Surgical interventions for infantile nystagmus syndrome

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy and safety of surgical interventions for infantile nystagmus syndrome (INS).

Background

Appendix 1 contains a glossary of medical terms used in the protocol.

Description of the condition

Nystagmus refers to a group of eye disorders that are characterised by rhythmic eye oscillations, where the primary abnormality is in the regulation of the slow eye movements. A smooth drift of the eyes away from the target (or desired gaze position), is then followed by a corrective saccade, a return slow eye movement, or both. It can be further characterised as pendular nystagmus if the corrective eye movement is slow, and termed jerk nystagmus if the corrective eye movement is fast. After strabismus, nystagmus is the second most common paediatric ocular motor disorder (Tychsen 1991). Nystagmus affects from one in 2000 to one in 10,000 people worldwide; congenital forms comprise 80% of cases whilst acquired forms comprise 20% (Dell’Osso 1975; Sarvananthan 2009). Nystagmus can be either physiological or pathological (Daroff 1978; Dell’Osso 1997). The physiological forms of nystagmus include vestibular, optokinetic and eccentric gaze (end‐point). Pathological nystagmus is divided into two categories: infantile‐onset (e.g. spasmus nutans syndrome, infantile nystagmus syndrome (INS), fusion maldevelopment nystagmus syndrome) (CEMAS Working Group 2001) or acquired (e.g. gaze‐evoked, see‐saw) (Maybodi 2003).

Infantile nystagmus syndrome is an involuntary ocular motor oscillation that manifests at, or most often shortly after, birth (Gottlob 1997) and persists throughout life (Dell’Osso 1985). Rarely, it begins in later life (Gresty 1991). People with INS are usually diagnosed in the first few months of life. Estimates of the prevalence of INS range from one in 1000 to one in 6000 births, the disparity being attributed to different populations and ethnicities, different classification schemes, misclassifications, or a combination of these (Forssman 1971; Heemes 1924; Norn 1964; Stayte 1993). Many people with INS have an underlying disorder of the visual system (Abadi 2002; Gelbart 1988; Weiss 1989), and approximately 30% of individuals with INS also have strabismus (Hertle 1999). The negative impact of nystagmus on vision has been described to be more profound than that associated with age‐related macular degeneration in adults (Pilling 2005).

Parameters used to describe INS oscillations include the type of waveform(s), and the amplitude, frequency, intensity and foveation periods of the waveform (Abadi 1986; Leigh 2006). Foveation periods are those portions of the waveform where the image of the point of regard is on or near the fovea and the eyes are stationary or only moving with a velocity less than some predefined limit. INS is characteristically bilateral and conjugate, with similar amplitude in both eyes. The intensity and foveation duration of the nystagmus, as well as its waveform, may vary in different gaze directions. The waveforms may also change with age (Hertle 1999; Reinecke 1988). An important diagnostic indicator is that this oscillation remains horizontal regardless of gaze position (Abel 2006; Dell’Osso 1997). In some cases, INS may have a latent component, whereby the waveform changes direction when covering one eye (Kestenbaum 1961). INS is reported to become worse with physiological factors, such as stress and motivated behaviours (Cham 2008; Salehi 2018). It usually damps with voluntary lid closure (Dell’Osso 1997) and often with convergence (Khanna 2006). INS does not occur during sleep and is diminished when gaze is directed to the null zone (i.e. the field of gaze in which the nystagmus intensity is minimal and best foveation occurs).

People with INS can exhibit a null zone laterally, and so an abnormal head posture may be adopted to shift the eyes into this null position (Abadi 2002; Dell’Osso 1974; Dell’Osso 1975; Hertle 2000; Stevens 2003). A vertical head posture/tilt may also be present in cases of horizontal nystagmus, when the null zone is perpendicular or tilted (Abadi 2002). This compensatory mechanism serves to minimise the nystagmus intensity and maximise visual acuity (Abadi 1991; Stevens 2003). The null region is usually stable, but it may shift in cases of periodic alternating nystagmus, smooth pursuit or optokinetic stimulation (Khanna 2006). Occasionally, head oscillations, which can increase on visual intent, may also be seen in people with INS (Gresty 1981).

