Bhatti, M. T.

El-Dairi, M.

Freedman, S. F.

Jiramongkolchai, K.

Proia, A. D.

English

CU FIND (Campbell University, Catherine W. Wood School of Nursing)

Campbell University CU FIND Osteopathic Medicine, Jerry M. Wallace School of Faculty Research and Publications 3-2016 Formation of macular inner nuclear layer cysts in optic atrophy K. Jiramongkolchai M. T. Bhatti A. D. Proia S. F. Freedman M. El-Dairi Follow this and additional works at: https://cufind.campbell.edu/medicine_school  Part of the Ophthalmology Commons, and the Osteopathic Medicine and Osteopathy Commons Recommended Citation Jiramongkolchai, K.; Bhatti, M. T.; Proia, A. D.; Freedman, S. F.; and El-Dairi, M., "Formation of macular inner nuclear layer cysts in optic atrophy" (2016). Osteopathic Medicine, Jerry M. Wallace School of. 458. https://cufind.campbell.edu/medicine_school/458 This Article is brought to you for free and open access by the Faculty Research and Publications at CU FIND. It has been accepted for inclusion in Osteopathic Medicine, Jerry M. Wallace School of by an authorized administrator of CU FIND. For more information, please contact long@campbell.edu. LettersFormation of Macular Inner Nuclear LayerCysts in Optic AtrophyMultiple studies have reported the presence of inner nuclearlayer (INL) cysts in the macula in association with optic atrophycaused by a wide variety of optic neuropathies.1–6 These INLcysts are distinguishable from cysts characteristic of macularedema by their lack of leakage on fluorescein angiography.4,5Gelfand et al.7 first described INL changes of the retina usingoptical coherence tomography (OCT) in a subset of multiplesclerosis (MS) patients and used the term ‘‘microcysts.’’ Theyhypothesized that the microcysts were the product ofbreakdown of the blood–retinal barrier and inflammationresulting in formation of cystic changes in the retina.Subsequent reports noted similar cysts in other types ofinflammatory optic neuropathies.8,9 Balk et al.10 and Sotirchoset al.11 hypothesized that INL cysts were the product of animmune response against aquaporin-4 channel found on Mu¨llercells. Their theory was supported by animal models in whichdeletion of aquaporin-4 led to induction of retinal inflammationand decreased capacity of Mu¨ller cells to regulate osmoticstress.12 Since these initial reports of INL cysts in inflammatoryoptic neuropathies, INL cysts have been identified in nonin-flammatory optic neuropathies, including Kjer dominant opticatrophy, optic pathway glioma, glaucoma, and Leber hereditaryoptic neuropathy,1,2,4,5 suggesting that the etiology of the cystsis noninflammatory especially given the lack of leakage onintravenous fluorescein angiography.5,13Histopathologically, INL cysts have been observed in opticnerve degeneration thought to be due to transsynapticdegeneration. Van Buren,11 and Gills and Wadsworth12described ‘‘cystic degeneration,’’ resembling INL cysts seenon OCT, following lesions of the optic nerve or chiasm.3,13However, these cysts are not seen in all patients with opticatrophy, and they seem to be more prevalent in youngerpatients with intact vitreous base, suggesting that vitreoustraction may have a role in their formation. The most directevidence of traction having a role in the formation of cystscame from Sigler et al.,14 who observed INL cysts in a minorityof patients following removal of an epiretinal membraneleading to damage of the retinal nerve fiber and ganglion celllayers. Therefore, Barboni et al.2 offered a hypothesis based onvitreous traction rather than transsynaptic degeneration, sincetranssynaptic degeneration would be expected to occur in alleyes over a sufficient period of time, and yet these cysts are notseen in all eyes.10 They highlighted the importance of anattached posterior hyaloid membrane preventing the collapseof the INL and proposed that the spaces that previously wereoccupied by the now degenerated cells became fluid filledspaces.2 Their theory was supported by Wen et al.,4 