following PPV for persistent FTMH after unsuccessful ocriplasmin therapy for FTMH with associated VMT.
Patients and Methods
A retrospective chart review of all eyes treated with intravitreal ocriplasmin (Jetrea, ThromboGenics, Iselin, NJ) was conducted at two retina practices between October 2012 and March 2014 to identify eyes treated for FTMH with associated VMT that failed to close and underwent subsequent PPV. All included individuals underwent ophthalmologic examination and spectral-domain optical coherence tomography (SD-OCT) prior to ocriplasmin, within 2 days after ocriplasmin injection, at 3 to 6 weeks after ocriplasmin, and up to 6 months following PPV. Macular hole aperture size was measured at the narrowest hole point in the mid retina parallel to the RPE, using the caliper function of the OCT device.2
A total of 51 ocriplasmin treated patients’ charts were reviewed. Four eyes in four individuals (7.8%) were identified that met inclusion criteria of treatment with ocriplasmin for FTMH and subsequent PPV for non-closure. The study population included one man and three women. The mean age was 60 (range: 49 to 72 years).75
The Table outlines baseline macular hole characteristics and follow-up measurements. All eyes had focal VMT associated with small or medium FTMH on SD-OCT prior to ocriplasmin, as classified by the criteria defined by the International Vitreomacular Traction Study Group.2 Case 1 had a medium-sized FTMH (311 µm), and the remaining three eyes had a small FTMH (136 to 216 µm). Following ocriplasmin, OCT showed VMT release in all eyes by 4 days after injection. The FTMH aperture size increased in all cases, with the increase ranging from 48 to 217 µm. OCT features after ocriplasmin revealed smooth scalloped edges to the FTMH with attenuation of the external limiting membrane, photoreceptor ellipsoid layer, and interdigitation zone bands (Figures 1B and 2B), with no difference other than hole size when compared to scans prior to ocriplasmin.
Serial spectral-domain OCT in patient 2. (A) Before ocriplasmin treatment, a small (216 µm) full-thickness macular hole (FTMH) with focal vitreomacular traction (VMT) can be seen. There is focal attenuation of the external limiting membrane, photoreceptor ellipsoid layer, and interdigitation zone bands at the site of the FTMH. (B) Two days after ocriplasmin, VMT is released with increased FTMH size and increased perifoveal intraretinal cysts. (C) Three months after PPV, there is focal discontinuity in outer photoreceptor layers in the area of the closed FTMH. (D) Six months after PPV, there is continued discontinuity of outer photoreceptor layers.
Serial spectral-domain OCT scans of patient 4. (A) Initial scan shows a full-thickness macular hole (FTMH) (136 µm) with associated focal vitreomacular traction (VMT) and attenuation of the external limiting membrane, photoreceptor ellipsoid layer, and interdigitation zone bands at the site of the FTMH. (B) Two days after ocriplasmin VMT is released with increased size of the FTMH to 353 µm. The FTMH has smooth scalloped edges with the development of intraretinal cysts. (C) Ten days after ocriplasmin, a macula-involved retinal detachment developed. (D) Six months after PPV, there is anatomic reattachment and FTMH closure with discontinuity in outer photoreceptor layers in the area of the FTMH (arrow), which improved at 9-month follow-up (E). A new epiretinal membrane is present at both 6- and 9-month follow-up (D and E, respectively).
Three eyes proceeded to PPV at 3 to 8 weeks after ocriplasmin injection. The fourth patient developed a retinal detachment 10 days after ocriplasmin injection, requiring PPV at that time. PPV for macular hole repair was combined with indocyanine green-assisted internal limiting membrane peel, endolaser, and sulfur hexaflouride tamponade in all cases.
Three months after PPV, the FTMH was anatomically closed in all eyes. OCT showed discontinuity in the outer photoreceptor ellipsoid band in the area of the original FTMH in all eyes (Figures 1C and 2D). Six months after PPV, OCT showed improved appearance of the outer photoreceptors, but some focal discontinuity in the outer photoreceptor layers remained (Figures 1D and 2E). Of the four patients, only patient 4 had diffuse outer photoreceptor abnormalities in areas peripheral to the FTMH seen at 6 months after PPV (Figure 2).
The pre-ocriplasmin visual acuity (VA) was 20/70 in three eyes and 20/200 in one eye. Six months after PPV, VA improved in three eyes (20/30 to 20/60), two of which improved by two or more lines. The eye that only improved one line (20/70 to 20/60) also had a history of amblyopia, with a best recorded VA of 20/50. The eye with the retinal detachment had an overall change in VA from 20/70 to 20/200 at 6 months after PPV, which included cataract surgery 3 months after PPV. However, on the most recent follow-up 1 year after vitrectomy, VA was 20/70.
During PPV, all four eyes were noted to have pathology requiring endolaser. Patient 1 had peripheral lattice degeneration, patient 2 had an operculated hole that was not seen on examination prior to surgery, and patient 3 had a suspicious area of peripheral vitreoretinal traction. Patient 4 experienced photopsia after injection, and a retinal tear requiring laser retinopexy 4 days after injection was noted. Ten days after injection, this patient developed additional retinal tears and a macula-off retinal detachment. Following PPV, patient 4 noted a subjective decrease in colors and brightness with diffuse outer photoreceptor changes found on OCT (Figure 2). None of the patients in this study were evaluated with electroretinogram.
