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Cerebrospinal Fluid Pressure and the Eye 38 39 Authors: William H Morgan1, Chandrakumar Balaratnasingam1, Christopher RP Lind2, Steve 40 Colley3, Min H Kang1, Philip H House1 and Dao-Yi Yu1 41 42 Corresponding author 43 William H Morgan 44 Email: billmorgan@lei.org.au 45 Phone: +61 8 9381 0873 46 47 1. Lions Eye Institute 48
University of Western Australia 49 2 Verdun St 50 Nedlands, WA 51 Australia 6009 52 53
2. School of Surgery 54 University of Western Australia 55 West Australian Neurosurgical Service 56
Sir Charles Gairdner Hospital 57 Hospital Avenue 58 Nedlands, WA 59 Australia 6009 60
61 3. Royal Perth Hospital 62
Wellington St, 63 Perth, WA 64 Australia, 6000 65
66 Keywords: Intraocular pressure, Physiology, Glaucoma, Optic Nerve 67 68 Word count: Abstract – 94, Text – 3,000 69 5 figures 70 70 references 71 72 73
Subtitle 74
Cerebrospinal Fluid Pressure and the Eye 75 76 77
78
79
Abstract 80
Cerebrospinal fluid pressure (CSFP) interacts with intraocular pressure (IOP) and blood pressure 81
(BP) to exert a major influence upon the eye, particularly the optic nerve head region. There is 82
increased interest regarding the influence of CSFP upon disorders affecting this region, in particular 83
glaucoma and idiopathic intracranial hypertension. Additionally, a high proportion of astronauts 84
develop features similar to idiopathic intracranial hypertension that persist for years after returning 85
to Earth. The factors that affect the cerebrospinal fluid pressure influence upon the optic nerve and 86
globe are likely to influence the outcome of various ophthalmic disorders. 87
88
INTRODUCTION 89
The optic nerve head separates the central nervous system and CSFP from the intraocular structures 90
and IOP. The lamina cribrosa and its constituent neural, vascular and connective tissue elements are 91
very sensitive to alterations in pressure across this region, with flow on effects into the rest of the 92
eye. Such changes influence the occurrence of glaucoma, idiopathic intracranial hypertension (IIH) 93
and venous occlusions. 94
95
ANATOMY 96
The optic nerve subarachnoid space (ONSAS) surrounds the optic nerve as it leaves the cranial 97
cavity up to the posterior globe where it is terminated anteriorly by the sclera.[1] Along its path 98
there are numerous trabeculae and septae whose shape varies with some thickening towards the 99
termination of the subarachnoid space (fig 1).[2] Internal to the ONSAS lies the pia mater then the 100
optic nerve proper. Externally lies the dura mater and intraconal orbital tissue. On closer 101
examination using tracer and specialised immunohistochemical stains, lymphatic structures 102
containing CSF material can be identified in the tissue surrounding the termination of the optic 103
nerve subarachnoid space.[3-5] These lymphatic structures appear more prominent in lower 104
mammals, such as rodents.[6 7] 105
106
PRESSURES AND DIFFERENCES 107
Intraocular pressure averages 15 mmHg with a normal range of 10 to 21 mmHg in most 108
populations[8] and is generated by the balance between production from the ciliary body and egress 109
through the trabecular meshwork and uvea. There is a small increase with age from 15.8mmHg at 110
age 50 to 16.1mmHg at age 80, although this effect is linked to the rise in systemic blood 111
pressure.[9] 112
113
Cerebrospinal fluid is formed in the choroidal plexus and flows through the ventricular system into 114
the subarachnoid space where some is thought to flow down the optic nerve subarachnoid space 115
traversing the trabeculae and septae present in the ONSAS.[10] The bulk of CSF is thought to drain 116
out through the arachnoidal granulations, however, up to 30% of CSF drains out via lymphatics in 117
the olfactory bulb and optic nerve subarachnoid space in lower mammals[11] with an unknown 118
proportion flowing out through these systems in primates and humans (fig 1). The CSFP, like IOP, 119
is pulsatile having a small phase difference with peak IOP lagging behind peak CSFP but their 120
trough pressures coincide.[12] Unlike IOP, The CSFP is markedly altered by postural changes, with 121
the normal range of CSFP in the lateral decubitus position being 5 to 15 mmHg but in the sitting 122
