CLINICAL COURSE OF VITREOMACULAR ADHESION MANAGED BY INITIAL OBSERVATION

VISHAK J. JOHN, MD,* HARRY W. FLYNN, JR., MD,* WILLIAM E. SMIDDY, MD,* ADAM CARVER, MD,† ROBERT LEONARD, MD,† HOMAYOUN TABANDEH, MD,‡ DAVID S. BOYER, MD‡

Purpose: The purpose of the study was to investigate the clinical course of patients with idiopathic vitreomacular adhesion (VMA). Methods: A noncomparative case series of patients who had clinical symptoms and spectral-domain optical coherence tomography findings consistent with VMA. The VMA was graded based on the optical coherence tomography findings at initial and follow-up examinations. Grade 1 was incomplete cortical vitreous separation with attachment at the fovea, Grade 2 was the Grade 1 findings and any intraretinal cysts or clefts, and Grade 3 was the Grade 2 findings and the presence of subretinal fluid. Results: One hundred and six eyes of 81 patients were identified as having VMA by spectral-domain optical coherence tomography at 3 clinics. The mean age was 73 years and the mean time of follow-up was 23 months. Forty-three eyes (41%) had Grade 1 VMA, 56 eyes (52%) had Grade 2 VMA, and 7 eyes (7%) had Grade 3 VMA. By the last follow-up, spontaneous release of VMA occurred in 34 eyes (32%), and pars plana was performed in 5 eyes (4.7%). Mean best-corrected visual acuity was 0.269 logarithm of the minimum angle of resolution or 20/37 at baseline (range, 20/20–20/200) and logarithm of the minimum angle of resolution 0.251 or 20/35 at the last examination (range, 20/20–20/400). Conclusion: In this selected patient cohort with mild symptoms, the clinical course of patients with VMA managed by initial observation was generally favorable. RETINA 34:442–446, 2014

he clinical and spectral-domain optical coherence incomplete separation of the posterior vitreous with Ttomography (SD-OCT) features of vitreomacular persistent attachment confined to the fovea is more traction (VMT) syndrome have been described previ- common than is clinically symptomatic. The subset ously.1,2 Typical symptoms include decreased vision, of eyes with adhesion limited to the fovea may be central , photopsia, and micropsia. clinically distinct from eyes with broader zones of The emergence of SD-OCT has demonstrated that vitreomacular adhesion (VMA) and has been termed vitreofoveal adhesion or focal VMA.3–7 The SD-OCT From the *Department of , Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, allows documentation of the baseline and ongoing Florida; †Department of Ophthalmology, Dean McGee Eye Institute, effects and extent of VMA, specifically those with University of Oklahoma School of Medicine, Oklahoma City, central visual symptoms associated with VMA.3,4,8,9 Oklahoma; and ‡Retina-Vitreous Associates Medical Group, Los Angeles, California. Vitreous adhesion and presumed traction have addi- Supported in part by the National Institutes of Health (NIH), tionally been hypothesized to have a role in the Bethesda, MD, Grant NIH P30-EY014801 and an unrestricted pathogenesis of many macular conditions, including grant to the University of Miami from Research to Prevent Blind- ness, New York, NY. neovascular age-related , macu- V. J. John and A. Carver have no financial/conflicting interests to lar hole, and diabetic macular edema.10–12 disclose.H.W.Flynn:Santen,Vindico;W.E.Smiddy:AlimeraSci- entific; R. Leonard: Regeneron; H. Tabandeh: Alcon, Allergan, Bausch The purpose of this study was to investigate the & Lomb; D. S. Boyer: Aeripo, Alcon, Allegro, Allergan, Bausch & clinical course of patients with VMA defined by Lomb,Bayer,Genentech,GSK,Merck,Neurotech,Novartis,Ophthal- SD-OCT imaging, and followed with noninterventional micsORA, Pfizer, Inc., QLT, Inc., Regeneron Pharmaceuticals. fi Reprint requests: Harry W. Flynn, Jr., MD, 900 NW 17 Street, management. A classi cation of VMA based on the Miami, FL 33136; e-mail: hfl[email protected] SD-OCT findings is proposed as part of this study.