The ability to effectively treat INS has been hindered by the failure to ascertain the exact mechanism(s) underpinning the condition. Currently, INS cannot be cured, but its effects can potentially be treated. Treatment is indicated to improve the following INS characteristics: visual acuity, abnormal head posture, the appearance of the oscillations, effective field of best vision, and oscillopsia. Treatments that lessen the oscillations without affecting normal eye movements are preferred. Several treatment options exist that aim to maximise visual acuity by extending and/or lowering slow‐phase velocities during foveation periods and minimising oscillopsia, although the latter is rarely problematic (Leigh 1988). The intensity of the nystagmus can be reduced pharmacologically, optically, or surgically (Khanna 2006; Wang 2006). Visual acuity is first improved by correcting any significant refractive error. Contact lenses can improve visual acuity by resolving ametropia and improving INS waveforms over a range of gaze positions (Biousse 2004; Taibbi 2008). Prisms can be incorporated into the prescription; in cases of people with INS whose nystagmus damps with convergence, base‐out prisms are used to induce vergence (Spielmann 2000). Several medications have been found to be effective in reducing the intensity of certain types of INS; they can either decrease the nystagmus centrally or peripherally (Comer 2006; Dell’Osso 2011; Thurtell 2010). However, surgery remains the mainstay of INS treatment (Hertle 2010; Hertle 2011; Hertle 2017). Eye muscle surgery has been available since the 1950s as an option to correct for abnormal head positioning by moving the eyes into the null zone, where the nystagmus is reduced (Anderson 1953; Kestenbaum 1954).

Description of the intervention

Surgical treatment for people with INS is primarily aimed at shifting the null zone to the primary gaze position, or correcting abnormal head tilts/turns, or both. Additional reported benefits include broadening of the null region, minimising nystagmus intensity at all gaze angles and increasing foveation times (Dell’Osso 1973; Wang 2006). The age at which these procedures are performed varies from a few months of life, up to adolescence and adulthood. Six main surgical interventions have been used in INS management, as follows.

• Anderson‐Kestenbaum procedures (Anderson 1953; Kestenbaum 1954) involve recession of the pair of rectus muscles responsible for the direction of the face turn, or the antagonist muscles, or surgery on all four muscles.

• Vertical recti surgeries (including recession‐resection of the vertical recti, combined recession of the vertical recti muscles and weakening of the oblique muscles, full tendon‐width horizontal transposition of the vertical recti muscles) are less common but are proposed to have a similar mechanism of action as the Anderson‐Kestenbaum procedures. Bilateral superior recti recession, with inferior oblique myectomy, are typically performed for INS patients with chin depression (Hertle 2009). To correct head tilt, the insertion of the vertical recti muscles can be offset horizontally to overcome the cyclo‐torsional effect; e.g. for right head tilt the following procedures should be performed: right superior rectus nasal horizontal transposition, right inferior rectus temporal transposition, left superior rectus temporal transposition and left inferior rectus nasal transposition (von Noorden 1993). Bilateral superior oblique weakening combined with inferior rectus recession is proposed for a chin‐up head posture (Greenberg 2007; Hertle 2010).

• Maximal retro‐equatorial recession of the horizontal recti muscles involves recession of all four horizontal recti around the equator of the globe (medials 10 mm and laterals 12 mm from insertion).

• Artificial divergence surgery is used when INS damps with convergence. This surgery aims to reduce nystagmus by encouraging the patient to exert fusional convergence reserves to overcome the induced exophoria (Spielmann 2000).

• Tenotomy‐resuture describes the detachment and re‐attachment of all horizontal recti to their original insertion, without resection or recession.

• Myectomy involves extirpating completely or partially all four horizontal recti muscles, without reattachment.

How the intervention might work

Surgical treatment of INS is most commonly performed in individuals with anomalous head postures secondary to eccentric null regions (Neely 1999). The Anderson‐Kestenbaum resection and recession procedure aims to relocate the nystagmus null zone to the primary position to eliminate any head turn, along with the benefit of reducing the nystagmus itself (Anderson 1953; Kestenbaum 1954; Parks 1973). The artificial divergence procedure is performed in individuals who can damp their nystagmus with convergence (Cuppers 1971; Spielmann 2000). In people with INS without an abnormal head posture, large recessions of the horizontal recti muscles are undertaken with the intent of damping the nystagmus amplitude, improving foveation times and secondarily improving visual acuity and the ability to recognise objects more quickly (Alió 2003; Atilla 1999; Boyle 2006; Erbagci 2004; Helveston 1991; Sprunger 1997; von Noorden 1991).

