Authors: Stella Sheeba, Rocco Cavaleri, Simon Summers, Cherylea Browne
Categories: Neurology, Neurological injury, Rehabilitation medicine, TRAUMA MANAGEMENT, 1506, 1713
Source: BMJ Open
Concussion is a form of mild traumatic brain injury that disrupts brain function. Although symptoms are mostly transient, recovery can be delayed and result in persistent postconcussive symptoms (PPCS). Vestibular and oculomotor dysfunction are among the most debilitating impairments associated with PPCS. However, pharmacological interventions for these impairments are associated with deleterious side effects. Accordingly, increasing research has examined the utility of non-pharmacological interventions for PPCS. The aim of this review is to synthesise and evaluate the effectiveness of non-pharmacological interventions for the treatment of vestibular and oculomotor dysfunction for patients with PPCS.
Systematic searches of MEDLINE, PubMed, Web of Science and Scopus will identify randomised controlled trials employing non-pharmacological treatments for vestibular and/or oculomotor dysfunction for PPCS. Such interventions may include, but are not limited to, vestibular rehabilitation, optokinetic stimulation and vestibulo-ocular reflex exercises. Assessments of oculomotor function will include versional eye movements, vergence eye movements, visual-fixation movements and accommodation response. Assessments of vestibular function will include the Fukuda Step test, functional balance tests, force displacement tests, and subjective reports of balance disruption or vertigo. Where appropriate, meta-analyses of standardised mean differences will be conducted using a random effects model for continuous outcomes. For dichotomous outcomes (improved vs not improved following treatment), effects will be expressed as relative risk. The impact of heterogeneity will be calculated using the I^2^ statistic. The Physiotherapy Evidence Database scale will be used to determine the methodological quality of individual studies and Grading of Recommendations, Assessment, Development and Evaluations used to assess the certainty and quality of evidence for each outcome.
Ethical approval is not required for this review. Findings will be disseminated through peer-reviewed publications and conference presentations.
CRD42021254720.
Keywords: TRAUMA MANAGEMENT, Neurology, Rehabilitation medicine, Neurological injury
A concussion, or mild traumatic brain injury (mTBI), is the most common form of traumatic brain injury.^1 2^ These injuries are induced by impulsive forces to the head, face or neck, resulting in the disruption of brain function.^3^ Common symptoms associated with a concussion include headaches, dizziness, mood changes, light sensitivity, fatigue and impaired concentration.^4–7^ While these acute symptoms resolve within days for most people, a subset of individuals do not recover fully and experience symptoms that persist beyond 3 months.^7–10^ These individuals are categorised as having ‘persistent postconcussive symptoms’ (PPCS).^7 9 11^ It is estimated that 5%–43% of individuals with concussion experience postconcussive symptoms, with 22% presenting with three or more persistent symptoms.^12 13^ Given that there are currently no universal guidelines for diagnosing PPCS, prevalence rates vary significantly across studies.
Vestibular and oculomotor dysfunction are well-documented in patients with PPCS.^14–18^ The vestibulo-ocular reflex (VOR) is a complex reflex that serves to maintain balance and spatial orientation by stabilising the gaze during head movement.^19^ Case studies have shown VOR disruption in those with PPCS.^20 21^ Common complaints of vestibular dysfunction include dizziness, vertigo, nausea, fogginess, unsteady gait and postural instability.^15 22^ The most common oculomotor disorders following a concussion are convergence insufficiency (affecting the ability of eyes to work together to clearly see nearby objects) and accommodative insufficiency (difficulty when focussing on a nearby object).^23^ Symptoms associated with oculomotor dysfunction include difficulty tracking objects, motion sensitivity, eye strain or eye fatigue for near vision, and headache.^15 22^ Importantly, evidence has shown that these symptoms of vestibular and oculomotor dysfunction are strong predictors of delayed recovery for patients with PPCS.^14 15 18^
Given the impacts of vestibular and oculomotor dysfunction in patients with PPCS, there is a need for effective treatment strategies. Both pharmacological and non-pharmacological interventions are available to treat VOR dysfunction. However, pharmacological treatments have been associated with side effects in up to 16.9% of participants, including sedation, drowsiness and dizziness.^24–28^ Further, while pharmacological treatments may alleviate concussive symptoms, research suggests such interventions may mask underlying neural dysfunction,^15^ delay central compensatory mechanisms and contribute to delayed recovery.^10^ Non-pharmacological interventions are therefore recommended commonly.^10^
Non-pharmacological treatments based on individual disciplines (eg, oculomotor vision treatment or vestibular rehabilitation) have shown mild to moderate effectiveness in treating specific symptoms in patients with PPCS.^29^ Other studies have supported interdisciplinary collaboration for patients in this population, such as combining non-invasive brain stimulation with vestibular rehabilitation.^30 31^ A previous review by Rytter et al^29^ on non-pharmacological treatments for patients with PPCS synthesised the effectiveness of interdisciplinary rehabilitation. While the researchers found studies with positive results, the review excluded younger populations.^29^ Given that younger age groups are prone to develop PPCS,^32 33^ informative studies in this population may have been overlooked. Further, the previous review was conducted on generalised symptoms of PPCS rather than focussing on treatments for specific symptoms. These exclusions may have limited the results of the search strategy and subsequent analysis of their findings. Further investigations of non-pharmacological treatments targeting symptoms such as vestibular and oculomotor dysfunction in the PPCS population is warranted. Novel therapies such as non-invasive brain stimulation have yet to be synthesised in this field. This study presents a protocol for a systematic review and meta-analysis that aims to synthesis and evaluate the effectiveness of non-pharmacological interventions for the treatment of vestibular and oculomotor dysfunction in patients presenting with PPCS.