position being 0 to -10 mmHg at eye level. [13] Although IOP doesn’t change as much as CSFP 123
with postural change it does increase by 2 to 4mmHg when lying down from sitting.[14] Hence, one 124
should take into account the posture when interpreting results of CSFP measurements. CSFP tends 125
to reduce with age in adulthood, from mean 11.5mmHg in less than 50 year olds to 9.0mmHg in 70 126
year olds.[15] 127
128
Production and drainage of both CSF and aqueous are influenced by hydroxysteroid dehydrogenase 129
with increased CSFP effect in obesity.[16] Stimulation of certain regions of the rat brain increases 130
IOP, CSFP and blood pressure to varying degrees and varying latency.[17] It is likely that other 131
humeral and neural stimuli influence CSFP and IOP. 132
133
MEASUREMENT OF CSFP 134
Currently, invasive techniques involving lumbar puncture or cranial burr holes are required for 135
CSFP measurement. The development of non-invasive techniques for CSFP measurement would be 136
a major advance for diagnosis and monitoring of various disorders. Previous attempts using 137
transcranial Doppler, tympanic membrane reflectivity and optic nerve sheath diameter by 138
ultrasound or magnetic resonance imaging have given largely inaccurate measurements.[18 19] The 139
two most promising avenues being currently explored are refinement of ophthalmodynamometric 140
measures of venous pulsation pressure (fig 2) and balancing intracranial/orbital ophthalmic artery 141
flow velocities.[20-22] Some groups have begun using multivariate algorithms incorporating blood 142
pressure and body mass index as indirect indicators of CSFP, however one should remain aware of 143
the limitations and dependencies of this technique.[23 24] 144
145
146
147
OPTIC NERVE SUBARACHNOID SPACE PRESSURE 148
RELATIONSHIP TO INTRACRANIAL PRESSURE 149
It has been assumed that ONSAS pressure is equivalent to intracranial pressure and is likely to be 150
the case in healthy animals.[25] However, the work of Killer and co-authors clearly demonstrates 151
the presence of significantly large trabeculae, resembling fenestrated sheets along the ONSAS 152
pathway (fig 1)[26] and that in some conditions, such as normal tension glaucoma and others, there 153
is relative stasis of CSF flow along this pathway.[27] They may alter fluid flow along the ONSAS 154
although the flexibility of the septae may not impede pressure transmittance. However, significant 155
trabecular changes such as following meningitis or other diseases may effectively block CSF flow 156
and cause a disruption of pressure transmittance. In the normal situation we tend to assume that the 157
ONSAS pressure is equivalent to intracranial pressure, however, another factor must be considered 158
and this is the orbital tissue pressure found to be 2.6 to 4.4mmHg in the supine position using 159
needles inserted into the orbit.[28 29] Tissue pressure measurement using needle insertion tends to 160
give a slightly higher value than when less invasive micropipette techniques are used,[30] so true 161
orbital tissue pressure may be lower than these values. When a person is sitting or standing and the 162
intracranial pressure falls to zero or below at eye level, this is likely to be transmitted along the 163
ONSAS. If orbital tissue pressure is greater than the intracranial pressure then it will tend to 164
compress and, hence, collapse the ONSAS and force CSF fluid back into the intracranial 165
compartment. It may also compress regions of the ONSAS causing loculation with lack of pressure 166
transmission. This presumed influence of orbital tissue pressure is supported by experimental data 167
(Fig 2) in the dog where below CSFP 0mmHg the ONSAS pressure remains at 0mmHg. 168
169
170
THE OPTIC NERVE RETROLAMINAR TISSUE PRESSURE 171
The retrolaminar tissue pressure (RLTP) is the interstitial pressure within the optic nerve neural 172
tissue just posterior to the lamina cribrosa. It is not always equivalent to ONSAS pressure with a 173
variable pressure difference occurring across the pia mater indicating some pial elastic effect upon 174
the RLTP.[25] When there is a low external pressure the elasticity of the pia mater tends to elevate 175
RLTP and this has been demonstrated experimentally whereby at ONSAS pressures of zero in the 176
