A Randomized Controlled Trial ComparingSoft Contact Lens and Rigid Gas-PermeableLens Wearing in Infantile Nystagmus

Pavitra Jayaramachandran, MBchB, BSc, Frank A. Proudlock, MSc, PhD,* Nita Odedra, BOptomSci, MSc,Irene Gottlob, FRCOphth, MD, Rebecca J. McLean, MSc

Objective: To perform the first randomized controlled trial comparing soft contact lens (SCL) with rigid gas-permeable lens (RGPL) wearing in infantile nystagmus (IN), using spectacle wear as a baseline.

Design: Randomized, controlled cross-over trial with an intention-to-treat design.Participants and Controls: A total of 24 participants with IN (12 idiopathic, 12 with albinism).Methods: Participants were randomized into 1 of 2 treatment arms receiving the following sequence of

treatments (2e3 weeks for each treatment): (A) spectacles, SCL, RGPL, and spectacle wear; or (B) spectacles,RGPL, SCL, and spectacle wear.

Main Outcome Measures: The main outcome measure was mean intensity of nystagmus at the null regionviewing at 1.2 m. Secondary outcome measures included the same measure at 0.4 m viewing and across thehorizontal meridian (measured over a �30� range at 3� intervals) for distance and near. The nystagmus foveationcharacteristics were similarly assessed over �30� and at the null region at 1.2 m and 0.4 m viewing. Visualoutcome measures included best-corrected visual acuity (BCVA) at 4 m and 0.4 m, gaze-dependent visual acuity(GDVA) (i.e., visual acuity when maintaining gaze angles over a �30� range at 10� intervals) at 4 m, and readingperformance at 0.4 m derived from the Radner reading chart.

Results: There were no significant differences between SCL and RGPL wearing for any nystagmus char-acteristics or compared with spectacle wearing. The BCVA, reading acuity, and critical print size were significantlyworse for SCL wearing compared with RGPL and baseline spectacle wear (P<0.05), although mean differenceswere less than 1 logarithm of the minimum angle of resolution (logMAR) line.

Conclusions: Nystagmus was not significantly different during SCL and RGPL wearing in IN, and contactlens wearing does not significantly reduce nystagmus compared with baseline spectacle wearing. The wearing ofSCL leads to a small but statistically significant deterioration in visual function compared with both RGPL andspectacle wearing at baseline, although mean effect sizes were not clinically relevant. Ophthalmology 2014;-:1e10 ª 2014 by the American Academy of Ophthalmology.

Supplemental material is available at www.aaojournal.org.

Infantile nystagmus (IN) is an involuntary, rhythmic to andfro movement of the eyes that develops within the first 6months of life.1 Infantile nystagmus can be associated witheye disease, such as albinism, retinal disease, low vision, orvisual deprivation in early life, or may not be associatedwith any other visual deficits (i.e., idiopathic). Nystagmusleads to reduced visual acuity (VA) caused by theexcessive motion of images on the retina.2,3 Many in-dividuals with nystagmus also adopt an abnormal headposition to maintain their eyes in the “null region.” This is aregion of gaze where the nystagmus is at its least intense andusually where the nystagmus quick phase changes direc-tion.4 The incidence of IN has been estimated to be 1.4 in1000,5 and the impact of IN is significant, not onlyaffecting visual functioning but also psychosocial aspectsof life.6

Treatments for IN are now emerging, although few ran-domized controlled trials have been performed to investigate

� 2014 by the American Academy of OphthalmologyPublished by Elsevier Inc.

treatments for IN. Treatments that have been evaluatedinclude optical, pharmacologic, and surgical options, as wellas therapies such as retrobulbar botulinum toxin injections7

and biofeedback.8 Randomized controlled trials are nowbecoming available comparing pharmacologic agents, suchas memantine and gabapentin.9 Although surgicalprocedures are difficult to assess using randomizedcontrolled trials, several larger studies, consisting mainlyof case series design, have investigated surgicalinterventions. The Kestenbaum procedure, to correctabnormal head postures, has been demonstrated as leadingto a reduction in nystagmus and improvements in VA inIN.10 More recently, tenotomy of the horizontal eyemuscles has been reported to improve VA in IN.11

Optical correction is important in IN because refractiveerrors are frequent with high levels of astigmatism.12

Several studies, consisting mainly of retrospective studiesand small case series or reports, have investigated the

1ISSN 0161-6420/14/$ - see front matterhttp://dx.doi.org/10.1016/j.ophtha.2014.03.007

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effects of contact lens use in nystagmus with conflictingresults. Early studies report that rigid gas-permeable lens(RGPL) wearing reduces the amplitude and frequency of thenystagmus, and improves VA by up to 3 Snellen linescompared with spectacle wearing.13e15 Results for softcontact lens (SCL) use in nystagmus are more variable, withsome studies reporting improvements in eye movement andVA,16,17 whereas others show no changes or variable out-comes.18,19 Improvements in VA with the use of contactlenses compared with spectacles have been attributed toreduced optical aberrations, an enlarged retinal image, andan increased peripheral visual field.17 It has beenhypothesized that the reduction in nystagmus with contactlens wear may be due to increased afferent feedback fromthe inner eyelids and conjunctiva.20,21 Potential mechano-receptors include Meissner and other corpuscular endings inthe eyelid margins, as well as Krause corpuscles in thepalpebral, bulbar, and fornix conjunctiva.22 Although theresponse characteristics of these sensory endings are notclear, similar corpuscular mechanoreceptors in the skin arerapidly adapting receptors that respond vigorously to rapidmotion and vibration. The cornea also is the most denselyinnervated surface in the human body, although contactlens wearing could lead to desensitization of this input.