This protocol was prepared in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols.^34^ The protocol has been registered with the International Prospective Register of Systematic Reviews. The Cochrane Handbook of Systematic Reviews will also be used to guide the completion of this review.^35^
What is the effectiveness of non-pharmacological interventions for the treatment of symptoms associated with vestibular and oculomotor dysfunction in patients with postconcussive symptoms compared with sham treatment or control?
Searches will be conducted in MEDLINE, PubMed, Web of Science and Scopus from database inception. No limits will be placed on language or location of publication. Keywords and Medical Subject Headings related to PPCS treatments for vestibular and oculomotor dysfunction will be used where possible. The core search strategy, which will be modified as needed for each database, is presented in box 1. This core strategy was developed for PubMed and approved by a librarian, experienced in reviews of biomedical literature.
The clinical trials registries of the WHO (who.int/ictrp/en), USA (ClinicalTrials.gov), UK (ukctg.nihr.ac.uk) and Australia/New Zealand (anzctr.org.au) will be searched. Google Scholar will also be searched using derivations of “vestibular”, “oculomotor” and “post-concussion” for additional studies. Due to the large number of papers retrieved through Google Scholar searches, only the first 100 articles for each search will be screened for relevance. The reference lists of all full-text articles included in the review will be analysed to identify additional trials. Only peer-reviewed studies from these sources satisfying the eligibility criteria will be included in the systematic review. Where data cannot be extracted from the studies themselves, attempts to contact study authors for primary data will be made. Authors will be contacted two times, 1 week apart. If no response is received in this timeframe, the data will be considered irretrievable.
Only peer-reviewed randomised controlled trials (RCTs) (available as full-text) employing non-pharmacological interventions for the treatment of vestibular and/or oculomotor dysfunction for patients with PPCS will be included. Concussion is defined as temporary unconsciousness or confusion caused when a forceful impact on the head, face or neck alters brain function.^36^ For this review, PPCS is defined as the persistence of postconcussive symptoms for greater than 3 months after a concussion.^7 9 11^ No restrictions will be placed on participant age or gender. Only RCTs will be included in this review.
Studies of non-pharmacological treatment for vestibular and oculomotor outcomes will be included. A non-pharmacological treatment refers to an intervention where pharmaceutical medications are not considered part of the treatment.^37^ Such interventions may include, but are not limited to, vestibular rehabilitation, optokinetic stimulation and VOR exercises. These interventions will be compared with control groups that may be either no treatment or sham conditions. Interventions that have been delivered standalone or in combination with other interventions will also be included. Studies that include participants taking pharmacological treatments that may influence vestibular or oculomotor outcomes, such as gabapentin or memantine (treatments for abnormal eye movements)^38^ or vestibular suppressants (such as clonazepam and other benzodiazepines),^39^ will be excluded from this review.
Primary outcomes will include measures of oculomotor and vestibular function. Outcomes that assess both constructs concurrently will also be analysed. Assessments of oculomotor function will include analyses of (i) versional eye movements (pursuit, saccades), (ii) vergence eye movements (convergence and divergence), (iii) visual-fixation movements (gaze holding, optokinetic responses, VORs) and (iv) accommodative response. Measurement outcomes of oculomotor function are listed in table 1. Studies presenting continuous data (amplitude, duration, peak velocity and accuracy of eye movements) and dichotomous data (‘improved’ or ‘not improved’ following treatment) will be included.
