IOVS Papers in Press. Published on March 31, 2015 as Manuscript iovs.14-15869
Influence of Translaminar Pressure Dynamics on the Position of the Anterior Lamina Cribrosa Surface Running title: Translaminar pressure dynamics and LC position Dae Seung Lee,1 Eun Ji Lee,1 Tae-Woo Kim,1 Young Ho Park,2 Jungeun Kim,2 Joon Woo Lee,3 SangYun Kim2
1
Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul
National University College of Medicine 2
Department of Neurology, Seoul National University Bundang Hospital, Seoul
National University College of Medicine 3
Department of Radiology, Seoul National University Bundang Hospital, Seoul
National University College of Medicine Supported by a grant from the National Research Foundation of Korea funded by the Korean Government (no. 2013R1A1A1A05004781). The funding organizations had no role in the design or conduct of this research. The authors have no proprietary or commercial interest in any of the materials discussed in this article. Word count: 4,003 Corresponding author: Eun Ji Lee, M.D. Assistant Professor Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam, Gyeonggi-do 463-707, Korea Tel.: +82-31-7877378 Fax: +82-31-7874057 E-mail : [email protected] 1
Copyright 2015 by The Association for Research in Vision and Ophthalmology, Inc.
1
Abstract
2
Purpose: To determine how the translaminar pressure difference (TLPD) and
3
gradient (TLPG) influence the position of anterior lamina cribrosa (LC) surface.
4
Methods: Twenty-six eyes of 26 healthy subjects were subjected to enhanced-
5
depth-imaging volume scanning of the optic nerve using spectral-domain optical
6
coherence tomography (SD-OCT). The anterior LC surface depth (LCD) relative to
7
the Bruch’s membrane (BM) opening was measured at 11 equidistant planes, and
8
the LC thickness (LCT) was measured at three locations (superior midperipheral,
9
midhorizontal, and inferior midperipheral). Intraocular pressure (IOP) and lumbar
10
cerebrospinal fluid pressure (CSFP) were measured on the same day as the SD-
11
OCT examination. The TLPD was defined as the difference between IOP and CSFP
12
(i.e., IOP – CSFP), and the TLPG as the TLPD divided by LCT (i.e., TLPD/LCT).
13
Results: Subjects were aged 63.4±8.0 years and comprised 12 males and 14
14
females. Regression analyses revealed a significant association between a larger
15
mean LCD and male gender (P=0.002), and between a larger central LCD and male
16
gender (P≤0.012), larger TLPD (P=0.048) and higher TLPG (P=0.029). There was no
17
significant association between IOP, CSFP, and LCT, and either the mean LCD
18
(P=0.438, 0.368, and 0.416, respectively) or central LCD (P=0.284, 0.085, and 0.144,
19
respectively).
20
Conclusions: A larger central LCD was associated with larger TLPD and higher
21
TLPG in healthy eyes, which indicates that the translaminar pressure dynamics may
22
play a role in the position of the anterior LC surface relative to BM opening in healthy
23
human eyes. 2
24
The lamina cribrosa (LC) is a key structure in the pathogenesis of glaucoma. It has
25
been postulated that intraocular pressure (IOP)-related stress may cause
26
compression or posterior deformation of the LC, which may induce kinking or
27
pinching of the axons that pass through the laminar pores, leading to a blockade of
28
axoplasmic transport of the retinal ganglion cell axons.1–6 In addition, the
29
compressive effect on the laminar capillaries in the course of LC deformation may
30
confer ischemic insult to the axons.6,7 On the other hand, even in the absence of LC
31
deformation, IOP can still increase the strain within the LC and induce laminar
32
connective-tissue remodeling, which may compromise axon physiology.8–11 Moreover,
33
the increased LC strain may have a substantial influence on the axonal flow where
34
the LC is thin, because those axons may experience a steep transition between IOP
35
and retrolaminar tissue pressure, termed the translaminar pressure gradient
36
(TLPG).8,12–16
37
Because the LC forms a barrier between two differentially pressurized
38
compartments: the intraocular space with a higher pressure (IOP) and the
39
retrobulbar space with a lower pressure [retrobulbar cerebrospinal fluid (CSF)
40
pressure (CSFP), a pressure gradient is formed across the LC. The pressure
41
difference between the two compartments is termed the translaminar pressure
42
difference (TLPD), and is defined as IOP – CSFP. At a given IOP, subjects with a
43
lower CSFP have a larger TLPD, which can result in posterior deformation of the
44
LC.17,18 Conversely, in subjects with a higher CSFP, the TLPD is smaller, and thus
45
the LC is less likely to be deformed.