Tenotomy with reattachment is performed with the aim of damping the nystagmus, broadening the null region and increasing foveation periods (Hertle 2006; Wang 2006). Though the mechanism of benefit(s) remains unclear, it has been suggested that disruption of feedback from the enthesis — the junction between the eye muscles and the eyeball — leads to reduction in the oscillation of the eyes (Hertle 2009). In recent years, myectomy of the extraocular muscles, either completely or largely removing them (Lingua 2016; Sinskey 2002), has also been described in relation to treating INS; however, some raise concerns regarding the procedure’s detrimental and irreversible effects on other eye movements, the ability to maintain single binocular vision and undesirable changes in patients’ appearance (Dell’Osso 2018). 

Vertical and torsional head posture surgeries include the recession‐resection of vertical rectus muscles, combined recession of vertical recti and weakening of the oblique muscles (Greenberg 2007; Pierse 1959; Roberts 1996; Yang 2004), and full tendon‐width horizontal transposition of the vertical recti (von Noorden 1993). These procedures may be performed when the abnormal head posture is in the vertical plane (chin elevation/depression) or torsional (head tilt or multiplanar). The aim when correcting a chin‐down head posture, for example, would be to weaken the elevators of the eyes with a combined recession of the superior recti and myectomy of the inferior obliques. For a chin‐up position, the aim would be a weakening procedure of the ocular depressors and tenectomy of the superior obliques with a recession of the inferior recti (Hertle 2010).

Why it is important to do this review

Although INS cannot be cured, its effects can potentially be reduced with intervention(s). Several potential options exist, including surgical, pharmacological and optical treatments. As previously outlined, broadly these procedures aim to reduce the intensity and the effect on vision of the involuntary ocular oscillations, correct abnormal head posture and maximise visual performance over as wide a range of gaze angles as possible.

Despite the range of interventions available and currently applied in practice for the management of INS, there is no clear consensus and no accepted clinical guidelines regarding the relative efficacy and safety of the various treatment options. Whether a specific type of surgery is best for treating a given case of INS remains debatable. Furthermore, heated debate has arisen in the literature between advocates and opponents of certain surgical procedures (Dell’Osso 2018; Hertle 2017). Surgical interventions vary widely in their level of invasiveness, ranging from detachment and reattachment of the extraocular muscles in situ, to complete extirpation of these muscles. A better understanding of the surgical options, along with their associated side effects, will assist clinicians in evidence‐based decision‐making in relation to the management of INS.

Understanding the evidence surrounding the efficacy and safety of surgical interventions for INS is especially important, given that many surgical strategies are non‐reversible, and are often performed on children. Therefore, a systematic review is essential to inform surgeons, healthcare practitioners, patients and their families/caregivers, and the wider community of the best available research evidence, as a basis for informing clinical decision‐making when considering surgical options for INS. This review will also identify gaps in the evidence, in order to inform future research in the field.

Objectives

To assess the efficacy and safety of surgical interventions for infantile nystagmus syndrome (INS).

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) only. As we anticipate there will be few RCTs published in the field, we will include a narrative synthesis of non‐RCT evidence in the discussion of the review.

Types of participants

We will include studies where people were diagnosed with INS (which may also be termed idiopathic infantile nystagmus, congenital motor nystagmus or congenital idiopathic nystagmus, sensory nystagmus or sensory defect nystagmus), as defined by the study authors. We will include studies where the participants with INS had underlying disorders of the visual system (e.g. optic atrophy, macular hypoplasia, albinism, retinal disorders, etc.).

Studies that include other congenital types of nystagmus (e.g. fusion maldevelopment nystagmus and spasmus nutans) in the study population will be excluded. Studies involving participants with acquired forms of nystagmus will also be excluded.