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. Measurement outcomes of vestibular function are listed in table 2. Studies presenting continuous data (amplitude, duration, error count) and dichotomous data (‘improved’ or ‘not improved’ following treatment) will be included.
Assessments of combined vestibulo-oculomotor function will include VORs and vestibular/ocular-motor screening with inclusion of continuous (velocity, accuracy) and dichotomous (‘improved’ or ‘not improved’) data. Measurement outcomes of vestibulo-oculomotor function are listed in table 3. A secondary outcome will include any information provided on adverse events associated with the non-pharmacological interventions for PPCS.
The Cochrane Data Collection Form for Intervention Reviews^40^ will be used to extract study characteristics and outcome data. This will include extraction of the following study details (author, year, sample size, study design, date of publication, country of publication), participant characteristics (sample size, diagnosis/symptoms, age, sex), treatment characteristics (modality, duration, number of sessions), outcome measures, treatment effects (mean and SD). Two review authors will pilot the form on a randomly selected subset of 10% of included studies.^35^ Pilot testing of the forms will include a computation of the reviewers’ reliability. Reviewers will extract data independently and in duplicate from each eligible study.
Search results will be exported to EndNote citation software (EndNote X9) for automated removal of duplicates. Duplicates overlooked by the program will be manually removed. After removal of duplicates, two independent reviewers will screen the remaining articles by title and abstract for relevance using Covidence software (https://www.covidence.org/) in accordance with the prespecified 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.
The methodological quality of each RCT will be assessed using the Physiotherapy Evidence Database (PEDro) scale.^41^ This tool demonstrates high inter-rater reliability and assesses internal and external validity.^41^ Additionally, the PEDro scale has been identified as more relevant than other tools commonly used to appraise rehabilitation-based intervention studies.^42^ 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 6 or more will be classified as high quality, studies scoring 4 or 5 will be considered moderate quality and studies scoring less than 3 will be classified as low quality.^41^
The reporting quality of each RCT will be assessed using the Consolidated Standards of Reporting Trials guidelines.^43^ These guidelines offer a standard way for authors to prepare reports of trial findings, facilitating their complete and transparent reporting, and aiding their critical appraisal and interpretation.^43^
If sufficient 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^44^ in accordance with the guidelines provided in the Cochrane Handbook of Systematic Reviews.^35^ The GRADE system uses the following criteria for assigning ‘grades’ of
To ensure consistency of GRADE judgements the following criteria will be applied to each domain equally for all key
If insufficient data is available for meta-analysis, the GRADE criteria will be modified for a narrative synthesis in accordance with the guidelines presented by Murad et al.^45^ The potential influence of publication bias will be evaluated using Begg’s funnel plot.^46^
For continuous data, standardised mean differences between end-scores will be calculated. If studies report baseline differences between active and control groups, relative changes from baseline will be calculated. If data are available from at least two studies, meta-analyses will be performed using the software provided by the Cochrane Collaboration, Review Manager (RevMan V.5.4.1).^47^ A random-effects model will be used as methodological heterogeneity is inevitable in practitioner-administered interventions.^48^ For dichotomous data (‘improved’ or ‘not improved’ following treatment), effect measures will be expressed as relative risk.^49^ A p value of <0.05 will be deemed statistically significant.
The impact of heterogeneity will be calculated using the I² statistic and interpreted as 0%–40% may be unimportant; 30%–60% may represent moderate heterogeneity; 50%–90% may represent substantial heterogeneity and 75%–100% represents considerable heterogeneity.^35^ Separate meta-analyses will be performed for each intervention. If insufficient data is available for meta-analysis, data will be synthesised descriptively.
SSheeba and RC have both worked as on-field health professionals responsible for the assessment and management of sports-related concussions. The initial concept of this review was inspired by discussions with patients during follow-up assessments in which several indicated a need for additional non-pharmacological management strategies. There has been no further patient or public involvement beyond this early inspiration.
Limiting data to full-text published articles may introduce bias through exclusion of data in grey literature. Given that studies with desirable or significant results are more likely to be granted publication, a ‘publication bias’ may increase estimations of reliable estimates.^50^ There is also a possibility of low-level evidence for treatments of vestibular and oculomotor dysfunction in patients with postconcussive symptoms. The methodological appraisals conducted throughout this review will identify if this is the case such that recommendations to strengthen the body of evidence can be made.
This review does not require ethical approval. Results of this review will be presented at scientific meetings and published in peer-reviewed journals. All publications and presentations related to the study will be authorised and reviewed by the study investigators.
The reviewers have commenced preliminary searches of relevant databases. This review is expected to be completed by March 2023.
Not applicable.