CONTROVERSIES IN CARE

Treatment for Vitreomacular Interface Disease Spectrum: Vitrectomy, Pneumatic Vitreolysis, or Ocriplasmin?

EDITED BY MICHAEL COLUCCIELLO, MD

Symptomatic vitreomacular interface disease spectrum disorders have become an increasingly recognized issue recently, given the advancing age of our population and the availability and usage of high-resolution spectral-domain OCT, which often discloses the underlying cause of vision loss.

Ocriplasmin (Jetrea, Thrombo-Genics, Iselin, NJ) is a pharmacologic (bioengineered, truncated form of human serine protease plasmin) vitreolysis agent that the FDA approved in October 2012 for the treatment of vitreomacular traction (Figure; VMT) and full-thickness macular holes (FTMH).

Figure. Optical coherence tomography image of vitreomacular traction.

The properties of ocriplasmin allow it to liquefy the vitreous and separate it from the retina, both of which are necessary to successfully release VMT. Ocriplasmin gives patients an alternative to vitrectomy for treating VMT or FTMH, allowing for the treatment of VMT spectrum disorders without the concern for the high rate of cataract formation seen with pars plana vitrectomy.

Data on Efficacy

Pooled ocriplasmin clinical trials (MIVI-TRUST) data indicate that a statistically significantly larger percentage of eyes with VMT and no concurrent epiretinal membrane had VMT resolution by 28 days after one intravitreal injection of ocriplasmin (29.8%) vs a placebo injection (7.7%).¹

Factors predictive of treatment success with ocriplasmin include age younger than 65 years, FTMHs 400 µm or smaller, vitreomacular adhesion diameter less than 1,500 µm, absence of ERM, and phakic lens status.

Results from the ocriplasmin phase 3 clinical trials showed efficacy for ocriplasmin when used to treat a small FTMH. A single ocriplasmin intravitreal injection resulted in higher rates of FTMH closure (40.6%) at postinjection day 28 vs placebo (10.6%).¹

Hole closure was more likely when FTMH width was smaller at baseline: 58.3% with small FTMHs at baseline (diameter <250 µm) had FTMH closure at day 28 vs 36.8% of medium (250-400 µm) and 0% (0/19) of large macular holes (diameter >400 µm).

The presence of an epiretinal membrane with VMT reduces the chances of success with ocriplasmin. Isolated ERM without associated VMT has not been evaluated for treatment with ocriplasmin.

The Down Side

Concerns exist, however, with the ocriplasmin approach to VMT/FTMH. The cost of a single dose is nearly $4,000. The success rate is low compared to vitrectomy surgery (although an attempt with intravitreal ocriplasmin treatment does not preclude later vitrectomy).

Vitrectomy remains the treatment of choice for many symptomatic cases; PPV has success rates up to 75%.² If ocriplasmin does not induce the release of the VMT within one month after injection, it likely will not.

Many patients treated with intravitreal ocriplasmin will experience flashes and floaters before they improve. Also, reports have emerged of lens subluxation (most likely due to enzymatic lysis of zonules) and reports of vision loss/color desaturation with its use (although this was almost uniformly spontaneously reversible).³ Also, ocriplasmin must be stored in its original package in a special freezer able to sustain a temperature of -4°F (-20°C) or lower.

Other Alternatives

Pneumatic vitreolysis may be a reasonable alternative to treat vitreomacular interface disease spectrum disorders. In 1995, Chan and associates first reported on the clinical use of an intravitreal gas bubble to treat macular holes.⁴

Recently, a series showed that six of 15 patients (40%) had VMT successfully released within one month, and nine of those 15 patients (60%) had VMT successfully released within six months with a single intravitreal injection of 0.3 mL of 100% C₃F₈.⁵

So without the benefit of a randomized clinical trial comparing the various methods of treating VMT/FTMH, how do we proceed? We are fortunate this month to have the perspectives of Mark Johnson, MD, and Michael Ober, MD, on this evolving area in vitreoretinal medicine.

REFERENCES

Begin With Observation

MICHAEL D. OBER, MD

The options for patients with symptomatic vitreomacular adhesion (VMA) have changed significantly in the past 14 months. These options now include observation, intravitreal injection of ocriplasmin, vitrectomy, and less frequently used alternatives, including intravitreal injection of an expansile gas bubble (pneumatic vitreolysis).

My approach is based on patient history, examination findings, and OCT imaging. Patient history is critical to determine the extent to which VMA-related symptoms impact individual activities. The threshold for intervention is different for every patient, and that line is greatly influenced by detailed conversations.

Patients with hobbies or professions that rely heavily on visual details are more likely to opt for early intervention. Examination findings also alter the balance of treatment.

I would usually initially counsel a patient with risk factors for vitrectomy complications (phakia, previous retinal detachment, etc.) toward more conservative options. Finally, OCT provides several details that may alter the potential success rate of ocriplasmin as discussed below and, therefore, favor or dissuade its use.

The Role of Observation

Compared with ocriplasmin and vitrectomy, relatively little is known about the natural history of VMA. Despite this, observation remains a viable and frequently used option.

John et al¹ recently shared retrospective information on 106 eyes from three institutions, with VMA initially managed by observation. They found that 32% of eyes (34) showed spontaneous resolution of VMA, while 15% (16) progressed (including four to macular hole).

Furthermore, the MIVI-TRUST study showed that only 3.2% of patients in the sham injection group lost vision.² These findings support observation for the safe initial management of mild VMA, especially when accompanied by frequent return visits.