who foundINL cysts exclusively in relatively young patients with severeglaucoma. In all of these reports, the cysts were confinedmostly to the papillomacular bundle area.We hereby propose a purely mechanical mechanism for theformation of INL microcysts that would explain why these cystsare seen more commonly in nonglaucomatous optic atrophy ofyounger patients with intact vitreous and are confined mostlyto the papillomacular bundle area. Observational case series ofOCT in children with glaucoma and nonglaucomatous opticatrophy support our hypothesis.6 The anatomical configurationof the INL predisposes it to cyst formation for several reasons(Fig. 1):The INL contains the cell bodies of the majority of neuronalcells of the retina (horizontal cells, amacrine, andbipolar cells). These cells form the short verticalFIGURE 1. (A) Schematic cross section through the normal macula of a young patient. (B) Schematic cross-section of the same maculademonstrating cystic formation in optic atrophy. As optic atrophy occurs, in the parafoveal area where the GCL normally is the thinnest, the effect ofthe progressive loss of ganglion cell and thinning of the retinal nerve fiber layer (RNFL) is marked. Although the RNFL and GCL thin, vitreoustraction on the Mu¨ller footplates prevents the retina from collapsing and, therefore, the INL, where Mu¨ller cell bodies are located, expands andcystic spaces form (medical illustrator: Rob Flewell, CMI).iovs.arvojournals.org j ISSN: 1552-5783 989This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Downloaded from iovs.arvojournals.org on 08/26/2019synapses with the photoreceptors that sandwich theINL.Lateral connections within the INL are facilitated by thehorizontal and amacrine cells.The INL contains the cell bodies of the Mu¨ller cells, whichare important vertical glia that span the entire retinafrom the internal limiting membrane (footplates of theMu¨ller cells are tightly attached to the vitreous)15,16 tothe external limiting membrane (junction betweenMu¨ller cells and photoreceptors).The ganglion cell layer (GCL) in the papillomacular bundle ismore than one cell layer in thickness, compared to theremaining retina in which it is only one cell layer thick.Therefore, in optic atrophy involving the papillomacularbundle, injury to the GCL results in a relatively large loss ofcellular volume. Combined with vitreous traction on thefootplates of the Mu¨ller cells, the mechanical vertical andhorizontal stresses within the INL result in the formation ofcystic spaces.We examined the retina of a postmortem eye from a 63-year-old woman with bilateral (left greater than right) optic nerveatrophy since the age of 12 years secondary to a pituitaryadenoma. Histopathological sectioning revealed that the INLcysts were more frequent and larger in the left compared to theright macula, in addition to the INL being thicker in the leftthan the right eye even though the number of cells was similar(Fig. 2). Despite the interval of 41 years between the time ofoptic nerve injury and death, there was no decrease in thenumber of cells in the INL to confirm transsynaptic degener-ation.Therefore, we believe that INL microcysts are not indicativeof retrograde transsynaptic degeneration but rather the productof localized ganglion cell loss and vitreous traction on theMu¨ller cell footplates combined with vertical and horizontalstress on the INL. In keeping this hypothesis, cysts in the INLoften were more described in optic neuropathies affectingcentral vision because the GCL in the papillomacular bundle isa multi-cell rather than single-cell layer in thickness.Kim Jiramongkolchai1M. Tariq Bhatti1,2Alan Proia3Sharon F. Freedman1Mays A. El-Dairi1Departments of 1Ophthalmology, 2Neurology, and 3Pathology,Duke University, Durham, North Carolina, United States.E-mail: mays.el-dairi@dm.duke.eduAcknowledgmentsSupported by the Heed Foundation and the Knights Templar Grant.The sponsor or funding organization had no role in the design orconduct of this editorial. The authors alone are responsible for thecontent and writing of this paper.Disclosures: K. Jiramongkolchai, None; M.T. Bhatti, Novartis(C); A. Proia, None; S.F. Freedman, Pfizer Pharmaceuticals (C);M.A. El-Dairi, Prana pharmaceuticals (C)References1. Abegg M, Zinkernagel M, Wolf S. Microcystic maculardegeneration from optic neuropathy. Brain. 