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'The Influence of Translaminar Pressure Gradient and Intracranial Pressure in Glaucoma:
Review
Short title- Intracranial pressure and glaucoma – a review
David Andrew Price1, BS, Alon Harris2,* MS, PhD, FARVO, Brent Siesky, PhD2, Sunu
Mathew1, MBBS.
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1. Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana
University School of Medicine, Indianapolis, IN, USA

2. Icahn School of Medicine at Mount Sinai, New York, NY, USA

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Corresponding author:

Alon Harris, MS, PhD, FARVO

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Department of Ophthalmology

Icahn School of Medicine at Mount Sinai

1468 Madison Avenue, Annenberg 22-86

New York, NY 10029

T 212-241-6752

palonharris@gmail.com

Financial disclosures and Conflict of interest.

No funding was received for this work. There are no conflicts of interest.

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 Dr. Alon Harris would like to disclose that he receives remuneration from Shire, CIPLA and
AdOM for serving as a consultant. Dr. Harris also holds an ownership interest in AdOM and
Oxymap.

All relationships listed above are pursuant to Indiana University and Icahn School of Medicine at
Mount Sinai’s policies on outside activities.

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 ABSTRACT: The current evidence associating intracranial pressure (ICP) with glaucoma, the

translaminar pressure gradient hypothesis, and anatomic factors likely affecting the relationship

between ICP and retrolaminar tissue pressure including the size of optic canal and lamina

cribrosa thickness are reviewed. Additionally, the evidence of diurnal and positional variation on

the translaminar pressure gradient, effects of glaucoma medications, evidence of ICP helping to

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maintain cerebrospinal fluid flow in the optic nerve to prevent glaucomatous damage, and the

effect of intraocular pressure variation in glaucoma are also reviewed. We find that while low

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ICP is associated with glaucoma disease in most studies, evidence is mixed on how closely ICP

matches retrolaminar tissue pressure, and it appears the relationship is affected by the size of the

optic canal, thickness of the lamina cribrosa, and lymphatic outflow from the optic nerve. Future
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studies can likely strengthen associations by measuring and controlling for some of these factors.

Keywords: Intracranial pressure; Glaucoma; Translaminar pressure gradient; Intraocular

pressure
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 INTRODUCTION

Intraocular Pressure (IOP, measured in mmHg) has long been regarded as the main risk

factor for progression of glaucoma.1 However, damage can worsen despite maintaining IOP

within the target range,2 and recently progression of primary open-angle glaucoma (POAG) and

blood flow changes in the eye have been found to be correlated with intracranial pressure (ICP,

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measured in mmHg) in multiple studies.3-5 Herein we review current knowledge and hypotheses

of effects of ICP in glaucoma.

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MATERIALS AND METHODS

PubMed was searched through September 29, 2019 using combinations of the following

keywords: intracranial pressure, cerebral spinal fluid pressure, glaucoma, translaminar pressure
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gradient, translaminar pressure difference, retrolaminar tissue pressure, optic nerve subarachnoid

space pressure, intraocular pressure, lamina cribrosa, optic nerve head, MR-ICP, two-depth

transcranial Doppler, ophthalmodynamometry, positional variation, posture variation, diurnal

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variation, age, prostaglandin, carbonic anhydrase inhibitor, and beta-blocker. Relevant articles

were read in full and further relevant articles were identified based on reviewing citations.
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REVIEW

Low ICP Is Associated with Glaucoma Progression

Several studies have found low ICP associated with glaucoma. Berdahl et al.

retrospectively studied patients undergoing lumbar puncture (LP), finding lower ICP (9.1 ± 0.77

mmHg, p<0.0001) in patients with normal-tension glaucoma (NTG) compared to age-matched

controls (11.8 ± 0.71mmHg). Conversely, patients with ocular hypertension but no glaucomatous

damage had elevated ICP compared to age-matched controls (12.6 ± 0.85 vs. 10.6 ± 0.81 mmHg,

p < 0.05), suggesting that increased ICP may provide a countering force to IOP.3 Subsequently,

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 in a prospective study of 43 glaucoma patients and 71 control patients without glaucoma using

LP, Ren et al. found ICP is lower in NTG (9.5 ± 2.2 mmHg) vs. high tension glaucoma (11.7 ±

