Effect of intravitreal C₃F₈ gas in patients with vitreomacular traction

Posterior vitreous detachment, typically occurring between the ages of 45 and 65 years, is defined as the separation of the vitreous body from the internal limiting membrane of the retina and is a physiological age-related process [1]. When the vitreous fails to detach completely, vitreomacular adhesion (VMA), showing no retinal abnormalities, or vitreomacular traction (VMT), with detectable retinal changes on optical coherence tomography, is the consequence. Typical symptoms of VMT are decreased vision and metamorphopsia [2].

Current treatment options include observation, when patients are either asymptomatic or when symptoms do not aggravate, or medical therapy with ocriplasmin and pars plana vitrectomy, which remains the mainstay of treatment when there is no indication for ocriplasmin or the treatment fails. Data from the Microplasmin for Intravitreal Injection–Traction Release Without Surgical Treatment (MIVI-TRUST) trial showed the nonsurgical success of VMT release within 28 days in 41.7% of cases, which was statistically significant, and closure of the macular hole (MH) in 30% [3].

Three studies, conducted by Rodrigues et al., Steinle et al., and Chan et al., investigating the release rate of VMT and MH closure using intravitreal perfluoropropane (C₃F₈) gas showed very promising results [4‐6]. The purpose of the present case series was to further examine the effect of a single intravitreal C₃F₈ gas injection with patients showing symptomatic VMT with or without MH.

A retrospective case series of patients who elected to undergo an intravitreal C₃F₈ injection for the treatment of symptomatic VMT syndrome, including when associated with MH, between March 2013 and September 2015 was performed at the Department of Ophthalmology at the Medical University of Graz. In total, seven eyes of six patients, with a mean age of 60.4 years (range, 43–75 years), were treated with a C₃F₈ gas injection. All patients underwent baseline testing of Snellen visual acuity, biomicroscopy of the anterior and posterior segment, and spectral domain optical coherence tomography (SD-OCT). This case series was in accordance with the Declaration of Helsinki, and the approval of the ethics committee of the Medical University of Graz was obtained.

All intravitreal injections of expansile gas were carried out in an operating room and were in all cases performed by the same surgeon. Following the use of topical 1% Tetracaine anesthetic, the patients were prepared for surgery using an eyelid speculum, drape, and lavage of the conjunctival sac with povidone-iodine; subsequently, up to 0.3 ml of 100% C₃F₈ gas was injected. Three eyes received 0.2 ml and four eyes 0.3 ml of 100% C₃F₈ gas. Using a 30-gauge needle on a 1-ml tuberculin syringe, the gas was injected through the pars plana at a distance of 3.5 mm from the limbus. In all patients, an anterior chamber paracentesis was performed.

After surgery, the patients were told to avoid supine positioning because of the risk of cataract formation. Postoperatively, the patients had to use ofloxacin eye drops three times daily for 4 days. The patients were followed up for 1–2 weeks after gas injection and subsequently at least monthly until release of VMT.

The primary outcome measure was the release rate of VMT validated using SD-OCT at 1 month. Secondary measurements of interest included release of VMT within 6 months, change in central foveal thickness and in best-corrected VA, and closure of the MH. Only a change of best corrected visual acuity (BCVA) of two or more Snellen lines was regarded as significant.

To be included in this case series, the patients had to present with an SD-OCT-confirmed VMT with an adherence diameter of less than 1500 μm.

Exclusion criteria were patients who had undergone a vitrectomy or intravitreal injection before or who had an active ocular infection, an age-related macular degeneration or a glaucoma, an operative ocular intervention less than 3 months earlier, or presented with a retinal detachment in the other eye. Informed consent from all patients was obtained for inclusion in the study.

Seven eyes of six patients underwent an intravitreal 100% C₃F₈ gas injection for the treatment of VMT and MH. Three of the patients were male and three female; both eyes of one woman were assessed. The patient demographics as well as the pre- and posttreatment characteristics are listed in Table 1.

Three of the seven eyes (42.86%) had concurrent epiretinal membranes (ERM), among which one (14.26%) presented with concurrent diabetic retino- and maculopathy. Mean time from diagnosis to operation was 63 days (range, 6–223 days; SD = 75.86) and mean adhesion diameter was 328.57 μm (range, 63–803 μm; SD = 235.66). The patient with the extent of adhesion of 803 μm did not have VMT release. Traction release by 1 month after injection was observed in three of the seven eyes (42.86%), while a further three eyes detached within 6 months (85.71% final release rate). In two of the three eyes with concurrent ERM there was VMT release; however, not within 1 month but after 5 and 10 weeks. Furthermore, in one of one eye with concurrent diabetic retino- and maculopathy there was release within 10 weeks. One of the six patients had a small MH (201 μm) with VMT. Although the VMT released successfully after 1 week the MH did not close and hence underwent vitrectomy. The average number of days until VMT resolution was 54 (range, 7–173 days; median 28). Visual acuity improved by two or more Snellen lines in 42.86% and remained stable in 57.14% of cases.

