Interventions for eye movement disorders due to acquired brain injury: Cochrane systematic review
Acquired brain injury can cause eye movement disorders which may include: strabismus, gaze deficits and nystagmus, causing visual symptoms of double, blurred or 'juddery' vision and reading difficulties. A wide range of interventions exist that have potential to alleviate or ameliorate these symptoms. There is a need to evaluate the effectiveness of these interventions and the timing of their implementation.
We aimed to assess the effectiveness of any intervention and determine the effect of timing of intervention in the treatment of strabismus, gaze deficits and nystagmus due to acquired brain injury. We considered restitutive, substitutive, compensatory or pharmacological interventions separately and compared them to control, placebo, alternative treatment or no treatment for improving ocular alignment or motility (or both).
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (containing the Cochrane Eyes and Vision Trials Register) (2017, Issue 5), MEDLINE Ovid, Embase Ovid, CINAHL EBSCO, AMED Ovid, PsycINFO Ovid, Dissertations & Theses (PQDT) database, PsycBITE (Psychological Database for Brain Impairment Treatment Efficacy), ISRCTN registry, ClinicalTrials.gov, Health Services Research Projects in Progress (HSRProj), National Eye Institute Clinical Studies Database and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The databases were last searched on 26 June 2017. No date or language restrictions were used in the electronic searches for trials. We manually searched the Australian Orthoptic Journal, British and Irish Orthoptic Journal, and ESA, ISA and IOA conference proceedings. We contacted researchers active in this field for information about further published or unpublished studies.
We included randomised controlled trials (RCTs) of any intervention for ocular alignment or motility deficits (or both) due to acquired brain injury.
Data collection and analysis
Two review authors independently selected studies and extracted data. We used standard methods expected by Cochrane. We employed the GRADE approach to interpret findings and assess the quality of the evidence.
We found five RCTs (116 participants) that were eligible for inclusion. These trials included conditions of acquired nystagmus, sixth cranial nerve palsy and traumatic brain injury-induced ocular motility defects. We did not identify any relevant studies of restitutive interventions.
We identified one UK-based trial of a substitutive intervention, in which botulinum toxin was compared with observation in 47 people with acute sixth nerve palsy. At four months after entry into the trial, people given botulinum toxin were more likely to make a full recovery (reduction in angle of deviation within 10 prism dioptres), compared with observation (risk ratio 1.19, 95% CI 0.96 to 1.48; low-certainty evidence). These same participants also achieved binocular single vision. In the injection group only, there were 2 cases of transient ptosis out of 22 participants (9%), and 4 participants out of 22 (18%) with transient vertical deviation; a total complication rate of 24% per injection and 27% per participant. All adverse events recovered. We judged the certainty of evidence as low, downgrading for risk of bias and imprecision. It was not possible to mask investigators or participants to allocation, and the follow-up between groups varied.
We identified one USA-based cross-over trial of a compensatory intervention. Oculomotor rehabilitation was compared with sham training in 12 people with mild traumatic brain injury, at least one year after the injury. We judged the evidence from this study to be very low-certainty. The study was small, data for the sham training group were not fully reported, and it was unclear if a cross-over study design was appropriate as this is an intervention with potential to have a permanent effect.
We identified three cross-over studies of pharmacological interventions for acquired nystagmus, which took place in Germany and the USA. These studies investigated two classes of pharmacological interventions: GABAergic drugs (gabapentin, baclofen) and aminopyridines (4-aminopyridines (AP), 3,4-diaminopyridine (DAP)). We judged the evidence from all three studies as very low-certainty because of small numbers of participants (which led to imprecision) and risk of bias (they were cross-over studies which did not report data in a way that permitted estimation of effect size).
One study compared gabapentin (up to 900 mg/day) with baclofen (up to 30 mg/day) in 21 people with pendular and jerk nystagmus. The follow-up period was two weeks. This study provides very low-certainty evidence that gabapentin may work better than baclofen in improving ocular motility and reducing participant-reported symptoms (oscillopsia). These effects may be different in pendular and jerk nystagmus, but without formal subgroup analysis it is unclear if the difference between the two types of nystagmus was chance finding. Quality of life was not reported. Ten participants with pendular nystagmus chose to continue treatment with gabapentin, and one with baclofen. Two participants with jerk nystagmus chose to continue treatment with gabapentin, and one with baclofen. Drug intolerance was reported in one person receiving gabapentin and in four participants receiving baclofen. Increased ataxia was reported in three participants receiving gabapentin and two participants receiving baclofen.
