ORIGINAL STUDY

Microcystic Macular Changes in Primary Open-angle Glaucoma Joanne C. Wen, MD, Sharon F. Freedman, MD, Mays A. El-Dairi, MD, and Sanjay Asrani, MD

Purpose: To describe microcystic macular changes in patients with moderate to advanced primary open-angle glaucoma. Patients and Methods: Eleven eyes of 6 unrelated patients were retrospectively identified based on a disproportionately preserved macular thickness on optical coherence tomography (OCT) despite severe peripapillary retinal nerve fiber layer thinning. Patient demographic, history, and examination findings were reviewed. Results: All identified patients were African American, relatively young (mean age, 43.8 y) and 5 of the 6 patients were males. Examination of individual macular OCT sections through areas of disproportionately preserved macular thickness invariably demonstrated numerous small cystic cavities within the inner nuclear layer. These microcystic changes were seen in areas of the macula that corresponded with areas of glaucoma-related ganglion cell loss, therefore mimicking the normal appearance of retinal thickness in the macular region. No other retinal pathologies were identified on the macular OCT to account for these changes. Conclusions: This study describes microcystic macular changes in mostly young, African American males with moderate to advanced primary open-angle glaucoma. Vitreous adherence to the internal limiting membrane preventing retinal collapse is a proposed mechanism. The disproportionately preserved macular volume may confound the diagnosis of glaucoma in these patients. Key Words: microcysts, primary open-angle glaucoma, inner nuclear layer cysts or pseudocysts

(J Glaucoma 2016;25:258–262)

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laucomatous damage is characterized by a progressive loss of retinal ganglion cells and their axons.1 Optical coherence tomography (OCT) allows for an objective and quantitative assessment of this degeneration in the retina and optic nerve. A number of studies have demonstrated that changes detected by OCT of the peripapillary retinal nerve fiber layer (RNFL) and the macula correlate well with changes detected on functional tests such as standard automated perimetry.2–6 In patients with advanced glaucoma, severe peripapillary RNFL thinning is evident on OCT and is typically associated with diffuse thinning on macular retinal thickness maps (Fig. 1). We identified a group of unrelated patients in the setting of moderate to advanced glaucoma with severe peripapillary RNFL Received for publication December 15, 2013; accepted August 21, 2014. From the Department of Ophthalmology, Duke University Eye Center, Durham, NC. Disclosure: The authors declare no conflict of interest. Reprints: Sanjay Asrani, MD, Department of Ophthalmology, Duke University Eye Center, 2351 Erwin Road DUMC 3802, Durham, NC 27710 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000129

thinning, and a disproportionately preserved macular retinal thickness, which could confound the diagnosis of glaucoma using OCT.

METHODS This study was approved by the institutional review board of Duke University. We retrospectively identified 6 patients from our OCT database of adult glaucoma patients with severe peripapillary RNFL thinning (n = 160 total patients from 2010 to 2012) who had a normal macular thickness and normal macular topography in the absence of other ocular pathologies. Each patient had a comprehensive ocular examination, including best-corrected visual acuity, anterior segment examination, dilated biomicroscopic examination of the macula, and optic nerve. Patients also had spectral domain optical coherence tomography (SDOCT; Spectralis, Heidelberg Engineering, CA) imaging of the optic nerve and macula. Two patients underwent fluorescein angiography.

