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Intravitreal gas injection for the treatment of full-thickness macular holes

      The benchmark treatment for full-thickness macular hole (FTMH) is pars plana vitrectomy (PPV), internal limiting membrane peel, and intraocular gas tamponade. Closure rates exceeding 90% are commonly reported.
      • Gotzaridis S.
      • Liazos E.
      • Petrou P.
      • Georgalas I.
      Short-acting gas tamponade with strict face-down posturing for the treatment of idiopathic macular hole.
      PPV necessitates an operating room procedure. Vitrectomy for macular hole (MH) carries operative risks, including retinal breaks, iatrogenic retinal trauma, or lens touch.
      • Jackson T.L.
      • Donachie P.H.
      • Sparrow J.M.
      • Johnston R.L.
      United Kingdom National Ophthalmology Database study of vitreoretinal surgery: report 2, macular hole.
      Postvitrectomy cataract surgery rates may be as high as 92% at 3 years.
      • Jackson T.L.
      • Donachie P.H.
      • Sparrow J.M.
      • Johnston R.L.
      United Kingdom National Ophthalmology Database study of vitreoretinal surgery: report 2, macular hole.
      A less-invasive treatment for some FTMHs with associated vitreomacular traction (VMT) is intravitreal injection of ocriplasmin (Jetrea; ThromboGenics NV, Leuven, Belgium). Two trials found that this treatment resulted in closure of 40.1% of small to medium FTMHs (aperture <400 μm) associated with focal VMT (<1500 μm).
      • Stalmans P.
      • Benz M.S.
      • Gandorfer A.
      • et al.
      Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes.
      Complications with ocriplasmin include transient disruption of the ellipsoid layer or subfoveal lucency on optical coherence tomography (OCT), enlargement of the base diameter of MHs, and electroretinographic abnormalities.
      • Feng H.L.
      • Roth D.B.
      • Hasan A.
      • et al.
      Intravitreal ocriplasmin in clinical practice: predictors of success, visual outcomes, and complications.
      • Dugel P.U.
      • Tolentino M.
      • Feiner L.
      • Kozma P.
      • Leroy A.
      Results of the 2-year Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) randomized trial.
      • Warrow D.J.
      • Lai M.M.
      • Patel A.
      • Raevis J.
      • Berinstein D.M.
      Treatment outcomes and spectral-domain optical coherence tomography findings of eyes with symptomatic vitreomacular adhesion treated with intravitreal ocriplasmin.
      Intravitreal gas injection has been used to treat both VMT and MH successfully.
      • Warrow D.J.
      • Lai M.M.
      • Patel A.
      • Raevis J.
      • Berinstein D.M.
      Treatment outcomes and spectral-domain optical coherence tomography findings of eyes with symptomatic vitreomacular adhesion treated with intravitreal ocriplasmin.
      • Day S.
      • Martinez J.A.
      • Nixon P.A.
      • et al.
      Intravitreal sulfur hexafluoride injection for the treatment of vitreomacular traction syndrome.
      • Rodrigues I.A.
      • Stangos A.N.
      • McHugh D.A.
      • Jackson T.L.
      Intravitreal injection of expansile perfluoropropane (C3F8) for the treatment of vitreomacular traction.
      • Steinle N.C.
      • Dhoot D.S.
      • Quezada Ruiz C.
      • et al.
      Treatment of vitreomacular traction with intravitreal perfluoropropane (C3F8) injection.
      • Chan C.K.
      • Wessels I.F.
      • Friedrichsen E.J.
      Treatment of idiopathic macular holes by induced posterior vitreous detachment.
      • Jorge R.
      • Costa R.A.
      • Cardillo J.A.
      • Uno F.
      • Bonomo P.P.
      • Farah M.E.
      Optical coherence tomography evaluation of idiopathic macular hole treatment by gas-assisted posterior vitreous detachment.
      • Mori K.
      • Saito S.
      • Gehlbach P.L.
      • Yoneya S.
      Treatment of stage 2 macular hole by intravitreous injection of expansile gas and induction of posterior vitreous detachment.
      • Chen T.C.
      • Yang C.H.
      • Yang C.M.
      Intravitreal expansile gas in the treatment of early macular hole: reappraisal.