These previous case reports noting apparent reduction innystagmus with contact lens wear prompted us to perform arandomized controlled crossover trial comparing RGPL andSCL wear in participants with idiopathic infantilenystagmus (IIN) and in IN associated with albinism, usingspectacle wear as a baseline. To date, no randomizedcontrolled trials have been performed to explore the use ofcontact lenses in IN, and there has been no direct compar-ison made between RGPL and SCL treatments. Our primaryhypothesis is that RGPL wear leads to a reduction innystagmus intensity compared with SCL wear. The rationalebehind this hypothesis is that the unyielding materials usedto construct RGPL are likely to generate more feedback ofeye movements than the pliable materials used in makingSCL. In general, users find RGPL less comfortablecompared with SCL for this reason. We have used spectaclewear as a baseline for the study, because the participantsinvariably wear some form of refractive correction beforethe study, and the most commonly worn method of refrac-tive correction is spectacle wear. This also allows us tocompare the 2 contact lens treatments with spectacle wear.

Our main outcome has been to evaluate the change innystagmus intensity at the null region when viewing targetsat 1.2 m to address whether contact lens wear directly in-fluences nystagmus. We have used nystagmus intensity asthe main outcome measure rather than measures of fovea-tion, such as the eXpanded Nystagmus Acuity Function(NAFX). This is because faster periods of the nystagmuscycle, such as more rapid periods of the slow phase andnystagmus quick phases, are likely to generate more salientfeedback cues for rapidly adapting mechanoreceptors thanslow eye movements occurring during the foveation period.A recent study has demonstrated that nystagmus intensityshows the least testeretest variability compared with othernystagmus parameters (McLean RJ, Gottlob I, ProudlockFA. Are eye movement recordings or visual acuity the better

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outcome measure for nystagmus: a test-retest analysis.ARVO Meeting Abstracts 2012;53:510). Intensity also is animportant measure in relation to cosmesis. For secondaryoutcomes, we have measured changes in best-corrected vi-sual acuity (BCVA) at distance (4 m) and near (0.4 m) andother visual outcomes, such as reading.

Methods

Trial Design and Study Setting

An unmasked controlled crossover study was performed andstratified for type of IN with a balanced randomization (1:1). Thestudy participants were recruited and examined at the LeicesterRoyal Infirmary, United Kingdom, between September 2010 andOctober 2011 after written informed consent was obtained fromparticipants before commencing the trial. The study was approvedby the Leicestershire, Northamptonshire, and Rutland EthicsCommittees and adhered to the tenets of the Declaration of Hel-sinki. The trial was registered on the International StandardRandomised Controlled Trial Number Scheme (80219391).

Participants and Procedures

Eligible for inclusion were adult subjects (aged >16 years) with IN(idiopathic or associated with albinism) and no simultaneousinvolvement in other trials. We excluded participants if they hadperiodic alternating nystagmus, corneal trauma, or any previouscomplications associated with contact lens wear. We also excludedpatients if the waveform under binocular viewing was consistentwith a diagnosis of fusion maldevelopment nystagmus syndrome(or manifest latent nystagmus), that is, mainly with deceleratingslow phases. Twenty-four subjects with IN were recruited (12idiopathic and 12 associated with albinism). Participants wererecruited from neuro-ophthalmology clinics in the Leicester RoyalInfirmary, United Kingdom, or from an existing patient database.The study population demographics can be viewed in Table 1(available at www.aaojournal.org). The nystagmus waspredominantly in the horizontal plane for all participants.

Inclusion/exclusion criteria and diagnoses were all confirmedon the first visit with a full ophthalmologic and orthoptic assess-ment, including slit-lamp examination, fundus examination, VAassessment, optical coherence tomography, and eye movementrecordings. All participants underwent electroretinograms and vi-sual evoked potentials according to the International Society forClinical Electro-physiology of Vision standards to determinewhether they had any retinal abnormalities or abnormal chiasmalcrossing.23 Albinism was confirmed by a combination ofasymmetry of visual evoked potential responses, fovealhypoplasia, and iris transillumination. Participants who showedno other pathology than nystagmus were diagnosed with IIN.Five of the participants with IIN were confirmed as beingfamilial, of which FRMD7 mutations were detected in 2participants. None of the participants with IIN showed significantfoveal hypoplasia on optical coherence tomography examination.

Interventions and Randomization

A computer-generated, stratified balanced (allocation ratio 1:1)randomization scheme was used with a permuted block design. Ablock size of 6 participants based on the type of nystagmus wasused (2 blocks of albinism [n ¼ 12] and 2 blocks of idiopathic [n ¼12]; Table 1, column 3; available at www.aaojournal.org), andrandomization was made to receive RGPLs or SCLs as the firsttreatment arm with a baseline of spectacle wear being recorded

Jayaramachandran et al � Optical Treatment of Infantile Nystagmus

before and after treatments. Participants and investigators were notmasked to the randomization scheme. Each participant received thefollowing sequence of treatment (i) 2 to 3 weeks spectacle wear(baseline), followed by (ii) 2 to 3 weeks of first type of contactlens, followed by (iii) 2 to 3 weeks of second type of contactlens, followed by (iv) 2 to 3 weeks of spectacle wear (back tobaseline) (Fig 1, available at www.aaojournal.org). During thecontact lens period, the study participants were instructed to weartheir lenses for as long as comfortable each day but notexceeding 8 hours.

