The Effectiveness of Non-pharmacological Treatments for Vestibular and Oculomotor Decits in Post-concussive Syndrome: a Protocol for a Systematic Review and Meta-analysis

Background: Concussion is a form of mild traumatic brain injury (mTBI) that disrupts brain function. Although symptoms are mostly transient, recovery can be delayed and result in post-concussive syndrome (PCS). Vestibular and oculomotor decits are among the most debilitating impairments associated with PCS. Non-pharmacological interventions provide treatment with limited side effects in comparison to pharmacological interventions. The aim of this review is to synthesise and evaluate the effectiveness of non-pharmacological interventions that have been used to target vestibular and oculomotor decits in PCS. Methods: Advanced searches will be conducted in electronic databases to identify articles eligible for inclusion. Studies employing non-pharmacological treatments for vestibular and/or oculomotor dysfunction in PCS will be included if they meet the eligibility criteria. Outcomes will be those pertaining to measures of oculomotor and vestibular function, in addition to adverse events. Meta-analysis will be undertaken using a random effects model followed by an assessment of clinical signicance for each outcome as published in literature. Discussion: While non-pharmacological interventions are used commonly to treat vestibular and oculomotor decits in PCS, the effectiveness of these treatments is yet to be completely elucidated. The present review will explore the effectiveness of non-pharmacological treatments for vestibular and oculomotor decits in PCS to inform practice and future research.

The Effectiveness of Non-pharmacological Treatments for Vestibular and Oculomotor De cits in Post-concussive Syndrome: a Protocol for a Systematic Review and Meta-analysis dysfunction in PCS will be included if they meet the eligibility criteria. Outcomes will be those pertaining to measures of oculomotor and vestibular function, in addition to adverse events. Meta-analysis will be undertaken using a random effects model followed by an assessment of clinical signi cance for each outcome as published in literature.
Discussion: While non-pharmacological interventions are used commonly to treat vestibular and oculomotor de cits in PCS, the effectiveness of these treatments is yet to be completely elucidated. The present review will explore the effectiveness of non-pharmacological treatments for vestibular and oculomotor de cits in PCS to inform practice and future research.
Systematic review registration: PROSPERO CRD42021254720 Background Traumatic brain injuries (TBIs) occur in approximately 69 million individuals each year (1). These injuries are induced by impulsive forces to the head, face, or neck, resulting in the disruption of brain function (2). According to a recent study, the most common causes of TBI were falls (47.2%), road accidents (13.7%), and blunt head trauma (15.4%) (3). However, there is a clear trend of under-reporting these types of injuries (4)(5)(6)(7)(8).
Given the impacts of vestibular and oculomotor de cits in PCS, there is a need for effective treatment strategies. Both pharmacological and non-pharmacological interventions are available to treat VOR de cits. However, such pharmacological treatments are commonly associated with side effects, including sedation, drowsiness and dizziness (28). Further, while pharmacological treatments may alleviate concussive symptoms, research suggests such interventions may mask underlying neural dysfunction (20), delay central compensatory mechanisms and contribute to prolonged recovery (15). Others nd inconclusive support of pharmacology in PCA (29). Non-pharmacological interventions are therefore recommended commonly. Here, we present a protocol for a systematic review and meta-analysis that aims to synthesis and evaluate the effectiveness of non-pharmacological interventions used to target vestibular and oculomotor functional de cits in PCS.

Methods/design
This protocol was prepared in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) (30).The protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42021254720).

Review question
What is the effectiveness of non-pharmacological treatments for vestibular and oculomotor de cits in post-concussive syndrome?
Search strategy Searches will be conducted in MEDLINE, PubMed, Web of Science and Scopus. The clinical trials registries of the World Health Organisation (who.int/ictrp/en), US (ClinicalTrials.gov), UK (ukctg.nihr.ac.uk) and Australia/New Zealand (anzctr.org.au) will also be searched. No limits will be placed upon language or location of publication. Keywords and medical subject headings (MeSH) related to PCS treatments for vestibular and oculomotor de cits will be used. The core search strategy, which will be modi ed depending upon the requirements of each database, is presented in Table 1. Table 1. Advanced search strategy (Concuss* OR PCS OR post-concuss* OR "mild traumatic brain injury" OR mTBI OR coup-countercoup OR "head injury" OR "head trauma" OR "second impact syndrome") AND (Vestibular ocular re ex OR vestibular OR VRT OR gaze OR stabili#ation OR exercise OR repositioning OR oculomotor OR Physical Therapy OR habituation OR postural OR balance OR stimulation OR TMS OR rTMS OR tACS OR tDCS OR ECS OR TBS).

Other resources
Google Scholar will be searched using derivations of "vestibular", "oculomotor", and "post-concussion" for additional studies. Due to the large quantity of paper retrieved through Google Scholar searches, only the rst 100 articles for each search will be screened for relevance. The reference lists of all relevant articles will be analysed to identify additional trials. Studies from these sources satisfying the eligibility criteria will be included in the systematic review.

