Intracranial pressure variability in migraine;
A prospective study to evaluate changes in intracranial pressure during different migraine attack phases

Background
Migraine is a common, multifactorial brain disorder characterised by chronic,
recurrent, disabling attacks of headache with autonomic features (migraine
without aura), and, in one third of patients, transient neurological aura
symptoms (migraine with aura). Although the pathophysiology of the migraine and
aura are reasonably well understood, the triggering mechanisms for the
initiation of migraine attacks and the possible role of changes in intracranial
pressure (ICP) in relation to the headache phase are unknown. Clinically,
diseases with known ICP changes (e.g. tumor cerebri; post-dural puncture
headache) share characteristics with migraine, including headaches, nausea and
vomiting. However, the relationship between ICP changes and migraine remains
unclear. Recently, a non-invasive method to measure ICP using evoked
otoacoustic emissions (EOAEs) has been developed allowing more frequent and
multiple measurements without the side effects of an invasive technique. This
provides an opportunity to study and establish the full profile of ICP changes
over time in migraine, including interictal, prodromal, ictal, and post-ictal
phases. Knowledge of the role of ICP changes in migraine may increase our
understanding of migraine pathophysiology.

Objectives
Our main hypothesis is that ICP shows a dynamic profile over the course of
different attack phases in migraine. Therefore, we aim to detect dynamic
changes in ICP in relation to different phases of the migraine attack. In
concreto, the main objectives are:
- To compare ictal ICP to interictal ICP in migraineurs and correlate this with
clinical characteristics;
- To compare ictal ICP reactivity to interictal ICP reactivity in migraineurs
and correlate this with clinical characteristics;
- To compare the baseline ICP (reactivity) of migraineurs versus healthy
controls
Secondary objectives per part of the study include:
- Part I; To correlate measurements via in situ manometry with non-invasive
EOAE-based ICP measurements;
- Part II/III; To compare interictal ICP (reactivity) in migraineurs to
baseline ICP (reactivity) in healthy controls;
- Part IV; To correlate measurements via lumbar manometry with non-invasive
EOAE-based ICP measurements in migraine and helathy controls;
- Part V; To correlate measurements via lumbar manometry with non-invasive
EOAE-based ICP measurements in patients from the Neurology inpatient/
outpatient clinic, with various indications for lumbar puncture.

Methods and Design
Non-invasive ICP measurements (via an EOAE-based technique using an earplug in
the external auditory meatus, comparable to tympanic temperature measurements
without any known hazards) will be performed in different study groups:

Part I * EOAE based ICP measurement will be performed twice in patients who
have routine, in situ manometry, for on-site validation of this non-invasive
technique.
Part II * In migraine patients (without aura), EOAE based ICP measurements will
be performed prospectively during a migraine attack (within 0-3 hours from the
onset of the headache preferably prior to taking the anti-migraine therapy) and
in the interictal phase (>3 days after attack termination). If possible,
measurements will also be performed in the prodromal (between 4-48 hours prior
to the acute attack) and the post-ictal phase (2-24 hours post pain relieve).
Measurements will be performed in three different body positions (upright;
supine; and supine with body position in 20* extension) at patient homes.
Part III * In healthy volunteers * matched to migraineurs in part II - EOAE
based ICP measurements will be performed twice in three different body
positions.
Part IV * in subjects participating in a biochemical study (CME P07.079), who
undergo lumbar puncture and lumbar manometry as part of routine technique, EOAE
based ICP measurements will be performed in different body positions.
Part V * in patients visiting the Neurology inpatient clinic and outpatient
clinic undergoing normal diagnostic lumbar puncture, EOAE based ICP
measurements will be performed in different body positions.

Within-subject comparisons will be performed using appropriate statistics with
significance level set at p<0.05.

As mentioned above, the non-invasive measurements of ICP are comparable to
measuring temperature through an ear thermometer, i.e. not painful, restricted
in time needed (maximum 5 minutes) and without any known side effects. The only
discomforts subjects might report is the lack of tolerance for the noise
emitted by the ear probes, or a lack of tolerance for having an earplug placed
in the ear canal, although this is unlikely since healthy volunteers in
previous pilot studies did not report this experience.

In phase I of the proposed study, measurements are to be performed in patients
on Intensive and Medium Care units (ICU/ MCU), who are often unable to give
informed consent (i.e. legally incapable or incapable of giving informed
consent). We deeply considered the possibility of not including such a pilot
group in this study. Considering on one hand the fact that the measurement is
of non-invasive nature, of very short-lasting time, without side effects and
exposes a very low burden to participants, and considering on the other hand
the importance of a validation part in our study that enables us to accurately
and reliably assess output from this new technique, we feel patient burden and
scientific gain are well-balanced. We feel that this study will help the
development and accuracy of non-invasive techniques for ICP measurements,
enabling reliable use in clinical practice (in ICU/ MCU patients) in some
years.