Use of Spectral-domain OCT to Evaluate Vitreomacular Adhesions in AMD

FRANCESCA MOJANA, MD ∙ WILLIAM R. FREEMAN, MD

Age-related macular degeneration (AMD) has a multifactorial pathogenesis. However, there is a genetic basis for the fundamental development of the disease.^1-3 The major defect is in the outer retina and retinal pigment epithelium (RPE) layers and appears to affect the control of the immune response in that area.^4-7 There has been interest in the role of the vitreous in this condition, and it has been observed that posterior vitreous detachment (PVD) may play a role in this disorder.⁸

It has been also suggested that PVD is less common in AMD patients than others and that vitreomacular adhesion is more common in AMD.^9-11 It is possible that vitreomacular adhesion or traction might affect the response rate of macular edema secondary to choroidal neovascularization (CNV) to anti-VEGF or other therapies. This has been suggested because, from a clinical practice perspective, some eyes respond well to anti-VEGF therapy, and some appear to be resistant. If vitreomacular adhesion plays a role in resistance, this might open up a new therapeutic avenue in selected cases of CNV due to AMD.¹⁰

STUDY DESIGN AND METHODS

For the past three years, we have evaluated different spectral domain OCT (SD-OCT) devices in eyes with AMD in order to better understand the role, if any, of abnormal vitreomacular adhesion or vitreomacular traction in this disease. We have predominantly used two instruments, the Heidelberg Spectralis (Heidelberg Engineering, Vista, CA) and Opko OTI (Opko Health, Miami, FL) devices. Both are SD-OCT devices that provide real-time simultaneous slit-lamp ophthalmoscopy (SLO) images of the retina, which has enabled us to evaluate not only vitreomacular relationships, but to do this in comparison to retinal structures seen by SLO imaging of the fundus.^12-15 These devices allow, for the first time, high-quality imaging of the posterior hyaloid and, in many cases, the ability to separate that structure from the inner retina. The use of simultaneous imaging allows us to visualize subtle details not possible with time-domain OCT.

It is important for the retina specialist to be familiar with and to train office-imaging personnel to evaluate hyaloid adherence patterns over the posterior pole and also to be able to evaluate PVD. This requires focus on the inner retina and, if no membrane is seen, a study more anteriorly, involving focusing in the mid-vitreous cavity — both in the visual axis and in the periphery. This is useful because it usually allows identification of the posterior hyaloid membrane. Indeed, we have shown that the use of SD-OCT combined with SLO allows detection even of intact vitreous cortex in eyes in which there is no vitreous detachment or abnormality.¹⁶

In our initial clinical study, we analyzed patients with AMD diagnosed by complete ophthalmologic examination and ETDRS vision testing.¹⁷ We determined that a Weiss ring or a clearly mobile posterior hyaloid structure moving freely in the vitreous was a complete PVD.¹⁸ Eyes with AMD were confirmed using fundus photography and fluorescein angiography, and we eliminated any patients with diabetes and other diseases, including uveitis, which could confound the vitreomacular relationship in AMD. Our initial studies were performed with the Opko/OTI. We then began using the Heidelberg Spectralis when that instrument became available in 2008. We were careful to also study control patients without AMD or retinal disease to evaluate our ability to diagnose vitreous detachment using SD-OCT.

The Spectralis and Opko instruments both provide the operator with a simultaneous confocal image of the retina in infrared light. The axial resolution of these instruments is on the order of 7 μm, and both machines incorporate a simultaneous SLO. In the sensing arm of the OCT, a beam splitter redirects part of the light returned from the eye toward a confocal optical receiver. Both OCT and confocal signals carrying the information about the reflectivity of the target are collected by a dual input, which displays two images on a screen under computer control. A strict topographic correspondence of the OCT cross-sectional image and the SLO image allows the operator to sweep the cursor all over the posterior pole, focusing on specific notable areas.