dog, the retrolaminar pressure is 3 mmHg and remains at this level until the ONSAS and 177
intracranial pressures rise to 3 mmHg or above (fig 2).[25] Above this pressure, the tension exerted 178
by the pia mater reduces and the RLTP tends to equilibrate directly with the ONSAS. When the 179
intracranial pressure is low there are likely to be two mechanisms that buffer the RLTP: the orbital 180
tissue pressure tending to compress the ONSAS and the elasticity of the pia mater. 181
182
PRESSURE DIFFERENCE AND PRESSURE GRADIENT ACROSS 183
THE LAMINA CRIBROSA 184
185
Tissue pressure measurements across the optic nerve into the retrolaminar region demonstrate a 186
pressure gradient across the lamina cribrosa (fig 3).[25 31] In the dog, having an intraocular 187
pressure of 15 mmHg and RLTP of 3mmHg at CSFP 0 mmHg with a lamina thickness of 531μm, 188
the average translaminar pressure gradient is 23 mmHg/mm tissue and this doubles to 47 189
mmHg/mm tissue as the intraocular pressure rises to 28 mmHg.[25] In the human, the posterior 190
(collagenous) lamina thickness measures mean 341μm compared to 539 μm for the combined glial 191
and collagenous lamina. The normal human TLPG is estimated at being between 20 and 33 192
mmHg/mm tissue, with the true value likely being closer to 33mmHg/mm given indirect evidence 193
that the gradient exists occurs across the collagenous lamina.[32 33] 194
195
Forces which act upon tissues are caused directly by pressure gradients and so the magnitude of 196
force and its effect upon a tissue can be minimised by reducing the gradient.[34] Practically 197
speaking this means that a thicker lamina cribrosa can spread out the gradient over a greater 198
distance and hence reduce the sheer and stress acting across this tissue. The corollary is that a 199
thinner lamina cribrosa amplifies the pressure gradient. Patients with established glaucoma have 200
lamina thinning and tend to progress at a greater rate for given IOP.[35] 201
202
203
204
PHYSIOLOGICAL FUNCTIONS ALTERED BY PRESSURE 205
GRADIENTS 206
In primate models of raised IOP and CSFP, orthograde and retrograde axonal transport are inhibited 207
at the level of the lamina cribrosa with accumulation of intracellular material including 208
mitochondria and other vesicles. Axonal transport accumulation occurs mainly at the posterior 209
lamina region in animal glaucoma models.[36] Orthograde axonal transport is inhibited in rabbit 210
vagus nerve when the pressure difference exceeds 30mmHg and the gradient exceeds 45 211
mmHg/mm.[37] It has not been shown experimentally whether the pressure difference or gradient 212
has greatest effect upon axonal transport. 213
214
When the intraocular pressure is raised leading to an elevated translaminar pressure gradient, 215
significant neurofilament changes occur within several hours followed by changes in the 216
microtubules which are structures vital for axonal transport conductance.[38 39] These cytoskeletal 217
changes are likely to be fundamental to the cause of the axonal transport changes. Cytochrome 218
oxidase activity also increases in the collagenous lamina region with increased TLPG indicating 219
increased metabolic requirements in this region.[40] 220
221
The central retinal vein traverses the lamina cribrosa and is subject to the translaminar pressure 222
gradient particularly because the venous transmural pressure is close to zero,[41 42] meaning that 223
the surrounding tissue pressure generally affects the pressure within the vessel lumen. It is likely 224
that the pressure gradient falls along the central retinal vein as it traverses the lamina cribrosa. 225
Assuming such, a gradient of 33 mmHg/mm is much higher that the typical 0.7mmHg/mm found in 226
venules.[43] Venous endothelial cells within the posterior (collagenous) laminar region are closer 227
morphologically speaking to arterial endothelial cells than to other venous endothelial cells (Fig 4), 228
demonstrating that they are subject to higher sheer stresses as a result of the pressure gradient.[33 229
44] It is possible that these sheer stresses and morphological changes are exacerbated when the 230
pressure gradient is increased in glaucoma. 231
232
INTERACTIONS WITHIN THIS REGION 233
Both IOP and CSFP are pulsatile, being influenced by the cardiac cycle with CSFP having an 234