46
The ability of the LC to tolerate a given TLPD without being deformed may be 3
47
associated with the material properties (e.g., compliance, stiffness, or structural
48
rigidity) and geometry (e.g., thickness, shape, or curvature) of the LC and the
49
peripapillary connective tissues.6,19 For example, eyes with a stiffer LC may be more
50
resistant to deformation when the LC thickness is the same. Likewise, for a fixed LC
51
stiffness, it is possible that eyes with a thinner LC are more susceptible to LC
52
deformation. Regardless of its susceptibility to deformation, a thinner LC also
53
contributes to a steeper TLPG as a result of the reduced distance between the
54
intraocular space and the retrolaminar space, and may interrupt both orthograde and
55
retrograde axoplasmic transport.1–5
56
Studies have found a link between a larger TLPD or TLPG and glaucoma. It has
57
been shown that patients with primary open-angle glaucoma had a lower lumbar
58
CSFP than nonglaucomatous control subjects.20,21 Other studies have shown that
59
patients with normal-tension glaucoma have a lower lumbar CSFP and a larger
60
TLPD than those with high-tension glaucoma.22,23 Moreover, a larger TLPD was
61
correlated with glaucomatous neural-rim loss or visual-field defects.22,23 Based on
62
the notion that the translaminar pressure dynamics may influence LC deformation
63
and optic-nerve axoplasmic transport, it can be speculated that eyes with a larger
64
TLPD or TLPG may have an increased susceptibility for glaucomatous damage.
65
In this context, it would be of interest to know how translaminar pressure dynamics
66
(i.e., TLPD or TLPG) influence the LC position. Several experimental studies have
67
demonstrated that a larger TLPD is associated with posterior LC displacement.17,18
68
However, there have been no reports on how either TLPD or TLPG could influence
69
the LC in living human eyes. 4
70
The purpose of the present study was to determine the influence of TLPD or TLPG
71
on the anterior LC surface depth (LCD), as evaluated by enhanced-depth-imaging
72
(EDI) spectral-domain optical coherence tomography (SD-OCT).
73 74 75
Methods
76 77
This study was based on the data of healthy subjects included in the Study for
78
Usefulness and Standardization of Cerebrospinal Fluid and Plasma Amyloid
79
Biomarkers in Alzheimer’s Disease, which is an ongoing prospective study of
80
patients with Alzheimer’s disease and healthy participants at the Neurocognitive
81
Behavior Center in collaboration with Glaucoma Clinic of Seoul National University
82
Bundang Hospital. The present study was approved by the Seoul National University
83
Bundang Hospital Institutional Review Board. Informed written consent to participate
84
was obtained from all subjects, according to the Declaration of Helsinki.
85 86
Study subjects
87
Subjects were enrolled by the advertisement between May 2012 and April 2014. All
88
subjects submitted to a complete ophthalmic examination, including visual acuity
89
assessment, Goldmann applanation tonometry, refraction test, slit-lamp
90
biomicroscopy, gonioscopy, dilated stereoscopic examination of the optic disc,
91
fundus photography (VX-10 fundus camera, Kowa, Tokyo, Japan), measurement of
92
central corneal thickness (Orbscan II, Bausch & Lomb Surgical, Rochester, NY, USA), 5
93
corneal curvature (KR-1800, Topcon, Tokyo, Japan), and axial length (IOL Master,
94
Carl Zeiss Meditec, Dublin, CA, USA), and EDI SD-OCT (Spectralis OCT,
95
Heidelberg Engineering, Heidelberg, Germany) scanning of the optic disc and
96
circumpapillary retinal nerve fiber layer (RNFL). IOP was measured three times at
97
15-minute intervals, and the mean of the three values was considered as the
98
baseline IOP. Subjects underwent CSF sampling with CSFP measurement on the
99
same day as the ophthalmic examination (see Evaluation of CSFP).