Each surgeon was asked to recall whether the vitreous was noted to be qualitatively different during the surgery. None of the surgeons reported any subjective difference of the vitrectomy in this group of patients compared to patients who had not been treated with ocriplasmin.
Subgroup analysis of the MIVI-TRUST study data revealed that eyes treated with ocriplasmin demonstrated statistically significant macular hole closure rates of 58% compared to 16% of placebo-injected eyes with small (less than or equal to 250 µm) to medium (less than 400 µm) size FTMH with VMT.3 Of the remaining 42% of patients who did not have FTMH closure following ocriplasmin, the long-term visual and anatomic outcomes were not reported. In this series, all four eyes with previous ocriplasmin therapy had anatomic closure of FTMH with one surgery. Improved visual acuity was noted in three eyes following PPV. Vision did not improve in one eye following PPV, which may be related to development of a macula-off retinal detachment within 2 weeks of intravitreal ocriplasmin.
This series of patients suggests that complex vitreoretinal interface abnormalities not only result in FTMH formation but also may predispose to an increase in FTMH size after ocriplasmin despite successful release of VMT, although it is difficult to determine whether the enlargement can be attributed to development of a PVD or the natural course of FTMH alone. The extramacular vitreomacular interface in these patients may exert more tangential forces on the retina, resulting in FTMH enlargement. These vitreoretinal interface abnormalities may contribute to peripheral retinal pathology requiring intraoperative treatment with endolaser in all four eyes in this series. However, this did not appear to affect FTMH closure after vitrectomy in these eyes. Additionally, the tractional forces from the internal limiting membrane may also play a role in the development of FTMH, as all cases in this series had the internal limiting membrane peeled at the time of surgery and all had successful closure. A presentation on the experiences of retinal surgeons performing vitrectomy on ocriplasmin-treated eyes was in agreement with the surgeons of the patients in this study that there was no significant qualitative difference of the vitreous noted during vitrectomy.4
The pre-marketing percentage of patients experiencing retinal tears or detachments was similar in both the placebo and ocriplasmin groups (2%).1 Post-marketing experiences of retinal surgeons using ocriplasmin demonstrate a comparable or decreased rate of ocular adverse events experienced when compared to the pre-marketing data, including progression of VMT to FTMH (8.71%), retinal tear (1.99%), and retinal detachment (2.65%).5,6
The rate of retinal detachment (patient 4) in this study is consistent with the pre- and post-marketing data (1 of 51, 1.96%). A larger phase 4 study (Ocriplasmin Research to Better Inform Treatment; ORBIT) is under way to better understand the real world complications of ocriplasmin. Of note, in this present series, all four patients experienced VA decline to 20/200 or worse within 1 to 4 days of ocriplasmin injection, consistent with results from the combined MIVI-TRUST data.7
In this small retrospective series of ocriplasmin-treated eyes without FTMH closure after injection, subsequent PPV led to anatomic closure. Enlargement of FTMH in all eyes and multiple retinal tears and retinal detachment in one eye following ocriplasmin highlight the complexity of forces at the vitreoretinal interface. Further study is warranted to ultimately determine whether ocriplasmin affects visual and anatomic outcomes in eyes that may require PPV for FTMH non-closure.
- Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. 2012;367:606–615. doi:10.1056/NEJMoa1110823 [CrossRef]
- Duker JS, Kaiser PK, Binder S, et al. The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology. 2013;120(12):2611–2619. doi:10.1016/j.ophtha.2013.07.042 [CrossRef]
- Stalmans P, Duker JS, Kaiser PK, et al. OCT-based interpretation of the vitreomacular interface and indications for pharmacologic vitreolysis. Retina. 2013;33:2003–2011. doi:10.1097/IAE.0b013e3182993ef8 [CrossRef]
- Garg S. Vitrectomy after ocriplasmin for vitreomacular traction or macular hole (VAVOOM) study. Paper presented at the American Society of Retina Specialists annual meeting. , August 9–13, 2014. , San Diego, CA. .
- Shah SP, Jeng K, Fine HF, et al. Postmarketing surveillance survey of adverse events of ocriplasmin (Jetrea). Poster presented at the Association for Research in Vision and Ophthalmology annual meeting. , May 4–8, 2014. , Orlando, FL. .
- Hahn P, Chung MM, Flynn HW, et al. Safety profile of ocriplasmin for symptomatic vitreomacular adhesion – a comprehensive analysis of pre- and post-marketing experiences. Poster presented at the Association for Research in Vision and Ophthalmology annual meeting. , May 4–8, 2014. , Orlando, FL. .
- Kuppermann BD. Ocriplasmin for pharmacologic vitreolysis. Retina. 2012;32:S225–S231. doi:10.1097/IAE.0b013e31825bc593 [CrossRef]
Baseline Macular Hole Characteristics and Follow-Up Measurements
|Case No.||VA Before Ocriplasmin||VA 1 Week After Ocriplasmin||VA 3 Months After PPV||VA 6 Months After PPV||FTMH Size Before Ocriplasmin||FTMH Size After Ocriplasmin||Increase in FTMH Size||Condition Treated With Endolaser|
Baseline Macular Hole Characteristics and Follow-Up Measurements