Refraction and Contact Lens Fitting

On the first visit, refraction and slit-lamp examination of theanterior eye (including tear film assessment) was performed by anoptometrist. Corneal curvature, iris and pupil diameter, andpalpebral aperture were measured. Participants were issued a newprescription if required and asked to obtain new spectacles thatthey should wear for 2 weeks before the next visit. All participantswere regular spectacle wearers before the study. Quasar asphericRGPLs were used for the trial (No. 7 Contact Lenses Ltd., Hast-ings, UK), which are of a spherical back surface design and areable to correct up to 4 diopters of astigmatism. The first choice ofRGPL was that with the flattest keratometer reading. Two types ofhigh water content SCLs were used: Hydro Cyl soft toric lenses(Cantor and Nissel Ltd, Brackley, UK), an accelerated stabilizationdesign lens; and Proclear (Coopervision Ltd, Fareham, UK), a toriclens with prism ballast design. The type of SCL prescribed was thatproviding the best fit for the participants. For both RGPLs andSCLs, fit was assessed, including centration and movement forRGPL orientation, stabilization, and movement for SCLs. Lenseswere inserted on the eye, and lens fit and vision were recheckedbefore lenses were issued to the participants. Participants wereindividually taught how to handle and care for both types of lensesand advised to contact the research team if they had any problems.

At the end of the trial, to explore the possibility of misalignmentof SCLs in the participants, an SCL was marked at the 6 o’clockposition using a nontoxic marker pen (Sharpie Ultra Fine, SanfordLP, Oak Brook, IL), placed in the eye of one of our study partic-ipants and recorded over time using a video camera.

Tests and Analysis for Outcome Measures

Eye Movement Recordings. Eye movements were recorded on allvisits using an infrared video pupil tracker with head movementcompensation (EyeLink eye tracker, SensoMotoric InstrumentsGmbH, Berlin, Germany) in 2 dimensions (horizontal and vertical)at a sample rate of 250 Hz. The eye tracker has a resolution of0.005 degree and noise level of less than 0.01 degree root meansquare. Participants sat 1.2 m from a rear projection screen onwhich visual stimuli were projected using an Epson EMP 7900video projector (image size on screen: 1.50 m wide and 1.125 mhigh; resolution: 1024�768 pixels; Epson UK Ltd, HemelHempsted, UK). For near viewing, participants sat 0.4 m from anAcer AL2202W flat screen monitor (image size: 0.475 m wide and0.297 cm high; resolution 1680�1050 pixels, Acer UK Ltd, Ply-mouth, UK). Participants followed a fixation target (1� diameter),moving every 8 seconds, in 3� steps across the horizontal meridian,from �30� to the left to þ30� to the right. To maintain a fixed headposition, a chin rest was used with support pads for the cheeks tominimize horizontal head rotations. To ensure that all participantswere optimally refracted for eye movement recordings, in additionto small framed lenses issued for daily wear, large framed spec-tacles with the same prescription were ordered for each participantto wear while performing eye movement recordings on the baselinespectacle wearing visits (visits 2 and 5).

Eye Movement Analysis. Although participants and in-vestigators were not masked to the treatment, analysis of the eyemovement data was performed under masked conditions byrandomly allocating each file name with a coded number that wascreated using an Excel template (Microsoft Corp, Redmond, WA).The file name orders were verified subsequent to analysis using thetime stamp in the eye movement recording file (not available to theinvestigator during the analysis). Although eye movement datawere collected from both eyes, only data collected from thedominant eye were used for analysis because the nystagmus wasconjugate in all participants.

For all nystagmus outcome measures, the largest block of datawithout blinks (minimum 2 seconds of data) at each fixation pointwere analyzed (i.e., for all 21 fixation points from �30� to þ30�).Calibration of the data was achieved offline by fitting best fit lines tomean positions measured during foveations of each of the 3� stepswhen the dominant eye was fixing the target. Periods of inattentionto the stimuli were identified and discarded from the analysis. Ateach location, the amplitude, frequency, and intensity of nystagmus(amplitude � frequency) and the eXpanded Nystagmus AcuityFunction (NAFX) were calculated. The NAFX is an objectivemeasure of foveation quality that can predict potential BCVA inpatients without afferent visual deficits (developed by L. F. Del-l’Osso, available at: www.omlab.org, accessed November 21,2011). For the main outcome measure, nystagmus intensity at thenull region when viewing targets at 1.2 m was calculated as theminimum nystagmus intensity after smoothing of the data to removea small amount of random “jitter” between points (a 5-point averagewas used). Mean intensity also was estimated at the null regionduring near viewing (0.4 m) and across all horizontal positions(from �30� to þ30�) at 1.2 m and 0.4 m. The NAFX also wascalculated at the null region and across all horizontal positions for1.2 m and 0.4 m. The NAFX values were used to calculate thelongest foveation domain (LFD) as a measure of null region width.This is defined as the range of visual acuities (predicted by NAFX)that are within 10% of the peak predicted VA. This was estimatedusing the methods previously described by Serra et al,24 where asecond order polynomial is fitted to the values plotted as adecimal fraction.

Visual Outcomes

The logarithm of the minimum angle of resolution (logMAR)BCVA was measured under binocular and monocular viewing witheither eye, using the Precision Vision Visual Acuity Testing(PVVAT) system (Precision Vision, La Salle, IL) for distanceviewing at 4 m (black modified Early Treatment Diabetic Reti-nopathy Study optotypes at 1.0 candelas/m2 on a white backgroundat 179 candelas/m2; Weber contrast ¼ 99.4%). The logMAR nearvision Early Treatment Diabetic Retinopathy Study optotype charts(Good-lite Co, Elgin, IL) were used to test BCVA for near viewingat 0.4 m under well-lit conditions at a consistent level of illumi-nation. All BCVA measurements were performed while the par-ticipants used their preferred head position.

