1. Laminar and Prelaminar Tissue Displacement During Intraocular Pressure Elevation in Glaucoma Patients and Healthy Controls
R4 황규연/Pf.박찬기
Ophthalmology Volume 118, Number 1, January 2011

2. Introduction Lamina cribrosa of the optic nerve head
the primary site of axonal damage in glaucoma
is composed of fenestrated plates of connective tissue and elastic fibers lined by astrocytes.
The connective tissue plates contain pores that form channels through which bundles of retinal ganglion cell (RGC) axons pass.
provides structural and functional support to the RGC axons and divides the intraocular and intraorbital portions of the optic nerve.

4. Biomechanical paradigm of Glaucomatous pathophysiology
Mechanical damage
Compromised vascular supply
Increased translaminar pressure gradient

5. Introduction Intraocular pressure(IOP)
the primary known risk factor for the development and progression of open-angle glaucoma
IOP alone or in combination with other factors?
how the lamina responds to IOP, leading to axonal damage
Displacement of the lamina in response to IOP elevation
cause the pores to deform and pinch the traversing axons extension, compression, or shearing of axons within the lamina contributes to the loss of neural function in glaucoma.
Optic nerve head astrocytes : altering their physiologic relationship with axon bundles, connective tissues, and vasculature  axonal loss and tissue remodeling

6. Introduction
Experimental studies on acute IOP-related laminar deformation
ex vivo models
animal models where the lamina was studied after histomorphometry
theoretical models of the human eye
 None of these experiments were based on a direct visualization of the lamina in vivo.
using spectral-domain (SD) or Fourier-domain signal detection
allows highspeed image acquisition with high axial resolution
possible clinically to visualize the lamina directly
accurate concordance between SD OCT and serial histologic sections, including identification of the anterior laminar surface

7. Introduction acute IOP elevation 2) Prelaminar tissue displacement
1) Laminar displacement
In SD-OCT
patients with open-angle glaucoma
age-matched healthy control subjects
young control subjects
acute IOP elevation

8. Patients and Methods ; participants
Inclusion criteria for patients
a clinical diagnosis of open-angle glaucoma with documented progressive optic disc change and visual field damage compatible with glaucoma
visual field mean deviation better than -10 dB.
Exclusion criteria for patients
a threat to fixation
treated IOP of 25 mmHg or more
previous filtering eye surgery.
Inclusion criteria for controls
normal eye examination results with normal appearance of the optic disc and fundus
IOP of 20 mmHg or less.
The exclusion criterion for controls
ocular surgery, with the exception of cataract surgery more than 1 year before the study.

9. Patients and Methods ; SD-OCT
Confocal Scanning Laser Tomography (HRTII)
To measure the optic disc size for analysis
Spectral-Domain Optical Coherence Tomography(SD-OCT)
a noninvasive imaging technology using low-coherence interferometry to generate in vivo high- resolution cross-sectional images of ocular structures.
1 randomly chosen study eye
radial scanning pattern (12 high-resolution 15° radial scans, each averaged from 30 B-scans, with 768 A-scans per B-scan)
the scanning speed was A-scans per second
serial (baseline and during IOP elevation) image acquisition at precisely the same locations.
undilated pupils.

10. Patients and Methods ; Elevation of IOP
Experimental Elevation of Intraocular Pressure
An ophthalmodynamometer (Inami, Tokyo, Japan)
used to apply a fixed external force through the inferior lid with the device held perpendicular to the globe
A force of 30 to 40 Pa  an IOP increase of approximately 10 mmHg(a level at which SD OCT image quality was not compromised)
The ophthalmodynamometer was kept in place during the second set of SD OCT imaging.
The IOP was elevated until imaging was completed, usually within 2 minutes.
The IOP measure
a Tono-Pen (Innova Medical Ophthalmics, Toronto, ON, Canada)
at baseline and then again during IOP elevation

11. Patients and Methods ; Analysis
4 best corresponding scans /12 scans
The vertical distance from the reference line to the anterior prelaminar tissue surface and anterior laminar surface was measured at equidistant points along the reference line for the 2 sets of images.
the anterior laminar surface and termination of Bruch’s membrane–retinal pigment epithelium were visible clearly
Photo- shop CS3 and Image J
Prelaminar tissue thickness : the difference between the prelaminar tissue surface to the anterior laminar surface.
reference line : line joining the Bruch’s membrane– retinal pigment epithelium opening
The software: 2 sets of registered images (baseline and elevated IOP images) to be viewed in quick succession to verify that the Bruch’s membrane–retinal pigment epithelium border remained stable
The laminar displacement(LD) and prelaminar tissue displacement(PTD) : the mean difference between the corresponding vertical distances from the reference line in the baseline and elevated IOP conditions,
anterior laminar surface : the highly reflective region beneath the prelaminar tissue
positive values : posterior displacement
negative values : anterior displacement.

