Ocular motor outcomes after bilateral and unilateral infantile cataracts

Vision Research 46 (2006) 940–952 www.elsevier.com/locate/visres

Ocular motor outcomes after bilateral and unilateral infantile cataracts Richard V. Abadi a,¤, Joanne E. Forster a, I. Christopher Lloyd b a

b

University of Manchester, Faculty of Life Sciences, P.O. Box 88, Manchester M60 1QD, UK Manchester Royal Eye Hospital, Department of Ophthalmology, Oxford Road, Manchester M13 9WH, UK Received 18 July 2005; received in revised form 27 September 2005

Abstract We wished to study how the severity and duration of early onset visual deprivation aVects eye alignment and ocular stability. Thirtythree patients (aged 1 week to 12.8 years) with infantile cataracts (16 bilateral, 17 unilateral) were examined for periods up to 61 months. Twenty-three patients were considered to have cataracts, which were a major obstacle to vision (major form deprivation), 9 of whom underwent surgery within 8 weeks of birth (mean and SD D 5.2 § 2.3 weeks) and 10 after 8 weeks (mean and SD D 33.9 § 29.7 months). Eye alignment and Wxation stability was measured using infrared recording systems and video. Visual acuity was assessed using forcedchoice preferential looking techniques in the neonates and infants and with optotypes in the children. Fifteen of the 23 (65%) patients who experienced major form deprivation exhibited a nystagmus, of which 11 (73%) were manifest latent nystagmus (MLN). Nineteen of the 23 (85%) had strabismus. Of the nine patients who underwent early surgery (68 weeks), two displayed a preoperative nystagmus whilst between 10 and 39 months post-operatively 8 (89%) exhibited a nystagmus. Of the group of 10 patients with minor cataracts only 2 (1 late surgery, 1 no surgery) had nystagmus and 2 strabismus. We conclude that following optimal post-operative management of infantile cataracts a sustained nystagmus—typically an MLN—is the most likely ocular motor outcome, even when the period of deprivation is as short as 3 weeks.  2005 Elsevier Ltd. All rights reserved. Keywords: Infantile cataracts; Visual deprivation; Nystagmus; Manifest latent nystagmus; Strabismus

1. Introduction The prevalence of infantile cataracts is approximately 3 in 10,000 live births (James, McClearon, & Waters, 1993; Stayte, Reeves, & Wortham, 1993; Rahi, Dezateux, & the British Cataract Interest Group, 2000), with bilateral opacities being more common than unilateral (Lambert & Drack, 1996; Stayte et al., 1993; Taylor, 1998). Cataracts vary greatly in their morphology and position, with some progressing with time (Lambert & Drack, 1996; Taylor, 1998). Consequently a decision must be made as to whether the cataract is signiWcantly interfering with visual function. Small, mild cataracts or those that are eccentrically placed with respect to the visual axis are frequently managed by

*

Corresponding author. Tel.: +44 161 200 3875; fax: +44 161 200 3887. E-mail address: [email protected] (R.V. Abadi).

0042-6989/$ - see front matter  2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.visres.2005.09.039

observation. Dense and large cataracts necessitate immediate management (Lambert & Drack, 1996; Taylor, 1998). Past studies on the visual outcomes have tended to concentrate on visual acuity (VA) measures (Birch & Stager, 1998; Kushner, 1995; Maurer & Lewis, 1993; Pratt-Johnson & Tillson, 1981), stressing the VA beneWts of early surgery (i.e., within the Wrst 8 weeks), particularly when linked to appropriate optical correction and full compliance with occlusion. To date, the literature describing primary gaze Wxation behaviour (i.e., eye alignment and ocular stability) of patients with infantile cataracts has been, in the main, qualitative (Birch & Stager, 1998; Kushner, 1995; Maurer & Lewis, 1993; Parks, Johnson, & Reed, 1993; Pratt-Johnson & Tillson, 1981). These reports frequently documented the presence of a “nystagmus” but did not quantify the amplitude, frequency, waveform and beat direction of the oscillations. Generally, nystagmus tends to develop as a

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consequence of the cataract type. Parks and his colleagues (1993) reported 100% of their infants with a total cataract, and 43% of those with a nuclear cataract developed a nystagmus. Nystagmus has also been reported to be more frequent in bilateral rather than unilateral infantile cataract (Lambert & Drack, 1996; Maurer, Lewis, & Brent, 1983; Wright, Christensen, & Noguchi, 1992); its overall prevalence depending on the age of the child and the stage in the management programme (Bradford, Keech, & Scott, 1994; Parks et al., 1993; Spierer, Desatnik, Rosner, & Blumenthal, 1998). Thus there appears to be a strong relationship between early visual form deprivation with an absence of binocularity and/or the presence of a nystagmus. The timing of surgery, and therefore the duration of deprivation, has been considered an important factor in the development of nystagmus (Lambert & Drack, 1996; Maurer & Lewis, 1993; Taylor, 1998). Past studies have documented the presence of a pendular nystagmus after 10–12 weeks of life in untreated, total cataracts (Bradford et al., 1994) and, if surgery is left until 6 months post-natally, past reports suggest that a nystagmus will invariably occur (Gage, Abadi, Lloyd, & Thompson, 2001; Lloyd, Kriss, Taylor, & Russell-Eggitt, 1994; Popovic, Thaung, & Abrahamsson, 1997; Rogers, Tishler, Tsou, Hertle, & Fellows, 1981). On the other hand, Wright and his colleagues (1992) reported that when surgery was undertaken after 10 months of age, in a group of 29 patients with bilateral major cataracts (e.g., total and nuclear), only 20% developed nystagmus post-operatively. Such disparities in the reported incidence of nystagmus often reXect the diVerences in sample size and sample homogeneity as well as methods of recording Wxation stability. As non of these studies used eye movement recording systems to assess the presence or nature of the involuntary ocular oscillations, the precise prevalence is unknown. In this present study, we wished to determine longitudinally the ocular motor outcomes of 23 neonates and 10 infants and children with infantile cataracts. In particular, we wished to establish Wxation stability and eye alignment during primary gaze. Twenty-three of the 33 were classed as having cataracts which were a major obstacle to vision (major form deprivation) and nine underwent surgery within 8 weeks of birth. Our results will show that in spite of early surgical intervention and optimal post-operative management, the large majority of patients in due course exhibited a nystagmus (65%) and a strabismus (85%). On the other hand, only 20% of the patients who experienced a minor visual deprivation exhibited either a nystagmus and/ or a strabismus. These Wndings support the view that early pattern vision is a primary factor in ensuring normal ocular alignment and stable primary gaze holding. 2. Materials and methods 2.1. Subjects Thirty-three patients (aged 1 week to 12.8 years) with infantile cataracts took part in this study, 12 of whom were