Types of interventions

We will include studies that considered all types of surgical interventions, such as:

• artificial divergence;

•  Anderson‐Kestenbaum procedure (and its variations);

• retro‐equatorial recession of the horizontal recti;

• four horizontal rectus muscle tenotomy with reattachment;

• recession‐resection of vertical recti;

• combined recession of the vertical rectus muscles and weakening of the oblique muscles;

• full tendon‐width horizontal transposition of the vertical recti;

• myectomy of the extraocular muscles without reattachment.

We will consider a range of comparators, including:

• no intervention;

• other surgical interventions;

• non‐surgical interventions;

• pharmacological interventions;

• non‐pharmacological interventions (e.g. optical, acupuncture, biofeedback treatment and afferent stimulation of the neck or forehead).

Types of outcome measures

For both primary and secondary outcomes (Alió 2003; Dell’Osso 1973; Hertle 2006; Neely 1999; Sprunger 1997; Wang 2006), if data are not reported at six months' follow‐up, we will accept measures taken between three and 12 months' follow‐up. We will not exclude studies from the review solely because no outcome data are available.

Primary outcomes

The primary outcomes will be the change in binocular best‐corrected distance visual acuity, measured using any acuity measure (e.g. LogMAR, Snellen, Teller acuity, grating).

Secondary outcomes

• Head posture, measured in degrees.

• Amplitude of the nystagmus waveform, quantified using any of the following techniques from bilateral eye movement recordings: video‐recording, electro‐oculography and the use of magnetic search coils.

• Frequency of the waveform, quantified as described above.

• Intensity (amplitude multiplied by frequency) of the waveform, quantified as described above.

• Foveation period durations of the waveform, quantified as described above; these may be measured directly by defining them in terms of thresholds for eye velocity and distance from the intended target. Alternatively, the Nystagmus Expanded Acuity Function (NAFX) or similar methods may be used (these are functions that extrapolate potential visual acuity based on measurements of the foveation characteristics of nystagmus waveforms).

• Visual recognition times, measured as search times (which may include number of saccades, duration and number of fixations).

• Quality‐of‐life and patient‐reported outcome measures (including patient satisfaction, pain from the procedure, length of hospital stay, repeated and/or further surgeries) and functional measurements obtained using validated questionnaires, such as the National Eye Institute Visual Function Questionnaire or the VF‐14 measurement of visual impairment.

Adverse effects

Adverse effects related to the surgical intervention (including loss of vision, development or worsening of strabismus, surgical injury to the eye, postoperative infection, and loss of ocular rotation) will also be considered.

Although minimal clinically important differences are not established for these outcome measures, the key differences of interest (as determined by clinical consensus) are as follows:

• A 2‐line difference in binocular best‐corrected distance visual acuity.

• At least 5 degrees of change in head posture.

• A decrease in intensity (amplitude multiplied by frequency) of the waveform.

• An increase in foveation period durations of the waveform.

• Decreased visual recognition times.

• No permanent adverse effects after surgery (e.g. double vision, loss or significant limitation of eye movement).

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist will search the following electronic databases. There will be no restrictions on language or year of publication.

• Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (latest issue) (Appendix 2).

• MEDLINE Ovid (1946 to present) (Appendix 3).

• Embase Ovid (1980 to present) (Appendix 4).

• ISRCTN registry (www.isrctn.com/editAdvancedSearch) (Appendix 5).

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) (Appendix 6).

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) ( www.who.int/ictrp) (Appendix 7).

Searching other resources

We will undertake additional searches, by reviewing the reference lists of included RCTs, to identify any other studies potentially relevant to this review.

Data collection and analysis

Selection of studies

We will adopt a two‐stage process to identify relevant RCTs for this review. Two review authors (KMC and LAA) will each assess titles and abstracts returned from the electronic searches, to identify trials potentially relevant to the review. We will retrieve the full‐text articles of studies considered to be relevant, or potentially relevant, by at least one review author. KMC and LAA will independently evaluate the full‐text articles to judge their suitability for inclusion in the review, according to the characteristics outlined in Criteria for considering studies for this review. Potential disagreements in judgement will be resolved by discussion between the two review authors, or in consultation with a third review author (if required).

If additional information is considered necessary to determine the eligibility of a trial, we will contact the study authors. If a response is not received within four weeks, the information in the full‐text will be used to determine eligibility. Details relating to the reason for excluding studies that progress to the full‐text review stage will be included in a ‘Characteristics of excluded studies’ table.

