The optic nerve head as a foramen in the ocular coats

Transcription

1 BASIC SCIENCE REVIEW Optic Nerve Head Histopathology in High Axial Myopia Jost B. Jonas, MD,*w Kyoko Ohno-Matsui, MD,z and Songhomitra Panda-Jonas, MDw Purpose: To describe particularities of the optic nerve head of axially highly myopic eyes. Methods: Measurements were obtained from enucleated globes and from population-based studies. Results: Morphologic optic disc particularities in high axial myopia included enlarged disc size (secondary macrodisc), widening and temporal translocation of the papillary Bruch s membrane (BM) opening, parapapillary gamma and delta zone, elongation and thinning of lamina cribrosa and peripapillary scleral flange, steeper translamina cribrosa pressure gradient, decreased peripapillary choroid thickness, longer distance between peripapillary arterial circle and optic disc, optic cup flattening, presumably a stretching of the lamina cribrosa pores, and peripapillary intrachoroidal cavitations. These changes may be explained by growth of new BM in the retroequatorial region in the process of emmetropization or myopization as overshooting of the emmetropization process. Conclusions: The intrapapillary and parapapillary changes in the highly myopic optic nerve head may be reason for the increased susceptibility for glaucomatous optic nerve damage in high axial myopia. The widening of the papillary BM opening and the potential shift of the optic nerve head s 3 layer into temporal direction, both potentially leading to the development of parapapillary gamma zone may be of interest for elucidating the process of emmetropization/myopization. The optic nerve head as a foramen in the ocular coats close to the posterior pole is needed for the exit of the optic nerve fibers and retinal vein, and for the entry of the central retinal artery. As part of the wall of the eye, it stabilizes the pressure difference between the intravitreal compartment with the intraocular pressure and the retrolamina compartment with the optic nerve tissue pressure and the retrobulbar cerebrospinal fluid pressure (Fig. 1). It additionally supports the ocular coats in keeping the shape of the globe constant. This pressure difference has also been called the translamina cribrosa pressure difference. 1 4 As the tissue around the optic nerve head is composed of different layers, the optic nerve head can also be regarded as a hole in 3 layers: a hole in Bruch s membrane (BM) (ie, the papillary BM opening or the primary BM defect), a hole in the choroid flanked by the peripapillary border tissue of Elschnig and Jacoby, and a hole in the peripapillary scleral flange which forms a bridge between the posterior sclera and the lamina cribrosa and which also forms the roof of the orbital cerebrospinal fluid space (Fig. 2). The morphology of the optic nerve head in high axial myopia is strongly influenced by the process of axial elongation in association with the development of axial myopia. 5 8 Key Words: myopia, high myopia, myopic retinopathy, Bruch s membrane, optic disc, secondary macrodisc, lamina cribrosa, peripapillary scleral flange, arterial circle Zinn-Haller, glaucoma (J Glaucoma 2017;26: ) Received for publication July 26, 2016; accepted September 20, From the *Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Eye Center, Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China; wdepartment of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany; and zdepartment of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan. Disclosure: J.B.J: consultant for Mundipharma Co. (Cambridge, UK); patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or antiangiogenic factor; patent number: ), and patent application with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europa ische Patentanmeldung ). S.P.-J.: patent holder with Biocompatible UK Ltd. (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; patent number: ), and patent application with university of Heidelberg (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europa ische Patentanmeldung ). K.O.-M. declares no conflict of interest. Reprints: Jost B. Jonas, MD, Universita ts-augenklinik, Theodor- Kutzer-Ufer 1-3, Mannheim 68167, Germany ( jost.jonas@ medma.uni-heidelberg.de). Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: /IJG FIGURE 1. Histophotograph showing a glaucomatous optic nerve head with the thinned lamina cribrosa (between green arrows), separating the intravitreal space (with the intraocuar pressure) (green asterisk) from the retro-lamina space with the orbital cerebrospinal fluid pressure (red asterisk). Figure 1 can be viewed in color online at J Glaucoma Volume 26, Number 2, February