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male and 21 female. Sixteen of the patients had bilateral and 17 unilateral infantile cataracts. Twenty patients (61%) presented with their cataracts between 1 and 24 weeks with the remaining 13 (39%) presenting between 26 weeks and 12.8 years of age. A total of 19 patients underwent surgery. Early surgery (i.e., 68 weeks; mean and SD D 5.2 § 2.3 weeks) was carried out on 9 patients and late surgery (i.e., 78 weeks; mean and SD D 33.9 § 29.7 months) was undertaken on 10 patients. None of the patients had any associated ocular or systemic abnormalities, and none of the cohort developed post-operative glaucoma, retinal detachments, etc. Informed consent was obtained according to tenets of the Declaration of Helsinki. All patients underwent a full ophthalmological examination before and after cycloplegic dilation by one of the authors (ICL). 2.2. Grading the cataracts Cataract morphology, density and position were evaluated with a slit lamp and ophthalmoscope when the patients were both undilated and dilated. Transmission or absorption characteristics of some of the cataracts were also computed (see Forster, Abadi, Muldoon, & Lloyd, in press; Gage et al., 2001, for further details). An 11 point ordinal grading scale (0–11) was assigned to the range of infantile cataracts and related to the severity of the cataract. The cataracts were divided into those which cause minor forms of visual deprivation and best left in situ and regularly observed (i.e., grades 64.0) and those which were considered to constitute a major visual deprivation and require (subject to parental permission) surgical removal (grades 75.0). Included in the Wrst group were lamellar, sutural, sectoral and posterior polar opacities and in the second group were total, cortical, posterior polar, nuclear, posterior lenticonus and persistent hyperplastic primary vitreous cataracts. Cataracts were surgically removed in 19 out of 23 cases to avoid major form deprivation (Tables 1 and 2) and in 2 out of 10 cases in patients with minor opacities (Tables 3 and 4). 2.3. Eye movement recording Binocular and monocular eye alignment and Wxation stability were assessed during primary gaze using one of two infrared limbal reXection recording systems (ACS Applied Research Developments, Manchester, UK and Skalar Medical, Delft, The Netherlands). Eye movement signals from both eyes were sent either directly to a 4-channel chart recorder or relayed to a computer for oV-line analysis. For the younger patients (<5.0 years of age), the ACS sensor units were mounted in a pair of goggles (Fig. 1) and the patient’s head was stabilised by either the parents or one of the authors. The system was linear to §20° and resolution was in the order of 5–10 min of arc. Binocular and monocular recordings were principally made in the primary

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Table 1 Pre and post-operative Wxation states after bilateral major form deprivation (n D 10) Subject

Age of presentation: Follow-up period

Age at surgery

Cataract morphology

Deprivation factor (0–10)

Ocular alignment

Ocular motor Wxation (amplitude/frequency)

Relative VA

Pre-Op

R

L

0.4 0.4 0.1 0.7 1.0 0.3 0.3 0.3 0.9 1.0

0.4 0.6 <0.1 0.4 0.7 0.7 0.3 0.3 0.4 0.3

Post-Op

Mean amplitude/frequency 1 2 3 4 5 6 7 8 9 10

1 Week: 10 months 1 Day: 14 months 8 Weeks: 25 months 7 Weeks: 21 months 14 Weeks: 11 months 2.9 Years: 17 months 7.5 Years: 18 months 5 Years: 9 months 3 Weeks: 15 months 8 Years: 7 months

4 Weeks 6 Weeks 8 Weeks 8 Weeks 14 Weeks 3 Years 4.5 Years 5.5 Years No surgery No surgery

Nuclear Lamellar + Sutural Nuclear Post-lenticonus Lamellar Nuclear Lamellar Nuclear Post-polar Cortical

R D 6, L D 6 R D 7, L D 7 R D 8, L D 8 R D 8, L D 5 R D 7, L D 7 R D 7, L D 7 R D 5, L D 3 R D 6, L D 6 R D 4, L D 6 R D 3, L D 5

NAD RCS ADS ! LCS ADS ! LCS NAD ! LCS RCS RDS NAD NAD NAD

S S CN CN S CN <1.0°/3.0 Hz MLN S

LN 3.0°/2.0 Hz MLN 3.0°/4.5 Hz CN MLN 3.5°/3.0 Hz MLN 3.0°/1.0 Hz MLN 1.0°/3.0 Hz MLN 2.0°/2.5 Hz S S S

ADS, alternating divergent strabismus; LCS, left convergent strabismus; RDS, right divergent strabismus; RCS, right convergent strabismus; NAD, no apparent deviation; S, steady; CN, congenital nystagmus; LN, latent nystagmus; MLN, manifest latent nystagmus. Arrows (!) indicate change in Wxation status over time, R, right eye; L, left eye. Relative VA is a measure of the expected norm, with 1.0 equivalent to a match and values less than 1.0 indicating a reduced VA. See text for further details.