One study compared a single dose of 3,4-DAP (20 mg) with placebo in 17 people with downbeat nystagmus. Assessments were made 30 minutes after taking the drug. This study provides very low-certainty evidence that 3,4-DAP may reduce the mean peak slow-phase velocity, with less oscillopsia, in people with downbeat nystagmus. Three participants reported transient side effects of minor perioral/distal paraesthesia.
One study compared a single dose of 4-AP with a single dose of 3,4-DAP (both 10 mg doses) in eight people with downbeat nystagmus. Assessments were made 45 and 90 minutes after drug administration. This study provides very low-certainty evidence that both 3,4-DAP and 4-AP may reduce the mean slow-phase velocity in people with downbeat nystagmus. This effect may be stronger with 4-AP.
The included studies provide insufficient evidence to inform decisions about treatments specifically for eye movement disorders that occur following acquired brain injury. No information was obtained on the cost of treatment or measures of participant satisfaction relating to treatment options and effectiveness. It was possible to describe the outcome of treatment in each trial and ascertain the occurrence of adverse events.
Rowe Fiona J, Hanna Kerry, Evans Jennifer R, Noonan Carmel P, Garcia-Finana Marta, Dodridge Caroline S, Howard Claire, Jarvis Kathryn A, MacDiarmid Sonia L, Maan Tallat, North Lorraine, Rodgers Helen
Interventions for eye movement disorders due to acquired brain injury
What is the aim of this review?
The aim of this Cochrane Review was to find out what treatments work well to improve eye position and eye movement disorders due to acquired brain injury, and when is the best time to use them.
The evidence on the benefits and harms of treatments for eye movement disorders due to acquired brain injury is currently very low-certainty.
What was studied in this review?
Acquired brain injury is any injury that occurs after birth and causes damage to the brain's function. Strabismus is a condition in which the eyes are out of alignment, with one or both eyes turned in, out, up or down. Ocular motility (eye movement) disorders are defects that prevent normal movement of the eyes. Nystagmus is a condition where the eye movements are not steady and, instead, the eyes wobble. Treatment options include eye therapy, glasses, prisms, occlusion, botulinum toxin or surgery, to reduce the deviation or movement of the eyes. Currently there are no clear recommendations on when is best to provide these treatments, how much these treatments cost and whether treatments are of benefit to people with eye alignment and movement disorders occurring after acquired brain injury.
What are the main results of this review?
Cochrane researchers found five relevant studies with a total of 116 participants. One study was from the UK and looked at botulinum toxin compared to observation in people with recent onset sixth nerve palsy. One study from the USA compared eye movement training with sham (false) training in people with mild traumatic brain injury. Three studies took place in Germany or the USA and compared medical drug treatments in people with acquired nystagmus. The review provides:
∙ low-certainty evidence that people with sixth nerve palsy may have a slightly better chance of a reduction in visual symptoms when given botulinum toxin compared with no treatment.
∙ very low-certainty evidence on eye movement treatment for people with brain injury due to trauma and use of medical drugs for nystagmus, where treatments show slightly better improved symptoms.
How up-to-date is this review?
Cochrane researchers searched for studies that had been published up to 26 June 2017.
Implications for practice
We were unable to fully address the aims and objectives of this review due to the limited number of trials identified, the low to very low-certainty evidence, and the variations in the conditions being treated. Gabapentin and 4-aminopyridine may reduce oscillatory eye movements and improve visual acuity and participant-reported symptoms. Botulinum toxin may improve participant symptoms earlier than observation in people with sixth nerve palsy. Very low-certainty evidence on oculomotor rehabilitation suggested improved reading ability, binocular accommodation aptitude and near point of convergence in comparison to sham training. Adverse events these were specific to the interventions but were mainly mild and transient.
Implications for research
There is a clear need for good quality trials to be conducted in order to improve the evidence base for restitutive, substitutive, compensatory and pharmacological therapies for eye movement disorders following acquired brain injury. Further research is also required to consider the effect of acute versus long-term timing of interventions for these conditions.
Standardisation of research design and core outcome measures is of importance taking into consideration the types and dosages of drugs. Key characteristics for a future trial would be: adequate sample size based on sound estimates of clinically meaningful effect size; multi-centre recruitment sites; computer-generated randomisation schedule with concealed allocation; use of a core outcome set and measures (COMET-initiative); a double-masked trial design when possible (i.e. appropriate masking of participants and trial personnel); published protocol; and full outcome reporting following a pre-determined statistical analysis plan.Get full text at The Cochrane Library
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