2 Jonas et al J Glaucoma Volume 26, Number 2, February 2017 FIGURE 2. Histophotograph showing an optic nerve head with its 3 layers: the papillary Bruch s membrane opening or primary Bruch s membrane defect (line A ), a hole in the choroid flanked by the peripapillary border tissue (line B ), and a hole in the peripapillary scleral flange (line C ) which forms a bridge between the posterior sclera and the lamina cribrosa and which also forms the roof of the orbital cerebrospinal fluid space (red asterisk). Figure 2 can be viewed in color online at Recent histomorphometric investigations have suggested that the volume of the sclera and choroid increase from birth to the end of the second year of life, and remain constant after that date In a parallel manner, during the first 2 years of life, a larger volume of choroid and sclera is correlated with longer axial length, while later on, choroidal volume and scleral volume are statistically independent of axial length. 11 It suggested that during the first 2 years of life, the eye grows spherically by an increase in tissue volume of sclera and choroid to arrive at almost adult dimensions at the end of the second year of life, similar as the growth of the brain. Later in the process of emmetropization, a further elongation of the eye serves for fine-tuning of the length of the optical axis in dependence of the necessities given by the optical characteristics of the cornea, anterior chamber and lens This elongation of the globe after the end of the second year of life may occur by a rearrangement of available tissue, as scleral and choroidal volume are not correlated with axial length after the end of the second year of life. 4 6 With longer axial length, the scleral thinning takes place predominantly posterior to the equator, the more marked the closer to the posterior pole, while scleral thickness in the pars plana region does not differ significantly between highly myopic eyes and eyes with normal axial length. 7,8 Correspondingly, axial elongation associated choroidal thinning is the more marked the closer to the posterior pole. 14 These relationships are valid in eyes with primary axial myopia. It is in contrast to secondary high axial myopia caused by congenital glaucoma, in which a secondary so called buphthalmos develops. In that situation, a marked axial elongation is driven by the increased intraocular pressure during the first 2 years of life. In eyes with congenital glaucoma and secondary axial high myopia, all ocular coats are thinned in all regions of the eye, including a scleral thinning in the pars plana region and a stretching and thinning of the cornea. 15 It is in contrast to primary axial myopia in which the dimensions of the cornea and scleral thickness in the pars plana region do not differ from those of not axially elongated eyes. 12,16 One may infer that the process of axial elongation as fine-tuning of the length of the optical axis, in an attempt of moving the position of the foveola into the focus of the optical system of the anterior ocular segment, affects only the posterior segment, since in primary axial myopia, in contrast to secondary axial myopia in congenital glaucoma, the sclera in the pars plana region is unaffected by the axial elongation. It has remained unclear so far which factors the axial elongation in families with hereditary occurrence of high axial length depends on. Recent studies have revealed that more than 20 genes were associated with myopia. 17 These genes, however, explained <5% of the normal variation in refractive error in the study population so that the role of these genes in the development of axial myopia has remained elusive yet. Assuming that the process of emmetropization (and the process of myopization as an overshooting of the process of myopization) may be organized in a feedback mechanism with a sensory part and an effector part, one may wonder in which region of the globe the sensory part and the effector part may be located Previous studies on experimental myopia in animals have strongly suggested that the sensory part is located mainly in the retroequatorial region of the eye These studies have shown that a so called peripheral defocus leads to axial elongation as measured by sonography. This assumption is strengthened by clinical observations, that eyes with a congenital scar in the fovea; for example, due to a toxoplasmotic inflammation, usually do not develop high axial myopia although central vision is completely lost. In contrast, eyes which lose their retroequatorial retinal tissue due to a confluent retinal laser coagulation as treatment of retinopathy of prematurity, can develop high axial myopia. 