Gaze-dependent visual acuity (GDVA) was recorded with thePVVAT system using the methodology described by Yang et al,25

where VA is measured from 30� to the left to 30� to the right at10� intervals by moving the head to fixed horizontal rotationsusing a head-mounted laser and markings on the examination roomwall. The GDVAgives ameasurement that represents the level of VAdeficit across the whole horizontal meridian of gaze angles. Twomeasures were derived from the GDVAmeasures: (i) the average VAalong the whole horizontal meridian (from�30� toþ30�) and (ii) thewidth of the null region using the LFD method described earlier.

The Radner reading chart also was administered, whichconsists of reading short sentences of reducing font size (from

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1.2 to �0.2 logMAR equivalents, called the “logarithm of thereading acuity determination” [logRAD]). The Radner readingchart was used to assess (i) the reading acuity, the smallest font thatcan be read on the chart; (ii) the maximum reading speed (i.e., theaverage reading speeds of the 3 font sizes where the text was readthe quickest); and (iii) the critical print size, the font at whichreading speed decreases to less than 80% of the maximum readingspeed (Fig 2, available at www.aaojournal.org). Participants wereasked to comment on subjective changes in VA and nystagmusfor each form of contact lens relative to spectacle wear (i.e., wasthere an improvement, no change, or deterioration in vision orseverity of nystagmus). Participants were asked to comment onany side effects they experienced, and ease of handling of thelenses by the participants was documented.

Sample Size

The power calculation was based on testeretest data derived fromprevious pharmacologic and surgical studies on individuals with IN(n ¼ 36) (McLean RJ, Gottlob I, Proudlock FA. Are eye movementrecordings or visual acuity the better outcome measure fornystagmus: a test-retest analysis. ARVO Meeting Abstracts2012;53:510). The standard deviation of differences in repeated-measures data of nystagmus intensity at the null region whenviewing at a distance 1.2 m was 3.52�/s. To detect a 20%improvement in nystagmus intensity (change of 2.7�/s) wouldrequire 24 participants for a statistical power of 90% (a ¼ 0.05)and a dropout rate of 15%. This would be sufficient to detect achange of approximately 1 line in predicted logMAR VA usingNAFX at the null region or less than half a line across all positionsalong the horizontal meridian (from 30� to the left to 30� to theright in 3� steps). It would also allow a detection of a 13% changein nystagmus intensity across all positions.

Statistical Analyses

A logarithmic transformation was applied to the main outcomemeasure, nystagmus intensity, so that data approximated tonormal distributions. A linear mixed model was used to analyzethe data, including the treatment received (SCL or RGPL wear),type of nystagmus (albinism or idiopathic), and treatmentsequence (SCL followed by RGPL, or RGPL followed by SCL)as separate fixed factors. For the intention-to-treat analysis, lastobservation carried forward was used to account for missing data(for 4 participants who dropped out, and therefore data were notcollected for both contact lens treatments and final spectaclewearing phase).

For all other eye movement and VA comparisons, linearmixed models were used to compare the 2 contact lens treatments(SCL, RGPL) and baseline (spectacle wear), including type ofnystagmus (albinism or idiopathic) and viewing distance (4, 1.2,or 0.4 m) as fixed factors. Because small time-dependent changeswere noted between the first and last baseline spectacle wearvisits (e.g., at distance nystagmus intensity for all positions andBCVA was reduced on last spectacle wear visit compared withthe first spectacle wear with a significance of P<0.1), the averageof the 2 visits was used as the measure for baseline spectaclewear. A Bonferroni correction was used to adjust for the 3-waycomparison of treatment groups. Reading parameters wereanalyzed using the Friedman test (with Dunn’s multiple com-parison test) because the data deviated significantly from normaldistributions. Subjective responses for the 2 contact lens treat-ments were compared using the Gamma statistics to comparegraded ordinal data.

Because of the possibility of misalignment of SCLs in partici-pants that could lead to inadequate neutralization of astigmatism,

4

we investigated the effect of astigmatism on VA when wearingcontact lenses. The cylinder for each eye was compared with thedifference in monocular VA measured for contact lens wear andspectacle wear using a linear mixed model including a factor forthe eye tested in the model.

Results

Participant Adherence

Figure 3 illustrates the flow of participants through the study. Ofthe 24 participants recruited to the study, 4 dropped out.Participant 12 withdrew from the trial because of ill health (notrelated to the study, and data were collected for the first 2 visits),participant 6 had difficulty inserting the contact lenses (data werecollected for the first 2 visits), participant 15 withdrew becauseof unforeseen family circumstances (data were collected for thefirst 2 visits), and participant 19 was lost to follow-up and couldnot be contacted after the first visit (data were collected for the firstvisit). Missing data were accounted for using last observationcarried forward. Full data sets were successfully recorded on allother participants for all visits.

The protocol for the study stated that participants would beexamined at 2- to 3-week intervals after each phase began. Noparticipants were examined at less than 2 weeks; however, in somecases, participants did exceed the 3-week period during the contactlens wearing phases. For the SCL phase, 4 participants exceeded 3weeks (28e35 days); 2 participants damaged the original SCLs andrequired new lenses, which were sent via post (participants 17 and18), and 2 participants canceled and rebooked appointmentsbecause of other commitments (participants 8 and 23). For theRGPL phase, 4 participants exceeded the 3-week period (between24 and 70 days); 1 participant’s lens fit was not good and a new setof lenses was required (participant 18), 1 participant was unable toattend before 24 days (participant 2), and 2 participants rebookedappointments because of illness (participants 4 and 7).