Overall, the mean central foveal thickness decreased in patients with release of VMT from 517.5 μm (range, 335–780 μm; SD = 171.82) to 377.67 μm (range, 200–816; SD = 257.93) before and after treatment, respectively.

One patient showed macula edema with a consequent lamellar hole after the injection, whereas another patient developed a retinal tear with a retinal detachment with subsequent vitrectomy. No patient sustained complications during the intravitreal gas injection.

This case series describes the use of a single intravitreal 100% C₃F₈ gas injection for the treatment of VMT with and without MH. This very small retrospective case series showed a successful release rate of VMT within the first month in 42.86% of patients and within 6 months in 85.71%. Only one patient (14.29%) failed to respond and had to undergo vitrectomy shortly after injection because of a retinal tear and detachment. The patient (14.29%) presenting with an MH showed VMT release, but had to undergo vitrectomy as a consequence of the nonclosure of the MH.

A very heterogeneous sample of patients was included, with patients showing concurrent ERM (42.86%) and diabetic retino- and maculopathy (14.26%). Nevertheless, successful release occurred with a very high frequency despite this patient population not being considered ideal for high success rates. Two patients (28.59%) experienced adverse events after the intravitreal gas injection, such as macular edema, retinal tear, and retinal detachment.

In this case series, the individual visual acuity improvements were modest. Visual acuity improved by two or more Snellen lines in 42.86% and remained stable in 57.14% of patients. It is disputable if and to what extent the BCVA of the patient with diabetic retino- and maculopathy had slightly decreased, regarding the fact that this diagnosis can cause severe loss of vision with time. Additionally, in one patient with a BCVA of 1.0, an increase in visual acuity could not be expected.

The two MIVI-TRUST studies, demonstrating the treatment efficacy of one single intravitreal 125-μg injection of ocriplasmin, showed that at day 28 postinjection, 26.5% and 40.6% of patients had resolution of adherence and nonsurgical MH closure, respectively. Both results were statistically significant [7]. The Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) study reported even higher rates: 41.7% of patients in the ocriplasmin group had VMT release on day 28. Closure of MH without any surgical intervention at 3 months was reported in 30% of cases [8]. Sharma et al. found the resolution of VMT to be as high as 50% and nonsurgical closure of MH to be 27% in their sample [9]. All these studies only reported on the results of VMT resolution 28 days after the intravitreal injection and did not note release rates after 6 or 12 months, even though the OASIS trial had a 24-month follow-up. With a longer observation interval, it can be assumed that the results would also have increased. Moreover a long-term follow-up is favourable in order to assess the final visual acuity. Transient visual loss has been described in previous studies and a longer observation period can aid in definite judgment. In addition, further and larger “real-world” clinical series with heterogeneous patient collectives will offer more insight regarding patient groups, adverse events, and efficacy. There were numerous ocular exclusion criteria in the MIVI-TRUST study, which can hence hardly be compared with the patient collective of everyday life. Ocriplasmin is a first-in-class drug and its safety profile is nowhere near completion. The primary endpoint of the first and main studies was changes on OCT, although these do not always go hand in hand with visual improvement or decline and thus more studies are needed focusing also on visual gain [7, 8, 10].

Day et al. conducted a study with patients receiving an intravitreal sulfur hexafluoride injection for the treatment of VMT. A release rate of 55.6% as well as the closure of MH in two of two patients within the first month was documented, with the results being even better than with ocriplasmin. However, the study involved only nine patients compared with 464 treated with ocriplasmin in the MIVI-TRUST study, which makes these results hard to compare as it is harder to conclude about a population with fewer participants [7, 11]. Furthermore, the study did not include patients with ERM or other concurrent retinal diseases, which are according to Haller et al. favorable factors for pharmacologic release and hence could have increased their release rate [10, 11]. To date, only one study has been published with injection of sulfur hexafluoride (SF₆) gas and further studies including patients with, for example, ERM are required to confirm these results.

Vitrectomy remains the gold standard for treatment of symptomatic VMT, showing release rates of up to 98%, nonetheless entailing the risk of intra- and postoperative complications [12]. It is dependent on a very experienced surgeon and requires patient suitability for surgery, which is not always the case in patients of advanced age. The main complication of cataract formation postoperatively is also worth considering, since this requires another surgery, if not automatically performed in the same intervention. Given the high success rate of vitrectomy, documented also after the completion of pharmacological therapy, it is possible in the future to perform vitrectomy as a second-line therapy only in cases where medical therapy has failed. With pharmacologic vitreolysis previous to vitrectomy, no additional side effects have been identified so far—on the contrary, Lopez-Lopez et al. even considered whether it could be used coadjuvantly by speeding up the surgery and minimizing its complications [3, 13].