23 In contrast, eyes with retinopathy of prematurity which were treated by intravitreal bevacizumab instead of laser coagulation tended to develop less axial myopia. 24 If the yet not fully described system in the retroequatorial region detects that the axial length does not fit with the optical properties of the cornea, anterior chamber and lens, the length of the optical axis is elongate or is elongation is stopped. This elongation of the globe is not an overall enlargement of the eye, as it is mostly the sagittal diameter which increases while the horizontal diameter and vertical diameter increase for a considerably lower amount ,25 In eyes with an axial length r24 mm, horizontal and vertical diameters increased by 0.44 and 0.51 mm, respectively, for each mm increase in axial diameter, while in eyes with an axial length >24 mm, the horizontal and vertical globe diameter increased by 0.19 and 0.21 mm, respectively, for each mm increase in axial diameter. 25 Clinical and anatomic studies have demonstrated that axial elongation is associated with a marked thinning of the choroid predominantly at the posterior pole. 14 If the sclera was the primary tissue governing the axial length of the eye, one would expect a widening of the choroidal space as defined as the distance between the sclera and the retina. Also, the key parameter for axial length is the length of the optical axis as the distance between the corneal apex and the photoreceptor outer segment in close proximity to the retinal pigment epithelium (RPE) and BM. It is not the posterior outer surface of the sclera as one of the measurement points for determination of the ocular sagittal diameter. As the choroid separates the sclera from the photoreceptors outer segments, and as the subfoveal choroidal thickness fluctuates between morning and evening and is additionally dependent on other parameters, it is unlikely that the sclera could govern the optical axis length with sufficient precision of Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

3 J Glaucoma Volume 26, Number 2, February 2017 Optic Nerve Head Histopathology approximately 50 to 100 mm. Although an evidence or reference for this argument cannot be given, these anatomic findings and considerations may make one assume that it is not the sclera, but BM, which determines the length of the optical axis and secondary the axial length of the eye. Recent studies have revealed that the thickness of BM, in contrast to the thickness of choroid and sclera, is not associated with axial length, that is highly axially elongated eyes and eye with normal axial length do not differ significantly in the thickness of BM. 26 Also, recent examinations of the biomechanical properties of BM have shown that BM can withhold a relatively high stress and strain load, presumably a higher load than the sclera can withhold (M. Girard, Singapore, personal oral communication). It leads to the hypothesis that it is BM which influences the axial length of the eye, which in the case of axial elongation pushes the choroid backward against the sclera, which thus induces a thinning of the choroid predominantly at the posterior pole, and which secondarily leads to a thinning of the sclera passively following the pressure exerted by the elongating BM. It agrees with other studies which support the notion of BM as having function in addition to a mere diffusion barrier between the choroidal space and the retinal and vitreal space. 27 As a hypothesis, one may assume that the region of BM growth and elongation should be located close to the region of the sensory input; that is, the retroequatorial region. As BM is produced by the RPE, one would expect, if following the hypothesis, an increased productivity of the RPE in the retroequatorial region in terms of basal membrane formation, as the inner layer of BM is the basal membrane of the RPE. One would also expect that the density of the RPE cells in the retroequatorial region decreases with increasing axial length while in other regions of the eye, the RPE density should be independent of axial length. Interestingly, such findings have recently been obtained in a histomorphometric study. 