442 COURSE OF VITREOMACULAR ADHESION  JOHN ET AL 443

Patients and Methods

The study design was a noncomparative case series of patients for whom observational management was recommended at the initial examination by vitreoreti- nal surgeons at three centers. Symptomatic patients with VMA localized to the fovea, noted on SD-OCT, were identified and included in this study by virtue of an intention not to treat them based on either good presenting visual acuity or minimal symptoms. Fellow eyes of the patients with macular hole and advanced macular diseases (neovascular age-related macular degeneration and diabetic macular edema) affecting vision were excluded from the current study. Patient demographics and histories including age, gender, symptoms, best-corrected visual acuity (BCVA), and duration to last follow-up examination were recorded. The lens status and previous eye surgeries including intravitreal injections were also noted. The SD-OCT images at the initial and last visits were retrospectively placed into 3 categories that morphologically seemed to represent a spectrum of progressive traction (Figure 1). Grade 1 was incom- plete cortical vitreous separation with attachment at the fovea, Grade 2 was Grade 1 and intraretinal cysts or clefts, and Grade 3 was Grade 2 with the presence of subretinal fluid. Statistical analysis using chi-square, analysis of variance, and paired t-tests was performed on the study data.

Results

One hundred and six eyes of 81 patients were included. The cohort included 33 men (41%) and 48 women (59%). The mean age of the patients was 72.7 years with a range of 41 years to 92 years at the initial visit. The mean BCVA was 0.269 logarithm of the minimum angle of resolution (20/37). The median time of follow-up was 18 months with a range of Fig. 1. Grades of VMA based on the SD-OCT findings in the study of 1 month to 91 months. Previous interventions included patients managed by initial observation. A. Grade 1: incomplete separa- intraocular surgery in 43 eyes (some patients had tion of cortical vitreous with persistent vitreous attachment at the fovea and internal limiting membrane. B. Grade 2: Grade 1 + any intraretinal multiple previous procedures), including 37 eyes cyst, cleft, or schisis. C. Grade 3: Grade 2 + neurosensory elevation of the (35%) with surgery with intraocular lens retina from retinal pigment epithelium (subretinal fluid). placement, 2 eyes (2%) with combined cataract and glaucoma surgery, 3 eyes (3%) with panretinal SD-OCT findings is summarized in Tables 1 and 2. photocoagulation, and 4 eyes (4%) undergoing intra- In Grade 1 eyes, the VMA released spontaneously on vitreal injections. Sixty-seven patients (63%) were the OCT in 13 eyes (30%), was unchanged in 23 eyes, phakic at the time of initial visit, and 39 patients (37%) while the attachment progressed into a Grade 2 or 3 in were pseudophakic. 7 eyes. In Grade 2 eyes, VMA released spontaneously Using the study classification criteria (Figure 1), in 17 eyes (30%), remained unchanged in 31 eyes, and 43 eyes (41%) had Grade 1 VMA, 56 eyes (52%) progressed to Grade 3 in 8 eyes, including 3 eyes that had Grade 2 VMA, and 7 eyes (7%) had Grade 3 developed full-thickness macular hole, leading to sur- VMA at the initial visit. The clinical course of gery. Finally, within Grade 3 eyes, VMA released in 444 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2014  VOLUME 34  NUMBER 3

Table 1. Visual Acuity at Presentation and at the Last Follow-up for Each Grade of VMA in the Study of Patients Managed by Initial Observation Mean LogMAR (SD) at Mean LogMAR (SD) at Presenting VMA Grade No. Eyes Presentation the Last Examination P* Grade 1 43 0.21 (0.18) 0.21 (0.19) 0.88 Grade 2 56 0.30 (0.20) 0.32 (0.28) 0.54 Grade 3 7 0.43 (0.31) 0.34 (0.30) 0.34 *Paired t test. LogMAR, logarithm of the minimum angle of resolution; SD, standard deviation; VMA, vitreomacular adhesion.

