Evaluation of non-invasive intracranial pressure technology for use in glaucoma

Glaucoma is a collection of diseases that causes progressive degeneration of
optic neurons. Characteristic damage to axonal components of the optic nerve
head and the surrounding neuroretinal rim. Despite advances in clinical
management strategies, glaucoma continues to be the leading cause of
irreversible blindness worldwide. Glaucoma usually manifests with an elevated
IOP which is a causal factor for optic neuronal damage.

Recently, a number of studies have shown that ICP is a significant risk factor
for glaucoma. After emerging out of the lamina cribrosa and throughout its
whole course, the optic nerve is surrounded and bathed by CSF, running through
the subarachnoid space and generating the so-called retrobulbar pressure which
in essence is the same as ICP. The lamina cribrosa is under the influence of
two separate but possibly interdependent pressures - the posteriorly acting IOP
and the anteriorly acting ICP. Recent studies show that ICP is as responsible
for causing neuronal damage at the optic nerve head as elevated IOP.

Clinically, when there is an alteration of the ICP may be accompanied by somes
symptoms, such as headache, blurred vision, feeling less alert than usual,
vomiting, changes in the behavior, weakness or problems with moving or talking
and lack of energy or sleepiness. These symptoms can be caused by a bleeding
into the brain, too much cerebrospinal fluid, swelling in the brain, aneurysm,
blood pooling in some part of the brain, brain or head injury, brain tumor,
infections such as encephalitis or meningitis, hydrocephalus, high blood
pressure or a stroke.

But there is no validated method to determine the absolute value of ICP.
Invasive methods like external ventricular drainage or lumbar punctures present
risks such as hemorrhages, subdural hematomas, skin infections, cranial
fractures, ventriculitis, meningitis or fatal septicaemia, also technical
difficulties as surgical placement of catheters can be present, that limit them
to specialized centers. These methods can be repeated only in exceptional
cases. However, the ICP is recognized as an important indicator in the
follow-up of many pathologies (not only glaucoma).

Non-invasive monitoring of ICP via the auditory system is theoretically
possible because changes in ICP transfer to the inner ear through connections
between the cerebral spinal fluid and the cochlear fluids. Distortion-product
otoacoustic emissions (DPOAE) are produced by couples of pure tones at
frequencies fl and f2 that are chosen by the investigator and can take any
value between 0.7 and 8 kHz. When there is a damage in the brain (broke,
hemorrhage, ischemia, etc) usually that can affect the blood circulation and
the CSF which have a decompensation. Recently, we performed a study and showed
that distortion product otoacoustic emissions (DPOAEs) are highly sensitive to
small changes in ICP induced by changes in body position and these changes were
identical in glaucoma patients and controls. However, the concerning method
appeared not to allow for an absolute ICP measurement. (Reference study:
NL59638.042.16 *A method for non-invasive intracranial pressure measurement in
glaucoma*).

The aim of this project is to use an ear property that depends only on the ICP
(in any case, the absolute pressure that prevails in the inner ear) and
therefore does not require calibration to give access to the absolute ICP. This
property is the absorbance (the ability to let in the sound the acoustic energy
absorbed by the ear), which is optimal when the vibrating structures are not
energized, so when the pressure outside the ear (easy to measure and make in
variations in the external auditory canal - CAE) is exactly balanced by the
pressure inside. The absorbance measurement is performed routinely during
audiological tests, using automated commercialized devices, usable by trained
paramedic operator. It presents no risk or discomfort and can be repeated at
will.

Measuring absorbance we can understand the changes in the ICP. Changes in the
perilymphatic pressure produce variations in the middle ear which influence the
contraction of the stapedius muscle attached by a ligament to the stapes which
is the responsible of the stapes movement into the oval window. High ICP
increase perilymphatic pressure which displaces the stapes outward from the
oval window, when this happen we can see a smaller absorbance. In the case of
low ICP, perilymphatic pressure decrease and displaces the stapes inward of the
oval window which should produce a bigger absorbance.

That mean than perilymphatic pressure can reflect CSF pressure when the
cochlear aqueduct is working correctly. Cochlear aqueduct runs from
subarachnoid space and allowed the relation between CSF and ear fluids which in
the case of be altered would affect also at the middle ear. Thus, if the CSF
pressure (and consequently ICP pressure) provoked an alteration in
perilymphatic pressure and moving the stapes in the middle ear, we should be
able to repositioned the stapes using pressure through the ear canal which will
move the stapes and will make a pressure compensation.

The difference between this technique (absorbance) and the DPOAEs technique
(reference study: NL59638.042.16) is that with the absorbance we search
information about high or low ICP, while DPOAEs give us information about the
alteration of the ICP, which is really useful in the clinical practice but less
specific.

Recently, a pilot use of a commercial system of absorbance in the development
of audiological standards has shown that in 38 ears of healthy subjects between
20 and 30 years, the absorbance is maximum at on average P_cae = 0 mmH2O in
standing posture, 13 mmH2O in supine position, and 23 mm H2O in Trendelenburg
position (-20 °). This indicates that absorbance is indeed related to ICP. An
ear computational model was established from a well-accepted published ear
model (Zwislocki, 1963) and this model replicated the observed experimental
behavior by attributing the cause of changes in absorbance to ICP.

With this new technique we could avoid the complications in relation to the
invasive methods of ICP measuring (hemorrhages, subdural hematomas, skin
infections, etc) and being more specific about hyper/hypo ICP.

