Effects of Acetazolamide on intracranial pressure in glaucoma

Glaucoma is a chronic, progressive disease of the optic nerve in which there
are detrimental effects on field of vision and visual acuity which, if left
untreated, can lead to blindness. Historically, an elevated intraocular
pressure (IOP) was deemed to be the key factor in the pathophysiology, but,
recently, it was found that the relationship between IOP and intracranial
pressure (ICP) may be a crucial aspect (Berdahl et al. 2008; Ren et al. 2010).
This theory posits that alterations in IOP, ICP, or both can lead to a change
in the pressure gradient across the lamina cribrosa (LC) and cause it to bulge
and damage the nerve fibers.


The main treatment for glaucoma is IOP lowering medication. Acetazolamide is
given to glaucoma patients to lower their IOP, however, it is also given to
patients in neurology to lower ICP. If the difference between these two
pressures is important in the cause and progression of glaucoma, then lowering
both ICP and IOPx may not be the most successful means of treatment, and
lowering ICP more than IOP during a significant part of the day could even be
harmful.


A recent study determined that there is a linear relationship between
distortion product otoacoustic emissions (DPOAEs) and invasive ICP (METc
2016/599, submitted for publication). DPOAEs are sounds emitted by the inner
ear in response to tones at specified levels and frequencies. These emissions
represent ICP because there is a connection between the cranium and inner
fluids via the cochlear and endolymphatic aqueducts. Previous research has
also shown that DPOAEs can accurately represent changes in ICP (Büki et al.
1996; Voss et al. 2006; Williams et al. 2016; Bershad et al. 2014).


The proposed study investigates how ICP is affected in glaucoma patients who
are taking acetazolamide. Peak IOP changes have been shown to occur at 1-2
hours after ingestion but the time course for ICP changes has not been properly
assessed. Plasma levels peak at 1 hour post ingestion and continue to be
raised for at least 7 hours (Friedland, Mallonee, and Anderson 1977). ICP
will therefore be measured non-invasively using DPOAEs before the patient takes
their prescribed medication, and then intermittently for 2 hours following
ingestion to be sure we can characterize the changes in both ICP and IOP.
Healthy subjects will be used as a comparison to control for any changes that
are occuring due to diurnal fluctuations (Wostyn et al. 2011). To the best of
our knowledge, the effect of acetazolamide on ICP in glaucoma patients has
never been tested. We aim to gain better insight into the use of this drug in
the treatment of glaucoma.

The primary objective is to evaluate changes in ICP due to acetazolamide using
a noninvasive method of ICP measurement and to compare this with changes in
IOP. Healthy controls will be used to control for any effect of diurnal
fluctuations.

cross-sectional, observational

Patients will have one visit to the ophthalmology department to perform the
experiment. They will first be tested to detect the presence or absence of
DPOAEs. Subjects who meet the selection criteria will then undergo the DPOAE
testing. The test is completely non-invasive and will cause no discomfort for
the patients. It is important to note that only patients already taking oral
acetazolamide will be invited to participate and they will only be asked to
take their prescription as they normally would. Patients and healthy subjects
will spend 10 minutes for reception, additional questions, and DPOAE screening
and, if they meet the selection criteria, 2.5 hours for the experiment. The
total time will therefore be about 2 hours and 40 minutes, however only a
fraction of this time will be used for measurements as much of the allotted
time is waiting for the drug to enact changes. If abnormal eye screening
results are obtained for healthy subjects, they will be referred to their GP.
Detection of signs of glaucoma may cause psychological stress, however, an
early diagnosis will allow treatments to be initiated and therefore more
preservation of visual functioning. Glaucoma patients will not perform any
ophthalmological screening tests; therefore there is no risk of identifying any
other eye conditions.