Table 2 Pre and post-operative Wxation states after unilateral major form deprivation (n D 13) Subject

Age of presentation: Follow-up period

Age at surgery

Cataract morphology

Deprivation Ocular factor (0–10) alignment

Ocular motor Wxation (amplitude/frequency)

Relative VA

Pre-Op

R

L

0.7 0.6 1.0 0.9 1.6 0.7 0.7 1.7 <0.1 1.2 <0.1 <0.1 <0.1

0.2 0.2 <0.1 0.9 1.3 0.7 1.0 0.8 1.2 <0.1 1.2 1.1 1.2

Post-Op

Mean amplitude/frequency 1 2 3 4 5 6 7 8 9 10 11 12 13

1 Week: 21 months 1 Week: 20 months 1 Week: 23 months 1 Week: 39 months 6 Weeks: 12 months 14 Weeks: 17 months 12 Weeks: 21 months 6 Months: 27 months 4.5 Years: 19 months 5.2 Years: 6 months 6.1 Years: 47 months 3 Weeks: 14 months 12.8 Years: 7 months

3 Weeks 3 Weeks 3 Weeks 4 Weeks 8 Weeks 14 Weeks 18 Weeks 1.1 Weeks 1.2 Weeks 5.5 Years 6.5 Years No surgery No surgery

PHPV PHPV Post-polar, PHPV Nuclear PHPV Nuclear PHPV Post-lenticonus Post-lenticonus Post-lenticonus Nuclear Nuclear Nuclear

R D 10 L D 10 LD8 RD8 L D 10 LD7 RD9 LD 7 RD9 LD8 R D 10 R D 10 R D 10

NAD ! RDS LDS NAD ! LDS NAD ! RCS LDS NAD ! LCS NAD ! RCS NAD ! LDS RDS LCS, DVD RCS, DVD LCS RDS

S CN 2.5°/3.0 Hz S S S CN 2.5°/2.5 Hz S MLN 1.0°/2.0 Hz S MLN 3.5°/2.5 Hz S MLN S S S S S S S S MLN 2.5°/2.5 Hz MLN 1.5°/1.0 Hz MLN 7.0°/2.0 Hz MLN <1.0°/2.0 Hz

PHPV, persistent hyperplastic primary vitreous. DVD, dissociated vertical deviation, LDS, left divergent strabismus. Other abbreviations as for Table 1.

position of gaze, although on occasions recordings during eccentric gaze were taken. Stationary Wxation targets included light sources, toys and acoustic devices and were presented at 28 cm from the patient. Calibration was achieved either by moving the targets in a step-wise or sinusoidal fashion by §5° or §10°. When such calibration proved diYcult the infant’s head was rotated by a Wxed amount to give a vestibulo-ocular response. In older children the Skalar IRIS 6500 (Delft, The Netherlands) infrared limbal tracking system was used to record Wxation stability. The system was linear to §20° and resolution was in the order of 3 min of arc. Targets were backprojected onto a screen, which was placed 114 cm from the subject. Eye movements were calibrated by presenting a computer-driven pursuit stimulus that moved horizontally over a range of §10° in a sinusoidal manner at 0.32 Hz. A

chin rest, with supplementary cheek rests, was used to stabilise head position. The recording length at each visit depended upon the cooperation of the patient and parent. The nystagmus was invariably conjugate. On a number of occasions eye movements from one eye only could be recorded. All patients were examined at regular intervals and the length of time between visits depended very much on the age of the child and the length of time since surgery. Patients were seen every 2 weeks in the early post-operative period, with the length of time between visits increasing thereafter. The mean time between visits was 10 weeks for up to a period of 3 years. For patients or parents who were willing, additional eye movement recordings were undertaken on separate non-scheduled visits. The mean number of eye movement recording sessions per patient was 10. The eye movements of all patients were also

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Table 3 Fixation states after bilateral minor form deprivation (n D 6) Ocular motor Wxation (amplitude/frequency)

Subject

Age of presentation: Follow-up period

Age at surgery

Cataract morphology

Deprivation factor (0–10)

Ocular alignment

1 2 3 4 5 6

2 Weeks: 16 months 3 Weeks: 18 months 12 Weeks: 14 months 14 Weeks: 18 months 26 Weeks: 21 months 3.5 Years: 61 months

No surgery No surgery No surgery No surgery No surgery No surgery

Lamellar + Sutural Lamellar Lamellar Lamellar Sutural Lamellar + Sutural

R D 3, L D 3 R D 4, L D 4 R D 3, L D 3 R D 3, L D 3 R D 3, L D 3 RD3 LD3

NAD Large exophoria Exophoria Exophoria NAD NAD

Pre Op

Relative VA

Post OP

S S LN <1.0°/2.5 Hz S S S

R

L

0.3 1.1 1.0 0.7 0.9 0.5

0.3 1.1 0.6 0.7 0.9 0.5

Note none of the patients had surgery. Abbreviations as for Table 1.

Table 4 Pre and post-operative Wxation states after unilateral minor form deprivation (n D 4) Subject

Age of presentation: Follow-up period

Age at surgery

Cataract morphology

Deprivation factor (0–10)

Ocular alignment

1 2 3

6.3 Years: 20 months 6.9 Years: 15 months 10 Weeks: 22 months

6.5 Years 7 Years No surgery

Post-polar Lamellar PHPV

LD4 RD3 LD4

NAD RCS, R/L LCS

4

4.3 Years: 60 months

No surgery

Sectoral

LD1

NAD

Ocular motor Wxation (amplitude/frequency)

Relative VA

Pre Op

Post OP

R

L

S S

S MLN 2.5°/2.5 Hz S

1.2 <0.1 0.7

0.3 1.2 <0.1

S

1.0

0.7

Abbreviations as for Tables 1 and 2. R/L D right hypertropia.

