Nervous System Diseases

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Symptoms and General Pathology

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Stroke

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Brain Injuries, Traumatic

Brain Neoplasms

Vision, Low

Hemianopsia

Brain Diseases

Central Nervous System Diseases

Craniocerebral Trauma

Trauma, Nervous System

Central Nervous System Neoplasms

Nervous System Neoplasms

Vision Disorders

Sensation Disorders

Neurologic Manifestations

Blindness

Quality of Life

The patients will undergo baseline assessment and receive the intervention, being assessed after the intervention.

The patients will perform the same tests for assessment as in group A, however, no intervention will be done. They may enrol in the study as group B after completing group B participation.

The training of oculomotor functions is done on the biofeedback module of a microperimeter MAIA.

Biofeedback training

MONICA DAIBERT NIDO, MD

Monica Daibert Nido, MD

Patients with brain injury secondary to stroke, surgery, or trauma frequently suffer from homonymous hemianopia, defined as vision loss in one hemifield secondary to retro- chiasmal lesion. Classic and effective saccadic compensatory training therapies are current aim to reorganize the control of visual information processing and eye movements or, in other words, to induce or improve oculomotor adaptation to visual field loss. Patients learn to intentionally shift their eyes and, thus, their visual field border, into the area corresponding to their blind visual field. This shift brings the visual information from the blind hemifield into the seeing hemifield for further processing. Patients learn, therefore, to efficiently use their eyes "to keep the 'blind side' in sight". Biofeedback training (BT) is the latest and newest technique for oculomotor control training in cases with low vision when using available modules in the new microperimetry instruments. Studies in the literature highlighted positive benefits from using BT in a variety of central vision loss, nystagmus cases, and others.The purpose of this study is to assess systematically the impact of BT in a series of cases with hemianopia and formulate guidelines for further use of this intervention in vision rehabilitation of hemianopia cases in general.

Background

Patients with brain injury secondary to stroke, surgery, or trauma frequently suffer from homonymous hemianopia, defined as vision loss in one hemifield secondary to retro- chiasmal lesion. About 45% of stroke survivors have homonymous hemianopia. A deficit in vision and spatial perception can cause slowdown of the rehabilitation progress in physiotherapy.

According to Kerkhoff 1patients face three main visual behavioral problems: (1) impaired eye movements (including saccades) leading to defective visual and spatial exploration, (2) hemianopic reading deficit (hemianopic alexia) because of the parafoveal field loss and (3) deviated subjective midline. Hemianopic dyslexia is not simply the product of the visual field defect but is caused by a disorder of control of visual information processing and eye movements in reading.

Most important, the capability to read is fundamental for daily living and an essential prerequisite for education and success in our modern society, so this disorder can have a profound effect on patients' lives. Patients with visual field loss usually fail to adapt to their reading impairment (80% of cases). In these cases, word identification and the abilities to plan and guide reading eye movements are disturbed.

In spite of these facts, visual rehabilitation program on a larger scale is still missing in most rehabilitation centers and clinics. This is decurrent to the generalized belief that lesions of the lateral geniculate nucleus and striate cortex lead to a permanent loss of vision. According to scientific findings, this does not always have to be true.

Classic and effective saccadic compensatory training therapies are current.5 They aim to reorganize the control of visual information processing and eye movements or, in other words, to induce or improve oculomotor adaptation to visual field loss. Such therapies involve the systematic and repetitive practice of specific eye movements for reading or for visual exploration. Patients learn to intentionally shift their eyes and, thus, their visual field border, into the area corresponding to their blind visual field. This shift brings the visual information from the blind hemifield into the seeing hemifield for further processing. Patients learn, therefore, to efficiently use their eyes "to keep the 'blind side' in sight". The training-induced, efficient oculomotor adaptation to visual field loss becomes manifest as a change of reading (or visual exploration) eye-movement patterns and indicates the functional reorganization of the control of visual information processing and eye movements.6

Biofeedback training for active eye movement control was never used in hemianopia cases before. Biofeedback training (BT) is the latest and newest technique for oculomotor control training in cases with low vision when using available modules in the new microperimetry instruments.7-9 Studies in the literature highlighted positive benefits from using BT in a variety of central vision loss, nystagmus cases, and others.10-18 The purpose of this study is to assess systematically the impact of BT in a series of cases with hemianopia and formulate guidelines for further use of this intervention in vision rehabilitation of hemianopia cases in general.

Rationale for the study

The deviation of the subjective midline in hemianopia cases brings visual perception from a line of objects in the surrounds to be at a much higher-level of perception/cognition, thus disturbing reading, gait and balance. Besides that, impaired saccades also cause wrong exploration patterns and deteriorated visual search. It results in the prolonged exploration time of a scene and can lead to significant problems in daily life such as inability to navigate around various obstacles (cars, people and other objects). It also causes a cognitive deficit while extracting information from a visual scene. 1 A combination of factors such as reduced contrast sensitivity, impaired visual search and inaccurate fixation contributes to the matter.