      • Chan C.K.
      • Crosson J.N.
      • Mein C.E.
      • Daher N.
      Pneumatic vitreolysis for the relief of vitreomacular traction.
      • Yu G.
      • Duguay J.
      • Marra K.V.
      • et al.
      Efficacy and safety of treatment options for vitreomacular traction.
      • Claus M.G.
      • Feron E.
      • Veckeneer M.
      Pneumatic release of focal vitreomacular traction.
      • Tew T.
      • Chen T.
      • Yang C.
      • Yang C.
      Vitreomacular changes after intravitreal gas injection for idiopathic impending or early macular hole: an optical coherence tomography study.
      It has the attraction of being less invasive than vitrectomy, with probable cost savings over PPV and ocriplasmin. However, most work on gas injection for MH is retrospective and/or uses older imaging techniques, such as time-domain OCT. We sought to contribute prospective data using spectral-domain OCT.
      We conducted a prospective interventional case series. Consecutive patients with small and medium (<400 μm) primary FTMHs associated with focal VMT were considered for inclusion. Also considered were patients with incipient macular holes (almost full-thickness defects with only a thin retinal tissue bridge remaining) associated with focal VMT. Only the results for patients with full-thickness holes are reported here. Risks and benefits of treatment options, namely, intravitreal gas injection, intravitreal ocriplasmin, or vitrectomy, were discussed with patients. Those choosing intravitreal gas were invited to participate in the study.
      Patients with significant epiretinal membrane (judged at the discretion of the retinal specialist) were excluded. Additional exclusion criteria included the presence of neovascular age-related macular degeneration, foveal involving geographic atrophy, diabetic retinopathy, retinal laser, retinal vascular occlusion, or intraocular surgery/injection within the preceding 6 months.
      All patients had a slit-lamp examination and spectral-domain OCT imaging (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). Hole aperture was measured manually using the caliper function. The maximum horizontal length of VMT was measured, and the maximum foveal thickness was measured from the base of the retinal pigment epithelium to the top of retinal tissue at the fovea.
      The study was conducted in compliance with the Declaration of Helsinki and approval was obtained from the appropriate Research Ethics Board. Participants provided written informed consent.
      Topical and subconjunctival anaesthesia and topical disinfectant were administered; 0.3 mL of 100% perfluoropropane gas was injected intravitreally. An anterior chamber paracentesis was performed at the discretion of the treating physician.
      Participants were asked to bend their neck to look down at the ground briefly, once every 10 minutes while awake, for 3 days (a “head-bobbing manoeuvre”). Thereafter they were advised to posture face-down, 50 minutes out of every hour while awake, for 3 days. If at their 1-week review the VMT had released but the hole was still open, participants decided if they wished to undertake a further 4 days of face-down posturing.
      Participants were examined together with OCT imaging at approximately 1 week, and 1, 3, and 6 months after the injection.
      On the day of the gas injection, patients were provisionally scheduled for vitrectomy, on a date to follow their 1 month review. If the MH failed to close by 1 month, the patient proceeded to surgery soon thereafter. For these patients, follow-up intervals were thereafter at the discretion of the surgeon. FTMH closure was defined as apposition of retinal tissue across the hole. Bridging closure over residual fluid was considered closure.
      Outcomes investigated included the proportion of participants who had hole closure and the change in visual acuity.
      Snellen visual acuity, measured with habitual refraction and/or pinhole, was converted to logMAR acuity for analysis.
      Statistical analysis was performed using statistical software R.
      R Core Team
      R: A language and environment for statistical computing.
      Baseline parameters in the surgery and nonsurgery groups were compared using the Wilcoxon rank sum test. Mean baseline and final visual acuities within each group were compared using the Wilcoxon signed rank test.
      Eight eyes of 8 patients with FTMH were included in this prospective pilot study. The median age was 64.5 years (range 61–72 years). Six participants were female. All eyes were phakic. The median duration of symptoms was approximately 1 month (range 2 weeks to 6 months). Injections were administered between May 2016 and May 2017.