Data extraction and management

Two review authors (KMC and LED) will each extract study data (detailed in Appendix 8) using the online systematic review platform Covidence (Covidence). Each author will independently use the Covidence data extraction form that has been piloted for data extraction.  

Extracted information will include: details relating to the design of the study, country, setting, participant characteristics, interventions and comparators, outcomes, results and any other relevant information (e.g. funding source). We will extract quantitative data for our nominated primary and secondary outcomes, wherever possible. Potential discrepancies in data extraction will be resolved between the two review authors by discussion to reach consensus; if required, adjudication by a third review author will be sought. After reaching consensus, data will be exported into Cochrane's RevMan Web (RevMan Web 2019) by KMC; LED will verify the exported data.

If additional information is necessary for a primary or secondary outcome (to facilitate the extraction of quantitative data), we will contact the study authors. If a response is not received within four weeks, we will use the information in the full‐text. 

Assessment of risk of bias in included studies

Two review authors (KMC and LED) will independently assess the risk of bias in each of the eligible studies, according to the guidelines in Chapter 8 of the Cochrane Handbook for Systematic Review of Interventions (Higgins 2017). Specifically, we will evaluate the risk of bias in each of the following domains:

• selection bias (random sequence generation and allocation concealment);

• performance bias (masking of participants and personnel);

• detection bias (masking of outcome assessment);

• attrition bias (incomplete outcome data);

• reporting bias (selective reporting of outcomes);

• other bias (funding source, other conflicts of interest).

The risk of each bias will be judged as either low risk, unclear risk (due to either lack of information or uncertainty over the potential for bias) or high risk. We will resolve any disagreements in assessment will by discussion between the two review authors, with the capacity to consult a third review author, if required.

Measures of treatment effect

One review author (LB) will perform the data analyses using the approach described in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017).

As all outcomes are continuous, we will extract data on the change, from baseline, in means (and standard deviations of changes) of the outcome measures for the intervention and comparison group(s). If a measure of change from baseline is not reported, the means (and standard deviation) of the outcome for each group will be extracted. Treatment effects will be reported as the mean difference (MD), with 95% confidence intervals (CIs), between treatment groups.

Unit of analysis issues

The unit of analysis for this review will be the study participant. Given the nature of surgical interventions for nystagmus, it is predicted that trials will allocate individual participants (rather than individual eyes) to treatment groups. Although paired‐eye studies are not expected, we will include these trials if they are identified. If multiple‐armed studies are included, our first preference would be to combine all relevant experimental intervention groups of the study into a single group, and to combine all relevant control intervention groups into a single control group. If this is not deemed appropriate due to the experimental intervention groups not being sufficiently similar, we will select one pair of interventions and exclude the others, to best permit the pooling of data. 

If data from more than one eye per participant are included in a study analysis, we will follow the guidelines for analysing clustered or paired‐eye designs (as appropriate), as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). If one eye per participant is included in the analyses, there will not be a unit of analysis issue. If participants are randomised to treatment groups but data from both eyes are included and reported, we will analyse these as 'clustered data' (i.e. with an adjustment for within‐person correlation); it may be necessary to contact the study authors for more information for such analyses. 

Dealing with missing data

If any of the included trials have missing outcome data (e.g. lack of standard deviations), we will email the study authors to ask for this information. If a response is not received within four weeks, or if the study authors are not able to provide the requested details, we will use the information available within the full‐text paper. If confidence intervals or hypothesis tests are reported, we will seek to estimate the standard deviations using the RevMan Web calculator.

If possible, intention‐to‐treat (ITT) analyses will be performed. If imputed data are reported within the included study reports and were calculated using a robust method, these will be included in the analyses. We will not directly impute data ourselves. If ITT data are not available, an available case analysis (assuming that the data are missing at random) will be performed.

Assessment of heterogeneity

We will examine heterogeneity using the recommendations outlined in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017).

The clinical and methodological heterogeneity of included studies will be assessed by comparing trial designs, participant baseline characteristics (e.g. age, gender, eligibility criteria, etc.) and the risk of bias. We will measure statistical heterogeneity using the I² statistic (Higgins 2002). We will interpret an I² statistic of 60% or greater to be consistent with a risk of moderate heterogeneity (Ng 2014). To identify and quantify heterogeneity, we will consider both the magnitude and direction of effect of individual trials, and the strength of evidence for heterogeneity (using a P value of less than 0.10, from the Chi² test, as an indicator of significant heterogeneity).