Visual information extraction from the parafoveal visual field provides the basis for planning and guiding of reading eye movements. Therefore, patients with hemianopia have difficulties in shifting their gaze systematically from left to right (in right-sided field loss) or finding the beginning of a new line (in left sided field loss). Such eye movements are optimized by visual feedback. BT promotes luminous and auditory biofeedback, which potentializes its efficacy in vision rehabilitation.

BT in the microperimeter module provides the accurate and efficient oculomotor training necessary to relocate the subjective midline to the seeing field in 1-20 or even more, as needed. BT also improves dramatically fixation stability and saccades. The advantage of this training method over classic training is potentially great. Firstly, the highest retinal sensitivity convenient point can be identified considering the whole visual field. The microperimeter provides real time scrutiny of ocular movements on a screen, and the therapist is able to select precisely the trained retinal locus (FFT) to be used by the patient on top of the microperimeter visual field. Finally, according to the patients' response the FFT can be readjusted. Eight cases trained with BT for hemianopia in our low vision rehabilitation (LVR) service had marked improvements in fixation stability, and microperimeter fields.

Expansion of visual space in the direction of the blind field and compression of visual space in the direction of the seeing field may be a contributory factor to the altered perception of their egocentric directional sense and overall more veridical mapping of their visual space, as well as the resultant shift in their positional centre of gravity. We hypothesize that BT promotes this field relocation.

Conventional visual exploration training studies have confirmed that 10 to 25 training sessions in a 6-week period can be effective for hemianopia patients to adopt these strategies. BT is able to achieve significant results in 5 weekly sessions of 20 minutes each, according to 8 cases treated in our service.

Study hypothesis

The visual and audio parts of the BT program improve in a synergistic way oculomotor control through attention improvement and volitional eye movements towards pre-designated targets. Improved oculomotor control results in better fixation stability of eyes. Better fixation stability in turn results in better navigation for distance and near vision reading. Dual sensory BT is a therapy used in low vision for more than ten years, showing good results for near and distance vision in cases with macular degeneration and other pathologies. The study hypothesis, never tested before, is that BT in cases with hemianopia will impact positively oculomotor control and visual acuity as it was proven to do in cases with macular degeneration.

Significance of the study

Vision is a major sensory input to the human brain. Half of the afferent neuronal fibers projecting to the brain originate from the eyes. Intact visual abilities are an important condition enabling us to orient ourselves in our world. Pambakian and Kennard 20 reported that 50% of all neurological admissions into hospitals in the United Kingdom are due to a stroke and 30% percent of them are reported to have hemianopia.

Numbers of hemianopic patients reported in the Czech Republic are similar and somewhat lower due to differences in diagnostics and classification of nosological units.21 Visual impairments are present in 20 to 40% of patients in neurological rehabilitation centers.

If brain visual plasticity is possible to be achieved from conventional vision training methods, specialized training with BT needs to be investigated as a tool to improve significantly a cortical visual disorder. There is need for simple and more effective visual training which could be used in LVR in large scale for hemianopia cases. Furthermore, BT needs to be evaluated in terms of quality of life (QoL) improvement to the patients.

The objectives set for this trial is to verify if BT impacts on oculomotor control in cases with hemianopia and results in better fixation stability, reading speed and QoL in those trained with BT.

A group of patients have the intervention and another group has control tests. The control group crosses over to the interventional group

The assessor does not know if the patient is in the control group, treatment group or cross over group.

Biofeedback for Hemianopia Vision Rehabilitation

Biofeedback Training to Improve Fixation Stability, Visual Function Outcomes, and Quality of Life in Hemianopia Cases

As measure by the MAIA microperimeter at the BCEA 63% ellipse area.

Paracentral (2 central vertical columns) and total average in dB as measured by the MAIA microperimeter.

Measured with the Colenbrander 100% charts

As measured with the Massof - 48 questionnaire

University of Toronto

University Health Network, Toronto

Assistant Professor

Rare Diseases

Brain Tumor, Childhood

8-week audiovisual stimulation followed by 8-week no intervention

8-week no intervention followed by 8-week audiovisual stimulation

The MOT IVR audiovisual stimulation task involves the 3D multiple-object-tracking paradigm composed of 6-8 high-contrast spheres which features are adapted to the visual ability of individuals with low-vision (luminosity = 80 nits, size = 1° to 3° visual angle). The spheres move for 20s. following random linear paths, bouncing on one another and on the walls of a virtual 3D cube when collisions occur. The participant, comfortably seated, is asked to track the moving cued target among moving distractors for 20s. A spatial sound is correlated to the movement of the cued target. After 20s., the movement stops and the participant is asked to select, using a laser pointer, the cued sphere among the distractors (mark-all procedure). Speed of the spheres is regulated by a staircase 1:1 procedure. The stimulation can here be stopped by the participant if required. After 3 blocks of 15x20s., the system stops and goes on stand-by mode until the next session. Data are collected in real time.