      The mean hole aperture was 155 ± 96 μm (median 120.5 μm, range 21–320 μm). The mean maximum diameter of VMT was 313.5 ± 89 μm (median 338.5 μm, range 161–422 μm). Mean preprocedure logMAR visual acuity was 0.70 ± 0.34 [∼20/100] (median 0.59, range 0.30–1.18). Demographic and baseline characteristics are shown in Table 1.
      Table 1Demographic and baseline characteristics
      CaseAge, ySexDuration (months)Vision: logMAR (pre)Aperture (μm)VMT (μm)Max FT (μm)
      162M10.3097331370
      268F0.751116219484
      372F30.48125422414
      461F60.70214274505
      563F0.51.10105346388
      668M0.51.18320392402
      766F0.50.40242363320
      863F50.4821161743
      FT, foveal thickness; VMT, vitreomacular traction.
      Gas injection caused release of VMT in all eyes by the 1-week appointment.
      Gas injection resulted in closure in 3/8 (38%) FTMHs by the 1-month visit. One of these had bridging closure at 1 week and the patient elected to posture for a further 4 days (Fig. 1). The other 2 holes were open at 1 week, and the patients elected to posture for an additional 4 days (Fig. 2). For one of these cases, hole closure with persistent disruption of the ellipsoid layer was observed at the 1-month visit. This layer showed reconstitution at the 3-month visit.
      Fig 1
      Fig. 1(A) Baseline optical coherence tomography (OCT) image of the right eye of case 6, showing a full-thickness macular hole associated with focal vitreomacular traction (VMT). (B) One week after intravitreal gas injection, OCT shows release of VMT and bridging closure of the hole. (C) At the 1-month visit, OCT shows thickening of the tissue bridge and reduction in the outer retinal defect. (D) The outer retinal defect resolved by the 6-month review.
      Fig 2
      Fig. 2(A) Baseline optical coherence tomography (OCT) of the right eye of case 7, showing a full-thickness macular hole (FTMH) associated with focal vitreomacular traction (VMT). (B) Release of the VMT, but persistence of the FTMH 1 week after intravitreal gas injection. (C) Bridging closure is seen at 1 month, after an additional 4 days of face-down posturing. (D) A residual ellipsoid defect is improving at 6 months.
      All eyes in which the gas injection failed (n = 5) proceeded to PPV, internal limiting membrane peel, and gas tamponade, followed by 4–7 days of face-down posturing. Surgery was successful in all of these cases. One eye had combined phacovitrectomy. In one patient, retinopexy was performed for a small horse-shoe tear noted intraoperatively.
      Outcome data for participants are shown in Table 2.
      Table 2Outcome data for participants
      CaseVision logMAR (pre)Hole status 1 weekAdditional 4 days postureHole status 1 monthPPVHole status finalVision logMAR final
      10.30OpenYesOpenYesClosed0.30
      21.00OpenYesOpenYesClosed0.18
      30.48OpenNoOpenYesClosed0.30
      40.70OpenYesOpenYesClosed0.70
      51.10OpenNoOpenYesClosed0.48
      61.18ClosedYesClosedNoClosed0.40
      70.40OpenYesClosedNoClosed0.10
      80.48OpenYesClosedNoClosed0.30
      PPV, pars plana vitrectomy.
      Pertaining to baseline characteristics, there were no statistically significant differences between the nonsurgical success group (n = 3) and the surgical success group (n = 5) with respect to age (p = 0.76), hole aperture (p = 0.57), diameter of VMT (p = 0.98), maximum foveal thickness (p = 0.98), duration of symptoms (p = 0.54), or visual acuity (p = 0.97).
      For the nonsurgical group, mean baseline visual acuity was logMAR 0.68 ± 0.43 (∼20/96). The mean final acuity, at a median follow-up of 6 months (range 5.75–6.25), improved to logMAR 0.27 ± 0.15 (∼20/37), though this was not statistically significant (p = 0.25).
      For the eyes that underwent vitrectomy (n = 5), mean final visual acuity, at a median postvitrectomy follow-up of 5.5 months (range 2.75–6.25 months), was logMAR 0.39 ± 0.20 (∼20/49). This represented a nonsignificant improvement from a mean baseline of 0.72 ± 0.34 (∼20/105) (p = 0.18).