Eye Movement and Visual Outcomes

Figure 4 shows a representative participant with IIN illustratingoriginal eye movement data with intensity measurements, VA,and reading parameters.

Main Study Outcome

For the main outcome measure, nystagmus intensity at the nullregion (dominant eye analyzed) when viewing targets at 1.2 m,there was no statistically significant difference in nystagmus in-tensity during SCL and RGPL wear (F ¼ 0.001, P ¼ 0.974). Themean (� standard deviation) intensity was 11.35�/s (�6.96�/s) forSCL and 10.79�/s (�4.83�/s) for RGPL (mean difference ¼ 0.57�/s; 95% confidence interval, �1.25�/s to 2.45�/s). The treatmentorder (i.e., which contact lens was received first) and type ofnystagmus were not significant factors influencing nystagmus in-tensity (for treatment order: F ¼ 0.623, P ¼ 0.439; type ofnystagmus: F ¼ 0.112, P ¼ 0.741).

Comparison of Soft Contact Lens and RigidGas-Permeable Lens with Baseline Spectacle Wear

Nystagmus Parameters. There were no statistically significantdifferences between the 2 contact lens treatments or spectaclebaseline wear (using an average of the first and last visit forspectacle wear) for any of the eye movement parameters measured,which included nystagmus intensity, amplitude, frequency, andNAFX measured at distance and near for all positions and at the

Figure 3. Flow of participants through the study. RGPL ¼ rigid gas-permeable lens; SCL ¼ soft contact lens.

Jayaramachandran et al � Optical Treatment of Infantile Nystagmus

null region (Tables 2 and 3). There was also no difference in nullregion width measured using LFD. Distance had an effect on alleye movement parameters (with the exception of LFD andnystagmus frequency in all positions) because of nystagmusdamping during viewing at 0.4 m, with the result that all nystagmusparameters were lower during near viewing. The effect of distanceon nystagmus intensity was mainly due to a reduction in amplitudeduring near viewing with the effect being particularly obvious atthe null region (Table 2).

Visual Outcomes. Figure 5 shows the change in BCVA atdistance and near in albinism and idiopathic participants for the2 contact lens treatments and baseline spectacle wear underbinocular viewing conditions. The effect of treatment group was

highly significant statistically (F ¼ 6.028, P ¼ 0.003) becauseBCVA was reduced with SCL wear compared with both RGPL(P ¼ 0.004) and baseline spectacle wear (P ¼ 0.033) (P valuesfor all 3-way comparisons adjusted using Bonferroni correction).This effect was consistent in both albinism and idiopathic groupsand for distance and near viewing, although mean differencesbetween treatments were all less than 1 logMAR line differenceregardless of the comparison (Fig 5).

In contrast to the change in nystagmus intensity that wasreduced during near viewing (Table 1), BCVA worsened on nearviewing in both albinism and idiopathic groups (F ¼ 73.22,P<0.0001). This effect was greater in the idiopathic group,resulting in a significant interaction between type of nystagmus

5

Figure 4. Examples of eye movement measurements recorded from 1 individual with idiopathic nystagmus during soft contact lens (SCL), rigid gas-permeable lens (RGPL), and spectacles wear. A, Nystagmus intensity plots during distance viewing from �30� to þ30� with original eye movementillustrated above each plot for left (�30�), right (þ30�), and central (0�) gaze angles. The gray dashed lines indicate the mean intensity across all gaze angles(wide spaced dashed line) and at the null region (narrow spaced dashed line). The grey shaded area under the curve indicates values used for null region; the mainoutcome measure (B) shows gaze-dependent visual acuity (GDVA) measurements during distance viewing (4 m) with the gray dashed lines representing best-corrected visual acuity (BCVA) measurements for distance (4 m: wide spaced dashed line) and near (40 cm: narrow spaced dashed line). C, The plots from theRadner reading chart where reading speed in words per minute (wpm) is plotted against font size logRAD. Reading acuity (RA), critical print size (CPS),and maximum reading speed (MRS) are indicated with arrows. logMAR ¼ logarithm of the minimum angle of resolution.

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and viewing distance (F ¼ 17.87, P<0.0001). Idiopathicparticipants also had a statistically significantly better VA thanthose with albinism (F¼23.45, P<0.0001).

There were no statistically significant effects of the treatment onthe average gaze-dependent VA measure (i.e., VA averaged from30� to the left to 30� to the right in 10� intervals, F ¼ 0.756, P ¼0.476) or the null region width measure (i.e., LFD) derived fromthe gaze-dependent VA measurements (F ¼ 0.477, P ¼ 0.624).

Table 4 illustrates the changes in Radner reading chartoutcomes for the 2 contact lens treatments and spectacle

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baseline. The refractive treatment significantly influenced readingacuity (Friedman test: P ¼ 0.012) and critical print size (P ¼0.012) mainly because the outcomes were significantly poorerwith SCL compared with both RGPL and baseline spectaclewearing. However, there were no significant differences inmaximum reading speed for the 2 different treatment groups andbaseline spectacle wear (P ¼ 0.83).