4 eyes (57%), 1 eye improved to Grade 1, 1 eye each of the 3 VMA grades (Table 1). At the last exam- remained unchanged, and 1 eye progressed to a full- ination, the mean BCVA in the observation group thickness macular hole, prompting surgery. Thus, at (excluding the 5 operated patients) was 0.251 loga- the last examination, overall 34 eyes (32%) had spon- rithm of the minimum angle of resolution (20/35), taneously resolved VMA, 25 eyes (23%) had Grade 1 which was similar to the baseline visual acuity. VMA, 38 eyes (36%) had Grade 2 VMA, 4 eyes (4%) had Grade 3 VMA, and 5 eyes (5%) underwent pars plana vitrectomy (PPV). The differences in spontane- Discussion ous resolution rates for the various grades were not significant (P = 0.35). Similarly, the rates of worsening The main finding of this study is that the observa- anatomy in all presenting VMA grades were equiva- tional management of at least milder grades of VMA is lent (P = 0.64). a favorable initial option. The current study demon- All but 5 of the 106 eyes were observed throughout strated stability of BCVA between the initial and last the study. Those 5 patients (4.7%) underwent PPV examinations, a high rate of spontaneous VMA release (4 eyes for development of full-thickness macular (32%), and a low rate of progression to a more severe holes, and one for progressive loss of vision from anatomical configuration (16%). A grading scheme for VMA). Four of the operated eyes were Grade 2 at VMA based on the SD-OCT features was also useful initial visit, while one was Grade 3 at baseline. After for clinical monitoring by better defining subgroups in vitrectomy, the mean visual acuity at last follow-up in the current study and may be useful for standardizing the operated eyes was logarithm of the minimum angle the observations and outcomes in future studies. of resolution 0.30 or 20/40 (20/30, 20/30, 20/40, and Debate about whether persistently attached vitreous 20/100 in the 4 patients with macular hole, and 20/25 always represents actual traction has led to the use of in the patient operated for worsening VMA). At the the terms, VMT or VMA. The Microplasmin for last examination, all four patients with macular hole Intravitreal Injection-Traction Release Without Surgi- had successful closure and the progressive patient with cal Treatment (MIVI-TRUST) investigators used the VMA had improved foveal anatomy (resolution of term VMT when there were visual symptoms associ- retinal cyst and subretinal fluid). ated with VMA.13 The patients in that study repre- The BCVA among three VMA grades at presenta- sented relatively small zones of VMA, limited to the tion was significantly different (P = 0.012), with Grade fovea as documented by the OCT. In the pre-OCT era, 3 patients having the worst visual acuity at the initial only patients with relatively advanced VMA, as visit. There were no significant differences between observed by slit-lamp biomicroscopy, were clinically changes from the initial to the final mean BCVA in recognizable. These were categorized according to the