We developed a useful clinical classification, which we modified from published criteria.^19,20 Each posterior pole series of B-scans covers an area of approximately 8 mm x 8 mm. It is important to obtain high-quality scans and to realize that these instruments can perform both vertical and horizontal raster cuts of high quality. We found that the radial scans such as typically performed by the conventional time-domain OCT are not particularly valuable. In addition, time-domain instruments may show some evidence of vitreomacular adhesion at their resolution, but they do not permit confidence in the diagnosis in many cases. It is important to include the optic nerve in some views to evaluate the vitreous attach ment to this area, which is a common finding.

The retina specialist can divide patients into several categories. We prefer three major categories to determine vitreomacular adhesion:

1. No evidence of posterior hyaloid adhesion.
2. Persistent adhesion of hyaloid only to the optic disc.
3. Persistent adhesion of hyaloid to the macula (in any of the four quadrants).

It is important to realize that the absence of vitreoretinal adhesion and adhesion of the vitreous to the peripapillary region are normal variants. Eyes with persistent adhesion to the macula are the ones of interest. In eyes with an attachment of the hyaloid to the macula, the operator needs to determine the adhesion area; traction is diagnosed when there is a steep slope of the inner macular surface or a sharp angulation and localized deformation of the retinal profile, detected at the adhesion site of the hyaloid. Otherwise, vitreomacular traction was considered to be not present and the case was diagnosed as vitreous adhesion.

One can then perform further analysis of the relationship of the area of adhesion to a CNV membrane in eyes with exudative AMD. Careful scanning allows determination of the location and extent of the AMD lesion in relationship to the CNV membrane or residual of CNV, including scar. These instruments allow two-dimensional visualization of the pathology and also three-dimensional visualization (Figure 1).

Figure 1. Anatomic configuration of hyaloid adhesion and choroidal neovascularization complex: 3D reconstruction of hyaloid configuration in an eye with exudative AMD and vitreomacular traction: the surface of the retina and the continuous adhesion of the hyaloid are clearly seen. The surface of the retina is deformed at the site of hyaloid adhesion.

In eyes where there were clear vitreomacular traction and resistance to multiple injections of anti-VEGF drugs, we offered surgery to remove the adhesion. In all cases, during vitrectomy with a 20- or 25-gauge vitrector, we were able to demonstrate a vitreomacular adhesion when it was seen on SLO/SD-OCT. This was demonstrated with the soft-tip infusion cannula. In some eyes the retina was extremely edematous, (Figure 2). In such eyes, the inner retina can be thin and the cyst can be ruptured, possibly leading to a macular hole. It is important, therefore, in these eyes to exercise great caution in areas of cystic formation, such as are commonly seen in chronic cases that have not responded well to anti-VEGF therapy or which have had multiple recurrences after interruptions of therapy. In all cases, we continued with intravitreal anti-VEGF therapy at the conclusion of the case and every four weeks thereafter. In eyes receiving bevacizumab (Avastin, Genentech) therapy, we use double-dose bevacizumab (necessitating 0.1-mL volumes) injections every four weeks postoperatively.

Figure 2. Inner retinal changes in exudative age-related macular degeneration and vitreomacular traction. Severe cystoid macular edema has to be considered in the preoperative setting: the inner retinal surface is thin, and the removal of the hyaloid might lead to a macular hole.

We did find a number of eyes in which removal of vitreomacular traction did appear to flatten the retina, and this was associated with vision improvement. (Figure 3). Unfortunately, it also appears that such surgery is not associated with permanent drying of the retina; rather, it is still necessary to maintain regular monthly anti-VEGF treatment. One concern of our group is that the half-life of anti-VEGF drugs in vitrectomized eyes is shorter than in nonvitrectomized eyes and that anti-VEGF treatment in vitrectomized eyes may be suboptimal, even if higher doses are used. Of course, such concerns would be reduced if a long-acting delivery devices or drug formulation is developed.