Audiovisual stimulation

Michael Reber, PhD

Eric Bouffet, MD

Lucie Lafay-Cousin, MD

Sylvia Cheng, MD

Uri Tabori, MD

Inci Yaman Bajin, MD

Sebastien Perreault, MD

Valerie Larouche, MD

Brain malignancies are the most common cause of death from cancer in the pediatric population and a major source of morbidity amongst survivors. Many children with a brain tumour often suffer from visual field defects (hemianopia) dramatically impacting their daily life with poorer social interaction, difficulties learning, playing sports and engaging with peers. Practically, they bump into people and objects and have problems in finding their way in unfamiliar places and in detecting incoming objects in their blind field. There is growing recognition of the diverse and deep impact of hemianopia on physical and mental health, quality of life, and social outcomes of the affected individuals and their family. However, despite the frequent impact of brain tumours on the visual function and functional vision, ophthalmologic evaluations are not standard of care for all brain tumour patients and there are no standardized protocols of vision loss management in the pediatric population with hemianopia. There is an unmet need of restoring perception in the blind field in individuals with hemianopia consecutive to pediatric brain tumor.

Our laboratory has developed a visual rehabilitation procedure based on the combination of adaptative audio and visual target tracking in a 3D environment in virtual reality. Participants perform audiovisual stimulation at home in a headset, with remote control from the laboratory. Preliminary on data on paediatric patients with hemianopia consecutive to a brain tumour indicate feasibility and potential effectiveness of a 6-week Re:Vision program on visual fields, visual perception and quality of life.

Our objective is to evaluate the effectiveness of Re:Vision, an 8-week visual telerehabilitation program, on visual perception in 50 individuals aged 10-40 years old with hemianopia consecutive to a pediatric brain tumor in a phase IIa/b multi-centric clinical study across Canada.

This intervention provides more equitable access to individuals, with the ability to receive rehabilitation therapy at home without supervision by a healthcare professional, meaning that Canadians living outside urban centres could take advantage of specialized therapies with remote supervision. This is the first study that could lead to a major change in the management of these patients. It could open the door for visual rehabilitation strategies to other population of visually impaired children, significantly impacting public health strategies.

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.

Visual Telerehabilitation in Children, Adolescents and Young Adults With Hemianopsia Consecutive to a Brain Tumour

Effectiveness of a Visual Telerehabilitation Program on Visual Perception in Children, Adolescents and Young Adults With Hemianopsia Consecutive to a Brain Tumour.

It is not yet known if there will be a plan to make IPD available. Will decide after consulting with all site lead investigators.

Difference in brain activity (VEP EEG) between intervention and non-intervention groups and pre/post-intervention. Measures of N75, P100 and N175 latency (ms) and amplitude (microV) during monocular pattern reversal stimulation.

Difference in retinal fiber layer thickness (RNFL) between intervention and non-intervention groups and pre/post-intervention

Measures of optic tract density will be performed by diffusion tensor MRI (DTI - fractional anisotropy, tractography) between intervention and non-intervention groups and pre/post-intervention

Retinotopic visual stimulation will be performed by visual stimulation at 4 different retinal positions and measured using population receptive field (voxels value) between intervention and non-intervention groups and pre/post-intervention

Head position during the 3D-MOT will be measured as a function of time along the horizontal and vertical axes in degree and compared between each session.

Eyes positions during the 3D-MOT will be measured as a function of time along the horizontal and vertical axes in degree and compared between each session.

Difference in the number of points perceived in the Esterman binocular field test between intervention and non-intervention groups and pre/post-intervention

Difference in quality of vision questionnaire scores between intervention and non-intervention groups and pre/post-intervention. Scores are from 0 to 100. High scores represents better outcome.

Difference in the number of words per minute (at critical print size) between intervention and non-intervention groups and pre/post-intervention

Difference in fixation stability (BCEA 63%, degree square) between intervention and non-intervention groups and pre/post-intervention

Difference in contrast sensitivity (logit) bewteen intervention and non-intervention groups and pre/post-intervention

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Biofeedback for Hemianopia Vision Rehabilitation	NCT05397873	Hemianopsia, Ho... Brain Injury Stroke Brain Tumor Brain Trauma	Biofeedback tra...	18 Years - 90 Years	University Health Network, Toronto
Visual Telerehabilitation in Children, Adolescents and Young Adults With Hemianopsia Consecutive to a Brain Tumour	NCT06362434	Hemianopsia	Audiovisual sti...	10 Years - 40 Years	University Health Network, Toronto
Biofeedback for Hemianopia Vision Rehabilitation	NCT05397873	Hemianopsia, Ho... Brain Injury Stroke Brain Tumor Brain Trauma	Biofeedback tra...	18 Years - 90 Years	University Health Network, Toronto
Visual Telerehabilitation in Children, Adolescents and Young Adults With Hemianopsia Consecutive to a Brain Tumour	NCT06362434	Hemianopsia	Audiovisual sti...	10 Years - 40 Years	University Health Network, Toronto

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