Eligibility criteria
Types of participants No restrictions will be placed upon participant age or gender. Only populations with post-concussion syndrome (PCS) will be eligible for inclusion. For this review, PCS ide ned as any number of postconcussive symptoms persisting for greater than 3 months after a mTBI/concussion (12,14,16

Interventions
Studies of non-pharmacological treatment for vestibular and oculomotor functional outcomes will be included. Such interventions may include, but are not limited to, vestibular rehabilitation, optokinetic stimulation and VOR exercises. These interventions will be compared to control group comparisons that may be either no treatment or under sham conditions.

Outcomes
Primary outcomes will include measures of oculomotor and vestibular function. Assessments of oculomotor function will include versional eye movements (pursuit, saccades), vergence eye movements (convergence and divergence), and visual-xation movements (gaze holding, optokinetic responses, VOR). Assessments of vestibular function and balance will include the Fukuda Step test, functional balance tests, force displacement tests with eyes open and/or closed, as well as subjective reports of balance disruption and vertigo. A secondary outcome will include any information provided on adverse events associated with the non-pharmacological interventions for PCS.

Data management
Search results will be exported to a citation software (EndNote X9) for automated removal of duplicated articles. Duplicates overlooked by the programme will be manually removed. After the removal of duplicates, two independent reviewers will screen remaining articles by title and abstract for relevance using Covidence software (https://www.covidence.org/). These reviewers will subsequently retrieve fulltext versions of successfully screened articles and assess these according to the eligibility criteria. An additional reviewer will be consulted where any uncertainty or disagreement regarding the eligibility of studies arises. This selection process will be piloted by the two reviewers prior to commencement of the study screening process. Excluded studies and reasons for exclusions will be recorded.

Data extraction
Two reviewers will independently extract data from the nal list of included studies using a standardised data extraction form, after which the data will be entered into an electronic spreadsheet. The following data, where applicable, will be extracted: study details (author, year, sample size, study design, date of publication, country of publication), participant characteristics (sample size, diagnosis/symptoms, age, sex), treatment characteristics, outcome measures, treatment effects (mean and SD).

Assessment of methodological quality
The methodological quality of each study will be assessed using the Physiotherapy Evidence Database (PEDro) scale (31). This tool demonstrates high inter-rater reliability and assesses the internal and external validity (31). Additionally, the PEDro scale has been identi ed as more relevant than other tools commonly used to appraise rehabilitation-based intervention studies (32). Items will be scored as either present (1) or absent (0), and a score out of 10 will be achieved via summation. Disagreements will be resolved by discussion. Studies scoring six or more will be classi ed as high quality, and studies scoring ve or less will be classi ed as low quality.
If su cient data are available for meta-analysis, the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool will be used to assess the certainty and quality of evidence (33). Outcomes will be downgraded if the included studies have a signi cant risk of bias, considerable heterogeneity of results, do not meet the PICO criteria, contain a low sample size, or if con dence intervals (CI) cross the minimal clinically important difference (MCID).
Strategy for data synthesis Standardized mean differences (SMD) between end-scores will be calculated. If studies report baseline differences between active and control groups, relative changes from baseline will be calculated. Metaanalyses will be undertaken using a random effects model if data are available from at least two studies. A p-value of < 0.05 will be deemed statistically signi cant. Clinical signi cance will be assessed by comparing the results of the meta-analysis to the minimal clinical important difference (MCID) for each outcome as published in the literature. The impact of heterogeneity will be calculated using the I² statistic and interpreted as follows: 0%-40% may be unimportant; 30%-60% may represent moderate heterogeneity; 50%-90% may represent substantial heterogeneity; and 75%-100% represents considerable heterogeneity (34). Separate meta-analyses will be performed for each intervention. If insu cient data is available, data will be synthesized descriptively.

Discussion
To our knowledge, this review will be the rst to systematically explore the effectiveness of nonpharmacological treatments for vestibular and oculomotor de cits in PCS. This research may establish support for the discovery and optimization of treatments for targeted use in PCS populations. The review will also facilitate further research opportunities in this area.

Limitations
Limiting data to full-text published articles may introduce bias through exclusion of data in grey literature. Given that studies with desirable or signi cant results are more likely to be granted publication, a 'publication bias' may increase estimations of reliable estimates (35).

Ethics and dissemination
This review does not require ethical approval. Results of this review will be presented at scienti c meetings and published in peer-reviewed journals. All publications and presentations related to the study will be authorised and reviewed by the study investigators.

Review status
Page 7/10 The reviewers have commenced searching relevant studies on the electronic databases. This review is

Consent for publication
All authors consent to the publication of this manuscript.
Availability of data and material

Competing interests
The authors declare that they have no competing interests.

Funding
There is no funding to declare.
Authors' contributions SRS is the guarantor of the review protocol and wrote the draft protocol for the systematic review. All authors, SRS, RC, SJS, and CJB, contributed equally to the design, writing, and editing of the study protocol. All authors agree to be accountable for all aspects of the work to ensure the accuracy and integrity of the work are appropriately investigated and resolved.