Figure 3. Exudative age-related macular degeneration with vitreomacular traction, surgical outcome (patient #4). Vertical spectral-domain optical coherence tomography scans through the center of the macula are shown. Top: Baseline scan shows vitreous adherent to the apex of large cavities within edematous retina, and an underlying choroidal neovascularization complex; this fluid persisted despite eight previous monthly injections of intravitreal bevacizumab. Middle: Image shows center of macula one month after vitrectomy with removal of the attached hyaloid membrane. Fluid is reabsorbing (note: the scale is adjusted to facilitate direct comparison with the other scans). Bottom (same magnification as top) six months follow-up: complete reabsorption of intra- and subretinal fluid. Monthly bevacizumab treatment was continued after surgery. Vision improved by one line, from 20/400 to 20/320.

We are performing ongoing studies of vitreoretinal surgery in these eyes, and at the current time, we do not recommend this as a routine intervention, even in eyes with vitreomacular adhesion or prominent epiretinal membrane.

It is also interesting to analyze for the presence of vitreomacular adhesion in dry AMD. We did not expect to find an increase in such adhesion, but it is present.

RESULTS

Our initial study of vitreomacular attachment in AMD eyes involved 94 patients, but we have continued this study and have analyzed close to 200 patients. We continue to confirm our initial findings — namely, that vitreomacular adhesion is highly associated with macular disease in AMD. What was and remains of interest is that the increase in vitreomacular adhesion is present both in dry nonexudative AMD, as well as in exudative macular disease. It is also true that, compared to non-AMD eyes, there is approximately a sixfold increase in vitreomacular adhesion in wet AMD and a threefold increase in dry AMD.

There is a difference between vitreomacular adhesion and vitreomacular traction (Figure 4). Actual vitreomacular traction was also more common in exudative macular degeneration. In eyes with exudative disease, there is a relationship between the location of the CNV complex and the vitreomacular adhesion. This suggests that the exudative process increases adhesion in close proximity.

Figure 4. Classification scheme of hyaloid adhesion and vitreomacular traction seen with spectral optical coherence tomography. Top: Eye with non-exudative age-related macular degeneration and drusenoid detachment: the hyaloid is partially attached over the macula, including the fovea. We considered this as a “no traction” configuration, since no distortion is visible on the retinal surface and the angle of insertion of the hyaloid onto the retina is not steep. Bottom: Eye with choroidal neovascularization. The persistence of hyaloid adhesion causes vitreomacular traction over the choroidal neovascularization complex: a focal distortion of the retinal profile is visible at the site of hyaloid attachment.

What remains unclear is the causative relationship, if any, between the abnormally high incidence of vitreomacular adhesion and AMD. Other authors have suggested that vitreomacular adhesion might be considered a risk factor for the natural history of this disease.^11,21-23 It is our hypothesis that in AMD of the exudative or nonexudative variety, the processes causing outer retinal abnormalities also affect the Müller cells that span the full thickness of retina, and these cells become more firmly adherent to the posterior hyaloid. Our findings indicate that, in minimally classic exudative AMD, there is a higher incidence of focal vitreomacular adhesion; this may be the case because the disease is slower and perhaps more chronic in these eyes, thus permitting adhesion to form.

If an eye developed a PVD at a relatively young age prior to the development of the metabolic changes causing visible AMD, there might not be such an adhesion. If, however, the Müller's cells react to the AMD process and cause a stronger adhesion, then we see this using SD-OCT, and this higher incidence of adhesion is also seen if the exudative process develops. We do not believe that the adhesion or even the traction is the cause of AMD. Rather, traction may, in a small number of cases, exacerbate the edema and make treatment more difficult. Our study clearly shows that anterior-posterior forces, present at the surface of the retina, may exacerbate macular edema, which originally occurs secondary to the presence of leaking vessels in the CNV complex. Some authors have hypothesized that increases in the mechanical forces associated with abnormal vitreal attachments may result in the secretion of signaling factors by the Müller cells.²⁴