RESULTS The demographic and clinical findings of the 6 identified patients are shown in the Table 1. A total of 11 eyes were identified with microcystic changes within the inner nuclear layer (INL). All of the patients were African American and 5 of the 6 patients were male. The ages of the patients ranged from 33 to 51 years (mean, 43.8 y) at the time of diagnosis of the microcysts. All of the patients had minimal systemic illnesses and none were diabetic. All 6 of the patients were diagnosed with primary open-angle glaucoma (POAG) and had elevated intraocular pressures on presentation. The age at the time of glaucoma diagnosis ranged from 30 to 45 years (mean, 38 y). Four of the 6 patients had never undergone ocular surgery. Patient 3 had undergone trabeculectomy surgery in both the eyes and patient 6 had undergone trabeculectomy surgery in the right eye. The best-corrected visual acuity ranged from 20/20 to hand motion and optic nerve cupping ranged from a cup-to-disc ratio of 0.7 up to 1.0 at the time of diagnosis. None of the patients had any other macular pathology identified on dilated funduscopic examination. OCT scans revealed an attached hyaloid face in all eyes. In all cases, corresponding areas associated with significant peripapillary RNFL thinning were associated with a disproportionately preserved total (internal limiting membrane to retinal pigment epithelium) macular thickness on OCT (Fig. 1). Examination of individual macular OCT sections through these regions invariably demonstrated numerous small cystic cavities within the INL (Fig. 2). These INL cavities were located in areas underlying macular ganglion cell loss (Fig. 2) and therefore artificially maintained the total macular thickness. No other pathologies were identified on the macular OCT such as outer

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Microcystic Macular Changes in POAG

FIGURE 1. A, Severe thinning of the peripapillary retinal nerve fiber layer (RNFL) is typically associated with (B) decreased macular thickness. C, Severe thinning of the peripapillary RNFL with a (D) disproportionately preserved macular thickness in patient 1.

retinal changes or epiretinal membranes. Fluorescein angiography performed in 2 patients did not reveal any dye leakage in the macula (Fig. 3).

DISCUSSION We report microcystic macular changes in 11 eyes of 6 unrelated patients with glaucoma, who were identified by a discrepancy between the degree of peripapillary RNFL thinning and the amount of expected macular thinning. All patients had a normal macular thickness and topography despite peripapillary RNFL thinning and had no other ocular pathologies to account for these findings. A microcystic macular edema has been described in patients with multiple sclerosis and was associated with greater disease severity.7,8 Recent reports describe other cases of microcystic macular edema or microcystic macular changes associated with optic neuropathies of various etiologies including ischemic, compressive, hereditary, inflammatory, or traumatic.9–12 To our knowledge, this is the first series to specifically describe the INL microcystic macular changes in the context of glaucoma alone. All 6 of our patients were diagnosed with POAG based on a history of elevated intraocular pressures, optic nerve appearance, and visual field loss consistent with glaucoma. None of our patients had a history of multiple sclerosis or other causes of optic neuropathy. Careful examination of the fundus revealed no other abnormalities causing the microcystic changes. None of the patients had evidence of Copyright

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epiretinal membranes, vitreomacular traction, age-related macular degeneration, diabetic macular edema, posterior uveitis or macular telangiectasias, or recent intraocular surgery. Furthermore, none of the patients had evidence of distortion of the macula on OCT imaging, which would suggest vitreous traction. Other reports of macular microcystic changes have hypothesized an underlying inflammatory mechanism for the formation of these microcysts.7,8 However, fluorescein angiography in our patients did not reveal any dye leakage to support this mechanism. We hypothesize that the cystic cavities observed in our patients develop as a result of severe ganglion cell loss with trans-synaptic loss of structures within the INL in the presence of an intact hyaloid face and formed vitreous. Gills and Wadsworth13 studied cadaveric eyes from patients with ganglion cell loss due to optic nerve and chiasm lesions and found a decrease in INL cellularity on histopathologic examination, supporting a trans-synaptic degeneration mechanism. Furthermore, 2 of the eyes in their series were found to have INL cystic cavities much like what we have observed on OCT in our patients.13 We believe that the intact hyaloid face and vitreous provides generalized support of the macula, which prevents collapse and thinning after the loss of INL structures and results in these cystic cavities. A similar mechanism has been proposed for the development of intraretinal cystoid spaces in myopic eyes with posterior staphylomas.14 The rigidity of the internal limiting membrane is thought to prevent the retinal surface from conforming to the contour

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TABLE 1. Summary of Clinical Findings in Patients With Macular Microcystic Changes and POAG

Patient No./ Sex/Age (y) 1/M/33

2/M/51

3/M/49

4/F/44

5/M/49

6/M/37

Age at POAG Dx (y)