28 Following the hypothesis, one would assume the region of growth of BM is the retroequatorial region. As the density of the macular photoreceptors is directly related to the interphotoreceptor distance and thus influences the spatial resolution and maximal visual acuity, an enlargement of the BM in the macular region would be associated with a decreasing density of the macular photoreceptors and decreasing visual acuity. Studies have shown, however, that best-corrected visual acuity is independent of axial length. 29 Correspondingly, a recent study showed that the length of macular BM was independent of axial length, and that the increasing fovea-optic disc distance was mainly caused by the development and enlargement of parapapillary gamma zone, defined as a BM-free zone at the temporal optic disc border. 30 These findings with respect to the process of emmetropization/myopization and axial elongation have an influence on the ophthalmoscopical appearance of the optic nerve head in axially myopic eyes. Increasing axial length is associated with an enlargement of the optic nerve head, leading to secondary or acquired macrodiscs. 6,31,32 In addition, parapapillary atrophy increases with longer axial length The observation of an enlarged optic disc the border of which has been defined by the peripapillary ring or the extension of the pia mater of the optic nerve, may be due to the elongation and thinning of the sclera. 36 The enlargement of the papillary BM opening which forms the inner layer of the optic nerve head structure may be caused by the lengthening of BM in the retroequatorial region leading to tensions within BM most markedly at the posterior pole. This increase in the intra-bm tension may primarily lead to an enlargement of the papillary BM opening, and later if the intra-bm tension remains to the development of secondary defects in MBM in the macular region (so called secondary macular BM-defects) The enlargement of papillary BM opening causes the development of parapapillary gamma zone which has been defined as the region at the optic disc border without BM. 34,35 An additional mechanism for the development of parapapillary gamma zone may be a translocation of papillary BM opening into the temporal direction. 40 Assuming the region of BM growth in the retroequatorial region, the papillary BM opening would be pushed backward, while the optic nerve head scleral opening could partially stay behind. It would explain an overhanging of BM on the nasal side of the optic disc, and correspondingly a lack of BM on the temporal side of the optic nerve head. 41 The process of myopization and axial elongation associated mechanisms may also explain the histopathology of the optic nerve head in axially highly eyes. The optic disc morphology in axially highly myopic eye is characterized by a several features. These include a secondarily enlarged size of the optic disc (secondary macrodiscs) as defined by all the area within the peripapillary ring (Fig. 3). 6,31,32 It leads to a relative flattening of the optic cup so that the spatial contrast between the height of the neuroretinal rim and the depth of the optic cup is reduced (Fig. 4). Optic disc enlargement is also associated with an elongation and thinning of the lamina cribrosa (Fig. 5). 4 The thinning of the lamina cribrosa leads to a decreased distance between the intravitreal pressure compartment and the retrobulbar pressure compartment (Fig. 1). 4 The pressure in the latter is composed of the retrobulbar optic nerve tissue pressure and the orbital cerebrospinal fluid pressure The elongation of the lamina cribrosa with the retrobulbar optic nerve diameter remaining constant leads to an exposure of the posterior lamina cribrosa surface directly to the orbital cerebrospinal fluid compartment so that the peripheral lamina cribrosa in highly myopic eyes is no longer buffered by the solid tissue of the optic nerve (Fig. 5). The optic disc enlargement in highly myopic eyes is also associated with a widening of the papillary BM s opening, with BM opening forming the inner layer of the optic nerve head structure (Figs. 2, 6). As widening of BM s opening is more marked than the widening of the peripapillary ring diameter, widening of the papillary BM opening it is associated with the development and enlargement of parapapillary gamma zone, defined as BM-free zone (Fig. 6) As the presence of the choriocapillaris depends on the presence of BM, choroidal thickness in parapapillary gamma zone is reduced. 