      There was no significant difference between the mean final visual acuity in the surgical and nonsurgical groups (p = 0.54). Furthermore there was no significant difference in the amount of vision improvement between the groups (p = 0.65, Wilcoxon rank sum test).
      All participants reported good compliance with posturing, indicating that they had performed the head-bobbing and face-down posturing for at least 75% of the intended time.
      In this prospective pilot study, intravitreal gas injection obviated the need for vitrectomy in 3 of 8 eyes with FTMH.
      In 1995, Chan et al. first reported on the use of intravitreal gas injection for the treatment of MH.
      • Chan C.K.
      • Wessels I.F.
      • Friedrichsen E.J.
      Treatment of idiopathic macular holes by induced posterior vitreous detachment.
      Their study was performed before OCT, and so it is not known what proportion had associated VMT. Most cases received 0.3–0.5 mL of 100% C3F8. Some participants postured face-down beyond 4 weeks, and 10/11 (91%) Gass stage 1 holes resolved, 3/6 (50%) stage 2 holes closed, whereas no stage 3 holes closed.
      Other studies have evidenced the efficacy of intravitreal gas injection in the treatment of selected macular holes.
      • Mori K.
      • Saito S.
      • Gehlbach P.L.
      • Yoneya S.
      Treatment of stage 2 macular hole by intravitreous injection of expansile gas and induction of posterior vitreous detachment.
      • Chen T.C.
      • Yang C.H.
      • Yang C.M.
      Intravitreal expansile gas in the treatment of early macular hole: reappraisal.
      • Chan C.K.
      • Crosson J.N.
      • Mein C.E.
      • Daher N.
      Pneumatic vitreolysis for the relief of vitreomacular traction.
      ,
      • Tew T.
      • Chen T.
      • Yang C.
      • Yang C.
      Vitreomacular changes after intravitreal gas injection for idiopathic impending or early macular hole: an optical coherence tomography study.
      Various treatment paradigms have been used, with the use of both C3F8 and SF6 reported. Injected volumes range from 0.1 to 0.5 mL. Face-down-posture periods commonly have been between 3 and 5 days. Reported success with such approaches has been closure rates ranging from 25% to 53%.
      Jorge et al. found a higher success rate using 0.4 mL of 100% C3F8 to treat 6 patients with Gass stage 2 MHs associated with VMT.
      • Jorge R.
      • Costa R.A.
      • Cardillo J.A.
      • Uno F.
      • Bonomo P.P.
      • Farah M.E.
      Optical coherence tomography evaluation of idiopathic macular hole treatment by gas-assisted posterior vitreous detachment.
      Patients postured face-down for 2 weeks. Time-domain OCT confirmed closure in 5/6 (83%) cases.
      Intravitreal gas offers a number of treatment advantages. It is inexpensive, it is easy to administer in an office setting, and retinal specialists are typically experienced in its use in pneumatic retinopexy. In addition, patients can be treated at their initial consultation.
      In keeping with other studies, gas injection did not adversely affect hole closure for eyes that required subsequent vitrectomy in our series.
      • Mori K.
      • Saito S.
      • Gehlbach P.L.
      • Yoneya S.
      Treatment of stage 2 macular hole by intravitreous injection of expansile gas and induction of posterior vitreous detachment.
      • Chen T.C.
      • Yang C.H.
      • Yang C.M.
      Intravitreal expansile gas in the treatment of early macular hole: reappraisal.
      • Chan C.K.
      • Crosson J.N.
      • Mein C.E.
      • Daher N.
      Pneumatic vitreolysis for the relief of vitreomacular traction.
      ,
      • Tew T.
      • Chen T.
      • Yang C.
      • Yang C.
      Vitreomacular changes after intravitreal gas injection for idiopathic impending or early macular hole: an optical coherence tomography study.
      The median interval from injection to surgery was 44 days (range 41–57 days), reasonably similar to our standard waiting time for macular hole surgery.
      One consideration is the total posturing time should intravitreal gas fail. We found that in 2 cases an additional 4 days of posturing may have contributed to hole closure. In these cases the holes were open at 1 week, but closed at 1 month. This suggests that prolonged face-down posturing may be beneficial after intravitreal gas injection for MH. However, if the hole still fails to close, patients may find further posturing after vitrectomy more arduous. In our series, 3/5 participants whose treatment failed had performed the additional 4 days of posturing.
