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