46 The axial elongation associated enlargement of the optic nerve head region also is associated with the development and enlargement of parapapillary delta zone within gamma zone (Fig. 7). Delta zone includes the elongated and thinned peripapillary scleral flange which connects the inner half of the sclera with the lamina cribrosa and which may be considered as the biomechanical anchor the lamina cribrosa. 34,47 As the peripapillary arterial circle of Zinn-Haller is located at approximately the merging line of the optic nerve dura mater with the sclera, that is with the peripheral end of parapapillary delta zone, axial elongation is associated with a longer distance between Zinn- Haller s arterial circle and the lamina cribrosa which is Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved

4 Jonas et al J Glaucoma Volume 26, Number 2, February 2017 FIGURE 3. Histophotograph showing a secondary (or acquired) macrodisc in a highly myopic eye, with an elongated and thinned peripapillary scleral flange (black arrows), forming the roof of the orbital cerebrospinal fluid space (red asterisk), which is located between the optic nerve dura mater (green arrows) and the optic nerve pia mater (red arrows), the end of which forms the peripapapillary ring (between green double asterisk). Figure 3 can be viewed in color online at supplied by Zinn-Haller s arterial circle (Fig. 7). 48,49 The longer axial length of the globe may lead to a stronger pull of the optic nerve dura mater on the peripapillary sclera during eye movements, in particular during adduction, which may increase the stress and strain in the lamina cribrosa and which may also be associated with the development of suprachoroidal peripapillary cavitations The enlargement of optic disc within its border of the peripapillary ring may be caused by an indirect stretching FIGURE 5. A secondarily enlarged macrodisc in a highly myopic eye with an elongated and thinned lamina croibrosa (yellow arrows), and with the peripheral posterior lamina crirbosa surface (black arrows) [covered by the optic nerve pia mater (green arrows)] directly facing the orbital cerebrospinal fluid pressure space (red asterisk). Figure 5 can be viewed in color online at of the sclera. Correspondingly, the peripapillary scleral flange which normally has a thickness and a length of about 0.5 mm, gets markedly elongated up to 5 mm, while its FIGURE 4. A secondarily enlarged macrodisc of a right highly myopic eye with a shallow physiolpogical optic cup (black asterisk); peripapillary ring (black arrows); peripapillary aretrial circle of Zinn-Haller (red arrows), approximately marking the merging line bretween the opticnerve dura mater and the posterior line, with the area central to the arterial ring forming parapapillary delta zone (elongated and thinned pereipapillary scleral flange); yellow arrows: parapapillary gamma zone. Figure 4 can be viewed in color online at FIGURE 6. Fundus photograph (a) and corresponding optical coherence tomographic image (b), showing parapapillary alpha zone (between A and B ) with irregular pigmentation (a) and irregular retinal pigment epithelium with Bruch s membrane present (b), parapapillary beta zone (between B and C ) with visible choroidal vessels and sclera (a) and absence of retinal pigment epithelium with Bruch s membrane present (b), parapapillary gamma zone (between C and D with Bruch s membrane absent (b). Figure 6 can be viewed in color online at Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

5 J Glaucoma Volume 26, Number 2, February 2017 Optic Nerve Head Histopathology FIGURE 7. Fundus photograph of a highly myopic eye with parapapillary gamma zone (green arrows) and parapapillary delta zone, demarcated by the peripapillary arterial circle of Zinn- Haller (black arrows). Figure 7 can be viewed in color online at thickness can get reduced to as thin as 50 to 100 mm. 33,34,47 The elongation of the peripapillary scleral flange is of importance for the position of the peripapillary arterial circle of Zinn-Haller, which is located approximately at the merging point of the posterior sclera with the dura mater of the optic nerve. 48,49 The longer the peripapillary scleral flange, the larger is the distance between the arterial circle and the optic nerve head. It may potentially have importance for the blood supply of the lamina cribrosa. 