2.7 mmHg, p<0.0001) and control patients (12.9 ± 1.9 mmHg, p<0.0001) and also that the

difference between IOP and ICP was higher in both groups of glaucoma patients vs. controls.4 In

a prospective study of 27 patients, Siaudvytyte et al. found that ICP was lower in the NTG group

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(7.4 ± 2.7 mmHg) compared to controls (10.5 ± 3.0 mmHg) although the results were not

statistically significant (p>0.05).5 Instead of using LP to measure ICP, Siaudvytyte et al. used a

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non-invasive measure, two-depth transcranial Doppler, which although not as precise as LP but

has the advantages of no infection risk and easier repetition.5 In a population based study with

4,711 subjects, Jonas et al. used an equation based on blood pressure, age, and BMI to estimate
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ICP and performed multivariate analysis including IOP and ocular perfusion pressure as other

independent variables. They found that the difference between IOP and estimated ICP was

significantly associated with both glaucoma prevalence and decreased neuroretinal rim area.6 An

intervention study in monkeys found that chronic reduction in ICP through draining
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cerebrospinal fluid (CSF) resulted in decreased neuroretinal rim area vs. controls.7 Gallina et al.

analyzed patients following shunt placement for normal pressure hydrocephalus and showed that
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the product of shunt duration and ICP change was correlated with development of NTG.8 All

these studies together point towards an association between the presence of a low ICP and

development of glaucomatous changes.3-8 However, two studies have found no relationship

between ICP and glaucoma. Pircher et al. retrospectively studied 67 eyes in 38 patients with

NTG and found no significant correlation between mean visual field defect and the difference

between IOP and ICP.9 Weaknesses of the study by Pircher et al. were a lack of a control group

and not controlling for disease duration. Lindén et al. prospectively measured ICP using LP in 13

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 patients with NTG (10.3 ± 2.7 mmHg, p=0.24), finding no statistical difference vs. controls (11.3

± 2.2 mmHg),10 however the small size of the study made it susceptible to type II errors.

The Translaminar Pressure Gradient (TLPG)

Studies are ongoing to explain the relationship between ICP and glaucoma. The leading

hypothesis in studies finding an association is that ICP acts as an opposing force for IOP at the

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optic nerve head and lamina cribrosa (LC).3-6 The protective role of ICP is to limit the

translaminar pressure gradient (TLPG) which is the difference between IOP and retrolaminar

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tissue pressure (RLTP) divided by the thickness of the LC. This makes the TLPG dependent on

IOP, RLTP, and LC thickness. ICP contributes to the RLTP through increased optic nerve

subarachnoid space pressure (ONSP), which bolsters the RLTP. Morgan et al. hypothesized that
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orbital pressure and elasticity of the pia mater help to maintain RLTP when ICP is low, but

become less impactful when ICP is higher than ~3 mmHg, at which point the RLTP is mainly

dependent on ONSP.11

High TLPG creates a shearing force at the optic nerve head, contributing to glaucoma
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progression most likely through neuronal changes. Quigley et al. noted that there is a buildup of

proteins and cellular organelles at the LC when IOP is increased in primates to 30 mmHg for two
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hours or more, which clears when IOP is normalized to 10 mmHg for 4 hours, implying some

reversibility of initial blockade.12 Additionally, Zhang et al. lowered ICP from 11.4 ± 1.6 mmHg

to 2.7 ± 0.4 mmHg for six hours or increased IOP to 40 mmHg for six hours in separate groups

of rats, finding that both shifts decreased anterograde and retrograde axonal transport in rats

compared to controls one day after the intervention, though the difference disappeared at five

days afterward.13 In contrast, when IOP was increased further to within 25 mmHg of mean blood

pressure for six hours, axonal transport continued to be decreased at five days, and retinal

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 ganglion cell loss was observed.13 Zhang et al. later showed morphology and

immunohistochemical staining is similar between rats with elevated IOP and rats with depressed

ICP, implying similar effects on the optic nerve from the two shifts.14 Similarly in pigs,

Balaratnasingham et al. found elevating IOP to 40-45 mmHg for six hours reduced axonal

transport and induced cytoskeleton changes at the LC and prelaminar regions of the optic nerve,

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they did not look for a return of axonal transport.15 Subsequently, they showed that cytochrome