additional influence from the respiratory cycle (Fig 3). Both IOP and CSFP pulsatility affect optic 235
nerve tissue pressure pulsatility (Fig 3).[31] One important clinical observation is the phenomenon 236
of spontaneous venous pulsation close to the central retinal vein exit into the optic nerve, found in 237
95% of normal subjects. We have found that venous pulsation phase is in time with the IOP and 238
CSFP phase.[12] Classical theories had taught that pulsation would be counter phase to intraocular 239
pressure and that the systolic peak of intraocular pressure that would lead to venous 240
compression,[45 46] however recent work suggests that CSFP pulse drives venous pulse timing and 241
so has a more dominant effect upon key venous haemodynamic properties.[12] The reasons for 242
spontaneous venous pulsation are complicated and probably relate largely to the eye resembling a 243
Starling resistor.[47] Monkey and dog experiments demonstrate that an average 8 mmHg pressure 244
difference between IOP and CSFP is required for the induction of venous pulsation.[48-50] 245
246
247
ABNORMAL ANATOMY 248
Enlargement of the ONSAS 249
The ONSAS width is increased in many patients with raised CSFP. This is a significant relationship 250
and has been used to estimate intracranial pressure non-invasively with several algorithms being 251
published.[51 52] However, enlargement of the ONSAS may be due to other factors such as 252
loculation of CSF within the ONSAS. These may be part of the explanation for the observation that 253
ONSAS width is increased in some patients with normal tension glaucoma. 254
255
Myopia 256
High myopes tend to have a thin lamina cribrosa (207µm) compared to a normal 458µm. Lamina 257
thickness decreases in moderately advanced glaucoma patients (201µm) and myopic glaucoma 258
patients (78µm).[53] Such reductions in laminar thickness will double or quadruple the gradient 259
effect of the pressure difference. This is likely to influence progression rates of glaucoma and may 260
explain why patients with severe glaucoma and myopia tend to progress even at lower intraocular 261
pressure levels.[35 54 55] Myopes also have an increased width of the ONSAS termination and a 262
thin posterior sclera. Recent OCT scanning using swept source demonstrate that the posterior 263
staphylomata frequently seen in high myopes tend to overly the region of the enlarged ONSAS 264
termination (fig 5).[56] The presumed reason for the staphyloma is the pressure difference across 265
the thinned sclera between the intraocular pressure compartment and the ONSAS compartment 266
leading to posterior distortion of the sclera just as posterior distortion of the lamina cribrosa occurs 267
in glaucoma. The smaller degrees of optic disc excavation seen in high myopes with glaucoma may 268
in part be due to the fact that the gradient is occurring across and causing distortion of both the 269
sclera and lamina cribrosa. 270
271
Possible septal changes in ONSAS 272
In patients with idiopathic intracranial hypertension and normal tension glaucoma it has been 273
observed that there is a lower flow of CSF from the intracranial compartment along the ONSAS and 274
this may be due to thickened trabeculae leading to increased flow resistance along the ONSAS.[27 275
57] This reduced flow may have metabolic consequences by leading to stagnation and reduced 276
removal of toxic metabolites as well as reduced delivery of necessary metabolites to regions, 277
particularly near the termination of the ONSAS. It also may impact upon functioning of the 278
lymphatics and neural tissue within this region. 279
280
281
Raised translaminar pressure gradient 282
The TLPG is most simply described by the difference between IOP and RLTP divided by the 283
distance between the two pressure compartments. Physiologically speaking this means the 284
difference between intraocular pressure and ONSAS pressure, allowing for the buffering effects of 285
orbital pressure and the pia mater and divided by the lamina cribrosa thickness. One must also take 286
into account changes in posture if one is using CSFP measurements from the lumbar spine. The 287
caveats concerning general assumptions that the pressures are equivalent between the intracranial 288