2012;135:e225.2. Barboni P, Carelli V, Savini G, Carbonelli M, La Morgia C, SadunAA. Microcystic macular degeneration from optic neuropathy:not inflammatory, not trans-synaptic degeneration. Brain.2013;136:e239.3. Vanburen JM. Trans-synaptic retrograde degeneration in thevisual system of primates. J Neurol Neurosurg Psychiatry.1963;26:402–409.4. Wen JC, Freedman SF, El-Dairi MA, Asrani S. Microcysticmacular changes in primary open-angle glaucoma [publishedonline ahead of print September 26, 2014]. J Glaucoma.5. Wolff B, Azar G, Vasseur V, Sahel JA, Vignal C, Mauget-Faysse M.Microcystic changes in the retinal internal nuclear layerassociated with optic atrophy: a prospective study. J Oph-thalmol. 2014;2014:1–5.6. Jiramongkolchai K, Freedman SF, El-Dairi MA. Retinal Changesin Pediatric Glaucoma and Nonglaucomatous Optic Atrophy.Am J Ophthalmol. 2016;161:188–195.7. Gelfand JM, Nolan R, Schwartz DM, Graves J, Green AJ.Microcystic macular oedema in multiple sclerosis is associatedwith disease severity. Brain. 2012;135:1786–1793.8. Kupersmith MJ, Mandel G, Anderson S, Meltzer DE, Kardon R.Baseline, one and three month changes in the peripapillaryretinal nerve fiber layer in acute optic neuritis: relation tobaseline vision and MRI. J Neurol Sci. 2011;308:117–123.9. Kupersmith MJ, Sibony P, Mandel G, Durbin M, Kardon RH.Optical coherence tomography of the swollen optic nerve head:deformation of the peripapillary retinal pigment epithelium layerin papilledema. Invest Ophthalmol Vis Sci. 2011;52:6558–6564.10. Sotirchos ES, Saidha S, Byraiah G, et al. In vivo identification ofmorphologic retinal abnormalities in neuromyelitis optica.Neurology. 2013;80:1406–1414.11. Balk LJ, Killestein J, Polman CH, Uitdehaag BM, Petzold A.Microcystic macular oedema confirmed, but not specific formultiple sclerosis. Brain. 2012;135:e226.FIGURE 2. Histological sections of the maculas from the left (A) and right (B) eyes of a woman with left greater than right optic atrophy. Note theincreased number and size of the INL cysts (*), the increased thickness of the INL ([), and the greater reduction in cells in the GCL () in the leftcompared to the right eye. The number of nuclei in the INL appears similar in the two eyes. Hematoxylin and eosin. Scale bars: 50 lm.Letters IOVS j March 2016 j Vol. 57 j No. 3 j 990Downloaded from iovs.arvojournals.org on 08/26/201912. Pannicke T, Wurm A, Iandiev I, et al. Deletion of aquaporin-4renders retinal glial cells more susceptible to osmotic stress. JNeurosci Res. 2010;88:2877–2888.13. Gills JP Jr, Wadsworth JA. Degeneration of the inner nuclearlayer of the retina following lesions of the optic nerve. TransAm Ophthalmol Soc. 1966;64:66–88.14. Sigler EJ, Randolph JC, Charles S. Delayed onset inner nuclearlayer cystic changes following internal limiting membraneremoval for epimacular membrane. Graefes Arch Clin ExpOphthalmol. 2013;251:1679–1685.15. Purves D, Williams SM. The retina. In: Neuroscience, 2nd ed.Sunderland, MA: Sinauer Associates; 2001. Available at: http://www.ncbi.nlm.nih.gov/books/NBK10885/. Accessed Decem-ber 1, 2015.16. Levin LA, Kaufman PL. Adler’s Physiology of the Eye: ClinicalApplication, 11th ed. New York: Saunders/Elsevier; 2011:164–181.Citation: Invest Ophthalmol Vis Sci. 2016;57:989–991.doi:10.1167/iovs.15-18814Letters IOVS j March 2016 j Vol. 57 j No. 3 j 991Downloaded from iovs.arvojournals.org on 08/26/2019

Formation of macular inner nuclear layer cysts in optic atrophy

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Formation of macular inner nuclear layer cysts in optic atrophy

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