Assessment of reporting biases

We will investigate the risk of bias related to selective outcome reporting by comparing outcomes listed in the trial protocol or clinical trial registry entry (where available), with the outcome measures reported in the full‐text paper(s).

If at least 10 trials are included in a meta‐analysis, we will assess publication bias using a funnel plot. Asymmetry in the funnel plot will be interpreted in association with the trial characteristics, in consideration of factors such as sample size.

Data synthesis

If at least two trials report data relevant to any of the primary and secondary outcome measures, we will perform a meta‐analysis for that outcome. If fewer than three studies are available to include in the meta‐analysis, we will adopt a fixed‐effect model, otherwise a random‐effects model will be used. 

If we observe inconsistency between individual study findings (e.g. treatment effects in opposite directions, I² statistic of 60% or greater, or Chi² test P value less than 0.10), this indicates that a pooled estimate may not appropriately summarise the overall findings. As a result, we will describe the findings from individual study results. If there is significant statistical heterogeneity, but all the effect estimates are in the same direction, such that a pooled estimate appears to provide a reasonable summary of the individual trial results, we will perform a meta‐analysis. 

If a meta‐analysis is not considered appropriate, we will adopt other accepted methods for data synthesis, which may include a narrative or tabulated results summary (summarising effect estimates, combining P values, or vote‐counting based on the direction of effect) (Schünemann 2017a). 

Subgroup analysis and investigation of heterogeneity

If there are a sufficient number of trials included in this review (defined as at least two studies per subgroup), we will perform subgroup analyses for factors considered to potentially affect outcomes. These analyses will consider the potential effects of:

• type of surgery;

• age of the participant (average age under two years versus average age two years and over);

• absence or presence of associated sensory disorders;

• means used to assess relevant nystagmus parameters (e.g. location of null either by clinical examination or eye movement recording). 

Sensitivity analysis

We will perform a sensitivity analysis for the primary outcome measure, if there are a sufficient number of studies included in the review. This analysis will assess the effects of excluding studies that were: unpublished, or judged to have a high risk of bias in the domains of detection bias or reporting bias.  

Summary of findings

To summarise the results of the analyses, we will produce ‘Summary of findings’ tables using the approach recommended in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2017b). Separate ‘Summary of findings’ tables will be produced for the following key clinical comparisons:

• any surgical intervention versus no intervention;

• any surgical intervention versus any non‐surgical intervention;

• four horizontal rectus muscle tenotomy with reattachment versus no intervention;

• myectomy of the extraocular muscles without reattachment versus no intervention;

• myectomy of the extraocular muscles without reattachment versus any other surgical intervention.

We will use the GRADE Working Group approach to grade the certainty of evidence. Outcome measures, measured between the treatment groups at six months' follow‐up (with an acceptable follow‐up range between three and 12 months), will include:

• change in binocular best‐corrected distance visual acuity;

• change in head posture;

• change in intensity (amplitude multiplied by frequency) of the waveform;

• change in foveation period durations of the waveform;

• change in visual recognition times;

• proportion of participants with adverse effects with a probable causal link to the treatment (this outcome will be reported at any follow‐up period);

• change in quality‐of‐life (measured using a validated questionnaire).

Appendices

Appendix 1. Glossary of terms

Acquired – not inherited, but instead developing after birth.

Age‐related macular degeneration – a disease that blurs central vision (required for activities such as reading and driving). This condition is caused by a degeneration of light‐sensitive cells in the region of the retina known as the macula, which allows us to see fine details.

Ametropia – vision disorders (e.g. near‐sightedness, far‐sightedness, or astigmatism) that result in the eyes being unable to correctly focus clearly on objects without the aid of a refractive correction (e.g. glasses or contact lenses).

Amplitude – in nystagmus, the distance in visual angle (measured in degrees) between the start of the drift away from fixation (point of focus) and the start of the corrective eye movement in the opposite direction.

Base‐out prism – a triangular glass prism with the flat base positioned towards the patient’s ear (facing out), which is used to reposition an image to improve vision with both eyes open.