Table 2. Final Status of VMA in the Study of Patients Managed by Initial Observation Presenting VMA Grade No. Eyes Improved (%)* Stable (%)† Worse (%)‡ Grade 1 43 13/43 (30) 23/43 (53) 7/43 (16) Grade 2 56 17/56 (30) 31/56 (55) 8/56 (14) Grade 3 7 4/7 (57) 1/7 (14) 2/7 (28) *Improved: release of VMA. †Stable: VMA is still present, and no change. ‡Worse: progression from Grade 1 to Grade 2 or Grade 3, OR, progression from Grade 2 to Grade 3 or a macular hole or surgery, OR, progression from Grade 3 to a macular hole or surgery. VMA, vitreomacular adhesion. COURSE OF VITREOMACULAR ADHESION  JOHN ET AL 445 extent of the persistent vitreous attachment only as holes in the early 1990s,22 but few clinicians adopted observed by slit-lamp biomicroscopy.14 This subset that technique since that time. Recently, Rodrigues was deduced to be more likely to progress and surgical et al23 reported 40% rate of the VMA release at 1 – intervention was proposed.15 17 Initially, the rationale month after a single injection of expansile perfluoro- 18 for surgery was to avert macular hole formation, but propane (C3F8), confirmed by SD-OCT. With very subsequent clinical experience demonstrated that little adverse effects reported in the study, and the releasing apparent traction allowed partial normaliza- relatively low cost of the gas bubble, this pneumatic tion of anatomy and function in more clinically severe vitreolysis could be an alternative to the more invasive cases. In a retrospective case series of 36 patients surgical option of PPV.23,24 Approved in 2012 by the undergoing PPV for VMA, Davis et al19 demonstrated Food and Drug Administration, a pharmacologic inter- favorable visual outcomes (50% improved visual vention with the intravitreal injection of microplasmin acuity by $2 lines). In a pre-OCT era study, in 53 for the release of symptomatic VMA has been intro- symptomatic VMA eyes (diagnosed clinically) with duced for patients with visual loss to 20/25 or worse. a median follow-up of 5 years, most (64%) had In patients with VMT, 10% of patients injected with a decrease in visual acuity over time. Better visual saline had a release of vitreofoveal adhesion at 28 days acuity and resolution of cystoid edema on fluorescein compared with 26.5% of patients injected with micro- angiography were noted in 11% of the patients in the plasmin.13 It is possible that vitreoretinal surgeons study who underwent a complete posterior vitreous may use this pharmacologic option in the more severe 14 detachment. These findings seemed to justify surgi- VMA cases rather than less symptomatic milder cases, cal intervention in more severe VMA cases. in an attempt to avoid the need for future PPV. Con- The OCT allows more precise means for categori- versely, they may also use it to treat patients with milder zation and longitudinally monitoring of such patients. symptoms and less extensive VMA so as to halt pro- 20 fi Chan et al classi ed a subset of VMA on OCT as gression and avoid PPV. The ability of microplasmin to Stage 0 macular holes and postulated it as a group at induce posterior vitreous detachments and its use in risk for developing macular holes in the fellow eyes. 16 managing small macular holes with VMA has been Additionally, Gaudric et al documented the progres- demonstrated through the MIVI trials.13 However, its sion of VMA to full-thickness macular holes using value in eyes with good vision and minimal symptoms OCT in fellow eyes of some patients with macular fi 16 is less clearly de ned. The 32% spontaneous VMA hole. A 2012 OCT study of eyes with tractional release rate in the current study compared favorably cystoid macular edema secondary to VMT reported with the rate in the MIVI-TRUST study, raising ques- a complete and spontaneous posterior vitreous detach- 21 tions as to the value of ocriplasmin in milder cases. ment in 53% of eyes. The limitations of the current study include its However, the clinical course of patients with VMA is retrospective nature, relatively few patients, and not well established, especially when the degree of potential bias in that the individual attending physician visual loss is mild. The SD-OCT has identified many made the decision to assign patients to observational more patients with earlier, minimal, or mild visual loss management. Patients with both VMA and early symptoms,4,9 making indications for the management macular holes were not included in the current study. of milder cases even less clear. Many such patients Patients with VMA with more severe visual symptoms remain stable without surgical intervention, but the nat- were likely managed with PPV and, therefore, were ural history is not well established.1 The 32% rate of not included in the study. In contrast, patients with spontaneous VMA resolution in the current study might better visual acuity and minimal symptoms were be even higher with longer follow-up. The relatively selected by the study investigators for observational favorable anatomical course was commensurated with the stable mean BCVA for patients in the current study management. Thus, the study cohort may have (0.269 logarithm of the minimum angle of resolution represented a milder or at least different group of initially and 0.251 logarithm of the minimum angle of patients with VMA compared with MIVI-TRUST. resolution at the last follow-up examination). In conclusion, the present study demonstrates that the Surgical treatment consisting of PPV with a release clinical course of patients with relatively mild symp- of the vitreofoveal attachment, and possibly with tomatic VMA is often favorable during follow-up. consideration of internal limiting membrane peeling, Hence, patients with VMA diagnosed by SD-OCT has been the contemporary interventional option but with minimal or nonprogressive symptoms can be for VMA.15,17 Chan et al22 described the induction initially considered for noninterventional management. of a posterior vitreous detachment by injecting an Key words: vitreomacular traction, vitreofoveal expansile gas as a treatment for impending macular adhesion, microplasmin, macular hole. 446 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2014  VOLUME 34  NUMBER 3

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