Fig. 1. The ACS infrared limbal reXection eye movement recording system mounted in a pair of goggles.

video recorded (JVC GR-DVJ70, Victor Japan Ltd). Use of the ophthalmoscope and fundus camera supplemented the quantitative eye movement recordings. 2.4. Ocular motor characteristics Involuntary Wxation instability can take the form of either saccadic intrusions or a nystagmus. The essential diVerence

between these is the initial movement that takes the line of sight oV the target of regard (Abadi & Gowen, 2004; Abadi, Gowen, & Clement, 2003; Dell’Osso & DaroV, 1999). In the case of saccadic intrusions, it is an inappropriate fast movement, whilst with nystagmus it is a slow drift that moves the eyes oV target. Saccadic intrusions are typically involuntary, conjugate, horizontal, less than 1° in amplitude and have a variable frequency (Abadi & Gowen, 2004). When the velocity of the nystagmus slow phase was pendular or accelerating it was classed as congenital nystagmus (CN) (Abadi & Bjerre, 2002; Abadi & Dickinson, 1986; Abadi & Gowen, 2004; Abadi et al., 2003; Dell’Osso & DaroV, 1975; Dell’Osso & DaroV, 1999). If the slow phase was decelerating or linear, with the fast phase always beating towards the open eye, it was classed as a manifest latent nystagmus (MLN) (Abadi & Bjerre, 2002; Abadi et al., 2003; Abadi & Scallan, 2000; Dell’Osso, 1985; Dell’Osso & DaroV, 1979; Dell’Osso & DaroV, 1999). Patients with a latent nystagmus (LN) exhibit an MLN oscillation during monocular viewing but have steady Wxation during binocular viewing. Amplitude and frequency were deWned as peak-to-peak excursions of the oscillation and the number of cycles per second, respectively. 2.5. Ocular alignment A cover test was performed in conjunction with eye movement recording to determine the presence or absence of any manifest deviation or associated abnormal ocular movement (e.g., Dissociated Vertical Deviation). Measurements of the deviation were taken using the Krimsky prism reXection test or prism cover test. Binocularity was assessed

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using the prism reXex test 20
or 10
base out in younger children and the prism fusion range in older, more co-operative patients. Stereoacuity was determined using the TNO stereotest (Laméris Instrumenten bv, The Netherlands) and the Wirt Stereotest (Titmus, Virginia, USA). 2.6. Visual acuity In the case of the neonates and infants, binocular and monocular visual acuity (VA) were measured with Keeler grating acuity cards at 38 cm using forced-choice preferential looking techniques. In older children, single or linear optotype acuity was measured. The single optotypes did not have crowding bars. The same clinician (JEF) carried out all the acuity testing. Acuity values were compared with normative values. A mean normal longitudinal VA function was computed by taking the values from 9 previous studies (Gage, 2001). VA scores from our patients were then compared with the normative values to give a relative VA measure. A value of 1.0 represented an exact match with the normal data set, whereas values less than 1.0, represented a reduced VA. Thus relative acuity values of 1.0, 0.7 and 0.5 represent 0, 30 and 50% reductions in acuity compared with normal patients of an equivalent age. (Further details of the acuity measures can be found in Forster, Abadi, & Lloyd (in review)). 3. Results 3.1. Cataract categorisation and visual experience Each of the 33 patients were allocated to 1 of 4 possible categories based on the laterality of the cataract (bilateral/ unilateral) and its possible detrimental eVect on visual acuity (major/minor form deprivation). Twenty-three of the patients were classed as having experienced major form deprivation, 10 of whom had bilateral and 13 unilateral cataracts. Fig. 2A illustrates the time of surgical intervention and hence the length of the period of deprivation. Note that 9 of the 23 (39%) had been operated on by 8 weeks of age and a further 3 had been operated on by 24 weeks (i.e., 52%). Only 4 (2 bilateral and 2 unilateral) of the 23 remained phakic throughout the study. Ten patients were classed as having experienced minor form deprivation and all 10 experienced at least 18 months of early onset visual deprivation (Fig. 2B). A substantial majority of the minor form deprivation patients (n D 8, 80%) remained phakic throughout the study. 3.2. Bilateral major form deprivation Table 1 details the pre- and post-operative Wxation states of the 10 patients who experienced bilateral major form deprivation. By the end of the study, 7 of the 10 had nystagmus and 3 remained stable. Four of the 8 patients (50%) who underwent surgery exhibited a nystagmus (3 CN, 1 MLN) on primary gaze prior to surgery. Three patients (2