C oxidase activity is increased in the optic nerve at the LC when IOP is raised to 40-45 mmHg

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for 12 hours increasing the TLPG, but not in regions of the optic nerve where pressures are

increased without a gradient increase.16 A second mechanism could be venous metaplasia and

vascular flow changes. In humans, Kang et al. found that the central retinal venous endothelium
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resembles central retinal arterial endothelium at the posterior LC where the gradient force is

likely highest,17 and ocular blood flow changes are associated with glaucoma.18

The TLPG is estimated to be 20-33 mmHg/mm on average in humans.11,19 However,

there are challenges to using the TLPG in human studies, and to date, the main measure used in
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place of the TLPG is the difference between IOP and ICP, which is termed the translaminar

pressure difference. This method does not consider the thickness of the LC, though the LC can
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be non-invasively imaged. The more complex challenge is measuring RLTP, which to date has

not been measured non-invasively and would pose risk to subjects to measure invasively. While

ICP can be used as an estimate of RLTP, multiple studies in dogs have shown the retrolaminar

pressure is maintained at a floor pressure of ~3 mmHg when ICP falls below 3 mmHg.11,20

Morgan et al. used pressure transducers attached to micropipettes to measure TLPG and ONSP

in anesthetized mixed breed dogs, finding that the TLPG correlates well with difference between

ICP and IOP (r=0.93) and that the ONSP is almost identical to ICP.11 They noted that the lamina

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 cribrosa thickness was similar between dogs in their study, which would have reduced the

correlation value if it varied.11 However, Hou et al. implanted pressure transducers in the left

ventricle, left optic nerve SAS, and lumbar cistern of mixed breed beagles and found that ONSP

is both more loosely correlated with ICP and lower than ICP, with ONSP of ~5 mmHg

corresponding to ICP of ~9 mmHg.20 In a cadaver study where saline was infused into a

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ventriculostomy, a pressure gradient was observed along the optic nerve, and though ONSP

increased linearly with ICP, it increased at a slower rate and different eyes had different slopes of

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change.21 An inconsistent relationship between RLTP and ONSP with ICP could explain the

varied results in studying the association of ICP and glaucoma.

Anatomic Factors Affecting Retrolaminar Pressure

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Variation in size of the optic canal, structure of the optic nerve, and lymphatic outflow

may create an inconsistent relationship between ONSP and RLTP with ICP. Pircher et al. found

the cross-sectional area of the optic canal at the orbit opening is decreased in patients with NTG

compared to age and gender matched controls.22 Bidot et al. examined MRI images of patients
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with pseudotumor cerebri, finding that increased canal size was associated with increased visual

loss and higher grade papilledema.23 In patients with asymmetric papilledema, the optic canal
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was smaller in the eye with lower grade papilledema.24 The optic nerve sheath diameter (ONSD)

is known to expand with increased ICP, which imparts an outward force on the nerve sheath.

ONSD has strong sensitivity and specificity for predicting elevated ICP, but in patients with

narrow canals, there is a higher false negative rate, with patients having small ONSDs despite

elevated ICP.25 The subarachnoid space of the optic nerve has septa, pillars, and trabeculae

which likely create flow resistance and may have varying effects in different people.26 Finally,

there are lymphatic capillaries in the dura of the optic nerve which drain into the conjunctival

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 lymphatics, with the highest concentration in the bulbar area.27-29 Kaskar et al. performed a

mathematical modeling study of RLTP, and noted lymphatic outflow of CSF of 5-10% from the

optic nerve was required in order to match pressure relationships noted in a human cadaver

study,21 otherwise calculated RLTP was too high.30 Taken together, these studies indicate that the

relationship between ONSP and RLTP with ICP is likely influenced by multiple anatomic

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factors.

