Central nervous system tumors are the second most common malignancies in childhood. A brain
tumor and its treatment can affect the visual system at different levels, from the optic
nerves (through compression or infiltration), to sub-cortical structures such as the superior
colliculus (SC) and lateral geniculate nuclei (LGN) to optic tracts, optic radiations and
visual cortices. Children with brain tumors can present visual impairments like decreased
visual acuity and contrast sensitivity, loss of color vision, and visual field loss such as
hemianopsias. Individuals with hemianopsia present difficulties in detecting stimuli in the
defective visual field and show defective scanning and exploration. Moreover, they show a
rotation and compression of the auditory space leading to imprecise localization of sound
across both hemispaces. Hemianopsia patients naturally develop oculo-3D-MOTor strategies to
compensate for visual field loss, but visual rehabilitation procedure must still be developed
to optimize/improve visual perception in the blind field. Several studies demonstrated that
individuals with hemianopsia could improve visual perception in the damaged hemifield after a
stimulation procedure where auditory and visual stimuli were temporally and spatially
correlated. Such repetitive audiovisual stimulation programs induce a functional and
anatomical reorganization of the visual connectivity in sub-cortical and cortical structures
over time mediated by perceptual learning and synaptic plasticity.
The investigators have developed an audiovisual stimulation procedure using immersive virtual
reality (IVR) in head-mounted display (HMD) as a delivery platform. IVR is an emerging and
very promising approach for visual and auditory rehabilitation. There are currently limited
practical results whether this technology is suitable for low-vision patients to use at home
and if it can be deployed on a large scale. A few case report/series studies suggested a
potential effectiveness of IVR on visual perception in teenagers and young adults but more
information as to the potential of use and effectiveness of this technology is necessary.
Real-time measurement of task performance and neurophysiological signals while immersed in
virtual reality can bring many benefits, from monitoring experience-related factors to the
development of bio/neuromarkers. In Multiple Object Tracking in 3D (3D-MOT), visual tracking
and detection is directly influenced by the speed of the spheres and is tailored to the
participants' performance using an adapted design to efficiently reach perceptual threshold,
therefore constantly challenging the patient's perceptual abilities. Progress made by the
participants can be evaluated following real-time measures such as speed of the spheres,
percentage of positive hits and reaction time. These outcomes naturally increase over
sessions as a learning effect (generally around 5-6 sessions in our settings) but then
quickly stabilize. Further progress of performance is related to improvement in vision as a
strong correlation between performance at 3D-MOT and functional vision outcomes is observed
in our pilot studies.
Eye-tracking measures eye position and movement using pupil position to infer fixation, gaze
durations, saccadic velocities and saccadic amplitudes which altogether reveal strategies
that lead to successful detection and tracking. Eye-tracking has been extensively used during
the 3D-MOT task to describe the strategies of attention allocation during visual tracking.
Target/head/eye-tracking measures (positions recorded every 14 ms
- - 90Hz) will be used to
investigate the visual strategies (head movement, saccades, fixation, smooth pursuit)
developed by the participants to track the targets in 3D-MOT.
Visual field recovery and restoration from hemianopsia has been postulated to occur from both
improved function of perilesional tissue and recruitment of additional cortical structures to
assume the function of the permanently damaged centers. However, longitudinal studies
detailing functional and structural changes in the visual system before and after treatment
are lacking. EEG recordings in individuals with hemianopsia revealed some residual activity
in V1. Here, brain activity in V1 will be measured before and after treatment and in
comparison between control and treated group using visually evoked potential (VEP). Retinal
anatomy changes will be investigated between control and treated group by measuring the
ganglion cell complex (GCC) integrity and the retinal nerve fiber layer (RNFL) thickness,
indicative of retinal ganglion cell atrophy using spectral domain optic coherence tomography
(SD-OCT), a non-invasive imaging technique. Brain scans (Diffusion MRI, Retinotopy) will be
performed using a 3T MRI at the Toronto site (Advanced MRI, Toronto Western Hospital,
University Health Network) to visualize the integrity (optic radiation) and activity (primary
visual cortex) of the visual system between control and treated group.
Hypothesis: Home-based audiovisual 3D-MOT IVR stimulation program will improve visual
perception (primary outcome Esterman binocular field test, +3 points perceived) in the blind
field of individuals with hemianopsia and increase contrast sensitivity, fixation stability,
reading speed and quality of life (secondary outcomes).
Following the ORBIT model, a phase IIa/b, single blind (to assessor), prospective,
randomized, controlled, multi-centre, cross-over study involving 5 academic centres in Canada
(St Justine
- - Montreal, CHUL - Quebec, Alberta Children's Hospital - Calgary, BC Children's
Hospital - Vancouver and Hospital for Sick Children - Toronto) will be performed.