compartment, lumbar spine and ONSAS must be considered and weighed carefully at each set of 289
observations. So, an increased TLPG can theoretically be caused by increased intraocular pressure 290
and reduced CSFP and also by reduced buffering, i.e. a lower orbital tissue pressure and reduced 291
elasticity of the pia mater leading to greater transmittance of low pressures from the orbit and 292
ONSAS directly to the retrolaminar optic nerve. The classic example of raised TLPG is that of 293
standard glaucoma when intraocular pressure is elevated.[8] However, much recent work has shown 294
that compared to normal subjects, CSFP is reduced in primary open angle glaucoma especially in 295
normal tension glaucoma.[58 59] Additionally, recent work using a chronic low CSFP monkey 296
model demonstrates glaucoma like changes to the nerve fibre layer with disk rim haemorrhage.[60] 297
298
As one ages the intraocular pressure tends to rise gradually and CSFP tends to drop slightly. Orbital 299
tissues tend to atrophy with age leading to a sunken orbital appearance in many subjects and pia 300
mater changes may occur leading to reduced pressure buffering properties around the optic nerve, 301
all of which would tend to lower the RLTP and exacerbate the TLPG. It is of some concern that 302
prostaglandin analogues appear to hasten orbital fat atrophy.[61] It should be clearly stated and 303
understood that the pressures within the orbit and the changes of orbital pressure and pia mater are 304
poorly understood at present. 305
306
Reduced or reversed translaminar pressure gradient 307
Idiopathic intracranial hypertension and other disorders that lead to a rise in CSFP are well known 308
causes of papilloedema comprising anterior optic nerve swelling with an anterior shift of the lamina 309
cribrosa along with retinal vein engorgement and tortuosity. Most of these features can be 310
understood by considering the effect of raised CSFP and subsequent raised retrolaminar tissue 311
pressure leading to a reversed pressure gradient with inhibition of orthograde axonal transport and 312
stasis predominantly within prelaminar and anterior (glial) laminar regions but also in the posterior 313
(scleral) laminar and retrolaminar regions.[62 63] The neural swelling is associated with 314
compression of the central retinal and other veins, which is compounded by the direct effect of the 315
raised CSFP causing elevated intraocular venous pressure.[64] This is thought to account for the 316
venous engorgement, and probably results in some reduced anterior optic nerve perfusion leading to 317
further damage to the ganglion cell axons. Idiopathic intracranial hypertension can be an aggressive 318
disease[65] but tends to respond well to treatments leading to a reduction in overall intracranial 319
pressure or local ONSAS pressure through either optic nerve sheath fenestration or ventricular 320
peritoneal shunting procedures.[66] The relative place of these therapies is still somewhat 321
controversial although optic nerve sheath fenestration may be effective in patients with less 322
trabecular obstruction to the ONSAS fluid flow pathway but may not reduce intracranial pressure 323
and headache.[66] This may account for the observation that a single optic nerve sheath fenestration 324
helps preserve vision in both eyes of just some subjects. 325
326
Multivariate models for estimating CSFP suggest that CSFP elevation may be a risk factor for 327
diabetic retinopathy development.[23] 328
329
Prolonged space flight 330
Prolonged space flight by astronauts in space for more than six months frequently (20%) leads to a 331
clinical syndrome bearing marked similarities to idiopathic intracranial hypertension with 332
papilloedema, also some cotton wool spots as well as choroidal folds and a hyperopic refractive 333
shift.[67] MRI scans show elevated optic disks with an anteriorly shifted macula and dilated 334
ONSAS.[68] These subjects have increased intracranial pressure, which persists for months and 335
years after their return to earth. The explanation for this phenomenon is likely to involve the fact 336
that in microgravity there is a cephalad fluid shift with increased venous pressures and impaired 337
lymphatic flow around the head.[69 70] Both factors may conspire to impede CSF outflow and lead 338
