Non‐surgical interventions for nystagmus developing in the first year of life (infantile nystagmus)
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and safety of non‐surgical interventions for nystagmus developing in the first year of life.
Background
Description of the condition
Nystagmus is an involuntary constant oscillatory movement of the eyes, which can be an isolated condition (Idiopathic) or can occur as part of eye and central nervous system disorders. Prevalence in the United Kingdom is 0.24% (Sarvananthan 2009), whereas in the United States the rate is 0.36% (preschool age) (Repka 2012). Nystagmus is known to have a significant impact on quality of life. It is known not only to affect visual function and as a result often leads to inability to drive, restrictions in occupation choice/opportunities, but also feelings about inner self and negativity about the future and relationships due to the cosmetic appearance. Nystagmus causes universal and often unrecognised distress affecting every aspect of everyday life (McLean 2012).
Traditional classification separates nystagmus into infantile/congenital where the onset is within the first year of life, and acquired, where the onset is typically after the first year of life. A more recent subclassification established in 2002 used the term "infantile nystagmus syndrome" to include all types of nystagmus occurring in the first year of life (National Eye Institute 2001).
Infantile nystagmus can be further subdivided into idiopathic (no other known associated abnormality) or sensory (known associated abnormality of the afferent visual system). Other types which may occur in the first year of life are manifest latent nystagmus (fusion maldevelopment nystagmus) and spasmus nutans. There is a much smaller subgroup which is associated with neurological abnormalities. We will not include spasmus nutans and nystagmus associated with neurological abnormalities in this review as the mechanism/aetiology differs.
Nystagmus occurring in the first year of life is often associated with reduced vision, and occasionally oscillopsia i.e. visual disturbance in which objects appear to oscillate, which is induced by the retinal image motion. There may be an associated null point or zone where the nystagmus is reduced. A compensatory head posture may be adopted to optimise vision by minimising the nystagmus.
Description of the intervention
At present, there is no gold standard for the treatment of nystagmus. Various treatments have been suggested including optical, medical and surgical. However, evidence is mostly limited to case reports, case series or both. There is also disagreement as to how to measure the benefits of treatment. The National Institute for Health and Care Excellence (NICE) guidance on one form of treatment (tenotomy of horizontal eye muscles) recommends further research and outlines outcome measures for efficacy.
As a result, there is very little evidence to guide clinicians as to the suitability and efficacy of available treatments. A variety of interventions have been described in nystagmus developing in the first year of life. This review aims to summarise the evidence available on the less interventional non surgical treatment options available for the treatment of nystagmus developing in the first year of life. Where evidence is lacking, it will highlight the need for further research. Pharmacological interventions will be addressed in a separate Cochrane Review.
Non‐surgical interventions include the following:
-
correction of refractive error in the form of spectacle or contact lens wear, including tinted where appropriate (often cycloplegic in children i.e. with paralysis of the ciliary muscle to determine the true refraction without accommodation;
-
use of contact lenses (refractive correction or plano);
-
the use of prism(s) fitted on to, or incorporated into, spectacles;
-
amblyopia management (either atropine penalisation or occlusion of the better seeing eye).
How the intervention might work
To obtain maximal visual acuity, the image of the object must be held steady on the fovea (a central depression in the retina in 'normal' eyes). This steady fixation is disrupted by nystagmus. The constant oscillation of the eyes result in position and velocity variability, and as a consequence, visual symptoms (mainly reduced vision, less frequently oscillopsia) occur due to the variable foveation time i.e. the amount of time the image is relatively stationary in the foveal area (Dell'Osso 1975; Dell'Osso 1992).
Refractive interventions work by maximally improving the clarity of the image viewed. This can be with spectacles, contact lenses and/or surgical or laser correction of the refractive error. In children and adults with or without nystagmus, contact lenses have been shown to provide better correction due to the patient viewing through the visual axis for a greater proportion of time, resulting in reduced chromatic and spherical aberration as well as prismatic effect in those with significant refractive error/astigmatism. This effect is likely to be enhanced in nystagmats due to the constant oscillatory eye movement.
In addition to the correction of refractive error and additional vergence and accommodative effort (Abadi 1979; Biousse 2004), there may be an additional effect with contact lens wear due to the proprioceptive signals from the surface of the eye providing a dampening effect on the nystagmus (Dell'Osso 1988; Taibbi 2008).