      Another treatment option for MH is intravitreal ocriplasmin. A randomised, sham-controlled study found the closure rate for small and medium FTMH, associated with VMT, to be 30%.
      • Dugel P.U.
      • Tolentino M.
      • Feiner L.
      • Kozma P.
      • Leroy A.
      Results of the 2-year Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) randomized trial.
      Ocriplasmin does not require posturing. However, the drug has been associated with complications, including transient loss of vision, transient disruption of the ellipsoid layer or subfoveal lucency on OCT, enlargement of MH base diameter, and electroretinographic abnormalities.
      • Feng H.L.
      • Roth D.B.
      • Hasan A.
      • et al.
      Intravitreal ocriplasmin in clinical practice: predictors of success, visual outcomes, and complications.
      • Dugel P.U.
      • Tolentino M.
      • Feiner L.
      • Kozma P.
      • Leroy A.
      Results of the 2-year Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) randomized trial.
      • Warrow D.J.
      • Lai M.M.
      • Patel A.
      • Raevis J.
      • Berinstein D.M.
      Treatment outcomes and spectral-domain optical coherence tomography findings of eyes with symptomatic vitreomacular adhesion treated with intravitreal ocriplasmin.
      Investigating the cost-effectiveness of ocriplasmin compared to standard-of-care in the United Kingdom, Bennison et al. found the additional cost per quality-adjusted life year gained to be ∼US$47,814 for the treatment of VMT with FTMH.

      Bennison C, Stephens S, Lescrauwaet B, Van Hout B, Jackson TL.Cost-effectiveness of ocriplasmin for the treatment of vitreomacular traction and macular hole [published online June 23, 2016]. J Mark Access Health Policy. https://doi.org/10.3402/jmahp.v4.31472

      They used ∼US$3452 as the drug + administration cost for ocriplasmin. It would be interesting to conduct a similar analysis for intravitreal gas. For our practice, the cost of 450 g of perfluoropropane gas, which should yield hundreds of doses, is ∼US$1577.
      Yu et al. conducted a meta-analysis that found the closure rate after intravitreal gas for FTMH with VMT to be 59%, in comparison with a rate after ocriplasmin of 36%.
      • Yu G.
      • Duguay J.
      • Marra K.V.
      • et al.
      Efficacy and safety of treatment options for vitreomacular traction.
      A possible advantage of intravitreal gas injection is that it is likely less cataractogenic than PPV. Although a longer follow-up period would have been informative regarding the risk of cataract formation, we noted that none of the 3 patients who had only gas injection were listed for cataract surgery during the study period, as opposed to 2 of the 4 participants who were phakic after vitrectomy.
      Strengths of our study are that it reports prospective work conducted at a single centre, using spectral-domain OCT. Limitations include the sample size, and the lack of comparator groups. However, reference can be made to success rates for ocriplasmin and for vitrectomy reported in the literature. Ocriplasmin was only provincially funded for patients older than 65 years. This may have meant that younger patients were less likely to choose ocriplasmin, introducing possible bias. We acknowledge that a randomized, controlled trial is the ideal means to assess any intervention. However, randomizing patients between less invasive treatment options (intravitreal injections) and a more invasive option (vitrectomy) has significant ethical considerations. We elected to report on patients who self-selected intravitreal gas injection.
      We suggest that intravitreal C3F8 injection is a reasonable treatment option for small to medium FTMH associated with VMT, for patients who hope to avoid vitrectomy through a less invasive treatment option, understanding that they will need to proceed to vitrectomy should this fail. Patients should be advised that prolonged face-down posturing may be required to maximize the chance of success, and that additional face-down posturing may be required after PPV should intravitreal gas fail.
      Disclosure: Statistical support was funded by the University of Calgary Surgical Fellowship Program. The program had no other involvement in decisions concerning this article.

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      1. Bennison C, Stephens S, Lescrauwaet B, Van Hout B, Jackson TL.Cost-effectiveness of ocriplasmin for the treatment of vitreomacular traction and macular hole [published online June 23, 2016]. J Mark Access Health Policy. https://doi.org/10.3402/jmahp.v4.31472