Effect of Anatomical Variations in Lamina Cribrosa

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The LC appears to play a role in glaucoma and does not respond consistently to changes

in ICP and IOP. The LC is a collagenous meshwork of trabeculae that sustains pressure forces

from both IOP and ICP. Retinal ganglion cell (RGC) axons, as well as capillaries, pass through
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the LC. As the LC is thinner than the sclera at the scleral canal, it is a relatively weak spot for

sustaining pressure changes. A thinner LC is associated with a faster rate of retinal nerve fiber

layer thinning in POAG,31 consistent with the TLPG hypothesis as a thinner LC increases the
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TLPG. Highly myopic patients have been found to have thinner LCs on average, possibly

explaining why glaucoma progression is more prevalent in myopic eyes.32 In-vivo testing of
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strain-relief on LC by Girard et al. in nine patients undergoing trabeculectomy showed that the

amount of tissue strain relief, which was calculated based on changes in LC displacement, was

significantly associated with reduction in retinal sensitivity to light.33 Additionally, strain relief

was not associated with IOP change following trabeculectomy, pointing to the importance of LC

anatomical variations between patients.33 Wang et al. manipulated both ICP and IOP in primates,

finding responses of LC architecture to pressure changes varied by subject, and changes were

greater with acute fluctuations in ICP vs. IOP.34 Changes in LC architecture were different

between acute and chronic elevations in IOP, likely reflecting collagen fiber recruitment to

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 counter high TLPG in chronic cases.35 Incorporating LC properties will be an important adjunct

in identifying and predicting the effects of ICP on ocular pathologies.

Maintenance of TLPG During Diurnal and Positional Variations

A concern with glaucoma is positional and diurnal variations in IOP, with the fear that

IOP is lower when measured during patients’ ophthalmology appointments when they are seated

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during the day compared to the value at night when patients are in the supine or lateral decubitus

positions.36 IOP is elevated at night vs. the day when position is controlled,37 but it is unclear if

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ICP also increases. Starcevic et al. found that nighttime ICP was significantly higher than

daytime ICP in rats.38 However, Lin and Liu found there was no significant variation in ICP

within the circadian rhythm in rats.39 Human studies have not been performed on diurnal ICP
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variation.

IOP is significantly elevated when patients are supine and some authors have proposed

adopting modified sleeping positions with the head elevated to maintain a lower IOP
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overnight.37,40-42 Some studies found a difference between positional IOP changes in glaucoma

and healthy eyes40,41 but others did not.42 However, ICP also changes with body posture and is
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significantly higher in the supine position,43 counterbalancing increased IOP. A modeling study

based on human physiologic parameters has estimated that TLPG is higher while upright vs.

supine due to IOP changes being smaller than ICP changes.44 Consistent with the modeling

study, Skrzypecki and Ufnal found IOP decreased less than ICP when rats were shifted from

supine to upright, likely leading to a higher TLPG in the upright vs. supine position.45 However,

as reviewed previously, the TLPG is a more complex calculation than the difference between

ICP and IOP, and RLTP is maintained at ~3 mmHg when ICP drops below that.11,20 Studies

measuring RLTP instead of ICP may find different results than current literature.

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 Effects of Age on TLPG

The TLPG may change as we age. Fleischman et al. studied average ICP by decade of

age in patients receiving LPs without pressure altering conditions, finding that ICP became

progressively lower, reaching a mean of 8.4 ± 2.4 mmHg (p<0.001) in the age 90-95 group vs.

the mean of 11.5 ± 2.8 mmHg age 20-49 control group, which may explain increased glaucoma

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incidence with advancing age.46 However, IOP has also been found to decrease with years of age

(coefficient = -0.085, 95% CI -0.57 to -1.03) in multivariate analyses of South Koreans,47 which

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may counter the decrease in ICP. Multiple studies have shown the thickness of the LC increases

with age, which lowers TLPG.48,49 No studies have combined analysis of all three factors, and it

is unclear whether patients with glaucoma undergo similar shifts with age as patients without
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glaucoma.

Effect of Glaucoma Medications on ICP

Oral carbonic anhydrase inhibitors are first line medical therapy to reduce ICP in patients with
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papilledema, however, it is unclear whether topical administration has the same effect. Studies

have shown plasma levels of topical dorzolamide and brinzolamide are much lower than what is
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required to produce effects in the kidneys and red blood cells,50,51 but we didn't find any studies

reporting ICP change or lack thereof. If dorzolamide or brinzolamide lower ICP, their effect on

glaucoma progression may be less than predicted by their effect on IOP. We found no evidence

linking prostaglandins or beta-blockers to ICP change.