Nystagmus occurring in the first year of life is thought to typically dampen on convergence, although this is not always the case. Where appropriate, base‐out prisms artificially move the image out, which in turn stimulates convergence dampening the nystagmus where there is a convergence null (Lee 2002). Prisms may also be used to move the images where there is a null point/zone with an associated compensatory head posture, either as short term pre‐operative assessment or less commonly as longer term management.
Why it is important to do this review
Nystagmus can have a significant impact on quality of life due to the visual and psychological effects. At present, there is very little evidence as to the suitability and efficacy of available treatments options, and disagreement as to how best to measure the effects of nystagmus and treatment. As a result, most clinicians are uncertain as to how to manage nystagmus, and are often unable to offer evidence‐based treatments. This review aims to summarise the available evidence to date for optical interventions for the treatment of nystagmus developing in the first year of life.
Objectives
To assess the efficacy and safety of non‐surgical interventions for nystagmus developing in the first year of life.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs) and quasi‐randomised RCTs. If we do not find any RCTs we will provide a narrative assessment of non‐randomised evidence in the 'Discussion' section.
Types of participants
We will include all participants (of any age) with nystagmus of onset in the first year of life, including idiopathic nystagmus, nystagmus associated with a sensory abnormality and manifest latent nystagmus. We will also include people who can be classified into more than one subtype.
We will exclude participants with nystagmus of onset in the first year of life that is associated with neurological abnormalities and spamus nutans.
People with nystagmus developing after one year of life will be addressed in a separate Cochrane Review.
Types of interventions
Non‐surgical interventions will include refractive correction (spectacles and contact lenses, excluding surgical and laser correction), contact lens wear (refractive and non‐refractive), prism therapy (to optimise the use of a null point e.g. base out prisms to stimulate convergence where there is dampening of nystagmus in the null point), amblyopia management (occlusion therapy, atropine penalisation, but excluding strabismus surgery), and optical devices that negate the effects of nystagmus by simulating the waveform. We will not include systemic pharmacological interventions in this review.
We will include studies in which the non‐surgical interventions have been compared to no intervention, another non‐surgical intervention, other intervention (e.g. surgical, pharmacological).
Types of outcome measures
Primary outcomes
-
Change in best corrected binocular visual acuity (log of the minimum angle of resolution (logMAR) or Snellen acuity) measured four to six months after intervention onset (to allow for refractive adaption in children)
Secondary outcomes
-
Estimated visual acuity using pattern reversal visual evoked potentials and/or eye movement recordings four to six months after intervention onset
-
Eye movement recordings using any available technique (e.g. video, infrared limbal tracker, electro‐oculogram) four to six months after intervention onset
-
Waveform measurements may include amplitude (minimum and mean), intensity, foveation time, position (mean, minimum mean, minimum, maximum, standard deviation), velocity (mean, minimum mean, minimum, maximum, standard deviation), null zone position and width
-
Expanded nystagmus acuity function (NAFX)
-
-
Head posture measured in degrees four to six months after intervention onset
-
Visual recognition times measured four to six months after intervention onset
-
Patient satisfaction and functional measurements (including validated questionnaires e.g. the National Eye Institute Visual Functioning Questionnaire 25 (VFQ‐25)) four to six months after intervention onset
Adverse outcomes
-
Adverse events directly related to optical interventions e.g. contact lens keratitis
-
Adverse events indirectly related to optical intervention
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library), MEDLINE, EMBASE, the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en. We will not use any date or language restrictions in the electronic searches for trials.
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), mRCT (Appendix 4), ClinicalTrials.gov (Appendix 5) and the ICTRP (Appendix 6).
Searching other resources
We will manually search the following conference proceedings from the inception of the meetings to the current date:
-
British Paediatric Ophthalmology and Strabismus Association (BIPOSA)
-
International Strabismological Association (ISA)
-
European Strabismological Association (ESA)
-
International Orthoptic Association (IOA)
-
The British and Irish Orthoptic Journal and the Australian Orthoptic Journal will be manually searched.
We will also contact authors of unpublished closed trials to ask if the data from initial results would be available for inclusion in this review.