12. Reference line
Bruch’s membrane–RPE opening
anterior laminar surface
Prelaminar tissue thickness
(A and C) the anterior laminar surface (B and D) the prelaminar tissue surface
LD : C-A PTD : D-B
Fig 2

13. Patients and Methods ; Analysis
performed by 1 observer
The reproducibility of the measurement technique
Duplicate measurements of LD and PTD in 4 radial sections each of 3 randomly selected patients and 3 age- matched control subjects.
Absolute differences between the 2 sets of LD and PTD measurements were computed.
The order
randomized and masked for subject and set (baseline or elevated IOP)
An analysis of variance
for evaluating group differences and for the reproducibility study.
Post hoc paired group comparisons were made with the Fisher least significant difference test.
Multiple regression analysis was performed to establish which independent variables determined LD and PTD.
Post hoc power calculations were performed for single and 2-sample t tests.
Statistical significance was assumed when P<0.05.

14. Results
Total
12.4±3.2
Table 1
(N=12)
MD: -2.8dB
(N=12)
(N=12)

15. Results
Total
0.5(3.3)
15.7(15.5)
Table 2

16. Results
Fig 3

17. Results * LD(R2 value) : 0.38 (P=0.049),
PTD(R2 value) : 0.44 (P =0.017)

18. Results
The difference in LD and PTD measurement reproducibility was not statistically different
mean±SD paired absolute differences in radial sections
3.5±4.9 µm and 4.0±2.9 µm (P= 0.931)
Reproducibility
glaucoma patients
age-matched controls
Reproducibility of LD measurements (µm)
1.4±0.5
5.6±6.4
Reproducibility of PTD measurements (µm)
6.2±2.5
1.8±0.6

19. optic disc surface changes
Summary
modest acute
increases in IOP
negligible LD in both glaucoma patients and healthy subjects.
optic disc surface changes
displacement of prelaminar tissue result from a reduction in blood volume or axoplasmic material
the lamina is relatively rigid
limitation
investigate the acute effects of IOP elevation on the optic nerve head

20. Discussion
Laminar stress and eventual deformation can have deleterious effects on axonal function
mechanical damage
compromised vascular supply
increased translaminar pressure gradient
optic disc surface
Anterior displacement
resulting from acute reduction in IOP
Trabeculectomy, a large IOP reduction after medical treatment
posterior displacement
Caused by IOP elevation
with increase in cupping
in animal studies and enucleated human eyes.
related to the degree of IOP change
In studies using imaging techniques:
optic disc positional changes  changes in laminar position (because the prelaminar tissue was assumed to be largely noncompressible)

21. Discussion
with a mean acute IOP elevation of 12.4 mmHg, the lamina was resistant to displacement in glaucoma patients, age- matched controls, and young controls.
Not concur with other studies
With IOP elevation, maximum movement in the optic nerve occurred near its center, with minimum movement at its periphery in enucleated eyes. (Arch ophthalmol. 1984)
elevated IOP caused the LC to deflect posteriorly without affecting its thickness. The majority of the posterior displacement in the LC occurred near the periphery of the ONH.(Br J Ophthalmol 1994)
The large methodologic differences(degree and duration of IOP increase, the techniques used to measure LD)

22. Fig. 3.Computational analysis of human LC biomechanics can be performed on eye-specific models. The middle row shows sagittal cross-sections of the model at low (left) and high (right) IOP. Deformations are exaggerated fivefold for clarity. Note how elevation of IOP induces posterior rotation of the peripapillary sclera, flattening of the cup floor, thinning of the LC and pre-laminar neural tissues and anterior movement of the central regions of the optic nerve relative to the LC. The bottom row highlights the deformations of the LC and vitreoretinal interface by overlaying low-IOP (green) and high-IOP (red) outlines, showing the stretching of the LC in the plane of the sclera, and the deepening of the cup. Note that these simulations were carried out assuming incompressible tissues; therefore the thinning of the LC and the pre-laminar neural region do not represent a reduction in tissue volume, only a redistribution. From Sigal et al.