Alternative Hypothesized Influences of ICP

A second hypothesis explaining why low ICP is correlated with glaucoma progression is

that CSF flow to the optic nerve is reduced or cut off when ICP is low or IOP is high. Mathieu et

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 al. showed that CSF flow to the optic nerve was reduced in mice with glaucoma vs. normal

controls.52 Boye et al. measured CSF flow velocity in humans, finding that flow in the optic

nerve is decreased in NTG patients.53 Jaggi et al. performed ligation using an elastic silicone

band with minimal tension in order to preserve axonal transport while blocking CSF

communication in the optic nerve, which resulted in axonal loss in sheep after CSF flow was

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blocked.54 In their study correlating ICP with ONSP, Hou et al. interpreted the breakdown in the

correlation between ICP and ONSP when ICP fell below 3 mmHg as a sign of exchange arrest,

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and theorize that pressure gradients between ICP and IOP are necessary to maintain CSF flow

and prevent glaucoma.20 If reduced CSF flow in the optic nerve is the mechanism of glaucoma,

increased ICP would be protective for a different reason than assumed in the TLPG hypothesis,
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though a similar type of relationship between ICP and IOP would likely exist. Of note, ONSP

would likely be a better predictor of pathology than RLTP if this hypothesis is true, as it would

be a better measure of CSF supply.

While low ICP appears to be a risk factor for progression of glaucoma, elevation of ICP
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may also pose some risks. In mice, Nusbaum et al. elevated ICP to 30 mmHg for 1 week which

resulted in axonal loss in the optic nerve and RGC death,55 consistent with disease processes in
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humans including papilledema. However, Shen et al. showed physiologic increases are damaging

as well, finding that increasing ICP from a mean of ~9 mmHg to ~15 mmHg for two weeks

resulted in similar levels of cell death and axonal loss in mice.56 Future studies evaluating ICP

shifts in primates should be conducted to validate the findings of physiologic ICP elevation being

damaging, which would be an important consideration as it has already been shown that

physiologically low ICP is associated with progression of glaucoma in humans.

Estimating Intracranial Pressure

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 Invasive measurement of ICP is costly and is associated with attendant risks including

infection. Currently, a barrier to using the TLPG in routine management of glaucoma is a lack of

proven non-invasive methods for measuring ICP, though multiple techniques are currently being

studied.57 Alternatively, ICP can be estimated using an equation that includes the variables of

age, BMI, and diastolic blood pressure. Using LP as a reference, Jonas et al. derived the

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equation, cerebrospinal fluid pressure = 0.446 x BMI + 0.166 [mmHg] x Diastolic Blood

Pressure [mmHg] – 0.18 x Age [Years] - 1.91 from a set of 72 Chinese patients to estimate ICP.

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When testing against LP measurements in a test group of 42 Chinese patients, they found an

insignificant difference between the estimated and actual ICP (p=0.29),58,59 however they did not

report limits of agreement or provide a figure illustrating the results. Kashara et al. tested the
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same equation in 39 Brazilian patients, finding a mean difference of 1.5 mmHg with 95% limits

of agreement of -5 to +8 mmHg between LP measured and equation estimated ICP.60 Overall,

while results were not as good as the most successful studies utilizing non-invasive methods,61-63

the strength of the results by Kashara et al. indicates that adjustments to non-invasively measured
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values based on patient age, BMI, and blood pressure may improve the precision of estimates,

and is something that can be considered in future development of non-invasive ICP measurement
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techniques.

Variation of IOP

IOP exhibits nycthemeral variation and is affected by blinking, squeezing the lids, and

saccade.64,65 While these short-term intra-day variations have not been extensively studied,

fluctuation in IOP between office visits was found to be a stronger predictor of progression of

visual field loss vs. mean IOP in the Advanced Glaucoma Intervention Study which included 401

patients and 509 eyes.66 Additionally, the study also found that the association between IOP

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 fluctuation and visual field loss was stronger in patients with low mean IOPs.67 Other studies

have had mixed results, finding both that increased IOP fluctuation was associated with

glaucoma progression,68,69 and that it was not.70,71 However, Kim and Caprioli point out that

increased fluctuation in IOP was correlated with increased mean IOP in several studies that

found no relationship between the amount of IOP fluctuation and visual field change, potentially

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masking a relationship and leading to the negative results.72 We found no studies combining

analyses IOP variation with ICP, though both have been hypothesized to be important factors in

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NTG.