Data collection and analysis
Selection of studies
The two review authors will independently screen the titles and abstracts resulting from the electronic and manual searches. We will include all RCTs and quasi‐randomised trials in the systematic review. We will provide a narrative assessment of non‐randomised clinical trials, retrospective studies, case series and case reports in the 'Discussion' section.
We will classify abstracts as "relevant", "potentially relevant" or "not relevant" for this review.
We will retrieve and review full‐text copies of articles for those abstracts that are classified as "relevant" or "potentially relevant". The two review authors will independently assess each article and determine whether to definitely include, definitely exclude or record each trial as unclear. There will be documented agreement between review authors and we will resolve discrepancies by consensus. Any studies that are classified as unclear, we will contact the trial report authors in an attempt to include or exclude the study from the review. For full‐text articles which have been excluded, we will tabulate and provide a reason for exclusion. We will report study findings according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement.
Data extraction and management
We will extract the following participants and trial characteristics (Table 1).
| Participant characteristics | Total number Gender Age Country Type of nystagmus Diagnostic criteria Comorbidities Baseline binocular visual acuity or changed in best corrected binocular visual acuity Orthoptic assessment Participant inclusion and exclusion criteria |
| Intervention | Intervention Frequency and treatment length |
| Study and methodology | Study design Trial identifiers Study size Randomisation Masking, allocation concealment Duration of each study |
| Primary outcomes | Change in best corrected binocular visual acuity (logMAR or Snellen chart) |
| Secondary outcomes | Estimated visual acuity using visual evoked potentials and/or nystagmus acuity functions such as NAFX Eye movement recordings using any available technique (e.g. video recording, infrared limbal tracker, electro‐oculography). Amplitude (mean and minimum); intensity; foveation time; position (mean, minimum mean in foveation window, standard deviation); velocity (mean, minimum mean in foveation window, standard deviation); null zone position and width. Head posture measured in degrees Visual recognition times Patient satisfaction and functional measurements (using validated questionnaires e.g. VFQ‐25) Economic data and cost analysis data |
| Adverse outcomes | Adverse effects (minor or major: reduction in visual acuity and blindness; double vision; cognitive effects; death) |
| Additional data | Treatment compliance and losses to follow‐up |
| Missing data | Intention‐to‐treat analysis if possible Trial authors contacted? |
| Data collection | Microsoft Excel® spreadsheet |
-
Participants: age, sex, diagnosis, presence of co morbidities, exclusion and inclusion criteria.
-
Methodology: quality of each full text articles will be collected including study design.
-
Intervention: the nature of the intervention and the specific intervention applied.
-
Adverse events and quality of life measurements:
-
we will categorise reported adverse events as major or minor.
-
-
Economic data and cost‐analysis data.
The two authors will independently extract data relating to the primary and secondary outcomes onto online standardised data collection forms, which will be developed and piloted by the review authors. We will resolve discrepancies by discussion. One author will enter data into the Cochrane Collaboration statistical software, Review Manager 2014, and a second author will check the entered data.
For any category of intervention where no RCTs exist, we will describe the full‐text studies of non‐randomised studies. We will summarise these observational studies in the 'Discussion' section and not include them in the meta‐analysis.
Assessment of risk of bias in included studies
The two authors will assess the risk of bias of the selected trials according to the methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will consider the following domains:
-
sequence generation;
-
allocation concealment (selection bias);
-
blinding (masking) of participants, personnel (performance bias) and outcome assessors (detection bias);
-
incomplete outcome data (attrition bias);
-
selective outcome reporting; and
-
other sources of bias.
In relation to the effect of masking, we will consider the risk of bias separately for detection bias and performance bias. For each criteria, we will assess the risk of bias as "low risk of bias", "high risk of bias", and "unclear risk of bias".
We will contact the authors of trials for additional information on domains judged to be "unclear". If the authors do not respond within four weeks, we will assign a judgment on the domain based on the available information. We will document agreement between review authors and resolve discrepancies by consensus.
Measures of treatment effect
We will express the primary outcome, secondary outcomes and adverse outcomes as continuous variables using the mean differences (MDs).
We will check for skewing of continuous data using the method described in section 9.4.5.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).
Where there is evidence of skewed data, we will not perform a meta‐analysis. We will only perform meta‐analyses on primary and secondary outcomes if appropriate.