Binocular – using both eyes together.

Congenital – present at, or before, birth.

Conjugate – both eyes behaving in almost identical ways.

Convergence – the coordinated movement of both eyes inwards when looking at an object up close.

Eccentric gaze or endpoint nystagmus – a drift of the eyes back towards the centre when held in extreme positions of gaze (e.g. far right or far left).

Extirpating – complete removal.

Fixation – point of focus.

Frequency – number of cycles of an oscillation (here, nystagmus) per second, measured in Hertz (Hz).

Infantile‐onset – an individual acquires, develops, or first experiences a condition during infancy.

Intensity – in nystagmus, the product of amplitude and frequency.

Monocular – with, for, or in one eye.

Nystagmus –involuntary eye movements in which an initial slow movement away from fixation is corrected either by a fast or slow movement back.

Oculomotor – defined strictly, this refers to a small brain region that controls four of the six eye muscles but sometimes the term is used more generally to refer all the brain structures that control eye movements, thereby enabling normal perception of the world.

Optokinetic nystagmus – an involuntary eye movement in response to the rotational movement of a full field visual image.

Oscillopsia – a visual disturbance in which objects that are stationary appear to oscillate (move).

Periodic alternating nystagmus – a horizontal nystagmus that repetitively reverses its direction every few minutes.

Recession – a surgical weakening procedure whereby an eye muscle is removed from its original position and repositioned further back on the eyeball.

Resection – surgical removal of part, or all, of a tissue. In strabismus and nystagmus, this is a surgical strengthening procedure whereby part of an eye muscle is cut off and the muscle length is shortened.

Saccade – the rapid eye movement performed when looking between two objects.

Smooth pursuit – an eye movement that keeps an image of a slowly moving object on the fovea (a tiny area in the macula that allows clearest vision).

Strabismus – an abnormality in the alignment of an eye such that only one eye actually views the intended target.

Vergence – a simultaneous movement of both eyes in opposite directions in order to maintain single, clear vision of an object simultaneously in both eyes.

Vestibular nystagmus – nystagmus resulting from a disturbance to the inner ear and to the system in the brain that is responsible for keeping an image steady on the eye during rapid head movements.

Visual acuity – measurement of the smallest target (e.g. a letter) that can be accurately identified.

Appendix 2. CENTRAL search strategy

#1 MeSH descriptor: [Nystagmus, Congenital] explode all trees #2 (infantile or idiopath* or congenital* or motor or sensory) near/4 nystagm* #3 INS near/4 nystagm* #4 #1 or #2 or #3 #5 MeSH descriptor: [Ophthalmologic Surgical Procedures] explode all trees #6 surg* #7 MeSH descriptor: [Oculomotor Muscles] explode all trees and with qualifier(s): [surgery ‐ SU] #8 MeSH descriptor: [Tenotomy] this term only #9 Kestenbaum:ab #10 (resect* or recession or surg* or transpos*) near/3 (rectus next muscle*) #11 (tenotomy or myectomy) #12 (artificial near/2 divergence) #13 (oblique next muscle*) near/3 weak* #14 #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 #15 #4 and #14

Appendix 3. MEDLINE Ovid search strategy

1. exp nystagmus, congenital/ 2. ((infantile or idiopath$ or congenital$ or motor or sensory) adj4 nystagm$).tw. 3. (INS adj4 nystagm$).tw. 4. or/1‐3 5. exp Ophthalmologic Surgical Procedures/ 6. surg$.tw. 7. Oculomotor Muscles/su [Surgery] 8. Tenotomy/ 9. Kestenbaum.ab. 10. ((resect$ or recession or surg$ or transpos$) adj3 rectus muscle$).tw. 11. (tenotomy or myectomy).tw. 12. (artificial adj2 divergence).tw. 13. (oblique muscle$ adj3 weak$).tw. 14. or/5‐13 15. 4 and 14