CN, 1 MLN) had uniplanar horizontal oscillations and one patient (Table 1, no. 3) exhibited a multiplanar nystagmus. However, some 10 months post-operatively, all but one (patient 3) of the 8 patients exhibited a uniplanar horizontal nystagmus. The predominant nystagmus type was an MLN (n D 5) (Fig. 3A) with an LN being recorded in only 1 patient (Fig. 3B) and a CN recorded in 1 patient. Some patients exhibited a number of Wxation behaviours over time. Fig. 4 illustrates the longitudinal outcomes of patient 5 (Table 1), who experienced a bilateral major form deprivation. She was initially stable, apart from very occasional saccadic intrusions prior to surgery at 14 weeks and also for the following 6 weeks (Fig. 4A). By week 24 (i.e., 10 weeks post-operative) she exhibited a burst of monophasic square wave saccadic intrusions (Fig. 4B, i), and single saccadic pulses (Fig. 4B, ii) as well as occasional bursts of CN (Fig. 4B, iii and iv). By 28 weeks of age, she exhibited an LN such, that during binocular viewing, Wxation was stable (Fig. 4C, i) whilst during monocular viewing, a jerk nystagmus with the fast phase beating towards the viewing eye was present (Fig. 4C, ii and iii). At 40 weeks post-natally, some 26 weeks after the operation a sustained MLN was now consistently recorded (Fig. 4D). The only individual who developed a post-operative multiplanar, as opposed to a horizontal uniplanar nystagmus, was patient 3 (Table 1). He had experienced a severe bilateral form deprivation (dense nuclear cataracts, grade 8) lasting for a period of only 8 weeks. There were no postoperative complications and follow-up showed excellent optical compliance. As in the cases of patients 4, 6 and 7 who also had severe bilateral infantile cataracts a CN was present pre-operatively. However, it is interesting to note that patient 3’s mother had an idiopathic CN. It could well have been that a familial predisposition to nystagmus, augmented by the early period of severe form deprivation, increased the likelihood of the more complex multiplanar, rather than the simpler uniplanar nystagmus. A small minority of the infants (n D 2), who had experienced bilateral major form deprivation, did not undergo surgery to remove their opacities yet remained stable. It is noteworthy that both patients had cataract morphologies that placed them on the border of the major/minor classiWcation, and so experienced milder levels of deprivation compared with their cohorts. 3.3. Unilateral major form deprivation By the end of the study 8 of the 13 patients had nystagmus and 5 remained stable. In contrast to the bilateral cataract group, the majority of infants with unilateral cataracts were steady prior to surgery (10 out of 11; 91%) (Table 2). However, in the long term, 6 out of the 11 exhibited a nystagmus, in spite of surgical intervention as early as 3 weeks in the case of 3 members of the group. The 2 patients who remained phakic also exhibited a nystagmus. Six out of the 8 (75%) had an MLN. As with the bilateral major form deprivation group, Wxation stability changes were also recorded over time. Fig. 5

R.V. Abadi et al. / Vision Research 46 (2006) 940–952

A

945

7

6

NUMBER OF PATIENTS

5

4 Bilateral n = 10 Unilateral n = 13 3

2

1

0 Nil

0-8 weeks

9-24 weeks

25-72 weeks

73-240 weeks

5-15 years

AGE AT TIME OF SURGERY

B

7

6

NUMBER OF PATIENTS

5

4 Bilateral n = 6 Unilateral n = 4 3

2

1

0 Nil

0-8 weeks

9-24 weeks

25-72 weeks

73-240 weeks

5-15 years

AGE AT TIME OF SURGERY

Fig. 2. Time of surgical intervention (A) in infants with major form deprivation (n D 23), (B) in infants with minor form deprivation (n D 10).

illustrates the Wxation behaviour of an infant (Subject 3, Table 2), who experienced a unilateral major deprivation for only a short period of 3 weeks. By 8 weeks of age he was still steady (Fig. 5, i), but 4 weeks later, irregular bursts of saccadic intrusions were recorded (Fig. 5, ii) and by 72 weeks (i.e., 69 weeks post-operatively) a sustained CN with either a pseudo-cycloid waveform (Fig. 5, iii (a)) or a jerk with extended foveation

waveform, was evident (Fig. 5, iii (b)). The two patients who remained phakic both exhibited an MLN. 3.4. Bilateral and unilateral minor form deprivation None of the six infants with bilateral minor form deprivation underwent surgery. All patients remained stable

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Fig. 3. (A) Manifest Latent Nystagmus [MLN (also called Type 4 MLN (Abadi & Scallan, 2000))]: Patient 11, Table 2. Right-beating and left-beating conjugate jerk nystagmus during right and left viewing, respectively. The nystagmus seen during binocular viewing was similar to that during left monocular viewing. All recordings were taken during primary gaze. (B) Latent nystagmus [LN (also called Type 1 MLN (Abadi & Scallan, 2000): Patient 1, Table 1)]. Note. Binocular viewing and left monocular viewing indicate that the eyes are steady. However, right monocular viewing shows a right-beating linear/ decreasing slow phase velocity jerk nystagmus. All recordings were taken during primary gaze.

binocularly and only patient 3 (Table 3) had a nystagmus (LN) during monocular viewing. A similar trend was seen in the infants who experienced a unilateral minor form deprivation. In this case, 3 of the 4 infants with unilateral minor deprivation were steady and the fourth exhibited an MLN (Table 4). A summary of the Wnal Wxation stability states during binocular and monocular viewing for all 33 patients is shown in Table 5. A logistic regression (Crawley, 2002) found that major cataracts signiWcantly increased the odds of a nystagmus (odds ratio for model >7.73, p < 0.03) whilst cataract laterality had no signiWcant eVect (odds ratio for model <1.2, p > 0.8).

3.5. Gaze and Wxation Thus far, all descriptions of Wxation stability have characterised what occurred when patients viewed stationary targets in the primary position. Coincidentally, as part of the calibration evaluations, we also measured Wxation stability during and after a change in gaze. During binocular viewing we found that infants and children often made a number of hypometric saccades instead of a single normometric saccade in order to reach the desired gaze position (i.e., §5° or §10°). In a couple of infants who had stable central Wxation, we also recorded occasional short 1–3 s bursts of CN at gaze positions beyond §20°. These oscillations may have reXected a large

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Fig. 4. Fixation behaviour over a 20-week period for a subject who had experienced bilateral major form deprivation for 14 weeks (Patient 5, Table 1). (A) 20 weeks (6 weeks post-operative), steady Wxation. (B) 24 weeks (10 weeks post-operative), a variety of conjugate saccadic intrusions: (i) bursts of monophasic square-wave saccadic intrusions; (ii) single saccadic pulses; (iii) saccadic Xutter and (iv) a congenital nystagmus (CN). (C) 28 weeks (14 weeks postoperative), Latent nystagmus (LN)—(i) steady Wxation during binocular viewing (note only the left eye (LE) trace is shown), (ii), right-beating on right monocular viewing and (iii) left-beating on left monocular viewing. (D) 40 weeks (26 weeks post-operative), MLN. (i) Left-beating manifest latent nystagmus (MLN) on binocular viewing, (ii) right-beating MLN on right monocular viewing, (iii) left-beating MLN on left monocular viewing. All recordings were taken during primary gaze.