Vitrectomy remains the gold standard for symptomatic VMA, with the highest anatomic success rate,³ but unfortunately, the well-known complications preclude its initial use for the majority of patients with mild changes.

Ocriplasmin’s Contributions

The introduction of ocriplasmin represented the first pharmacological treatment option for symptomatic VMA, including VMT and macular holes. Patient selection will likely increase the rather unsatisfying success rate detailed in MIVI-TRUST (26% for VMT and 40% for macular holes).

Frequently mentioned criteria include VMA <1,500 µm, avoiding use with ERMs, and limiting application to small, new macular holes. Also, phakic eyes injected with ocriplasmin fared better than pseudophakic eyes (resolution of VMA in 34.2% and 13.4%, respectively), and a still unexplained greater resolution of VMA was found in women (30.3%) vs men (18.7%).³

While ocriplasmin may be considered the least invasive surgical intervention for patients with VMA,⁴ 5.6% of ocriplasmin-treated patients lost >3 lines of vision, and 2% developed dyschromatopsia with corresponding electroretinogram changes.

Freund et al⁵ correlated ellipsoid layer alterations in one such patient and concluded that the enzymatic action of ocriplasmin may have a deleterious effect on the photoreceptors, which is at least partially reversible.

A Personal Viewpoint

In my opinion, this complication is a relative contraindication against peeling the hyaloid and ERM and/or ILM, until maximum photoreceptor integrity has been restored, which may prevent or delay surgical intervention in some patients.

Without a larger trial, it is difficult to recommend pneumatic vitreolysis given the available treatment alternatives. In concept, it appears to be the least controlled of the discussed methods to dislodge the adherent vitreous from the (rather delicate) fovea. However, given the paucity of complications experienced in reported patients and the favorable cost comparison, future studies are likely.⁶

In summary, the management of VMA continues to evolve, but good evidence exists to support initial conservative observation, as well as ocriplasmin and vitrectomy for appropriate candidates.

REFERENCES

Proceed With Caution

MARK W. JOHNSON, MD

Although treatment options for vitreomacular disorders are expanding,¹ vitreous surgery remains the gold standard for the vast majority of my patients. Its virtues are many, including high success rates, predictable visual outcomes, and the ability to tackle the full spectrum of vitreoretinal interface disease.

In fact, vitrectomy remains the only reasonable choice for patients with significant visual loss due to ERM, large macular hole, macular hole with ERM, broad VMT, focal VMT with ERM, myopic traction maculopathy, and most cases of traction DME.

Given the cost and inherent risk of vitrectomy, it is reasonable to consider nonsurgical induction of posterior vitreous detachment in the relatively small subset of eyes with significant vision loss due to focal VMT and no significant ERM, especially if associated with a small macular hole.

In theory, pharmacologic vitreolysis² is an attractive alternative to surgery in such eyes, given its potential for inducing a clean and complete PVD, releasing traction while avoiding cortical vitreous remnants that may lead to ERM formation or recurrence.³

Compared with vitrectomy, PVD induction by a safe and effective pharmacologic agent would be safer and easier, cheaper, and possibly better at providing fast visual rehabilitation with optimal and stable visual outcomes.

Poor Outcomes With Ocriplasmin

However, real-world experience with ocriplasmin has been disappointing, in part due to its low success rate, coupled with its high cost. More concerning, however, are the safety issues associated with ocriplasmin injection.

Patients often experience bizarre photopsias that are unassociated with PVD and suggest retinal dysfunction. Also commonly observed are loss/disruption of the outer retinal bands on OCT^4,5 and variable amounts of submacular fluid, both of which may persist at least in part for more than six months after injection.

Uncommonly, patients show other signs of acute panretinal dysfunction following injection,⁵ eg, severe VA loss, night blindness, dyschromatopsia, visual field loss, afferent pupillary defects, attenuation of retinal arteries, severely reduced ERG responses, and peripheral autofluorescence abnormalities.

The likely mechanism of ocriplasmin toxicity is enzymatic cleavage of laminin, which is present not only at the vitreoretinal interface but also throughout the retina (including in the interphoreceptor matrix),⁶ as well as in lens zonules and other ocular tissues.

It is not possible to predict which patients will experience severe adverse effects after ocriplasmin injection. Although toxic changes tend to improve over time, they may persist chronically, and more data are needed about the incidence, mechanism, and reversibility of such abnormalities.

It remains to be seen whether ocriplasmin can routinely deliver the excellent visual outcomes seen after vitrectomy for focal VMT⁷ and small macular holes. In light of these issues, I am currently not using ocriplasmin in my patients.

Other Options

Pneumatic vitreolysis is a second potential nonsurgical option for eyes with a small VMA, with or without a small macular hole. Data from several pilot studies have suggested that PVD can be induced more consistently in such eyes with an intravitreal injection of low-cost perfluoropropane gas than with a single ocriplasmin injection.^8,9

Retinal tears or other serious complications of either gas injection or PVD development are uncommon in treated eyes. Although such reports are encouraging, I have not yet used this approach in my patients because of the relative paucity of data, the small number of good candidates, and the lower success rate and predictability compared with vitrectomy.

Cases Calling for Observation

Finally, what about eyes with symptomatic VMA that have good visual acuity and no FTMH? Some might advocate early intervention, before visual function has dropped to the level that would justify surgical risk.

However, the natural course of such eyes has been shown to be quite favorable, with spontaneous vitreofoveal separation or stable VA being the rule and disease progression requiring vitrectomy occurring uncommonly.¹⁰

I believe such patients are best managed with observation, because the risk of intervention, even with ocriplasmin or pneumatic vitreolysis, does not seem justified. RP

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