Implications of new findings in the lamina cribrosa

Keywords::

• adaptive optics
• glaucoma
• lamina cribrosa
• laminopathy
• optical coherence tomography
• scanning laser ophthalmoscopy

Advances in ocular imaging have permitted increasingly improving visualization of the lamina cribrosa (LC). Newer imaging methods including enhanced depth imaging (EDI) optical coherence tomography (OCT) [1], swept-source (SS) OCT [2,3], and adaptive optics (AO) scanning laser ophthalmoscopy (SLO) [4], as well as algorithms to improve visualization of the LC in images obtained from these devices [5,6], have enabled more accurate evaluation of mid- and far-peripheral LC regions, which cannot be visualized in disc photography, conventional OCT or SLO. Studies using these newer imaging methods have revealed potential new parameters for the diagnosis and/or monitoring of glaucoma and enhanced our understanding of glaucoma pathophysiology.

Posterior LC displacement in glaucoma was suggested by clinical observation of deep, excavated optic disc cups in eyes with advanced glaucoma and was demonstrated in histologic studies of postmortem human glaucomatous eyes [7] or nonhuman primate eyes with experimental glaucoma [8]. An in vivo human study using EDI OCT also revealed that the LC was located more deeply within the optic nerve head in glaucomatous eyes than in normal ones [9]. Therefore, LC depth, which is usually defined as the distance between Bruch’s membrane opening and the anterior LC surface, may be useful as a diagnostic parameter to distinguish normal and glaucomatous eyes. To be a useful diagnostic parameter, confounding factors for the LC depth should be understood and controlled for.

Posterior LC displacement in glaucoma has reversible and irreversible components [10]. The reversible component of posterior LC displacement is associated with the intraocular pressure (IOP) level, as evidenced by the anterior LC displacement in response to IOP reduction after glaucoma filtering surgery [11]. Because IOP is not a confirmatory diagnostic criterion, but a risk factor for glaucoma, the IOP-induced reversible component of posterior LC displacement should be controlled for, when the LC depth is used as a diagnostic parameter. For example, if the IOP of a particular eye is significantly higher than the IOP level of the healthy subjects included in the normative database, the LC depth can be measured and compared with the normative database after the IOP has been lowered to the level of healthy subjects included in the normative database. Other potential confounding factors for the LC depth include age, optic disc tilting (or oblique optic nerve insertion into the globe), optic disc size (or LC size) and axial length.

Compression and/or fusion of laminar sheets, which leads to thinning of the LC, was observed in a histologic study of postmortem human glaucomatous eyes [7]. The mean LC thickness decreased as glaucoma advanced: 0.237 mm in normal eyes, 0.187 mm in mild glaucoma, 0.148 mm in moderate glaucoma and 0.083 mm in severe glaucoma [7]. A recent imaging study using EDI OCT confirmed this finding in patients with primary open-angle glaucoma and normal-tension glaucoma [12]. In a subsequent study, the diagnostic ability of LC thickness for glaucoma was demonstrated to be comparable to that of the circumpapillary retinal nerve fiber layer (RNFL) thickness [13]. However, LC thickness measurement using current imaging technology is less reproducible compared to circumpapillary RNFL thickness, because the posterior LC surface is not easily distinguished from retrolaminar tissue [14]. In addition, the slope of the change of LC thickness with worsening visual field mean deviation was steep in mild glaucoma but more gradual in moderate glaucoma and reached a plateau in severe glaucoma [12]. For this reason, LC thickness may have a limited role in evaluating disease progression in eyes with moderate or severe glaucoma.

Focal LC defects in glaucoma represent localized deformation or loss of laminar tissue [15]. Compared to the normal anterior LC surface that is usually smooth and curvilinear in cross-sectional OCT images of the optic nerve head, focal LC defects are detected as irregularities of the LC surface (partial thickness defects) or discontinuities of the LC tissue (full thickness defects) in localized LC regions [15]. This is a rediscovery of previous anecdotal histologic findings of localized LC ectasia in glaucoma due to focal collapse of laminar tissue [16,17]. Focal LC defects corresponded spatially to neuroretinal rim narrowing in glaucomatous eyes [15,18]. Additionally, focal LC defects were significantly associated with disc hemorrhage in glaucoma in two different studies using EDI OCT and SS OCT, respectively [19,20]. Therefore, focal LC defects may be a characteristic and pathognomonic finding of glaucomatous optic neuropathy and a promising structural parameter for glaucoma diagnosis.

LC pores have been used in glaucoma evaluation. Clinicians thought that more LC pores would be visible clinically at the bottom of the optic disc cup in eyes with more advanced glaucoma. Changes in LC pore size and shape were also noted in glaucomatous eyes in studies using color disc photography and SLO [21,22]. Application of AO technology to ocular imaging devices enabled more accurate and reproducible LC pore evaluation [4,23]. The LC pore area was significantly larger in glaucomatous eyes than in normal eyes and was significantly correlated with the axial length in normal eyes and with the untreated IOP in glaucomatous eyes [23]. In vivo longitudinal assessment of LC pore structure using AO SLO may be useful in evaluating IOP-related stress and strain within the LC beams and predicting glaucoma progression. Greater susceptibility of the superior and inferior optic nerve fibers in glaucoma has been attributed to larger LC pores in the superior and inferior LC regions based on the results of histologic studies. Longitudinal LC pore analysis in glaucoma suspects and subjects with ocular hypertension may reveal more detailed relationships between LC pore structure and susceptibility to glaucomatous damage.

Currently, structural tests for glaucoma focus on the retinal ganglion cell (RGC). Clinicians evaluate the structure and integrity of optic disc neural tissue (neuroretinal rim) and RNFL using ophthalmoscopy or photography. These structures can also be examined using ocular imaging devices such as SLO or OCT. Ganglion cell layer thickness in the macular area is also assessed quantitatively to help glaucoma diagnosis and monitoring. However, these structures (neuroretinal rim, RNFL and ganglion cell layer in the macular area) are either the cell bodies or the axons of RGCs. The LC is considered as the primary and principal site of damage to the RGC axons in glaucoma. Structural parameters regarding the LC – a key non-RGC structure – will provide clinicians another armamentarium for the glaucoma diagnosis and monitoring, and enable more personalized glaucoma management when combined with conventional analyses targeting RGC structures. Future studies are needed on automated detection and combined analysis of various LC parameters, including LC depth, LC thickness, focal LC defects and LC pore structure, as well as on establishing a normative database for these parameters.

Recent findings in the LC also enhance our understanding of glaucoma pathophysiology. Various mechanisms of LC deformation have been revealed or confirmed in human eyes in vivo [9,12,15,18,23]. The in vivo structure of the normal LC has a horizontal central ridge [24], which may be a sturdier portion of the LC and explain why the nasal and temporal LC regions are less susceptible to glaucoma than the superior and inferior regions. Although more conclusive evidence is needed, it is possible that LC changes may be the cause of initial RGC axonopathy in glaucoma. In medical dictionaries, laminopathies are defined as a group of rare genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina, which is a dense fibrillar network inside the nucleus of a eukaryotic cell. However, as ophthalmologists, we are using this term to describe ‘a disorder disrupting the normal structure or function of the LC in the optic nerve head’. Cellular and molecular mechanisms of laminopathy and RGC axonopathy should be elucidated more clearly to provide more conclusive evidence regarding the causal relationship between these two pathologies. Whether RGC axonopathy and laminopathy progress in a parallel fashion after the initial stage by affecting each other, also needs further investigation. If laminopathy is truly a cause of initial RGC axonopathy, novel treatment strategies directed to the LC are warranted to prevent initial RGC axonal loss.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.