central null. In another infant a transient rebound nystagmus was recorded. In this case, the infant, who had steady primary Wxation, was somewhat unsteady at 20° right gaze. On returning gaze back into the primary position, a 2.5°, 3 Hz left-beating jerk nystagmus was recorded for a period of 2–3 s. 3.6. Ocular alignment The prevalence of strabismus was very high amongst the group of 23 infants with major form deprivation (n D 19; 83%), 11 of whom had convergent and 8 divergent deviations. Whilst the bilateral group tended to exhibit a deviation very early on, the unilateral group tended to become strabismic at a much later stage. Strabismus was far less common in patients that experienced bilateral or unilateral minor form deprivation, with only 2 out of the 10 patients exhibiting a strabismus. Seventeen out of the 19 patients

who experienced a major visual deprivation also exhibited both a nystagmus and a strabismus. 3.7. Visual acuity Whilst this study was primarily concerned with ocular motor outcomes, it is useful to brieXy consider the Wnal VA scores. In general, for patients who experienced major form deprivation, ‘early’ surgery (<8 weeks of life) produced VA’s closer to the expected norm than did ‘late’ surgery (>8 weeks) or no surgery (Tables 1–4). It is as well to remember that acuity limits not only reXect the duration and depth of the visual deprivation, but also the nystagmus intensity, the slow phase eye velocity and the foveation time (Abadi & Bjerre, 2002; Abadi & Sandikcioglu, 1974; Abadi & Worfolk, 1989; Bedell & Loshin, 1991; Dell’Osso & DaroV, 1975 Dell’Osso & Jacobs, 2002). Secondary factors such as

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Fig. 5. Fixation changes recorded over a period of 14 months in a subject who experienced unilateral major form deprivation (Patient 3, Table 2). Traces for LE only are shown. (i) 8 weeks (5 weeks post-operative), steady; (ii) 12 weeks (9 weeks post-operative), bursts of monophasic square-wave intrusions; (iii) 72 weeks (69 weeks post-operative): (A) a sustained pseudo-cycloid congenital nystagmus (CN); (B) a sustained increasing velocity slow phase with an extended foveation congenital nystagmus (CN). All recordings were taken during primary gaze. Table 5 Summary of the Wnal Wxation states of all patients during binocular and monocular viewing (n D 33) Fixation state

Deprivation categories Major (n D 23)

Steady (S) Nystagmus

Minor (n D 10)

Bilateral (n D 10)

Unilateral (n D 13)

Bilateral (n D 6)

Binocular

Monocular

Binocular

Monocular

Binocular

Monocular

Binocular

Monocular

4 6

3 7

5 8

5 8

6 —

5 1

3 1

3 1

compliance with the optical correction and occlusion can also aVect acuity levels. 4. Discussion Eye alignment and ocular stability has been examined in 20 neonates and 13 infants and children who experienced diVering periods of visual form deprivation as a result of either a bilateral (n D 16) or a unilateral (n D 17) infantile cataract. Each patient was designated to have experienced a visual deprivation that was either classed as major or minor, based on a grading scheme (Forster et al., in press; Gage, 2001). This categorisation was based on the disruption to pattern vision caused by the morphology, size, position and density of the cataract. Fixation was measured for primary gaze during both binocular and monocular viewing of a stationary target. The reason for investigating monocular ocular stability was that previous eye movement studies indicated that the presence of an MLN would otherwise be overlooked if recording was limited to binocular viewing (Abadi & Bjerre, 2002; Abadi & Scallan, 2000; Dell’Osso, 1985; Dell’Osso & DaroV, 1979; Gage et al., 2001). In addition, it is well recognised that fatigue, attention and gaze direction can strongly inXuence the intensity of the nystagmus (Abadi & Bjerre, 2002; Abadi & Dickinson, 1986; Dell’Osso & DaroV, 1975; Dell’Osso & DaroV, 1999; Tkalcevic & Abel, 2005). We were therefore very mindful to ensure that these factors did not confound our

Unilateral (n D 4)

results and so we monitored gaze in the primary position and repeated eye alignment and ocular stability assessments frequently during each session. Our results show that those patients who had cataracts which constituted a major form deprivation—even for very limited periods prior to surgery—had a high probability of exhibiting a nystagmus (see Table 5). On the other hand, those patients who had cataracts which constituted a minor form deprivation generally remained steady, even though they had experienced a sustained (albeit minor) deprivation throughout the testing period and well into infancy. Most interestingly, the nystagmus type was invariably an MLN and was independent of cataract laterality. 4.1. Visual Wxation and the critical period The term “critical period” is often used to identify the time during visual development when rapid anatomical physiological and functional changes are taking place. During this time, the eVects of visual form deprivation on the developing visual system are most marked (Daw, 1995; Mitchell & MacKinnon, 2002). From past studies, it is clear that the period of maturation, and hence period of vulnerability, is made up of separate and speciWc sensory (e.g., VA) and motor (e.g., Wxation stability, ocular alignment) control systems which develop at diVerent rates. During Wxation of a stationary target three main control mechanisms are available for maintaining steady gaze—the