Table 5 (available at www.aaojournal.org) displays thepercentage of participants showing differences in visualoutcomes between the 2 contact lens treatments and compared

Table 2. Mean and Standard Deviations for Each Eye MovementParameter Under the 2 Different Types of Contact Lens Treat-ment Compared with Baseline Spectacle Wear (Average of 2

Measurements) for Near and Distance

Mean ± SD

SCL RGPL Spectacles (Baseline)

Mean � SD Mean � SD Mean � SD

Distance Viewing (1.2 m)Intensity (�/s)

Null region 11.35�6.96 10.79�4.83 11.77�6.45All positions 16.45�10.41 16.37�6.48 16.02�9.51

Amplitude (�)Null region 3.62�2.17 3.17�1.38 3.62�1.64All positions 4.33�2.38 4.21�1.52 4.26�2.04

Frequency (Hz)Null region 3.24�0.75 3.47�0.73 3.33�0.78All positions 3.75�0.68 3.89�0.66 3.75�0.65

NAFX (logMAR)Null region 0.23�0.16 0.24�0.14 0.23�0.14All positions 0.33�0.21 0.35�0.17 0.31�0.18

LFD (�) 22.96�13.24 21.17�11.95 27.71�16.18Near Viewing (0.4 m)Intensity (�/s)

Null region 8.83�5.41 7.87�4.24 9.10�4.89All positions 15.5�10.07 14.22�7.72 15.02�8.54

Amplitude (�)Null region 2.85�1.70 2.64�1.64 2.82�1.52All positions 4.05�2.39 3.71�1.80 3.94�1.97

Frequency (Hz)Null region 3.17�0.74 3.20�0.78 3.32�0.84All positions 3.76�0.68 3.77�0.67 3.80�0.69

NAFX (logMAR)Null region 0.17�0.16 0.14�0.13 0.17�0.10All positions 0.31�0.22 0.28�0.16 0.29�0.17

LFD (�) 24.79�10.13 26.67�12.79 27.13�12.87

LFD ¼ longest foveation domain; logMAR ¼ logarithm of the minimumangle of resolution; NAFX ¼ eXpanded Nystagmus Acuity Function;RGPL ¼ rigid gas-permeable lens; SCL ¼ soft contact lens; SD ¼ standarddeviation.

Table 3. Statistical Analysis (F statistic and P value) of Each EyeMovement Parameter for the 2 Types of Contact Lens TreatmentCompared with Baseline Spectacle Wear (Average of 2 Measure-ments) with Disease Type (Idiopathic or Albinism) and Distance

(1.2 or 0.4 m) Included in the Model

Statistical Comparisons

Treatment Disease Type Distance

F P F P F P

Intensity (�/s)Null region 0.74 0.48 0.32 0.58 32.22 0.000All positions 0.60 0.55 1.53 0.23 6.123 0.015

Amplitude (�)Null region 1.25 0.29 1.50 0.23 22.89 0.000All positions 0.87 0.42 2.23 0.15 7.969 0.006

Frequency (Hz)Null region 1.19 0.31 3.15 0.09 4.566 0.035All positions 0.84 0.43 0.95 0.34 0.378 0.540

NAFX (logMAR)Null region 0.56 0.57 0.74 0.40 41.27 0.000All positions 1.06 0.35 2.26 0.15 12.56 0.001

LFD (�) 2.19 0.12 0.16 0.69 2.02 0.16

LFD ¼ longest foveation domain; logMAR ¼ logarithm of the minimumangle of resolution; NAFX ¼ eXpanded Nystagmus Acuity Function.

Jayaramachandran et al � Optical Treatment of Infantile Nystagmus

with spectacle baseline. A higher proportion of participants showedclinically relevant differences for reading parameters comparedwith visual parameters, particularly for the comparison betweenSCL and either RGPL or baseline spectacle wear.

Subjective Changes. Participants (n ¼ 20) subjectively re-ported whether they perceived the contact lenses had (i)improved, (ii) not changed, or (iii) worsened their visioncompared with their baseline of spectacle wear (Table 6, availableat www.aaojournal.org). For SCL, the proportions were 12 of 40eyes (30%), 20 of 40 eyes (50%), and 8 of 40 eyes (20%),respectively; and for RGPL, the proportions were 16 of 40 eyes(40%), 22 of 40 eyes (55%), 2 of 40 eyes (5%), respectively(Gamma statistic: P ¼ 0.276). For subjective changes in theseverity of nystagmus, the proportions were 6 of 40 eyes(15%), 34 of 40 eyes (85%), and 0 of 40 eyes (0%) for SCL,respectively, and 14 of 40 eyes (35%), 24 of 40 eyes (60%),and 2 of 40 eyes (5%) for RGPL, respectively (Gammastatistic: P ¼ 0.269).

Side Effects and Handling of Lenses. Side effects reported byparticipants included blurring of vision, discomfort, dry eyes, andmovement of the lenses (Table 6, available at www.aaojournal.org).Participants reported significantly better ease of handling for RGPLlenses (n ¼ 20 “good” or “OK” and n ¼ 2 “poor”) compared with

SCL lenses (n ¼ 9 “good” or “OK” and n ¼ 9 “poor”) (Pearsonchi-square test: P ¼ 0.001).

Misalignment of Contact Lenses in Nystagmus. To explorethe possibility of misalignment of the SCL, a lens was marked at 6o’clock and recorded over time using a video camera in participant2. The SCL rotated out of position by approximately 30� with norealignment of the lens occurring via blinks or with time (Video 1,available at www.aaojournal.org).

The overall amount of astigmatism (i.e., cylinder in diopters) wascomparedwith the deterioration inmonocular VA (i.e., logMARVAduring contact lens wear e spectacle wear with left eye or right eyeviewing, both eyes included in statistical model). There was nosignificant effect of amount of astigmatism on deterioration in VAfor either SCL (F ¼ 0.216; P ¼ 0.645) or RGPL (F ¼ 0.285; P ¼0.597).