DISCUSSION

There are challenges and unresolved questions to measuring the TLPG which future studies
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could help to resolve. First, there is a question of how closely ICP, RLTP, and ONSP are

correlated. This is pivotal to elucidate because studies thus far have measured ICP, and ICP may

not be a good approximation of ONSP and RLTP. Morgan et al. and Hou et al. achieved different
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results when comparing ICP to ONSP.11,20 It is important to note that both studies were

performed in mixed breed dogs. While the instruments differed, Morgan et al. inserted
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micropipettes with attached pressure transducers and Hou et al. implanted pressure transducers, it

is unclear to us why the correlations between ICP and ONSP were radically different, and we

were unable to find an explanation in the literature. Further studies are required to establish the

true relationship because Morgan’s results imply ICP reliably estimates RLTP and ONSP, and

Hou’s results contrast these results. Data confirming that the size of the optic canal effects

glaucoma progression,22 papilledema,23,24 and ONSD25 lend support to Hou et al.’s findings that

ICP is not equivalent to ONSP,20 and that ONSP and RLTP are also effected by anatomic factors.

Future studies exploring the relationship between glaucoma and ICP can build on previous

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 knowledge by incorporating measurement of the optic canal size to improve specificity of

correlations and provide a better approximation of RLTP and ONSP compared to measuring ICP

alone.

A second challenge is that non-invasive measurement techniques of ICP are not currently

able to precisely estimate ICP, and further development is required to improve their accuracy and

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precision. Invasive measurement techniques pose risks to patients such as infection, limiting their

application in glaucoma studies.

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There is a wide range of study findings and proposed pathogeneses for glaucoma, possibly

reflecting the existence of multiple pathological mechanisms. Longitudinal and multifactorial

studies will likely be necessary to fully understand the pathogenesis of glaucoma, but there are
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several hypotheses that can be tested against each other. First, there is a hypothesis that

glaucoma damage is more likely to occur at night when the patient is supine due to elevated IOP.

However, the TLPG might be lower at night compared to when patients are upright during the
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day. Experiments varying the time animals with glaucoma are in each position could be used to

determine at which time damage is most prevalent. Second, there are multiple different
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hypotheses for the role of ICP, with the leaders being the TLPG hypothesis or that ICP maintains

CSF outflow. Differentiating RLTP from ONSP and comparing their correlations with glaucoma

progression would be a good test of the hypotheses. Thirdly, future studies can attempt to

differentiate how much effect low ICP has vs. IOP variation, or whether both factors have a

complementary impact. Fluctuation in TLPG may turn out to be a better predictor than IOP

fluctuation, which animal studies could help to answer. Answering these questions may help to

improve the precision of IOP targets for individual patients to balance their respective RLTPs,

and guide medication regimen decisions to maximize effect when glaucoma damage is most

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 likely to occur. Further, development of future glaucoma therapies will be aided by this

knowledge, and the efficacy of proposed therapies, such as sleeping with the head elevated to

lower nocturnal and recumbent IOP elevation,37,40-42 will be better assessed.

Quigley et al. and Zhang et al. both showed that axonal transport can resume and clear

built up metabolites when IOP normalizes after being elevated,12-14 implying frequent

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normalization of the TLPG may be enough to adequately dialyze the optic nerve head and

maintain retinal ganglion cells despite temporary elevations in the TLPG. Future studies

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monitoring diurnal TLPG may find that prolonged frequent periods of normal TLPG each day

are enough to prevent glaucoma progression, even if the TLPG is elevated at intermittently.

Finally, topical carbonic anhydrase inhibitors effect on ICP has not been studied. Studies
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directly measuring their effect on ICP could help to assess whether there may be reduced

protection when using this class of drops. Alternatively, large studies could look at glaucoma

progression when controlling for IOP when patients are on different types of medications.
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CONCLUSION
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Several studies have found ICP is associated with glaucoma however the relationship

appears to be modified by other factors such as the size of the optic canal. The leading

hypotheses explaining the importance of ICP include the TLPG hypothesis and that ICP

maintains CSF circulation in the optic nerve. There is still much unknown about the interplay of

ICP with the LC and IOP, and further study is required. As well, technology needs to advance so

that ICP and RLTP can be safely and precisely measured in patients.

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