54,55 The enlargement of the optic nerve head explains the thinning of the lamina cribrosa which may get stretched and secondarily thinned. 4 The thinning of the lamina cribrosa leads to a decreased distance between the intraocular space and the retrobulbar space and thus to a steepening of the translamina cribrosa pressure gradient. 1,4,42 45 The translamina cribrosa pressure difference and gradient has recently been discussed to potentially play a role in the pathogenesis of glaucomatous optic neuropathy. 1 3,42 45,56 The stretching of the optic nerve head including its intrapapillary components may explain why the depth of the optic cup in highly myopic eyes is reduced. The thinning of the peripapillary choroid is part of the general thinning of the choroid at the posterior pole in axially elongated eyes. 14,46 These optic disc changes, in particular the thinning and elongation of the lamina cribrosa, the thinning and elongation of the peripapillary scleral flange, the increased distance from the peripapillary arterial circle to the lamina cribrosa, the thinning of the peripapillary choroid, and the steepening of the translamina cribrosa pressure gradient may be reasons for an increased susceptibility for glaucomatous optic neuropathy in highly axially myopic eyes. 55,57 The cutoff at which the axial elongation associated enlargement of the optic nerve head starts has not fully been determined yet. Population-based and hospital-based investigations have suggested, that the optic disc and parapapillary atrophy start to enlarge at about a value of 8.00 D of refractive error or an axial length of approximately 26.5 mm. 58,59 In a parallel manner, beyond these values, the prevalence of myopic retinopathy and glaucomatous optic neuropathy steeply increased. 57,60 When assessing the disc size in highly myopic eyes, one may have to take into account a perspective distortion of the image of the optic nerve, caused by a movement of the optic disc in direction to the nasal wall of the globe A new aspect potentially influencing the morphology and the ophthalmoscopical appearance of the optic nerve head, in particular in highly myopic eyes, is the biomechanics of the optic nerve dura mater. In a recent study, Wang et al 50 assessed that the optic nerve head strains due to the pull by the optic nerve dura mater on the peripapillary sclera during a lateral eye movement of 13 degrees were as high as, or higher than, those resulting from an intraocular pressure of 50 mm Hg. 51 It was also discussed that peripapillary suprachoroidal cavitations found in highly myopic eyes with a prevalence of about 17% most often at the inferior peripapillary region are caused by the pull of the optic nerve dura mater on the temporal and inferior peripapillary sclera. 52,53,64 66 Correspondingly, peripapillary suprachoroidal cavitations are associated with an optic disc rotation around the vertical disc axis and high axial myopia. 66 In conclusion, high axial myopia is associated with numerous morphologic changes in the intrapapillary region and parapapillary region of the optic nerve head. They may be explained by primary changes in the retroequatorial region and may lead to an increased susceptibility for glaucomatous optic nerve damage. REFERENCES 1. Berdahl JP, Allingham RR, Johnson DH. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology. 2008;115: Ren R, Jonas JB, Tian G, et al. Cerebrospinal fluid pressure in glaucoma. A prospective study. Ophthalmology. 2010;117: Jonas JB, Wang N, Yang D, et al. Facts and myths of cerebrospinal fluid pressure for the physiology of the eye. Prog Retin Eye Res. 2015;46: Jonas JB, Berenshtein E, Holbach L. Lamina cribrosa thickness and spatial relationships between intraocular space and cerebrospinal fluid space in highly myopic eyes. Invest Ophthalmol Vis Sci. 2004;45: Jonas JB, Berenshtein E, Holbach L. Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space. Invest Ophthalmol Vis Sci. 2003;44: Jonas JB, Dichtl A. Optic disc morphology in myopic primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol. 1997; 235: Jonas JB, Gusek GC, Naumann GO. Optic disk morphometry in high myopia. Graefes Arch Clin Exp Ophthalmol. 1988; 226: Dichtl A, Jonas JB, Naumann GO. Histomorphometry of the optic disc in highly myopic eyes with absolute secondary angle closure glaucoma. Br J Ophthalmol. 