100
The inclusion criteria for eyes in this study were a best-corrected visual acuity of
101
≥20/40, a spherical refraction of –8.0 to +5.0 diopters (D), cylinder correction of –
102
3.0 to +3.0 D, and a normal-appearing optic disc without glaucomatous optic
103
neuropathy, pallor, or swelling of the optic disc. The exclusion criteria were any
104
ocular diseases other than cataract, a history of intraocular surgery including laser
105
treatment other than cataract extraction, and subjects with a neurologic disease, a
106
history of intracranial surgery or lumbar puncture prior to enrollment to this study, a
107
condition that could affect the intracranial pressure [idiopathic intracranial
108
hypo/hypertension, intracranial tumors, or medications (e.g., tetracycline, rofecoxib,
109
mannitol, and carbonic anhydrase inhibitor)], or any contraindication for lumbar
110
puncture [i.e., infectious diseases or infection around a lumbar puncture site,
111
elongated prothrombin time (international normalized ratio >1.7), thrombocytopenia
112
Influence of Translaminar Pressure Dynamics on the Position of the Anterior Lamina Cribrosa Surface Running title: Translaminar pressure dynamics and LC position Dae Seung Lee,1 Eun Ji Lee,1 Tae-Woo Kim,1 Young Ho Park,2 Jungeun Kim,2 Joon Woo Lee,3 SangYun Kim2
1
Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul
National University College of Medicine 2
Department of Neurology, Seoul National University Bundang Hospital, Seoul
National University College of Medicine 3
Department of Radiology, Seoul National University Bundang Hospital, Seoul
National University College of Medicine Supported by a grant from the National Research Foundation of Korea funded by the Korean Government (no. 2013R1A1A1A05004781). The funding organizations had no role in the design or conduct of this research. The authors have no proprietary or commercial interest in any of the materials discussed in this article. Word count: 4,003 Corresponding author: Eun Ji Lee, M.D. Assistant Professor Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam, Gyeonggi-do 463-707, Korea Tel.: +82-31-7877378 Fax: +82-31-7874057 E-mail : [email protected] 1
Copyright 2015 by The Association for Research in Vision and Ophthalmology, Inc.
1
Abstract
2
Purpose: To determine how the translaminar pressure difference (TLPD) and
3
gradient (TLPG) influence the position of anterior lamina cribrosa (LC) surface.
4
Methods: Twenty-six eyes of 26 healthy subjects were subjected to enhanced-
5
depth-imaging volume scanning of the optic nerve using spectral-domain optical
6
coherence tomography (SD-OCT). The anterior LC surface depth (LCD) relative to
7
the Bruch’s membrane (BM) opening was measured at 11 equidistant planes, and
8
the LC thickness (LCT) was measured at three locations (superior midperipheral,
9
midhorizontal, and inferior midperipheral). Intraocular pressure (IOP) and lumbar
10
cerebrospinal fluid pressure (CSFP) were measured on the same day as the SD-
11
OCT examination. The TLPD was defined as the difference between IOP and CSFP
12
(i.e., IOP – CSFP), and the TLPG as the TLPD divided by LCT (i.e., TLPD/LCT).
13
Results: Subjects were aged 63.4±8.0 years and comprised 12 males and 14
14
females. Regression analyses revealed a significant association between a larger
15
mean LCD and male gender (P=0.002), and between a larger central LCD and male
16
gender (P≤0.012), larger TLPD (P=0.048) and higher TLPG (P=0.029). There was no
17
significant association between IOP, CSFP, and LCT, and either the mean LCD
18
(P=0.438, 0.368, and 0.416, respectively) or central LCD (P=0.284, 0.085, and 0.144,
19
respectively).
20
Conclusions: A larger central LCD was associated with larger TLPD and higher
21
TLPG in healthy eyes, which indicates that the translaminar pressure dynamics may
22
play a role in the position of the anterior LC surface relative to BM opening in healthy
23
human eyes. 2
24
The lamina cribrosa (LC) is a key structure in the pathogenesis of glaucoma. It has
25
been postulated that intraocular pressure (IOP)-related stress may cause
26
compression or posterior deformation of the LC, which may induce kinking or
27
pinching of the axons that pass through the laminar pores, leading to a blockade of
28
axoplasmic transport of the retinal ganglion cell axons.1–6 In addition, the
29
compressive effect on the laminar capillaries in the course of LC deformation may
30
confer ischemic insult to the axons.6,7 On the other hand, even in the absence of LC
31
deformation, IOP can still increase the strain within the LC and induce laminar
32
connective-tissue remodeling, which may compromise axon physiology.8–11 Moreover,
33
the increased LC strain may have a substantial influence on the axonal flow where
34
the LC is thin, because those axons may experience a steep transition between IOP
35
and retrolaminar tissue pressure, termed the translaminar pressure gradient
36
(TLPG).8,12–16
37
Because the LC forms a barrier between two differentially pressurized
38
compartments: the intraocular space with a higher pressure (IOP) and the
39
retrobulbar space with a lower pressure [retrobulbar cerebrospinal fluid (CSF)
40
pressure (CSFP), a pressure gradient is formed across the LC. The pressure
41
difference between the two compartments is termed the translaminar pressure
42
difference (TLPD), and is defined as IOP – CSFP. At a given IOP, subjects with a
43
lower CSFP have a larger TLPD, which can result in posterior deformation of the
44
LC.17,18 Conversely, in subjects with a higher CSFP, the TLPD is smaller, and thus
45
the LC is less likely to be deformed.