Appendix 4. Embase Ovid search strategy

1. congenital nystagmus/ 2. ((infantile or idiopath$ or congenital$ or motor or sensory) adj4 nystagm$).tw. 3. (INS adj4 nystagm$).tw. 4. or/1‐3 5. eye surgery/ 6. surg$.tw. 7. surgical technique/ 8. extraocular muscle/ 9. muscle resection/ 10. tenotomy/ 11. Kestenbaum.ab. 12. ((resect$ or recession or surg$ or transpos$) adj3 rectus muscle$).tw. 13. (tenotomy or myectomy).tw. 14. (artificial adj2 divergence).tw. 15. (oblique muscle$ adj3 weak$).tw. 16. or/5‐15 17. 4 and 16

Appendix 5. ISRCTN search strategy

(infantile OR idiopathic OR congenital OR motor OR sensory) AND nystagmus

Appendix 6. ClinicalTrials.gov search strategy

(infantile OR idiopathic OR congenital OR motor OR sensory) AND nystagmus

Appendix 7. WHO ICTRP search strategy

infantile nystagmus OR idiopathic nystagmus OR congenital nystagmus OR motor nystagmus OR sensory nystagmus

Appendix 8. Data on study characteristics

Mandatory items		Optional items
Methods
Study design	· Parallel group RCT (i.e. people randomised to treatment)   · Within‐person RCT(i.e. eyes randomised to treatment)   · Cluster RCT(i.e. communities randomised to treatment)   · Cross‐over RCT   · Other, specify	Exclusions after randomisation Losses to follow up Number randomised/analysed How missing data were handled (e.g. available case analysis, imputation methods)   Reported power calculation? (Y/N), if yes, sample size and power     Unusual study design/issues
Eyes or Unit of randomisation/ unit of analysis	· One eye included in study, specifying how the eye was selected   · Two eyes included in study, both eyes received the same treatment, including specifying how analysed (best/worst/average/both and adjusted for within person correlation/both and not adjusted for within person correlation) and specifying if mixture one eye and two eye   · Two eyes included in study, eyes received different treatments,including specifying if correct pair‐matched analysis was performed
Participants
Country		Setting Ethnic group Equivalence of baseline characteristics (Y/N)
Total number of participants	This information will be collected for the total study population recruited into the study. If these data are only reported for the people who were followed up only, this will be indicated.
Number (%) of men and women
Average age and age range
Inclusion criteria
Exclusion criteria
Interventions
Intervention (n = ) Comparator (n = )	· Number of people randomised to each group · Intervention name and details
Outcomes
Primary and secondary outcomes as defined in the study reports	Outcomes (as specified in the study report)   Adverse effects reported (Y/N) Length of follow up and intervals at which outcomes were assessed.	Planned/actual length of follow up
Notes
Dates conducted	Specify dates of recruitment of participants mm/yr to mm/yr	Full study name: (if applicable) Reported subgroup analyses (Y/N)   Were trial investigators contacted?
Sources of funding
Declaration of interest
Included on trials registry?	Y/N (including registration number if available)

Contributions of authors

Kwang M Cham wrote the first draft of the protocol Background and Objectives. He also revised the draft after receiving input from the full authorship group, and complied the final draft for submission.  Laura E Downie wrote the first draft of the protocol Methods, and also revised the first draft of the full protocol.  Ljoudmila Busija had substantial input in editing the first draft of the full protocol.  Lionel Kowal had substantial input in editing the first draft of the full protocol.  Anat Bachar Zipori had substantial input in editing the first draft of the full protocol.  Larry A Abel had substantial input in editing the first draft of the full protocol.   All authors provided final approval of the submitted protocol.

Sources of support

Internal sources

• No sources of support supplied

External sources

• National Institute for Health Research (NIHR), UK.

  • Richard Wormald, Co‐ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.
  • This protocol was supported by the NIHR, via Cochrane Infrastructure funding to the CEV UK editorial base.

  The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Declarations of interest

KMC: none known. LAA: no direct conflicts of interest; one reimbursement by a non‐profit‐organised research workshop and one hour's expert witness testimony on nystagmus and stress. LB: Monash University received payments from Jesuit Social Services Limited (Victoria, Australia) and Charité – Universitätsmedizin Berlin for statistical consultancy work performed by LB. LK: none known. ABZ: none known. LED: has previously received funding to undertake clinical trials in the fields of dry eye disease and contact lenses, being unrelated to this work, from Allergan Pty Ltd, Alcon Pty Ltd, Azura Ophthalmics Pty Ltd and Coopervision Pty Ltd. 

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