Participants will be randomized into 2 groups: Group 1 receives no treatment for the first 8
weeks and then start the 3D-MOT IVR program. Group 2 starts with 3D-MOT IVR and then switches
to an observation period for 8 weeks. Using this cross-over design, outcome measures at week
8 (W8
- - Period 1) will assess the effectiveness of 3D-MOT stimulation between the control
non-treated (G 1) and treated (G 2) groups (independent measures).
Primary outcomes
assessment at week 16 (W16
- - Period 2) will measure the effectiveness of 3D-MOT IVR within
Group 1 (internal control, repeated measures) and the sustainability of the treatment in
Group 2 (repeated measures).
Visual assessments will be performed at baseline, 8 and 16 weeks
with follow-ups at 20 and 40 weeks (W21, W42).
Population:
Male and female individuals aged 10
- - 40 years old diagnosed with hemianopsia consecutive to
a brain tumour with no prior visual rehabilitation interventions.
Intervention:
3D-MOT in immersive virtual reality:
- - 1 session every 2 days (± 1 day) for 8 weeks (28 sessions total)
- 1 session = 3 blocks of 15 audiovisual stimulation tasks (2 min break between each
block).
- - 1 task = 20 seconds audiovisual IVR stimulation (3D-MOT + correlated sound).
Rest time
is 30 sec. to 2 min. between blocks. 1 session lasts 19 min. The duration of subject's
participation is 8 months, including follow-up. Treatment period: 8 weeks Follow-up
period: 6 months The expected frequency and duration of study visits (anticipated time
commitment) for study participants Screening/inclusion visit: 2-3 hours (visit 1) Period
change visit: 1.5 hours (visit 2) Final visit: 2 hours (visit 3) Follow-up visit 1
month: 1.5 hours (visit 4) Follow-up visit 6 months: 1.5 hours (visit 5)
Primary outcome, the Esterman binocular field testing will be performed at the ophthalmology
clinic of the participating centers at baseline, week 8, week 16 and follow-up at week 21 and
week 42.
There are no risks for participants enrolled in the study. The use of IVR may cause moderate
dizziness, nausea or disorientation for continuous stimulation above 10 minutes. If nausea,
dizziness or disorientation is experienced during IVR stimulation, stopping the VR
stimulation immediately restores normal condition.
Participants will be assessed for IVR sensitivity using the Virtual reality Induced Symptoms
and Effects (VRISE) questionnaire score at inclusion (exclusion criteria: three
- (3)
consecutive VRISE score <25).
At-home continuous VR stimulation will be 5 minutes of
continuous stimulation, below the critical 10 minutes threshold inducing effects and
symptoms.
Bias minimization:
- - Selection bias will be addressed by randomly assigning participants to treatment or
reference group using a permuted block randomization approach (block size = 2).
- - Attrition bias will be addressed by including all participants who were randomized into
the study (intention-to-treat analysis).
- - Performance and detection biases will be partially controlled for as primary outcome
assessors will be blind of the assigned group (single blinding).
- - Reporting bias will be minimized by reporting all statistically and clinically
significant and non-significant results in publications.
Procedures for monitoring subject compliance. Compliance will be monitored in real-time after
each block of tasks. Data are sent to dedicated and secured laboratory computer via Wi-Fi in
a .csv file containing the date, time, duration and performance of the 3D-MOT IVR stimulation
performed. If no files received for 72 hours, the research team will contact the participants
by phone and/or email to inquire about the absence of data received. Action will be taken
accordingly. Experience has shown that the main reason for the absence of data for 72 hours
is a lost Wi-Fi connection. As soon as Wi-Fi connection is restored, all non-sent data will
be sent automatically with timestamp.
Safety parameters:
AEs will be the safety endpoints. Known AEs induced by IVR stimulation are nausea, dizziness
and disorientation. The severity of these AEs will be scored using the validated VRISE
questionnaire40. Three
- (3) consecutive VRISE scores <25 is considered as an AE.
VRISE questionnaire will be recorded electronically (.csv file) after each home-based session
(every 2 days) and sent via Wi-Fi to a dedicated and secured laboratory computer in
real-time.
AE reporting will begin at the time of signing of the informed consent (screening) and will
continue until discharge from the study. AEs will be elicited by:
- - spontaneous report by participants, partner/caregiver and/or healthcare staff,
- by 3 consecutive VRISE scores < 25,
- by observation (by the investigators and/or healthcare staff).
AEs due to IVR
stimulation resolve as soon as the stimulation stops. Investigators will follow-up the
participant at 24 hours by phone or email assessing the severity of the AEs using the
VRISE questionnaire.
Statistical methods:
Analysis will be performed following an Intention-To-Treat (ITT) approach. Results will be
reported using descriptive statistics (including frequency distributions, a measure of
central tendency and a measure of dispersion) of the primary outcome, average VRISE scores
and secondary outcomes. Data will be analyzed using the statistical software JASP.
Statistical comparison between the 2 groups and strata for the primary outcome will be made
using Bayesian and frequentist two-way ANOVA with repeated measures.