Unit of analysis issues
The designs included in this review are likely to be parallel group studies. Randomisation is likely to occur on a per‐person basis with interventions applied to one or, more commonly, both eyes. If randomisation has occurred on a per‐person basis and results are reported on a per‐eye basis without adjustment for within person correlation, we will attempt to obtain further information from the trialists.
Dealing with missing data
We will perform an available case analysis. This assumes that missing data, including participants lost to follow up, are missing on a random basis. Where not specified, we will contact the original study investigators for information about the reason for missing data or loss of follow‐up to confirm that this assumption applies.
Assessment of heterogeneity
We will investigate heterogeneity by examining the forest plots for direction and size of the effects. We will calculate the I2 statistic which indicates the proportion of variability across studies due to heterogeneity, rather than sampling error. If I2 is sufficiently low (less than 50%), we will pool the results. If there is evidence of substantial statistical heterogeneity (i.e. I2 value is more than 50%) we will consider pooling data if the studies show the same direction of effect.
Assessment of reporting biases
We will search ClinicalTrials.gov (http://clinicaltrials.gov/) and metaRegister of Controlled Trials (mRCT) (http://www.controlled‐trials.com/mrct/) to identify registered but unpublished trials. In the event that sufficient trials (more than 10) are identified, we will use a funnel plot to attempt to identify the risk of reporting bias. We will address the risk of outcome reporting bias by tabulating the outcomes reported by each study. We will contact the trial authors for additional information regarding the choice of outcome reporting.
Data synthesis
If there is no substantial clinical or statistical heterogeneity (see Assessment of heterogeneity) we will pool data using a random‐effects model, unless there are three or fewer trials in which case we will use a fixed‐effect model.
Subgroup analysis and investigation of heterogeneity
We will perform subgroup analysis if we have enough trials (i.e. one or more trials in each subgroup). The groups for analysis will be divided into:
-
baseline binocular visual acuity (two subgroups: 1. BCVA 6/24 Snellen/0.6 logMAR or better, 2. BCVA worse than 6/24 Snellen/0.6 logMAR), and/or
-
underlying aetiology (three subgroups: 1. Idiopaths, 2. Albinism, 3. Other associated disorders).
We anticipate that subgroup analysis will be difficult to perform as there are very few studies and trials in this area. However, if sufficient trials are available in the future, subgroup analysis for visual and underlying aetiology may be useful in regards to quality of life and functional outcomes. Visual acuity depends on both optical and neural factors. Levels of visual acuity may determine quality of life in regards to driving, independence, employment etc. Subgroup analysis may be useful for underlying aetiology as this may affect level of nystagmus and visual outcome. This is unknown at present.
Sensitivity analysis
We will perform a sensitivity analysis excluding studies at high risk of bias in one or more domains.
| Participant characteristics | Total number Gender Age Country Type of nystagmus Diagnostic criteria Comorbidities Baseline binocular visual acuity or changed in best corrected binocular visual acuity Orthoptic assessment Participant inclusion and exclusion criteria |
| Intervention | Intervention Frequency and treatment length |
| Study and methodology | Study design Trial identifiers Study size Randomisation Masking, allocation concealment Duration of each study |
| Primary outcomes | Change in best corrected binocular visual acuity (logMAR or Snellen chart) |
| Secondary outcomes | Estimated visual acuity using visual evoked potentials and/or nystagmus acuity functions such as NAFX Eye movement recordings using any available technique (e.g. video recording, infrared limbal tracker, electro‐oculography). Amplitude (mean and minimum); intensity; foveation time; position (mean, minimum mean in foveation window, standard deviation); velocity (mean, minimum mean in foveation window, standard deviation); null zone position and width. Head posture measured in degrees Visual recognition times Patient satisfaction and functional measurements (using validated questionnaires e.g. VFQ‐25) Economic data and cost analysis data |
| Adverse outcomes | Adverse effects (minor or major: reduction in visual acuity and blindness; double vision; cognitive effects; death) |
| Additional data | Treatment compliance and losses to follow‐up |
| Missing data | Intention‐to‐treat analysis if possible Trial authors contacted? |
| Data collection | Microsoft Excel® spreadsheet |