Eye

30

OD

HM

38

1.0

OS

HM

38

0.99

OD

20/70

50

0.95

OS

20/30

52

0.95

OD

20/60

24

0.9

OS

4/200

26

0.9

OD

20/50

36

0.85

OS

20/60

36

0.9

46, severe diffuse thinning

OD

20/20

27

0.7

OS

20/20

27

0.85

OD

20/25

32

0.9

OS

20/40

26

0.65

53, superotemporal, inferotemporal thinning 45, superotemporal, inferotemporal thinning 42, severe, diffuse thinning 95, superotemporal thinning

32

45

44

41

36

Pre-tx IOP (mm BCVA Hg)

Cup-toDisc Ratio

OCT PPA RNFL Global Average (lm) 39, severe diffuse thinning 49, severe diffuse thinning 40, severe diffuse thinning 41, severe, diffuse thinning 51, severe diffuse thinning 39, severe diffuse thinning 49, severe diffuse thinning

OCT Macula Findings Numerous inner nuclear layer microcysts throughout macula Numerous inner nuclear layer microcysts throughout macula Numerous inner nuclear layer microcysts throughout macula Numerous inner nuclear layer microcysts throughout macula Numerous inner nuclear layer microcysts throughout macula Numerous inner nuclear layer microcysts throughout macula Numerous inner nuclear layer microcysts concentrated around fovea Numerous inner nuclear layer microcysts concentrated around fovea Few inner nuclear layer microcysts mostly around fovea Few inner nuclear layer microcysts concentrated around fovea Many inner nuclear layer microcysts in nasal macula No microcysts

BCVA indicates best-corrected visual acuity; Dx, diagnosis; HM, hand motions; OCT, optical coherence tomography; OD, right eye; OS, left eye; POAG, primary open-angle glaucoma; PPA, peripapillary; Pre-tx IOP, pretreatment intraocular pressure; RNFL, retinal nerve fiber layer.

FIGURE 2. Representative images, patients 1 and 2. A and C, Areas of retinal nerve fiber layer (RNFL) loss (outlined) seen on the red-free image that correlate to the location of microcystic changes. B and D, Macular optical coherence tomography (OCT) scans reveal microcystic changes within the inner nuclear layer (arrows) and an attached hyaloid face (arrowheads).

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of the staphyloma.14 The opposing forces transmitted through the retina result in the observed schisis cavities.14 In fact, a review of our macular OCT scans revealed an attached hyaloid face in all eyes (Fig. 2).

Microcystic Macular Changes in POAG

In the absence of high myopia or inflammatory conditions such as uveitis, we expect the vitreous cavity and hyaloid face to be quite formed in younger patients. Indeed it seems that a younger age has commonly been reported in

FIGURE 3. Patient 3. A, Area of retinal nerve fiber layer (RNFL) loss (outlined) seen on the red-free image that correlates to the location of microcystic changes. B, Macular optical coherence tomography (OCT) scan reveals microcystic changes within the inner nuclear layer (arrow). C and D, No dye leakage is observed on fluorescein angiography.

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association with INL microcystic macular changes.9,10,13 In the series by Gills and Wadsworth,13 the cystic cavities were only observed in the eyes of the 2 youngest patients (ages 3 and 12). Wolff and colleagues reported a mean age of 38 years for their patients and Abegg and colleagues found that youth was a risk factor for developing microcystic changes. Likewise, all of our patients were diagnosed with cystic cavities at a relatively young age (mean age, 43.8 y) and none was highly myopic. The rapid and severe loss of ganglion cells, from any cause, in the presence of an intact vitreous cavity and hyaloid face, most commonly found in young individuals, may represent a potential common mechanism. It will be interesting to see whether there is collapse of the microcysts and corresponding thinning of the macular thickness in the eyes of our patients as they develop posterior vitreous detachments in the future. Although cases of macular schisis associated with enlarged optic nerve head cups and elevated intraocular pressure have been reported,15,16 we believe our case series represents a separate syndrome. In these reported cases, the proposed mechanism is that fluid from the vitreous penetrates the thin remaining rim of the optic cup through small dehiscences and tracks into the retina, a process facilitated by elevated intraocular pressure.15,16 Compared with these reported cases, our patients were younger (all patients 51 y and younger vs. 4 of 5 patients 62 y and older) and predominantly African American males, whereas many of the reported patients are whites of both sexes.15,16 Furthermore, in all reported cases, the schisis cavities were seen in many different layers of the retina, varied greatly in size, and most had subretinal fluid present.15,16 All of our cases had relatively small, uniformly sized cavities found only in the INL, and none had subretinal fluid. In summary, we describe microcystic macular changes in mostly young, African American males with moderate to advanced POAG. Further studies are needed to elucidate the mechanism leading to formation of these changes and their functional implications. Our patients were uniquely identified based on a discrepancy between degree of peripapillary RNFL thinning and expected macular volume loss. Clinicians need to be aware of this condition as the disproportionately preserved macular volume may confound the diagnosis of glaucoma in these patients. REFERENCES 1. Quigley HA, Dunkelberger GR, Green WR. Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma. Am J Ophthalmol. 1989;107:453–464.



