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.