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Wxation, the vestibulo-ocular and a gaze holding system (the neural integrator). The vestibular system stabilises gaze during head movements whilst the neural integrator operates whenever the eyes are required to move away from primary gaze and maintain an eccentric position (Abadi & Gowen, 2004; Leigh & Zee, 1999; Sharpe, 1998). In this study, responses from the vestibulo-ocular and the gaze holding systems were intentionally excluded, Wrstly by keeping the head as still as possible and second by positioning the Wxation targets in primary gaze. Thus the presence of any recorded ocular motor instability would solely reXect a failure of the eYciency of the Wxation control system. The Wxation system has two distinct components. First, the visual system’s ability to detect retinal image drift and programme corrective eye movements. Second, the ability to attend to or “engage” a particular target of interest. Failure of either will disrupt steady Wxation and result in two distinct types of abnormal Wxation behaviour—saccadic intrusions/oscillations and nystagmus. Reports of ocular stability in normal infants, although sparse, have suggested that normal infants have the ability to keep their eyes relatively steady (Aslin & CuiVreda, 1983; Fielder, 1985; Hainline, Turkel, Abramov, Lemerise, & Harris, 1984; Hainline, 1993). However, occasional saccadic intrusions (e.g., monophasic square-wave intrusions) have been recorded whenever infants are in a reduced state of arousal or whenever they are disturbed during sleep (Fielder, 1985; Hainline, 1993). Bursts of monophasic square-wave intrusions have also been recorded in healthy infants aged between 2 and 7 weeks (Hainline et al., 1984), whilst adults can also display saccadic intrusions when tired or inattentive (Abadi & Gowen, 2004; Abadi et al., 2003; Abadi & Scallan, 2000; Gowen, Abadi, & PoliakoV, in press). Thus saccadic intrusions are a common physiological Wxational disturbance (Abadi & Gowen, 2004; Abadi, Scallan, & Clement, 2000; Herishanu & Sharpe, 1981; Hainline, 1988; Shallo-HoVman, Petersen, & Mühlendyck, 1989; Shallo-HoVman, Sendler, & Mühlendyck, 1990) and may well reXect a failure in patients to attend to, or actively engage in, Wxation (Abadi & Gowen, 2004; Abadi et al., 2003; Gowen et al., in press). It was therefore not surprising that most of our infants and children exhibited saccadic intrusions during one or more of the recording sessions. However, these intrusions tended to diVer in two ways from those previously reported in adults: Wrst, the amplitudes were often far bigger >3° as opposed to <1° and second, their frequency was less regular. Similar intrusions have been reported by Hertle and his colleagues (1998, 1999) and by Gottlob (1997), in patients who have later exhibited a CN. Nonetheless, we believe that the regular occurrence of saccadic intrusions in healthy observers (Abadi & Gowen, 2004; Abadi et al., 2003; Herishanu & Sharpe, 1981; ShalloHoVman et al., 1990) suggests that their presence in our cohort was not unusual apart from the somewhat larger amplitudes and the very occasional short bursts of intrusions.

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More importantly, the marked prevalence of MLN in 80% of our patients who displayed a nystagmus is a Wnding that needs further consideration. 4.2. Mechanisms underlying manifest latent nystagmus and congenital nystagmus In the past 15 years, Tusa and his colleagues (1991, 1992, 2001, 2002) have undertaken a number of detailed studies on monkeys to explore the extent to which visual-pattern deprivation during infancy results in strabismus and they found that by severely restricting visual inputs, (somewhat akin to our major deprivation category), during the Wrst 8 weeks of life, Wxation became unstable and an MLN was likely to occur. In addition, they established that visually deprived primates also show a reduction in the slow phase eye velocity during monocular optokinetic nystagmus whenever the Weld was moving in the nasal to temporal direction (Kiorpes, Walton, O’Keefe, Movshon, & Lisberger, 1996; Sparks, Mays, Gurski, & Hickey, 1986; Tychsen, Leibole, & Drake, 1996; Tusa, Mustari, Burrows, & Fuchs, 2001). Asymmetrical optokinetic responses have also been previously reported in human infants who had experienced prolonged disruption of binocular vision as a result of strabismus or form deprivation (Kommerell & Mehdorn, 1982; Maurer et al., 1983; Maurer & Lewis, 1993; Schor & Levi, 1980; Schor, 1983; van HoV-van Duin & Mohn, 1986; Westall & Schor, 1985). Recently, Wong and her colleagues (2003) have shown that the correction of strabismus within the Wrst 3 weeks of life in monkeys prevented the occurrence of ocular instabilities such as LN or MLN, whereas a delayed correction gave rise to a persistent strabismus, latent nystagmus, dissociated vertical deviation and pursuit/optokinetic nystagmus asymmetry. Interestingly, monocular optokinetic directional asymmetries are also present in normal neonates up to the age of 12 weeks. Thereafter, the subcortical pathway which controls the response is supplemented by cortical inputs and the optokinetic nystagmus becomes symmetrical (Atkinson & Braddick, 1981; Braddick, 1993; Lewis, Maurer, Chung, Holmes-Shannon, & Schaik, 2000; Maurer & Lewis, 1993; Tychsen, 1993; van HoV-van Duin & Mohn, 1986). Early visual deprivation therefore appears to aVect the normal development of the monocular optokinetic response. Although it has been suggested that the reduced monocular optokinetic nystagmus in the nasal to temporal direction may be due in part to the ongoing MLN (Dickinson & Abadi, 1990), a number of research groups have proposed that the subcortical nucleus of the optic tract is strongly implicated in the development of MLN in visually deprived primates (Mustari, Tusa, Burrows, Fuchs, & Livingstone, 2001; Tusa et al., 2001, 2002, 1991). It may be that the persistence of a nasal to temporal optokinetic asymmetry beyond the developmental boundaries of its expected disappearance could be a likely cause of LN and MLN. Over the years a number of oculomotor subsystems have been regularly proposed to account for the occurrence of

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CN (Abadi, 2002). These include smooth pursuit failure (Dell’Osso, 1967; Jacobs & Dell’Osso, 2004), abnormal feedback (Harris, 1995; Optican & Zee, 1984; Tusa, Zee, Hain, & Simonsz, 1992) and abnormal burst cell behaviour (Akman, Broomhead, Abadi, & Clement, 2005; Broomhead et al., 2000). It is very likely that, irrespective of the underlying mechanism, oculomotor calibration of egocentric localisation and the gain of the neural integrator are compromised in infants with major early-onset visual deprivation, and that delays in the removal of the cataract, even for 3 weeks, clearly signiWcantly aVects the normal development and stability of Wxation. 4.3. Clinical issues Four out of eight patients with bilateral major form deprivation exhibited unstable Wxation prior to surgery, two of whom had experienced only 8 weeks of visual deprivation. Cataract removal often led to a less disruptive level of instability. For example, patient 6 (Table 1) who had a CN pre-operatively, exhibited a more favourable MLN post-operatively. For some patients long-term post-operative binocular Wxation was steady, whereas monocularly, a jerk nystagmus was present (i.e., an LN). Both MLN and LN have been shown to be visually driven oscillations that are aVected by attentional factors and patient co-operation (Abadi & Scallan, 1999, 2000). Further support for this view comes from our observations of one infant who had steady Wxation but would occasionally display either a decelerating or a linear slow phase eye velocity jerk nystagmus, particularly when overtly attending to the task at hand. Recently, Abadi and Scallan (1999) reported how a patient, who had one eye enucleated at birth, exhibited an MLN that converted to a CN after either covering the subject’s only seeing eye or during periods of visual disengagement. Two explanations were proposed to account for the occurrence of the two separate waveforms—a neural integrator with an eccentric null, or an integrator that is under a variable gain control. De-coupling ocular instability from cognitive factors such as attention is clearly diYcult (Broomhead et al., 2000) and emphasises the need for regular and controlled ocular motor evaluation. Binocularity requires the visual axes to be aligned for all positions of gaze. During early infancy intermittent ocular misalignment is a common Wnding, with incidences ranging from 42.5 to 88.2% (Archer, Sondhi, & Helveston, 1989; Hainline, 1988; Horwood, 1993; Nixon, Helveston, Miller, Archer, & Ellis, 1985). The pre-disposition for a strabismus is high if retinal image quality is poor or the innervation to the extra-ocular muscles compromised during the critical period. Not surprisingly 83% of our infants who experienced major form deprivation and 20% of infants who experienced minor form deprivation exhibited an ocular misalignment and a sustained loss of binocularity. The prevalence of MLN which is invariably linked with strabismus, emphasises its coupling with a failure or loss of binocular function.

The signiWcance of cataract laterality and ocular motor outcomes is somewhat clouded by issues relating to optical correction, secondary opacities, occlusion and patient compliance. Clearly, any number of ophthalmological aspects such as the eVectiveness of surgery, aspects of the aphakic correction and the control of the possible amblyogenic factors could contribute to the Wnal ocular motor outcomes reported in this study. However, throughout each session of data collection we took great care that these factors were eliminated or at the very least, minimised. A sister paper will consider in greater detail the visual outcomes of the present patient group (Forster et al. (in review)). In conclusion our Wndings support the view that ocular stability is strongly dependent on the depth and length of the visual deprivation and that deprivation periods as short as 3 weeks can, and do, lead to a sustained nystagmus which was invariably found to be an MLN. Acknowledgments J.E.F. was the recipient of a UMIST Vision Centre Scholarship. We are grateful for the assistance of Gemma Hocking, Ellen Lee, Mark Muldoon, Caroline Thompson, Jon Whittle, and the Orthoptic Department of Manchester Royal Eye Hospital, UK. References Abadi, R. V. (2002). Mechanisms underlying nystagmus. Journal of the Royal Society of Medicine, 95, 231–234. Abadi, R. V., & Bjerre, A. (2002). Motor and sensory characteristics of infantile nystagmus. British Journal of Ophthalmology, 86, 1152–1160. Abadi, R. V., & Dickinson, C. M. (1986). Waveform characteristics in congenital nystagmus. Documenta Ophthalmologica, 64, 153–167. Abadi, R. V., & Gowen, E. (2004). Characteristics of saccadic intrusions. Vision Research, 44, 2675–2690. Abadi, R. V., Gowen, E., & Clement, R. A. (2003). Levels of Wxation. In L. Harris & M. Jenkin (Eds.), Levels of perception (pp. 213–229). New York: Springer-Verlag. Abadi, R. V., & Scallan, C. (1999). Manifest latent and congenital nystagmus waveforms in the same subject. A need to reconsider the underlying mechanisms of nystagmus. Neuroophthalmology, 21, 211–221. Abadi, R. V., & Scallan, C. (2000). Waveform characteristics of manifest latent nystagmus. Investigative Ophthalmology & Visual Science, 41, 3805–3817. Abadi, R. V., Scallan, C. J., & Clement, R. A. (2000). The characteristics of dynamic overshoots in square-wave jerks and in congenital and manifest latent nystagmus. Vision Research, 40, 2813–2819. Abadi, R,V., & Sandikcioglu, M. (1974). Electro-oculographic responses in a case of bilateral idiopathic nystagmus. British Journal of Physiology and Optics, 29, 73–85. Abadi, R. V., & Worfolk, R. (1989). Retinal slip velocities in congenital nystagmus. Vision Research, 29, 195–205. Akman, O. E., Broomhead, D. S., Abadi, R. V., & Clement, R. A. (2005). Eye movement instabilities and nystagmus can be predicted by a nonlinear dynamics model of the saccadic system. Journal of Mathematical Biology. doi:10.1007/S00285-005-0336-4. Archer, S. M., Sondhi, N., & Helveston, E. M. (1989). Strabismus in infancy. Ophthalmology, 96, 133–137. Aslin, R. N., & CuiVreda, K. J. (1983). Eye movements of preschool children. Science, 222, 74–75. Atkinson, J., & Braddick, O. (1981). Development of optokinetic nystagmus in infants: An indicator of cortical binocularity? In D. F. Fisher,

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