1998;82: Jonas JB, Holbach L, Panda-Jonas S. Scleral cross section area and volume and axial length. PLoS One. 2014;9:e Shen L, Xu X, You QS, et al. Scleral thickness in Chinese eyes. Invest Ophthalmol Vis Sci. 2015;56: Shen L, You QS, Xu X, et al. Scleral and choroidal volume in relation to axial length in infants with retinoblastoma versus adults with malignant melanomas or end-stage glaucoma. Graefes Arch Clin Exp Ophthalmol [Epub ahead of print]. 12. Vurgese S, Panda-Jonas S, Jonas JB. Sclera thickness in human globes and its relations to age, axial length and glaucoma. PLoS One. 2012;7:e Heine L. Beiträge zur Anatomie des myopischen Auges [Contributions to the anatomy of the myopic eye]. Arch Augenheilk. 1899;38: Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved

6 Jonas et al J Glaucoma Volume 26, Number 2, February Wei WB, Xu L, Jonas JB, et al. Subfoveal choroidal thickness: the Beijing Eye Study. Ophthalmology. 2013;120: Shen L, You QS, Xu X, et al. Scleral and choroidal thickness in secondary high axial myopia. Retina. 2016;36: Jonas JB, Nangia V, Sinha A, et al. Corneal refractive power and its associations with ocular and general parameters: the Central India Eye and Medical Study. Ophthalmology. 2011; 118: Verhoeven VJ, Hysi PG, Wojciechowski R, et al. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nat Genet. 2013;45: Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet. 2012;379: Smith EL III, Hung LF, Huang J, et al. Effects of optical defocus on refractive development in monkeys: evidence for local, regionally selective mechanisms. Invest Ophthalmol Vis Sci. 2010;51: Hasebe S, Jun J, Varnas SR. Myopia control with positively aspherized progressive addition lenses: a 2-year, multicenter, randomized, controlled trial. Invest Ophthalmol Vis Sci. 2014;55: Benavente-Pe rez A, Nour A, Troilo D. Axial eye growth and refractive error development can be modified by exposing the peripheral retina to relative myopic or hyperopic defocus. Invest Ophthalmol Vis Sci. 2014;55: Berntsen DA, Barr CD, Mutti DO, et al. Peripheral defocus and myopia progression in myopic children randomly assigned to wear single vision and progressive addition lenses. Invest Ophthalmol Vis Sci. 2013;54: Quinn GE, Dobson V, Davitt BV, et al. Progression of myopia and high myopia in the Early Treatment for Retinopathy of Prematurity study: findings at 4 to 6 years of age. J AAPOS. 2013;17: Harder BC, von Baltz S, Schlichtenbrede FC, et al. Intravitreal bevacizumab for retinopathy of prematurity: refractive error results. Am J Ophthalmol. 2013;155: e Jonas JB, Ohno-Matsui K, Holbach L, et al. Association between axial length and horizontal and vertical globe diameters. Graefes Arch Clin Exp Ophthalmol [Epub ahead of print]. Zur Publikation angenommen. 26. Jonas JB, Holbach L, Panda-Jonas S. Bruch s membrane thickness in high myopia. Acta Ophthalmol. 2014;92:e470 e Wang YX, Ran J, Yang LH, et al. Reversibility of retinal pigment epithelium detachment parallel to acute intraocular pressure rise. J Glaucoma. 2015;24:e16 e Jonas JB, Ohno-Matsui K, Holbach L, et al. Retinal pigment epithelium cell density in relationship to axial length in human eyes. Acta Ophthalmol [Epub ahead of print]. DOI: /aos Shao L, Xu L, Wei WB, et al. Visual acuity and subfoveal choroidal thickness. The Beijing Eye Study. Am J Ophthalmol. 2014;158: Jonas JB, Wang YX, Zhang Q, et al. Macular Bruch s membrane length and axial length. The Beijing Eye Study. PloS One. 2015;10:e Jonas JB, Gusek GC, Guggenmoos-Holzmann I, et al. Variability of the real dimensions of normal optic discs. Graefes Arch Clin Exp Ophthalmol. 1988;226: Xu L, Li Y, Wang S, et al. Characteristics of highly myopic eyes. The Beijing Eye Study. Ophthalmology. 2007;114: Jonas JB, Jonas SB, Jonas RA, et al. Histology of the parapapillary region in high myopia. Am J Ophthalmol. 2011; 152: Jonas JB, Jonas SB, Jonas RA, et al. Parapapillary atrophy: histological gamma zone and delta zone. PLoS One. 2012;7:e Dai Y, Jonas JB, Huang H, et al. Microstructure of parapapillary atrophy: beta zone and gamma zone. Invest Ophthalmol Vis Sci. 2013;54: Jonas JB, Holbach L, Panda-Jonas S. Peripapillary ring: histology and correlations. Acta Ophthalmol. 2014;92: e273 e Jonas JB, Ohno-Matsui K, Spaide RF, et al. Macular Bruch s membrane holes in high myopia: associated with gamma zone and delta zone of parapapillary region. Invest OphthalmoL Vis Sci. 2013;54: You QS, Peng XY, Xu L, et al. Macular Bruch s membrane defects in highly myopic eyes. The Beijing Eye Study. Retina. 