Discussion

Eye Movement Outcomes

In the first randomized controlled trial comparing the effectof SCL and RGPL wear for those with IN, we find nosignificant differences in nystagmus intensity between the 2forms of treatment. We also found no improvement in anynystagmus parameter with contact lens wear compared withthe baseline of spectacle wear. This is in contrast to severalcase reports and case series that observed an improvement innystagmus with contact lens wear.13,17e20 However, theseprevious reports all had small sample sizes (n ¼ 1 to n ¼ 5)compared with our study, and only 1 of the studies appliedhard contact lenses.13 The studies that applied SCL allowedfor a shorter adaption period to the lenses than we did,ranging from no adaption period18,20 to a maximum adap-tion period of 1 week.17,19 The study applying hard contactlenses allowed an adaption period of 10 weeks beforerecording the eye movements from 1 participant and

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Figure 5. Mean best-corrected visual acuity (BCVA) (error bars ¼ stan-dard error of mean) under the 2 contact lens treatments and baselinespectacle wear (average of 2 measurements) for albinism (open symbols) andidiopathic (filled symbols) participants for near (0.4 m, circles and solid lines)and distance (4 m, squares and dashed lines) viewing under binocularviewing conditions. logMAR ¼ logarithm of the minimum angle of reso-lution; RGPL ¼ rigid gas-permeable lens; SCL ¼ soft contact lens.

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reporting a reduction in the amplitude and frequency of thenystagmus.13 In addition, a previous retrospective study,assessing hard contact lens wear in 112 participants withIIN, descriptively reported a decrease in the amplitude andfrequency of nystagmus, although no statistical analysiswas reported.15 A sufficient adaptation time is animportant requirement for such studies because initialdiscomfort or pain is likely to lessen over time because ofdesensitization.

None of these previous studies reporting improvementsin eye movement were randomized controlled trials,

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although the type of participants was comparable to those inour study, including IIN and IN associated with albinism. Inour study, a masked analysis of calibrated eye movementswas performed on an appropriately powered sample size ofrepresentative participants who were randomly allocated tosequence of treatments. The effect size of change innystagmus intensity for RGPL compared with SCL wasapproximately 5%, and calculations based on our dataindicate that a sample size of >500 would be necessary toshow a significant difference for this effect size. Althoughthe effect size for RGPL wear compared with spectacle wearwas higher at 8.7%, a sample size of >200 would benecessary to demonstrate a statistically significant difference(n>650 for a 5% difference).

Damping of nystagmus on near compared with distanceviewing was noted for the 2 types of contact lenses andspectacle wear mainly because of a reduction in the ampli-tude of the nystagmus also leading to an improvement infoveation (Tables 2 and 3). These findings concur with thoseof Hanson et al,26 who observed nystagmus amplitudedecreasing with near viewing in some individuals. Whenviewing at 0.4 m, convergence damping led to animprovement in the predicted VA estimated from thenystagmus waveform using the NAFX function comparedwith viewing at 1.2 m. In contrast, we observed that themeasured VA was worse during near viewing, especiallyin the idiopathic group of participants (Fig 4). Assuggested by Hanson et al,26 these differences could beexplained by different methodologies used, and inparticular, differences in luminance between near anddistance charts. We opted to use the PVVAT automatedsystem (Precision Vision, La Salle, IL) for testing VAunder distance viewing, which uses a backlit Applemonitor (Apple Inc, Cupertino, CA) to provide high-contrast letters (Weber contrast ¼ 99.4%), whereas fornear acuity cards the contrast of the letters is dependent onthe room lighting and is consequently lower.

Other Exploratory Outcomes

We also observed that visual function, quantified usingBCVA, reading acuity, and critical print size, deteriorates toa statistically significant level with SCL wear. Mean dif-ferences were <1 logMAR/logRAD line for all visualoutcome measures, which is not a clinically relevant dif-ference. However, a proportion of participants showedclinically relevant differences, particularly for reading pa-rameters (e.g., 15% deteriorated by �2 logRAD lines forreading acuity and 30% for critical print size when wearingSCL compared with RGPL). The possibility that SCL couldbe detrimental in a subset of individuals with IN needs to beexplored further in a study appropriately powered for visualoutcomes. Of note, only 20% of participants subjectivelyreported deterioration in VA when wearing SCL, althoughonly 5% of participants reported deterioration in VA withRGPL wear. The overall tolerability of the contact lenseswas good. Only 1 of the 4 participants who dropped out ofthe study did so because of the inability to handle the lenses.Mild side effects of blurring and tearing on contact lenswear were reported. Overall, the IIN group demonstrated

Table 4. Results from the Radner Reading Test Showing Means (� Standard Deviation) Under the 2 Different Types of Contact LensTreatment Compared with Baseline Spectacle Wear (Average of 2 Measures) Along with Results from the Friedman Test

Parameter Group

SCL RGPL Spectacles (Baseline)

PMean � SD Mean � SD Mean � SD

Reading acuity (logRAD) Albinism 0.642�0.150 0.567�0.161 0.571�0.156 0.030Idiopathic 0.342�0.108 0.308�0.124 0.296�0.069 0.011

Critical print size (logRAD) Albinism 0.750�0.198 0.633�0.192 0.675�0.166 <0.0001Idiopathic 0.392�0.124 0.367�0.130 0.404�0.066 0.030

Maximum reading speed (wpm) Albinism 173.4�50.5 164.0�46.1 167.5�49.3 0.135Idiopathic 186.7�25.1 177.8�21.1 185.4�26.6 0.830

logRAD ¼ logarithm of the reading acuity determination; RGPL ¼ rigid gas-permeable lens; SCL ¼ soft contact lens; SD ¼ standard deviation; wpm ¼words per minute.