It would be of high interest to directly compare the use of an intravitreal injection of ocriplasmin, C₃F₈ and SF₆ gas, vitrectomy, and placebo for patients with VMT in a single clinical trial.

Rodrigues et al. were the first to investigate the use of an intravitreal injection of expansile C₃F₈ gas in treating VMT in 2013. Release of VMT was successfully observed in 40% of patients within the first month and increased to 60% within half a year [4]. In 2016, Steinle et al. assessed the posterior vitreous release rates after a single intravitreal injection of C₃F₈ for VMT treatment. At 1 month after injection, initial VMT release was 73% and increased to 83% by the final follow-up visit, which was on average 160 days [5]. The latest results in 2017 are from Chan et al., including 50 eyes, who reported on pneumatic vitreolysis with C₃F₈ in 86% of cases [6].

These studies show similar results of VMT release as those found at the Medical University of Graz. Rodrigues et al., on the one hand, included very few patients (15 eyes), while Chan et al., on the other hand, assessed 50 eyes, the largest collection of patients receiving a C₃F₈ gas injection to date. In all studies, including the case series performed in Graz, a very heterogeneous patient collective was included, with patients presenting with concurrent ERM, concurrent diabetes mellitus, exudative age-related macular degeneration, and MH. In the study conducted by Steinle et al., six eyes (20%) were included where previous intravitreal ocriplasmin injection had failed to release traction and one eye (3%) that had been included in another study receiving serial saline intravitreal injections. At the final follow-up, there was release in five of these six eyes (83%) and the eye with three intravitreal saline injections (one of one eye). This raises the question of whether a single C₃F₈ gas injection works more efficiently than ocriplasmin, and whether previous intravitreal injections aid in releasing traction or whether these adhesions would have perhaps released spontaneously.

Regarding ERM, Steinle et al. noted a success rate of 83% and suggested this therapy as a justifiable nonsurgical treatment in patients showing VMT and ERM [5]. In the case series of the Grazer Medical University, two out of three patients with concurrent ERM released traction, which is also a high rate but must be viewed critically owing to the small number of patients. However, these results are in contrast to those of Haller et al., who propose the absence of ERM as a positive predictive factor, which was associated with successful VMT release [10]. Rodrigues et al. also identified predictive factors that seem to have a positive impact on the traction release rate. All patients participating in the case series of the Medical University of Graz, who had a maximal horizontal VMA of lower than 750 μm (85.71%), showed a successful VMT release. These results strengthen the author’s assumptions. In the only patient who failed to respond, the extent of adhesion was 803 μm. The question arises of whether a larger adhesion diameter and thus a stronger tractive force are favorable for retinal tear and detachment, as was documented in this patient. However, the second postulated predictive feature of a maximal foveal thickness less than 500 μm cannot be seen in the case series of the Medical University of Graz. Three patients (42.86%) had a maximal foveal thickness of more than 500 μm, among whom two had VMT release within 6 months [4].

In none of the two studies was there a statistically significant improvement in mean visual acuity, which might be due to the relatively small number of included patients.

Successful closure of early-stage MH with gas injection was described as early as 1995 [14]. Rodrigues et al. included just one eye with an impeding MH at baseline, which progressed to a full thickness macular hole (FTMH) after C₃F₈ gas injection and eventually had to undergo vitrectomy for release of VMT. Steinle et al. had three eyes with FTMH of <200 μm at baseline, of which all three showed VMT release with gas and two had closure of their FTMH. The closure of stage 2 MH (<250 μm) was achieved, reported by Chan et al., in 66.7% of cases, while traction release was successful in all of these eyes. The Grazer case series notes one patient with an MH who had pneumatic release of VMT but required vitrectomy for closure of the persistent MH. It was previously described that MHs with a diameter of <200 μm have a higher chance of closure after medical therapy, which cannot be confirmed by the study done at the Medical University of Graz. The MH, however, did show a width of 201 μm and a single case is of very low significance [4, 5].

The main advantage of C₃F₈ gas is that it is easy to obtain, minimally invasive, and, last but not least, very cost-effective. Compared with a single injection of ocriplasmin, which costs about U.S. $ 3950, an intravitreal injection of C₃F₈ gas is much cheaper [15]. The choice of using C₃F₈ instead of SF₆ is based on the longer intravitreal persistence and therefore the theoretically better effect on VMT.

In conclusion, pneumatic vitreolysis with C₃F₈ gas is a promising nonsurgical option for treating VMT, with or without MH. The results of this case series suggest a further possibility of successful VMT release with a single intravitreal injection of C₃F₈ gas. Furthermore, C₃F₈ gas gives clinicians another option, besides ocriplasmin and SF₆, to manage VMT in a less invasive manner. Additional studies with most notably a larger patient population are needed to further investigate the risk/benefit profile of C₃F₈ gas and to directly compare C₃F₈ gas with other methods of medical and surgical vitreolysis.