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2. Bowd C, Zangwill LM, Berry CC, et al. Detecting early glaucoma by assessment of retinal nerve fiber layer thickness and visual function. Investig Ophthalmol Vis Sci. 2001;42: 1993–2003. 3. Hoh ST, Greenfield DS, Mistlberger A, et al. Optical coherence tomography and scanning laser polarimetry in normal, ocular hypertensive, and glaucomatous eyes. Am J Ophthalmol. 2000;129:129–135. 4. Greenfield DS, Bagga H, Knighton RW. Macular thickness changes in glaucomatous optic neuropathy detected using optical coherence tomography. Archiv Ophthalmol. 2003;121: 41–46. 5. Niles PI, Greenfield DS, Sehi M, et al. Detection of progressive macular thickness loss using optical coherence tomography in glaucoma suspect and glaucomatous eyes. Eye. 2012;26: 983–991. 6. Asrani S, Challa P, Herndon L, et al. Correlation among retinal thickness, optic disc, and visual field in glaucoma patients and suspects: a pilot study. J Glaucoma. 2003;12: 119–128. 7. Gelfand JM, Nolan R, Schwartz DM, et al. Microcystic macular oedema in multiple sclerosis is associated with disease severity. Brain. 2012;135(pt 6):1786–1793. 8. Saidha S, Sotirchos ES, Ibrahim MA, et al. Microcystic macular oedema, thickness of the inner nuclear layer of the retina, and disease characteristics in multiple sclerosis: a retrospective study. Lancet Nuerol. 2012;11: 963–972. 9. Abegg M, Dysli M, Wolf S, et al. Microcystic macular edema: retrograde maculopathy caused by optic neuropathy. Ophthalmology. 2014;121:142–149. 10. Wolff B, Basdekidou C, Vasseur V, et al. Retinal inner nuclear layer microcystic changes in optic nerve atrophy: a novel spectral-domain OCT finding. Retina. 2013;33:2133–2138. 11. Abegg M, Zinkernagel M, Wolf S. Microcystic macular degeneration from optic neuropathy. Brain. 2012;135(pt 12): e22:1–2. 12. Kaufhold F, Zimmermann H, Schneider E, et al. Optic neuritis is associated with inner nuclear layer thickening and microcystic macular edema independently of multiple sclerosis. PloS One. 2013;8:e71145. 13. Gills JP Jr, Wadsworth JA. Degeneration of the inner nuclear layer of the retina following lesions of the optic nerve. Trans Am Ophthalmol Soc. 1966;64:66–88. 14. Bando H, Ikuno Y, Choi JS, et al. Ultrastructure of internal limiting membrane in myopic foveoschisis. Am J Ophthalmol. 2005;139:197–199. 15. Zumbro DS, Jampol LM, Folk JC, et al. Macular schisis and detachment associated with presumed acquired enlarged optic nerve head cups. Am J Ophthalmol. 2007;144: 70–74. 16. Hollander DA, Barricks ME, Duncan JL, et al. Macular schisis detachment associated with angle-closure glaucoma. Archiv Ophthalmol. 2005;123:270–272.

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Microcystic Macular Changes in Primary Open-angle Glaucoma.

To describe microcystic macular changes in patients with moderate to advanced primary open-angle glaucoma...
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