to an increased average CSFP, which is not reduced or ameliorated by postural changes, i.e. by 339
standing . It is difficult to explain why the elevated CSFP persists for so long upon returning to 340
earth but the most likely explanation involves a permanent change in the outflow system, either 341
involving the arachnoidal granulations or the lymphatic outflow apparatus around the olfactory 342
bulb, optic nerve and other regions. It is possible that in space with CSF stagnation along the 343
ONSAS, toxic changes are occurring within the anterior optic nerve involving lymphatics leading to 344
some permanent change in CSF outflow in this region. 345
346
347
CONCLUSION 348
We hope to have demonstrated that the influence of CSFP upon the eye and in particular the 349
anterior optic nerve is significant and relevant to common ocular diseases. There is a rapidly 350
growing body of literature reporting significant effects of CSFP upon glaucoma as well as diseases 351
causing papilloedema and other disorders like diabetes. A simplistic understanding incorporating 352
only CSFP and intraocular pressure without considering lamina cribrosa properties, orbital tissue, 353
pia mater and subarachnoid space properties is unlikely to give a complete understanding of these 354
common disorders. Some of our understanding is hindered by the lack of an accurate non-invasive 355
measurement method for CSFP. 356
357
358
359
Competing Interest Statement 360
The authors of this paper have no competing interests 361
362
Funding Statement 363
Supported by an NHMRC project grant 1020367 364 365
366
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562
563
564
Figure Legend 565
566
Figure 1 567
Key anatomic features of the optic nerve and eye in relation to the optic nerve subarachnoid space 568
demonstrating the path to the intracranial cavity. The variation in trabeculae is shown and adapted 569
from Killer et al.[2] Glial lamina cribrosa (G) and scleral (collagenous) lamina cribrosa (S) are 570
shown. Central retinal artery is omitted for clarity. 571
572
Figure 2 573
The relationship of key pressures (± SEM) to intracranial cerebrospinal fluid pressure (CSFP) in the 574
dog. A strong linear relationship is seen between optic nerve subarachnoid space pressure (ONSAS 575
), retrolaminar tissue pressure (RLTP ), venous pulsation pressure (VPP) by 576
ophthalmodynamometry () and intracranial cerebrospinal fluid pressure (CSFP ) above 577
certain levels. Below these CSFP levels the pressures are constant. VPP is the minimum IOP 578
required to induce retinal vein pulsation. Lines of best fit are included. The difference between 579
ONSAS and RLTP occurs across the pia mater (pia) and the difference between intracranial CSFP 580
and ONSAS pressure is probably due to orbital pressure (orbit). 581
582
583
584
585
Figure 3 586
Micropipette tissue pressure measurements in dog (b) as the micropipette is passed from the 587
vitreous, prelaminar, lamina and into retrolaminar optic nerve. Oscillations from the respiratory and 588
cardiac cycles can be seen. Intraocular pressure (a), cerebrospinal fluid pressure (c) and blood 589
pressure (d). Lamina cribrosa was from 558 to 919μm. 590
591
592
Figure 4 593
Central retinal arterial (A, B, C) and venous (D, E, F, G) endothelial morphology. Confocal 594
microscope images and schematic outlines demonstrate endothelial morphology in the prelaminar, 595
anterior lamina cribrosa, posterior lamina cribrosa and retrolaminar regions. In posterior lamina 596
cribrosa region, venous endothelial cells (F) appeared similar to arterial endothelium displaying 597
spindle-shaped morphology. Scale bar, 50 µm. 598
599
600
601
Figure 5 602
Swept source OCT of eye with mild glaucoma (A) having a collagenous lamina cribrosa (LC) 603
thickness approximating 300�m. Some retrolaminar tissue (RLT) is shown. The choroid (C) and 604
sclera (S) are well developed. In the highly myopic eye the sclera (S) is thin, particularly under the 605
posterior staphyloma region, which overlies the large optic nerve subarachnoid space (ONSAS). 606
One trabecula (T) is clearly seen. The collagenous lamina cribrosa (LC) is very thin and the 607
retrolaminar tissue (RLT) is clearly seen. Scale bars shown. 608
609
610
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