23. Biomechanics of optic nerve head
Connective tissue : load-bearing tissue
Peripapillary sclera
Lamina cribrosa
Scleral canal wall
Axonal tissue : RGC axons
Cellular tissue : astrocytes, glial cells, endothelial cells, pericytes and BM

24. sclera Scleral thickness Scleral stiffness Thin
Scleral canal expansion : tightens the LC and increase resistance to posterior deformation
Shorter distance between intraocular space and CSF space : steepening of translaminar pressure gradient
Elastic

25. Acute mechanical response
Lamina cribrosa : minimal posterior displacement, in some cases anterior displacement
Scleral canal expanded → Tensile stretch imposed on the lamina by acutely expanding scleral canal, lamina thinning
Modeling studies : laminar stress and strain are significantly elevated

26. Discussion average LD resulting from IOP elevation
close to 0 in both patients and healthy controls
the lamina can be displaced anteriorly after IOP elevation and that the relationship between scleral canal opening, material properties, and LD likely are complex.
a type I statistical error?
the average LD in this study was statistically indistinguishable from 0, the practical relevance of this finding is unclear
statistically negatively related to optic disc size
If) optic disc↑ thinner posterior sclera and lamina, the lamina may be held more tautly within the sclera  more resistant to posterior displacement

27. Discussion significant PTD with elevated IOP
in healthy control subjects
20 μm for an average IOP elevation of 13 mmHg
A statistical difference in PTD was not noted among younger and older healthy subjects
when corrected for prelaminar tissue thickness
the percentage of prelaminar tissue displacement was 2-fold higher in younger controls compared with older age-matched controls, which in turn was approximately 2-fold higher compared with glaucoma patients. 2배 2배

28. Discussion a posterior optic disc displacement
28 μm with IOP of 45 mmHg(Burgoyne et al) in normal monkey eyes
with the same IOP level of 18 μm (Coleman et al).
These values are similar to those found in normal subjects in the present study
The extent of PTD in glaucoma patients was significantly less compared with that in controls.
a result of increased stiffness in the prelamina resulting from tissue remodeling associated with glaucomatous damage

29. Invest. Ophthalmol. Vis. Sci. March 30, 2011 vol. 52 no. 3 1896-1907

30. Discussion
Experimental in vivo studies where eyes have been fixed at different IOPs and analyzed histomorphometrically
permit unparalleled quantitative analyses
be prone to effects of tissue shrinkage or swelling from fixation protocols.
Studies in enucleated eyes
have the disadvantage of postmortem changes in connective tissue and lack of vascular supply
until the advent of SD OCT, it has not been possible to visualize the anterior laminar surface directly in the presence of the overlying prelaminar tissue and to quantify its displacement in a clinical setting.

31. Ophthalmol Vis Sci. 2011;52:1206–1219
Result
At FU1, neuroretinal rim decreased and anterior lamina cribrosa surface depth increased significantly (paired t-test, P 0.01); no change in RNFL thickness was detected.
At FU2, however, significant prelaminar tissue thinning, posterior displacement of neural canal opening, and RNFL thinning were observed.
Longitudinal SDOCT imaging can detect deep ONH changes in EG eyes, the earliest of which are present at the onset of HRT- detected ONH surface height depression.
These parameters represent realistic targets for SDOCT detection of glaucomatous progression in human subjects.

32. Limitations
shadowing from large vessels obscuring visualization of the lamina measurements may not have come from the entire laminar surface in radial scans
Reproducibility measurements of LD and PTD were different in patients and controls, with a higher variability in LD estimates in controls compared with patients.
The lamina was easier to visualize in patients because of higher contrast with prelaminar tissue.
tissue remodeling in the lamina with glaucomatous structural changes resulting in higher optical density
the degree of IOP elevation relatively short period (2 minutes)
Higher IOP, a longer duration, or both, may have yielded different observations