CONCLUSION

From the surgical perspective, we have shown some improvement in vision and anatomy by the use of vitrectomy. We have begun to consider tamponade as being important, and, in some cases, drainage of large pockets of fluid may be helpful. The type of tamponade, the need for drainage, and other surgical factors remain to be determined. Indeed, it is not clear that vitrectomy and removal of vitreomacular traction in the subset of eyes that are resistant to therapy and manifest clear traction is helpful in the long term. What is clear is that ongoing anti-VEGF therapy must also be given. RP

REFERENCES

1. la Cour M, Kiilgaard JF, Nissen MH. Age-related macular degeneration: epidemiology and optimal treatment. Drugs Aging. 2002;19:101-133.
2. Congdon N, O'Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122:477-485.
3. Klein R, Klein BE, Lee KE, Cruickshanks KJ, Gangnon RE. Changes in visual acuity in a population over a 15-year period: the Beaver Dam Eye Study. Am J Ophthalmol. 2006;142:539-549.
4. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389.
5. Dewan A, Liu M, Hartman S, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science. 2006;314:989-992.
6. Mori K, Horie-Inoue K, Kohda M, et al. Association of the HTRA1 gene variant with age-related macular degeneration in the Japanese population. J Hum Genet. 2007;52:636-641.
7. Nussenblatt RB, Ferris F 3rd. Age-related Macular Degeneration and the Immune Response: Implications for Therapy. Am J Ophthalmol. 2007;144:618-626.
8. Lambert HM, Capone A, Jr., Aaberg TM, Sternberg P, Jr., Mandell BA, Lopez PF. Surgical excision of subfoveal neovascular membranes in age-related macular degeneration. Am J Ophthalmol. 1992;113:257-262.
9. Weber-Krause B, Eckardt C. [Incidence of posterior vitreous detachment in the elderly]. Ophthalmologe. 1997;94:619-623.
10. Ondes F, Yilmaz G, Acar MA, Unlu N, Kocaoglan H, Arsan AK. Role of the vitreous in age-related macular degeneration. Jpn J Ophthalmol. 2000;44:91-93.
11. Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration? Am J Ophthalmol. 2007;144:741-746.
12. Wojtkowski M, Leitgeb R, Kowalczyk A, Bajraszewski T, Fercher AF In vivo human retinal imaging by Fourier domain optical coherence tomography J Biomed Opt 2002;7:457-463.
13. de Boer JF, Cense B, Park BH, Pierce MC, Tearney GJ, Bouma BE. Improved signal-to-noise ratio in spectral-domain compared with time-domain optical coherence tomography. Optics Letters. 2003;28:2067-2069.
14. Schmidt-Erfurth U, Leitgeb RA, Michels S, et al. Three-dimensional ultrahigh-resolution optical coherence tomography of macular diseases. Invest Ophthalmol Vis Sci. 2005;46:3393-3402.
15. Srinivasan VJ, Wojtkowski M, Witkin AJ, et al. High-definition and 3-dimensional imaging of macular pathologies with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology. 2006;113:2054e1 -14.
16. Mojana F, Kozak I, Oster SF, et al. Observations by spectral-domain optical coherence tomography combined with simultaneous scanning laser ophthalmoscopy: imaging of the vitreous. Am J Ophthalmol. 149:641-650.
17. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results. Am J Ophthalmol. 2008;146:218-227.
18. Kakehashi A, Kado M, Akiba J, Hirokawa H. Variations of posterior vitreous detachment. Br J Ophthalmol. 1997;81:527-532.
19. Uchino E, Uemura A, Ohba N. Initial stages of posterior vitreous detachment in healthy eyes of older persons evaluated by optical coherence tomography. Arch Ophthalmol. 2001;119:1475-1479.
20. Johnson MW. Perifoveal vitreous detachment and its macular complications. Trans Am Ophthalmol Soc. 2005;103:537-567.
21. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134:411-431.
22. Donoso LA, Kim D, Frost A, Callahan A, Hageman G. The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2006;51:137-152.
23. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122:598-614.
24. Schubert HD. Cystoid macular edema: the apparent role of mechanical factors. Prog Clin Biol Res. 1989;312:277-291.