46
The ability of the LC to tolerate a given TLPD without being deformed may be 3
47
associated with the material properties (e.g., compliance, stiffness, or structural
48
rigidity) and geometry (e.g., thickness, shape, or curvature) of the LC and the
49
peripapillary connective tissues.6,19 For example, eyes with a stiffer LC may be more
50
resistant to deformation when the LC thickness is the same. Likewise, for a fixed LC
51
stiffness, it is possible that eyes with a thinner LC are more susceptible to LC
52
deformation. Regardless of its susceptibility to deformation, a thinner LC also
53
contributes to a steeper TLPG as a result of the reduced distance between the
54
intraocular space and the retrolaminar space, and may interrupt both orthograde and
55
retrograde axoplasmic transport.1–5
56
Studies have found a link between a larger TLPD or TLPG and glaucoma. It has
57
been shown that patients with primary open-angle glaucoma had a lower lumbar
58
CSFP than nonglaucomatous control subjects.20,21 Other studies have shown that
59
patients with normal-tension glaucoma have a lower lumbar CSFP and a larger
60
TLPD than those with high-tension glaucoma.22,23 Moreover, a larger TLPD was
61
correlated with glaucomatous neural-rim loss or visual-field defects.22,23 Based on
62
the notion that the translaminar pressure dynamics may influence LC deformation
63
and optic-nerve axoplasmic transport, it can be speculated that eyes with a larger
64
TLPD or TLPG may have an increased susceptibility for glaucomatous damage.
65
In this context, it would be of interest to know how translaminar pressure dynamics
66
(i.e., TLPD or TLPG) influence the LC position. Several experimental studies have
67
demonstrated that a larger TLPD is associated with posterior LC displacement.17,18
68
However, there have been no reports on how either TLPD or TLPG could influence
69
the LC in living human eyes. 4
70
The purpose of the present study was to determine the influence of TLPD or TLPG
71
on the anterior LC surface depth (LCD), as evaluated by enhanced-depth-imaging
72
(EDI) spectral-domain optical coherence tomography (SD-OCT).
73 74 75
Methods
76 77
This study was based on the data of healthy subjects included in the Study for
78
Usefulness and Standardization of Cerebrospinal Fluid and Plasma Amyloid
79
Biomarkers in Alzheimer’s Disease, which is an ongoing prospective study of
80
patients with Alzheimer’s disease and healthy participants at the Neurocognitive
81
Behavior Center in collaboration with Glaucoma Clinic of Seoul National University
82
Bundang Hospital. The present study was approved by the Seoul National University
83
Bundang Hospital Institutional Review Board. Informed written consent to participate
84
was obtained from all subjects, according to the Declaration of Helsinki.
85 86
Study subjects
87
Subjects were enrolled by the advertisement between May 2012 and April 2014. All
88
subjects submitted to a complete ophthalmic examination, including visual acuity
89
assessment, Goldmann applanation tonometry, refraction test, slit-lamp
90
biomicroscopy, gonioscopy, dilated stereoscopic examination of the optic disc,
91
fundus photography (VX-10 fundus camera, Kowa, Tokyo, Japan), measurement of
92
central corneal thickness (Orbscan II, Bausch & Lomb Surgical, Rochester, NY, USA), 5
93
corneal curvature (KR-1800, Topcon, Tokyo, Japan), and axial length (IOL Master,
94
Carl Zeiss Meditec, Dublin, CA, USA), and EDI SD-OCT (Spectralis OCT,
95
Heidelberg Engineering, Heidelberg, Germany) scanning of the optic disc and
96
circumpapillary retinal nerve fiber layer (RNFL). IOP was measured three times at
97
15-minute intervals, and the mean of the three values was considered as the
98
baseline IOP. Subjects underwent CSF sampling with CSFP measurement on the
99
same day as the ophthalmic examination (see Evaluation of CSFP).
100
The inclusion criteria for eyes in this study were a best-corrected visual acuity of
101
≥20/40, a spherical refraction of –8.0 to +5.0 diopters (D), cylinder correction of –
102
3.0 to +3.0 D, and a normal-appearing optic disc without glaucomatous optic
103
neuropathy, pallor, or swelling of the optic disc. The exclusion criteria were any
104
ocular diseases other than cataract, a history of intraocular surgery including laser
105
treatment other than cataract extraction, and subjects with a neurologic disease, a
106
history of intracranial surgery or lumbar puncture prior to enrollment to this study, a
107
condition that could affect the intracranial pressure [idiopathic intracranial
108
hypo/hypertension, intracranial tumors, or medications (e.g., tetracycline, rofecoxib,
109
mannitol, and carbonic anhydrase inhibitor)], or any contraindication for lumbar
110
puncture [i.e., infectious diseases or infection around a lumbar puncture site,
111
elongated prothrombin time (international normalized ratio >1.7), thrombocytopenia
112