Jayaramachandran et al � Optical Treatment of Infantile Nystagmus

better VA compared with the albinism (Table 3) because offoveal deficits in albinism, including continuation of innerretinal layers across the fovea and shortening of coneouter segments.27

The deterioration of vision with SCL wear in our study ledus to explore possible misalignment of SCL in IN further. Wefound that the SCL rotated out of position by approximately30� with no realignment of the lens occurring via blinks orother means. Several factors have been reported as influ-encing the orientation of toric SCLs, including blinking, lidpressure and anatomy, gravity, and the degree of myopia.28

One possibility is that the quick phase of the horizontalnystagmus, in conjunction with the asymmetric distributionof mass vertically in the contact lens, could introduce atorsional force causing the SCL to misalign. Anotherpossibility could be the interaction between the horizontalnystagmus and the frictional forces, and the pressureimposed by the eye lid(s) might lead to lens misalignment.The possibility of SCL misalignment leading todeterioration in visual function in certain individuals withnystagmus also needs to be explored further.

Study Strengths and Limitations

There are several strengths to the study in that a rigorousexperimental design has been used with randomization ofparticipants and masking of the investigator during theanalysis of the main outcome of the study. Changes innystagmus have been characterized fully using methods thathave been developed over several years of running trials totest interventions in IN. A range of visual outcomes alsowere explored, including near (0.4 m) and distance (4 m)vision, BCVA along the horizontal meridian and the nullregion, and reading performance.

There are also limitations to our study. First, because ofthe nature of the study, neither the investigators nor theparticipants could be masked to the treatment arm that wasprescribed at any time. However, for the primary outcomemeasure, the investigator analyzing the eye movement datawas masked to the order of treatment to prevent anyinvestigator bias. It is also usual in a trial to lose participantsafter randomization, which can cause bias if attrition occursbetween the groups. For example, a participant who hasvery poor VA may not perceive as much benefit in the use ofcontact lenses as a participant with better VA and therefore

withdraw from the study before completion. However, wehave avoided attrition bias by applying an intention-to-treatanalysis to our data.

Second, although our participants were given a minimumof 2 weeks to acclimatize to the lenses before examinationwith the lenses, this may not be have been an adequate timefor full adjustment to lens wear for all participants. Despitethe reduced adaptation times, it is interesting to note thatparticipants wearing RGPL still did not have measurablyless nystagmus because increased afferent signaling mightbe expected because desensitization of efferent sensors maynot have had time to occur. Also, further studies couldbenefit from “wash-out” periods between contact lenstreatments (i.e., with a period of spectacle wear) to allowany ocular motor or visual effects to return to baseline.

Third, eye movement measures were recorded at 1.2 m topermit gaze angles of �30� to be achieved using a rearprojection screen (image width ¼ 1.5 m), which may resultin a small degree of convergence damping compared with atrue distance measurement (e.g., 4 m). Finally, the length oftime each day that lenses were worn by individual partici-pants was variable depending on factors such as discomfort,perceived benefit of lens wearing, and the patient’s dailyactivities. Unfortunately, compliance to contact lens wearcannot be objectively measured, although future studiescould measure compliance subjectively using diaries. Wealso acknowledge that people who have nystagmus are“slow to see,” and target acquisition time29 would be auseful additional outcome measure in future trials ofnystagmus treatment.

In conclusion, our study found no difference innystagmus intensity during RGPL and SCL wear. We alsofound that contact lenses do not significantly improvenystagmus compared with a baseline of spectacle wear. Weobserved that SCLs lead to a small but significant deterio-ration in VA compared with both RGPL and spectacle wear,although, overall, effect sizes were not clinically relevant.

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Footnotes and Financial Disclosures

Originally received: July 5, 2013.Final revision: March 6, 2014.Accepted: March 7, 2014.Available online: ---. Manuscript no. 2013-1081.

Ophthalmology Group, University of Leicester, Faculty of Medicine &Biological Sciences, Leicester Royal Infirmary, Leicester, United Kingdom.

Meeting Presentation: Jayaramachandran P, Proudlock FA, Odedra N,Gottlob I, McLean RJ. Optical treatment of nystagmus: a randomised,controlled, cross-over study. ARVO Meeting Abstracts, March 26, 2012,Fort Lauderdale, FL, 53:513. Proudlock FA, Jayaramachandran P, OdedraN, Gottlob I, McLean RJ. Optical treatment of infantile nystagmus. 2ndWorld Congress of Paediatric Ophthalmology and Strabismus, Milan, Italy,September 8e9, 2012.

*F.A.P. is co first author.

Financial Disclosure(s):The author(s) have no proprietary or commercial interest in any materialsdiscussed in this article.

Funded by the College of Optometrists and Ulverscroft Foundation. Contactlenses were provided by Cantor and Nissel Ltd (Brackley, UK) and No 7Contact Lenses (East Sussex, UK). The sponsor or funding organizationhad no role in the design or conduct of this research.

Abbreviations and Acronyms:BCVA ¼ best-corrected visual acuity; GDVA ¼ gaze-dependent visualacuity; IIN ¼ idiopathic infantile nystagmus; IN ¼ infantile nystagmus;LFD ¼ longest foveation domain; logMAR ¼ logarithm of the minimumangle of resolution; logRAD ¼ logarithm of the reading acuity determi-nation; NAFX ¼ eXpanded Nystagmus Acuity Function;PVVAT ¼ Precision Vision Visual Acuity Testing; RGPL ¼ rigid gas-permeable lens; SCL ¼ soft contact lens; VA ¼ visual acuity.

Correspondence:Rebecca J. McLean, MSc, Ophthalmology Group, University of Leicester,Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary,Leicester LE2 7LX, UK. E-mail: rjm19@le.ac.uk.