Loiselle (2018) (NL59638.042.16) study show how invasive data of ICP and DPOAE
phase are linearly related over an ICP of 3mmHg. With this evidence we can
continues to investigate about the relation between more ear functions, such as
absorbance in the ICP, looking for a more specific information.

In this study we combine absorbance measurements with DPOAEs, where the former
should provide an absolute estimate of ICP at different body positions and the
latter the change in ICP when going from one position to the other.

The aims of this study are (1) to determine if ear absorbance can be used to
non-invasively measure ICP and (2) to determine if ICP differs between glaucoma
patients and controls.

Study design:

This study is a cross-sectional, observational study.

Duration: 4 months for recruitment and data collection.

Subjects with healthy eyes who responded to our advertisement (see form E3),
and glaucoma patients who were selected from the Groningen Longitudinal
Glaucoma Study database, receive the information letter and the informed
consent form (see forms E1a-b and E2a-b). After informed consent is obtained,
subjects will undergo the following investigations:

Screening:

Healthy subjects will undergo a routine eye screening (see descriptions below),
while information from the patients will be taken from their hospital files.

Subjects with healthy eyes will also fill out a short questionnaire to
determine any familial ophthalmologic abnormalities (questions include eye
problems, ophthalmic history, and risk factors for glaucoma). The most
important glaucoma risk factors are high IOP and a first-degree relative having
glaucoma. By completing both the screening and questionnaire, we reduce the
probability that a control actually has glaucoma to less than 1%. Most other
common age-related eye diseases (macular degeneration and cataract) cause a
lowering of visual acuity. That is why we measure the acuity. We also make a
picture of the retina that enables the discovery of glaucoma and retinal
disease. If all these tests are negative, presence of a relevant eye disease is
very unlikely.

Both the patients and healthy subjects will be screened for the presence of
DPOAEs and for normal middle ear function with tympanometry.

If the selection criteria are met, the subjects will then complete the
experiment.

Eye screening tests:

Refraction and Visual Acuity: Measured by means of a letter chart.

Non-contact Tonometry: A pulse of air will be used to assess the subjects* eye
pressure, without any physical contact. A raised intraocular pressure is one
indicator of glaucoma.

Optical Coherence Tomography: A short scan that uses light to take
cross-sectional images of the retina will be used to screen for glaucoma.

A screening visual field examination: This test is performed after the subject
has placed his/her chin on the chin rest. A series of weak light stimuli are
projected onto a bowl-shaped background in which the patient/subject has to
press a button when he/she sees the stimulus. The stimuli vary in intensity
and position in the bowl. This test is performed to rule out field of view
defects.

Corneal Pachymetry: This test is performed to determine central corneal
thickness, which is influenced by IOP. A small probe is gently placed on the
front of the eye (cornea) to measure the thickness. This test is part of the
routine Glaucoma patient visits.

Procedures:

After the screening, subjects who meet the inclusion criteria will have their
blood pressure will be taken.

Next, the subjects will undergo two auditory tests in the ENT department.

DPOAEs: In this test, a small earpiece (similar to an MP3 player earphone) will
be inserted in the subject*s ear that will present 2 tones at specified levels
(at about the level of a vacuum cleaner, not loud enough to cause any damage)
and frequencies. This device will measure the DPOAEs in the subjects.

Ear absorbance: A small earpiece will be inserted in the subject*s other ear.
It will be presented a continuous tone in different frequencies (from 0.25kHz
to 8 kHz) and air pressure from - 600 daPa to 300 daPa. This device will
measure the absorbance curve of the ear.

These two tests will be performed in 7 body positions: 90, 45, 30, 20, 10, 0,
-10, -20 degrees (assuming a horizontal of 0). DPOAEs (Elios Echodia Device)
and ear absorbance (Titan Interacoustics) will be measure simultaneously (one
earpiece in each ear) at each position, that mean at the same time. In the
upright and -20 degree position they will be measured after allowing 45 seconds
to reach a steady state in ICP, while in the supine position they will remain
for 15 minutes before measurements are taken. In the other positions changes
from one to another will be spend around 30 seconds, to allowed the
normalization of the emissions.

IOP will be measured simultaneously with the two auditory tests using a
handheld tonometer.

The tilt table (Design approved by to the Terzake Deskundige) will have ankle
straps to safely secure the subject.

Patients and healthy subjects will have one visit to the ENT and ophthalmology
departments to perform the screening tests and if selected, the experiment.
Healthy subjects will undergo a routine screening test in the ophthalmology
department to rule out the presence of glaucoma. Screening in the ENT
department will take place for patients and healthy subjects and will include
assessment of any middle ear problems and a test to detect the presence or
absence of DPOAEs. If abnormal eye screening results are obtained for healthy
subjects, they will be referred to their GP, as will be the case for ear
abnormalities in all participants. Detection of signs of an eye or ear
condition may cause psychological stress, however, an early diagnosis will
allow treatments to be initiated and therefore more preservation of visual or
hearing functioning. Glaucoma patients will not perform any ophthalmological
screening tests; therefore there is no risk of identifying any other eye
conditions. Subjects who meet the selection criteria will then undergo the ear
absorbance and DPOAE testing. The tests are non-invasive but they will be
tilted on a table, which may cause minimal discomfort. Patients will spend 15
minutes for reception, additional questions, and screening and, if they meet
the selection criteria, 30 minutes for the experiment. The total time will
therefore be about 1 hour. Healthy subjects will require 30 extra minutes for
the eye screening, which will make their total participation time 1.5 hour.