2016;36: Ohno-Matsui K, Jonas JB, Spaide RF. Macular Bruch s membrane holes in choroidal neovascularization-related myopic macular atrophy by swept-source optical coherence tomography. Am J Ophthalmol. 2015;162: Panda-Jonas S, Xu L, Yang H, et al. Optic disc morphology in young patients after antiglaucomatous filtering surgery. Acta Ophthalmol. 2014;92: Reis AS, Sharpe GP, Yang H, et al. Optic disc margin anatomy in patients with glaucoma and normal controls with spectral domain optical coherence tomography. Ophthalmology. 2012; 119: Balaratnasingam C, Morgan WH, Johnstone V, et al. Histomorphometric measurements in human and dog optic nerve and an estimation of optic nerve pressure gradients in human. Exp Eye Res. 2009;89: Morgan WH, Yu DY, Cooper RL, et al. The influence of cerebrospinal fluid pressure on the lamina cribrosa tissue pressure gradient. Invest Ophthalmol Vis Sci. 1995;36: Morgan WH, Yu DY, Alder VA. The correlation between cerebrospinal fluid pressure and retrolaminar tissue pressure. Invest Ophthalmol Vis Sci. 1998;39: Morgan WH, Yu DY, Balaratnasingam CX. The role of cerebrospinal fluid pressure in glaucoma pathophysiology: the dark side of the optic disc. J Glaucoma. 1998;17: Jiang R, Wang YX, Wei WB, et al. Peripapillary choroidal thickness in adult Chinese: the Beijing Eye Study. Invest Ophthalmol Vis Sci. 2015;56: Jonas JB, Jonas RA, Jonas SB, et al. Lamina cribrosa thickness correlated with peripapillary sclera thickness. Acta Ophthalmol. 2012;90:e248 e Jonas JB, Jonas SB. Histomorphometry of the circular arterial ring of Zinn-Haller in normal and glaucomatous eyes. Acta Ophthalmol. 2010;88:e317 e Jonas JB, Holbach L, Panda-Jonas S. Peripapillary arterial circle of Zinn-Haller: location and spatial relationships. PLoS One. 2013;8:e Wang X, Rumpel H, Lim WE, et al. Finite element analysis predicts large optic nerve head strains during horizontal eye movements. Invest Ophthalmol Vis Sci. 2016;57: Demer JL. Optic nerve sheath as a novel mechanical load on the globe in ocular ductionoptic nerve sheath constrains duction. Invest Ophthalmol Vis Sci. 2016;57: Jonas JB, Dai Y, Panda-Jonas S. Peripapillary suprachoroidal cavitation, parapapillary gamma zone and optic disc rotation due to the biomechanics of the optic nerve dura mater. Invest Ophthalmol Vis Sci. 2016;57: Wang X, Rumpel H, Lim WE, et al. Author response: peripapillary suprachoroidal cavitation, parapapillary gamma zone and optic disc rotation due to the biomechanics of the optic nerve dura mater. Invest Ophthalmol Vis Sci. 2016;57: Hayreh SS. Blood supply of the optic nerve head and its role in optic atrophy, glaucoma, and oedema of the optic nerve. Br J Ophthalmol. 1969;53: Hayreh SS. Anatomy and physiology of the optic nerve head. Trans Am Acad Ophthalmol Otolaryngol. 1974;78: Burgoyne CF, Morrison JC. The anatomy and pathophysiology of the optic nerve head in glaucoma. J Glaucoma. 2001;10: S16 S Xu L, Wang Y, Wang S, et al. High myopia and glaucoma susceptibility. The Beijing Eye Study. Ophthalmology. 2007; 114: Jonas JB. Optic disc size correlated with refractive error. Am J Ophthalmol. 2005;139: Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

7 J Glaucoma Volume 26, Number 2, February 2017 Optic Nerve Head Histopathology 59. Xu L, Wang YX, Wang S, et al. Definition of high myopia by parapapillary atrophy. The Beijing Eye Study. Acta Ohthalmol. 2010;88:e350 e Liu HH, Xu L, Wang YX, et al. Prevalence and progression of myopic retinopathy in Chinese adults: the Beijing Eye Study. Ophthalmology. 2010;117: Nakazawa M, Kurotaki J, Ruike H. Longterm findings in peripapillary crescent formation in eyes with mild or moderate myopia. Acta Ophthalmol. 2008;86: Dai Y, Jonas JB, Ling Z, et al. Ophthalmoscopic-perspectively distorted optic disc diameters and real disc diameters. Invest Ophthalmol Vis Sci. 2015;56: Guo Y, Liu LJ, Xu L, et al. Optic disc ovality in primary school children in Beijing. Invest Ophthalmol Vis Sci. 2015;56: Spaide RF, Akiba M, Ohno-Matsui K. Evaluation of peripapillary intrachoroidal cavitation with swept source and enhanced depth imaging optical coherence tomography. Retina. 2012;32: Ohno-Matsui K, Shimada N, Akiba M, et al. Characteristics of intrachoroidal cavitation located temporal to optic disc in highly myopic eyes. Eye (Lond). 2013;27: Dai Y, Jonas JB, Ling Z, et al. Unilateral peripapillary intrachoroidal cavitation and optic disc rotation. Retina. 2015; 35: Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved