Visual Acuity Deficits in Children With Nystagmus and Down Syndrome JOOST FELIUS, CYNTHIA L. BEAUCHAMP, AND DAVID R. STAGER, SR PURPOSE:
To investigate the association between visual acuity deficits and fixation instability in children with Down syndrome and nystagmus. DESIGN: Prospective cross-sectional study. METHODS: SETTING: Institutional. STUDY POPULATION: Sixteen children (aged 10 months-14 years) with Down syndrome and nystagmus, and a control group of 93 age-similar children with unassociated infantile nystagmus. OBSERVATION PROCEDURES: Binocular Teller acuity card testing and eyemovement recordings. Fixation stability was quantified using the nystagmus optimal fixation function (NOFF). An exponential model based on results from the control group with unassociated infantile nystagmus was used to relate fixation stability to age-corrected visual acuity deficits. MAIN OUTCOME MEASURES: Binocular grating visual acuity and NOFF. RESULTS: Visual acuity was 0.2-0.9 logMAR (20/30-20/ 174 Snellen equivalent) and corresponded to a 0.4 logMAR (4 lines) mean age-corrected visual acuity deficit. Fixation stability ranged from poor to mildly affected. Although visual acuity deficit was on average 0.17 logMAR larger (P [ .005) than predicted by the model, most children had visual acuity deficit within the 95% predictive interval. CONCLUSIONS: There was a small mean difference between the measured visual acuity deficit and the prediction of the nystagmus model. Although other factors also contribute to visual acuity loss in Down syndrome, nystagmus alone could account for most of the visual acuity deficit in these children. (Am J Ophthalmol 2014;157: 458–463. Ó 2014 by Elsevier Inc. All rights reserved.)
A
BNORMALITIES
OF
VISUAL
FUNCTIONING
IN
children with Down syndrome are caused by uncorrected refractive error, limited accommodation (including limited accommodative effort), strabismus, nystagmus, and possibly abnormal cortical morphology.1–5 When wearing proper optical correction, these children usually have mild to moderate deficits in visual acuity,5–8 which are presumably the cumulative result of nystagmus (fixational instability) and cortical abnormalities, including, perhaps, amblyopia. Accurate assessment of visual functioning Accepted for publication Sept 23, 2013. From the Retina Foundation of the Southwest (J.F.); and Pediatric Ophthalmology and Center for Adult Strabismus (C.L.B., D.R.S.), Dallas, Texas. Inquiries to Dr Joost Felius, Retina Foundation of the Southwest, 9600 N. Central Expressway, Suite 200, Dallas, TX 75231; e-mail: jfelius@ retinafoundation.org
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in children with Down syndrome may be hampered by limitations in executive functioning and attention.9,10 Reportedly, up to 30% of patients with Down syndrome have nystagmus.5,11,12 Recent advances in the understanding of the relation between the various waveforms of nystagmus eye movements and visual acuity in patients with unassociated infantile nystagmus (typically referred to as ‘‘idiopathic infantile nystagmus’’ or ‘‘congenital nystagmus,’’ ie, infantile nystagmus in the absence of any other afferent visual system disease),13,14 as well as progress in delineating the functional improvements after nystagmus surgery in children,15,16 prompted us to investigate to what extent fixational instability may explain visual acuity deficits in children diagnosed with Down syndrome and nystagmus.
METHODS THE RESEARCH PROTOCOL AND INFORMED CONSENT FORM
for this cross-sectional study were approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. Written informed consent was obtained from a parent or legal guardian for each participant. This study was performed in accordance with the US Health Insurance Portability and Accountability Act. PARTICIPANTS:
Sixteen children (aged 10 months-14 years [median 3.5 years]) diagnosed with Down syndrome and nystagmus participated in this cross-sectional study carried out in the Visual Disorders and Eye Movements Laboratory at the Retina Foundation of the Southwest between August 2009 and July 2012. Children with cataracts or other apparent structural abnormalities in the eyes were excluded, as were children with severe developmental delay. The Table provides basic clinical data for this cohort. As can be seen from the Table, most children were myopic (and wore spectacle correction), while several had various amounts of (intermittent) strabismus. A group of 93 infants, children, and young adults with unassociated infantile nystagmus (aged 5 months-27 years [median 4.4 years]) from a previous study14 formed a comparison group; the diagnosis of unassociated infantile nystagmus in these children was based on eye-movement recordings and a complete ophthalmologic examination by the referring pediatric ophthalmologist.
VISUAL ACUITY:
Binocular, spectacle-corrected grating visual acuity was assessed with the Teller visual acuity cards
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TABLE. Patient Characteristics (Including Visual Acuity, Refractive Error, Strabismus, and Nystagmus Charactteristics) of the 16 Children With Down Syndrome and Nystagmus Included in This Study Patient No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Age (y)/Sex
Visual Acuity (logMAR)
Refractive Error [OD; OS] (D)
Strabismus
Nystagmus Type
NOFF (logits)
Foveation Fraction
0.8/M 0.9/M 2.1/F 2.4/M 2.8/M 2.8/M 3.1/F 3.4/F 3.7/M 4.1/M 4.3/M 5.9/F 5.9/F 7.3/M 8.9/F 14/M
0.63 0.53 0.76 0.83 0.65 0.89 0.88 0.43 0.94 0.46 0.51 0.45 0.35 0.18 0.69 0.46
N/A N/A þ0.25; þ0.25 1.00; 1.00 7.00; 5.00 7.00þ1.25370deg; 7.00þ1.253100deg 1.50þ1.50380deg; 1.50þ1.503100deg 1.00þ1.00360deg; 1.00þ1.003100deg 8.50þ1.00390deg; 7.50þ2.50390deg 12.00; 10.50 þ2.50þ1.00370deg; þ2.50þ2.503110deg 1.75þ2.25380deg; 2.00þ2.503110deg 12.50þ4.50375deg; 12.50þ6.003100deg 4.00þ3.753100deg; 2.50þ2.50375deg 3.50; 2.50 3.00þ2.503100deg; 3.00þ2.50380deg
Ortho Small-angle ET Ortho Ortho 8 ET, post-op 12 E(T) Ortho 10 E(T), post-op Ortho, post-op Ortho 25 E(T) Ortho, post-op 25 ET, post-op 3 X(T) Ortho Ortho
INS INS INS INS INS INS INS FMNS FMNS INS INS INS INS INS INS INS
1.00 1.07 0.73 2.57 1.34 2.05 0.22 0.44 2.93 0.18 1.34 1.77 3.07 0.23 4.59 0.99
0.27 0.75 0.32 0.07 0.21 0.11 0.56 0.39 0.05 0.46 0.79 0.15 0.04 0.56 0.01 0.73
D ¼ diopter; deg ¼ degrees; ET ¼ esotropia; E(T) ¼ intermittent esotropia; FMNS ¼ fusion maldevelopment nystagmus syndrome (manifest latent nystagmus); INS ¼ infantile nystagmus syndrome; N/A ¼ not available; NOFF ¼ nystagmus optimal fixation function; Ortho ¼ orthotropia; Post-op ¼ postoperative; X(T) ¼ intermittent exotropia.
(Stereo Optical, Chicago, Illinois, USA) using a staircase procedure and a forced-choice paradigm using either preferential looking or pointing, depending on the individual child’s abilities.17 Thus, this grating detection task poses minimal requirements on cognitive abilities of the child tested. Visual acuity was defined as the mean of the last 6 of 8 total staircase reversals on a logMAR scale. Because the mean normal visual acuity improves with age in early childhood, the visual acuity measurements were converted to visual acuity deficits (ie, logMAR units relative to published age-corrected mean normal values18–20) for part of the analysis. For clinical reference, the logMAR visual acuities were also given in Snellen-equivalent values using the formula: Snellen denominator ¼ 20 3 10(logMAR). EYE MOVEMENTS:
Nystagmus eye movements were recorded using a remote high-speed video system (EyeLink 1000; SR Research Ltd, Kanata, Ontario, Canada) while the child performed a simple fixation task for 20-30 seconds under binocular viewing. Children requiring refractive correction wore their spectacles. The recordings were lowpass filtered off-line and differentiated to obtain eye velocity information. Further details of instrumentation, calibration, and test protocol were published previously.14 Quantification of nystagmus eye movements centers around foveation periods: brief amounts of time (typically >20 ms duration; 1 during each oscillation of the nystagmus waveform) when the eyes are moving with sufficiently low velocity while the visual axis is in or near the direction of the target.13,21,22 The gold standard for quantifying
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FIGURE 1. Scatterplot showing binocular visual acuity as a function of age in children with Down syndrome and nystagmus. Symbols correspond to the nystagmus waveform types: infantile nystagmus (solid circles); manifest latent nystagmus (solid triangles). Most of these patients fell outside of the normal limits indicated by the shaded area. (Solid line and shaded area: mean normative values and 95% confidence limits as published in the literature.18–20)
foveation periods is the expanded nystagmus acuity function (commonly referred to as ‘‘NAFX’’),13 a mathematical algorithm that applies simultaneous criteria on eye position and eye velocity in order to determine which portion of each oscillation corresponds to an event of fixation or ‘‘foveation.’’ Here, a somewhat less stringent algorithm was used, the nystagmus optimal fixation function (or ‘‘NOFF’’),14,16 which was
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459
FIGURE 2. Bar graphs showing comparisons of fixation control and visual acuity deficit between patients with unassociated infantile nystagmus and the subgroup of 14 patients with Down syndrome who showed infantile nystagmus waveforms. (Left) The nystagmus optimal fixation function showed no significant mean difference between groups. (Right) The visual acuity deficit was significantly larger in the children with Down syndrome and nystagmus than in the patients with unassociated infantile nystagmus (P [ .016). IN [ (unassociated) infantile nystagmus; DS [ Down syndrome; NOFF [ nystagmus optimal fixation function.
designed as a more easily used method in young children who typically do not produce data of the quality necessary for analysis using the NAFX. Consequently, the NOFF is a trade-off between accuracy and feasibility and is intended for use in more challenging test situations. Its algorithm objectively searches for a clean portion in what could otherwise be very noisy data, with a 4-second ‘‘window’’ moving through the entire record and iteratively determining the fraction of data points that meet foveation criteria (simultaneous criteria on velocity and relative position). This foveation fraction (0.0-1.0) is then transformed using a logistic transformation (the result ranging from approximately 5 to þ5 logits) for purposes of calculation and statistics.14 DATA ANALYSIS AND MODELING:
An exponential function of the form a exp (NOFF/b), proposed and validated previously,14 was used to obtain an ensemble fit to the visual acuity deficit data as a function of nystagmus foveation properties as they were determined using the nystagmus optimal fixation function. The parameters for this model, a ¼ 0.13 logMAR and b ¼ 2.6 logits, were determined from a large cohort of children with unassociated infantile nystagmus in our laboratory (n ¼ 93, the comparison group).14 The protocols for both visual acuity measurement and the recording and analysis of eye movements for the comparison group were identical to those used in the present study.
RESULTS VISUAL ACUITY IN THE 16 CHILDREN WITH DOWN
syndrome and nystagmus spanned a large range from 460
0.2-0.9 logMAR or 20/30-20/174 Snellen equivalent (mean 0.58 logMAR, 20/76) with no association with age (linear regression, P ¼ .15). The mean visual acuity deficit with respect to age-matched norms was 0.40 logMAR (Figure 1), or 4 lines poorer than mean normal. Inspection of the eye-movement recordings obtained under binocular viewing conditions showed infantile nystagmus-type waveforms (pendular [n ¼ 8], jerk [n ¼ 3], combination of pendular and jerk [n ¼ 2]) as well as waveforms typical of fusion maldevelopment nystagmus (‘‘manifest latent nystagmus,’’ n ¼ 2). The type(s) of nystagmus waveforms did not appear to be associated with age. The overall mean value of the NOFF value in this group was 1.1 logits, corresponding to a mean foveation fraction of 0.24 (ie, 240 ms of foveation per second during a clean portion of the recording.). For the comparison between patients with Down syndrome and nystagmus and the cohort of patients with unassociated infantile nystagmus, we excluded the 2 patients with Down syndrome whose nystagmus waveforms were not typical of infantile nystagmus (ie, the 2 patients with manifest latent nystagmus). The cohort of 93 patients with unassociated infantile nystagmus had a mean NOFF value of 0.93 logits (SD 2.1) and mean visual acuity deficit of 0.25 logMAR (SD 0.22). The 14 children with Down syndrome and infantile nystagmus waveforms had similar NOFF value (0.96 logits [SD 1.7]; P ¼ .9, t test) but a larger age-corrected visual acuity deficit (0.41 logMAR [SD 0.20]; P ¼ .0112) (Figure 2). In the cohort of children with Down syndrome and infantile nystagmus, those with poorer fixation stability (lower NOFF value) tended to show larger visual acuity deficits than those with better fixation stability (higher
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FIGURE 3. Scatterplot showing the binocular visual acuity deficit (from mean normal) in children with Down syndrome and nystagmus as a function of the nystagmus optimal fixation function (NOFF). Symbols correspond to the nystagmus waveform types: infantile nystagmus (solid circles); manifest latent nystagmus (solid triangles). The solid and dotted lines denote the best fit and the 95% predictive interval, respectively, of a model14 fit to the unassociated infantile nystagmus data; this model shows an exponential decrease of visual acuity deficit with increasing foveation. The scale at the top gives the corresponding foveation fraction (ie, the fraction of points within the optimal portion of data meeting simultaneous position and velocity criteria).
NOFF value), as shown in Figure 3 (solid circles), where the visual acuity deficit is plotted as a function of the NOFF value. Also shown in Figure 3 are the data from the comparison group of patients with unassociated infantile nystagmus together with the best fit of the exponential model previously proposed for unassociated infantile nystagmus.14 Compared to the model fit, the 14 Down syndrome patients with infantile nystagmus showed a 0.17 logMAR (SD 0.20) larger visual acuity deficit for any given NOFF value (P ¼ .005, paired t test). Nonetheless, 11 of the 14 children (79%) fell within the 95% predictive limits of the exponential model (dotted lines in Figure 3). The data from the 2 Down syndrome children with manifest latent nystagmus are indicated by solid triangles in Figure 3. A similar relationship between visual acuity deficit and fixation stability appears to hold for these patients.
DISCUSSION USING A BEHAVIORAL TESTING METHOD THAT POSES ONLY
limited demands on the child’s cognitive and motor skills,7,8 we found mild to moderate visual acuity deficits in this group of children with Down syndrome and nystagmus averaging approximately 4 lines below ageVOL. 157, NO. 2
adjusted mean normal; all but 3 scored outside of the normal limits for their age. The number of participants in this sudy was small but spanned a wide age range throughout childhood, thus providing cross-sectional evidence of visual acuity failing to mature with age, as can be seen in Figure 1. Recordings of fixational eye movements showed waveforms typical of infantile nystagmus as well as waveforms typical of fusion maldevelopment nystagmus (traditionally known as ‘‘manifest latent nystagmus’’). In general, nystagmus in early childhood is not always accompanied by visual acuity deficits. The nystagmus optimal fixation function is a meaningful metric to quantify nystagmus severity, as its association with age-corrected visual acuity has been shown.14,23 NOFF values in this group of children with Down syndrome and nystagmus did not differ from those found in the larger group of patients with unassociated infantile nystagmus (Figure 2). The relationship between the NOFF values and the agecorrected visual acuity deficit in these 2 disease groups showed similarities: greater (better) NOFF values corresponding to smaller deficits in visual acuity (Figure 3). In fact, the data from all but 2 of the children with Down syndrome and nystagmus fell within the 95% predictive interval of the exponential model fitted to the data from the larger group of patients with unassociated infantile nystagmus (area between the dotted lines in Figure 3). However, Figure 3 also clearly shows a (small) systematic difference between the Down syndrome data and the model prediction: The children with Down syndrome and nystagmus on average showed a 0.15 logMAR (1.5 lines) larger visual acuity deficit than predicted based on the model. Therefore we conclude that of the 4-line overall visual acuity deficit in these children, all but 1.5 lines could be ‘‘explained’’ by nystagmus. It is typically not clear in children with nystagmus to what extent visual acuity deficits are caused by the reduced fixation stability or vice versa, although it seems plausible in the case of Down syndrome that the underlying cause is in reduced motor control. Interestingly, in a study of accommodation and bifocal spectacles in children with Down syndrome, Nandakumar and Leat24 reported a difference of approximately 1.5 lines in near visual acuity between test conditions with singlevision and bifocal lenses. A limitation of our study is that it did not control for under-accommodation, to which children with Down syndrome are prone,24,25 although it is debatable whether under-accommodation is the cause or a result of the visual acuity deficit.25 Other studies of visual function in children with Down syndrome have reported visual acuity levels similar to those presented here.6–8 Those studies typically included children with Down syndrome regardless of whether they also had nystagmus. Courage and associates6 provided separate results for the subset of their Down syndrome patients without nystagmus. Using behavioral test conditions apparently similar to ours, they found visual acuity deficits from normal in the same range as our results from children with
VISUAL ACUITY AND NYSTAGMUS IN DOWN SYNDROME
461
Down syndrome with nystagmus. It should be noted, however, that nystagmus was diagnosed by clinical observation rather than by eye-movement recordings in the Courage paper.6 It is therefore conceivable that some small nystagmus cases went undetected. However, we must conclude that although nystagmus may ‘‘explain’’ a significant portion of the visual acuity deficits in our data, this portion may nonetheless be relatively small and of the same order of magnitude as the variations observed in visual acuity deficit between studies. Ten to 30 percent of patients with Down syndrome have nystagmus.1,5–7,11,12,26 These reported numbers, however, are based on patients’ medical records or on direct observation in the test setting, not on eye-movement recordings. Therefore, fine nystagmus may have gone
undetected, and the actual incidence of nystagmus among individuals with Down syndrome may be higher. The nystagmus waveforms encountered in this study were predominantly of the infantile nystagmus types and a few fusion maldevelopment types. In contrast, AverbuchHeller and associates27 reported almost exclusively fusion maldevelopment–type nystagmus in their small group of Down syndrome adults. Although it is most likely that other factors also contribute to visual acuity loss in Down syndrome (cortical abnormalities, residual refractive error, cognitive limitations), nystagmus alone could account for a substantial extent of the visual acuity deficit in these children. Therefore, nystagmus treatment may potentially result in improved visual acuity in children with Down syndrome.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. The following disclosure was reported: J. Felius also received funding from the Vision of Children Foundation, San Diego, California, for a related project. This research was funded in part by a grant from the Communities Foundation of Texas, Dallas, Texas (J.F.). Contributions of authors: study design (J.F., C.L.B., D.R.S.); conduct of the study (J.F., C.L.B., D.R.S.); collection and management of the data (J.F., C.L.B., D.R.S.); data analysis (J.F.); preparation of the manuscript (J.F.); manuscript review and approval (J.F., C.L.B., D.R.S.).
REFERENCES 1. Bromham NR, Woodhouse JM, Cregg M, Webb E, Fraser WI. Heart defects and ocular anomalies in children with Down’s syndrome. Br J Ophthalmol 2002;86(12):1367–1368. 2. Creavin AL, Brown RD. Ophthalmic abnormalities in children with Down syndrome. J Pediatr Ophthalmol Strabismus 2009;46(2):76–82. 3. Haugen OH, Hovding G. Strabismus and binocular function in children with Down syndrome. A population-based, longitudinal study. Acta Ophthalmol Scand 2001;79(2):133–139. 4. Morton GV. Why do children with down syndrome have subnormal vision? Am Orthopt J 2011;61:60–70. 5. Stephen E, Dickson J, Kindley AD, Scott CC, Charleton PM. Surveillance of vision and ocular disorders in children with Down syndrome. Dev Med Child Neurol 2007;49(7):513–515. 6. Courage ML, Adams RJ, Reyno S, Kwa PG. Visual acuity in infants and children with Down syndrome. Dev Med Child Neurol 1994;36(7):586–593. 7. John FM, Bromham NR, Woodhouse JM, Candy TR. Spatial vision deficits in infants and children with Down syndrome. Invest Ophthalmol Vis Sci 2004;45(5):1566–1572. 8. Little JA, Woodhouse JM, Lauritzen JS, Saunders KJ. The impact of optical factors on resolution acuity in children with Down syndrome. Invest Ophthalmol Vis Sci 2007;48(9): 3995–4001. 9. Capone G, Goyal P, Ares W, Lannigan E. Neurobehavioral disorders in children, adolescents, and young adults with Down syndrome. Am J Med Genet C Semin Med Genet 2006; 142C(3):158–172. 10. Lanfranchi S, Jerman O, Dal Pont E, Alberti A, Vianello R. Executive function in adolescents with Down Syndrome. J Intellect Disabil Res 2010;54(4):308–319. 11. Dumitrescu AV, Moga DC, Longmuir SQ, Olson RJ, Drack AV. Prevalence and characteristics of abnormal head
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12. 13.
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posture in children with Down syndrome: a 20-year retrospective, descriptive review. Ophthalmology 2011;118(9):1859–1864. Wagner RS, Caputo AR, Reynolds RD. Nystagmus in Down’s syndrome. Ophthalmology 1990;97(11):1439–1444. Dell’Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol 2002;104(3):249–276. Felius J, Fu VL, Birch EE, Hertle RW, Jost RM, Subramanian V. Quantifying nystagmus in infants and young children: relation between foveation and visual acuity deficit. Invest Ophthalmol Vis Sci 2011;52(12):8724–8731. Hertle RW, Dell’Osso LF, FitzGibbon EJ, Yang D, Mellow SD. Horizontal rectus muscle tenotomy in children with infantile nystagmus syndrome: a pilot study. J AAPOS 2004;8(6):539–548. Hertle RW, Felius J, Yang D, Kaufman M. Eye muscle surgery for infantile nystagmus syndrome in the first two years of life. Clin Ophthalmol 2009;3:615–624. Birch EE, Hale LA. Criteria for monocular acuity deficit in infancy and early childhood. Invest Ophthalmol Vis Sci 1988; 29(4):636–643. Drover JR, Wyatt LM, Stager DR, Birch EE. The Teller acuity cards are effective in detecting amblyopia. Optom Vis Sci 2009;86(6):755–759. Mayer DL, Beiser AS, Warner AF, Pratt EM, Raye KN, Lang JM. Monocular acuity norms for the Teller Acuity Cards between ages one month and four years. Invest Ophthalmol Vis Sci 1995;36(3):671–685. Saloma˜o SR, Ventura DF. Large sample population age norms for visual acuities obtained with Vistech-Teller Acuity Cards. Invest Ophthalmol Vis Sci 1995;36(3):657–670. Cesarelli M, Bifulco P, Loffredo L, Bracale M. Relationship between visual acuity and eye position variability during foveations in congenital nystagmus. Doc Ophthalmol 2000; 101(1):59–72.
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22. Dell’Osso LF, Daroff RB. Congenital nystagmus waveforms and foveation strategy. Doc Ophthalmol 1975;39(1):155–182. 23. Felius J. Measuring nystagmus in infants and young children. In: Harris C, Gottlob I, Sanders J, eds. The Challenge of Nystagmus. Cardiff: Nystagmus Network; 2012:295–306. 24. Nandakumar K, Leat SJ. Bifocals in children with Down syndrome (BiDS) - visual acuity, accommodation and early literacy skills. Acta Ophthalmol 2010;88(6):e196–e204.
25. Anderson HA, Manny RE, Glasser A, Stuebing KK. Static and dynamic measurements of accommodation in individuals with Down syndrome. Invest Ophthalmol Vis Sci 2011;52(1):310–317. 26. Shapiro MB, France TD. The ocular features of Down’s syndrome. Am J Ophthalmol 1985;99(6):659–663. 27. Averbuch-Heller L, Dell’Osso LF, Jacobs JB, Remler BF. Latent and congenital nystagmus in Down syndrome. J Neuroophthalmol 1999;19(3):166–172.
John Keats (1795-1821): Physician and Surgeon
S
oon after his mother died in 1810, John Keats at the age of 14 was apprenticed to a local physician. In 1815, he then registered as a medical student at Guy’s Hospital in London and was soon promoted to the equivalent of a junior resident, assisting surgeons there. In 1816 he received his license to practice as a physician and seemed headed for a medical career. Poetry had the stronger attraction for him but his memories of his hospital experience did
not leave him. They show up in the third stanza of his 1818 ‘‘Ode to a Nightingale’’ where he remembers ‘‘.the weariness, the fever, and the fret, Here, where men sit and hear each other groan; Where palsy shakes a few, sad, last grey hairs. Where but to think is to be full of sorrow And leaden-eye despairs..’’ The hospital also doubtless exposed him to the tuberculosis that killed him a few years later, a tragic end that was not unique to physicians of that era.
Submitted by Ron Fishman MD of the Cogan Ophthalmic History Society.
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To investigate the association between visual acuity deficits and fixation instability in children with Down syndrome and nystagmus. DESIGN: Prospective cross-sectional study. METHODS: SETTING: Institutional. STUDY POPULATION: Sixteen children (aged 10 months-14 years) with Down syndrome and nystagmus, and a control group of 93 age-similar children with unassociated infantile nystagmus. OBSERVATION PROCEDURES: Binocular Teller acuity card testing and eyemovement recordings. Fixation stability was quantified using the nystagmus optimal fixation function (NOFF). An exponential model based on results from the control group with unassociated infantile nystagmus was used to relate fixation stability to age-corrected visual acuity deficits. MAIN OUTCOME MEASURES: Binocular grating visual acuity and NOFF. RESULTS: Visual acuity was 0.2-0.9 logMAR (20/30-20/ 174 Snellen equivalent) and corresponded to a 0.4 logMAR (4 lines) mean age-corrected visual acuity deficit. Fixation stability ranged from poor to mildly affected. Although visual acuity deficit was on average 0.17 logMAR larger (P [ .005) than predicted by the model, most children had visual acuity deficit within the 95% predictive interval. CONCLUSIONS: There was a small mean difference between the measured visual acuity deficit and the prediction of the nystagmus model. Although other factors also contribute to visual acuity loss in Down syndrome, nystagmus alone could account for most of the visual acuity deficit in these children. (Am J Ophthalmol 2014;157: 458–463. Ó 2014 by Elsevier Inc. All rights reserved.)
A
BNORMALITIES
OF
VISUAL
FUNCTIONING
IN
children with Down syndrome are caused by uncorrected refractive error, limited accommodation (including limited accommodative effort), strabismus, nystagmus, and possibly abnormal cortical morphology.1–5 When wearing proper optical correction, these children usually have mild to moderate deficits in visual acuity,5–8 which are presumably the cumulative result of nystagmus (fixational instability) and cortical abnormalities, including, perhaps, amblyopia. Accurate assessment of visual functioning Accepted for publication Sept 23, 2013. From the Retina Foundation of the Southwest (J.F.); and Pediatric Ophthalmology and Center for Adult Strabismus (C.L.B., D.R.S.), Dallas, Texas. Inquiries to Dr Joost Felius, Retina Foundation of the Southwest, 9600 N. Central Expressway, Suite 200, Dallas, TX 75231; e-mail: jfelius@ retinafoundation.org
458
Ó
2014 BY
in children with Down syndrome may be hampered by limitations in executive functioning and attention.9,10 Reportedly, up to 30% of patients with Down syndrome have nystagmus.5,11,12 Recent advances in the understanding of the relation between the various waveforms of nystagmus eye movements and visual acuity in patients with unassociated infantile nystagmus (typically referred to as ‘‘idiopathic infantile nystagmus’’ or ‘‘congenital nystagmus,’’ ie, infantile nystagmus in the absence of any other afferent visual system disease),13,14 as well as progress in delineating the functional improvements after nystagmus surgery in children,15,16 prompted us to investigate to what extent fixational instability may explain visual acuity deficits in children diagnosed with Down syndrome and nystagmus.
METHODS THE RESEARCH PROTOCOL AND INFORMED CONSENT FORM
for this cross-sectional study were approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. Written informed consent was obtained from a parent or legal guardian for each participant. This study was performed in accordance with the US Health Insurance Portability and Accountability Act. PARTICIPANTS:
Sixteen children (aged 10 months-14 years [median 3.5 years]) diagnosed with Down syndrome and nystagmus participated in this cross-sectional study carried out in the Visual Disorders and Eye Movements Laboratory at the Retina Foundation of the Southwest between August 2009 and July 2012. Children with cataracts or other apparent structural abnormalities in the eyes were excluded, as were children with severe developmental delay. The Table provides basic clinical data for this cohort. As can be seen from the Table, most children were myopic (and wore spectacle correction), while several had various amounts of (intermittent) strabismus. A group of 93 infants, children, and young adults with unassociated infantile nystagmus (aged 5 months-27 years [median 4.4 years]) from a previous study14 formed a comparison group; the diagnosis of unassociated infantile nystagmus in these children was based on eye-movement recordings and a complete ophthalmologic examination by the referring pediatric ophthalmologist.
VISUAL ACUITY:
Binocular, spectacle-corrected grating visual acuity was assessed with the Teller visual acuity cards
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.09.023
TABLE. Patient Characteristics (Including Visual Acuity, Refractive Error, Strabismus, and Nystagmus Charactteristics) of the 16 Children With Down Syndrome and Nystagmus Included in This Study Patient No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Age (y)/Sex
Visual Acuity (logMAR)
Refractive Error [OD; OS] (D)
Strabismus
Nystagmus Type
NOFF (logits)
Foveation Fraction
0.8/M 0.9/M 2.1/F 2.4/M 2.8/M 2.8/M 3.1/F 3.4/F 3.7/M 4.1/M 4.3/M 5.9/F 5.9/F 7.3/M 8.9/F 14/M
0.63 0.53 0.76 0.83 0.65 0.89 0.88 0.43 0.94 0.46 0.51 0.45 0.35 0.18 0.69 0.46
N/A N/A þ0.25; þ0.25 1.00; 1.00 7.00; 5.00 7.00þ1.25370deg; 7.00þ1.253100deg 1.50þ1.50380deg; 1.50þ1.503100deg 1.00þ1.00360deg; 1.00þ1.003100deg 8.50þ1.00390deg; 7.50þ2.50390deg 12.00; 10.50 þ2.50þ1.00370deg; þ2.50þ2.503110deg 1.75þ2.25380deg; 2.00þ2.503110deg 12.50þ4.50375deg; 12.50þ6.003100deg 4.00þ3.753100deg; 2.50þ2.50375deg 3.50; 2.50 3.00þ2.503100deg; 3.00þ2.50380deg
Ortho Small-angle ET Ortho Ortho 8 ET, post-op 12 E(T) Ortho 10 E(T), post-op Ortho, post-op Ortho 25 E(T) Ortho, post-op 25 ET, post-op 3 X(T) Ortho Ortho
INS INS INS INS INS INS INS FMNS FMNS INS INS INS INS INS INS INS
1.00 1.07 0.73 2.57 1.34 2.05 0.22 0.44 2.93 0.18 1.34 1.77 3.07 0.23 4.59 0.99
0.27 0.75 0.32 0.07 0.21 0.11 0.56 0.39 0.05 0.46 0.79 0.15 0.04 0.56 0.01 0.73
D ¼ diopter; deg ¼ degrees; ET ¼ esotropia; E(T) ¼ intermittent esotropia; FMNS ¼ fusion maldevelopment nystagmus syndrome (manifest latent nystagmus); INS ¼ infantile nystagmus syndrome; N/A ¼ not available; NOFF ¼ nystagmus optimal fixation function; Ortho ¼ orthotropia; Post-op ¼ postoperative; X(T) ¼ intermittent exotropia.
(Stereo Optical, Chicago, Illinois, USA) using a staircase procedure and a forced-choice paradigm using either preferential looking or pointing, depending on the individual child’s abilities.17 Thus, this grating detection task poses minimal requirements on cognitive abilities of the child tested. Visual acuity was defined as the mean of the last 6 of 8 total staircase reversals on a logMAR scale. Because the mean normal visual acuity improves with age in early childhood, the visual acuity measurements were converted to visual acuity deficits (ie, logMAR units relative to published age-corrected mean normal values18–20) for part of the analysis. For clinical reference, the logMAR visual acuities were also given in Snellen-equivalent values using the formula: Snellen denominator ¼ 20 3 10(logMAR). EYE MOVEMENTS:
Nystagmus eye movements were recorded using a remote high-speed video system (EyeLink 1000; SR Research Ltd, Kanata, Ontario, Canada) while the child performed a simple fixation task for 20-30 seconds under binocular viewing. Children requiring refractive correction wore their spectacles. The recordings were lowpass filtered off-line and differentiated to obtain eye velocity information. Further details of instrumentation, calibration, and test protocol were published previously.14 Quantification of nystagmus eye movements centers around foveation periods: brief amounts of time (typically >20 ms duration; 1 during each oscillation of the nystagmus waveform) when the eyes are moving with sufficiently low velocity while the visual axis is in or near the direction of the target.13,21,22 The gold standard for quantifying
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FIGURE 1. Scatterplot showing binocular visual acuity as a function of age in children with Down syndrome and nystagmus. Symbols correspond to the nystagmus waveform types: infantile nystagmus (solid circles); manifest latent nystagmus (solid triangles). Most of these patients fell outside of the normal limits indicated by the shaded area. (Solid line and shaded area: mean normative values and 95% confidence limits as published in the literature.18–20)
foveation periods is the expanded nystagmus acuity function (commonly referred to as ‘‘NAFX’’),13 a mathematical algorithm that applies simultaneous criteria on eye position and eye velocity in order to determine which portion of each oscillation corresponds to an event of fixation or ‘‘foveation.’’ Here, a somewhat less stringent algorithm was used, the nystagmus optimal fixation function (or ‘‘NOFF’’),14,16 which was
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FIGURE 2. Bar graphs showing comparisons of fixation control and visual acuity deficit between patients with unassociated infantile nystagmus and the subgroup of 14 patients with Down syndrome who showed infantile nystagmus waveforms. (Left) The nystagmus optimal fixation function showed no significant mean difference between groups. (Right) The visual acuity deficit was significantly larger in the children with Down syndrome and nystagmus than in the patients with unassociated infantile nystagmus (P [ .016). IN [ (unassociated) infantile nystagmus; DS [ Down syndrome; NOFF [ nystagmus optimal fixation function.
designed as a more easily used method in young children who typically do not produce data of the quality necessary for analysis using the NAFX. Consequently, the NOFF is a trade-off between accuracy and feasibility and is intended for use in more challenging test situations. Its algorithm objectively searches for a clean portion in what could otherwise be very noisy data, with a 4-second ‘‘window’’ moving through the entire record and iteratively determining the fraction of data points that meet foveation criteria (simultaneous criteria on velocity and relative position). This foveation fraction (0.0-1.0) is then transformed using a logistic transformation (the result ranging from approximately 5 to þ5 logits) for purposes of calculation and statistics.14 DATA ANALYSIS AND MODELING:
An exponential function of the form a exp (NOFF/b), proposed and validated previously,14 was used to obtain an ensemble fit to the visual acuity deficit data as a function of nystagmus foveation properties as they were determined using the nystagmus optimal fixation function. The parameters for this model, a ¼ 0.13 logMAR and b ¼ 2.6 logits, were determined from a large cohort of children with unassociated infantile nystagmus in our laboratory (n ¼ 93, the comparison group).14 The protocols for both visual acuity measurement and the recording and analysis of eye movements for the comparison group were identical to those used in the present study.
RESULTS VISUAL ACUITY IN THE 16 CHILDREN WITH DOWN
syndrome and nystagmus spanned a large range from 460
0.2-0.9 logMAR or 20/30-20/174 Snellen equivalent (mean 0.58 logMAR, 20/76) with no association with age (linear regression, P ¼ .15). The mean visual acuity deficit with respect to age-matched norms was 0.40 logMAR (Figure 1), or 4 lines poorer than mean normal. Inspection of the eye-movement recordings obtained under binocular viewing conditions showed infantile nystagmus-type waveforms (pendular [n ¼ 8], jerk [n ¼ 3], combination of pendular and jerk [n ¼ 2]) as well as waveforms typical of fusion maldevelopment nystagmus (‘‘manifest latent nystagmus,’’ n ¼ 2). The type(s) of nystagmus waveforms did not appear to be associated with age. The overall mean value of the NOFF value in this group was 1.1 logits, corresponding to a mean foveation fraction of 0.24 (ie, 240 ms of foveation per second during a clean portion of the recording.). For the comparison between patients with Down syndrome and nystagmus and the cohort of patients with unassociated infantile nystagmus, we excluded the 2 patients with Down syndrome whose nystagmus waveforms were not typical of infantile nystagmus (ie, the 2 patients with manifest latent nystagmus). The cohort of 93 patients with unassociated infantile nystagmus had a mean NOFF value of 0.93 logits (SD 2.1) and mean visual acuity deficit of 0.25 logMAR (SD 0.22). The 14 children with Down syndrome and infantile nystagmus waveforms had similar NOFF value (0.96 logits [SD 1.7]; P ¼ .9, t test) but a larger age-corrected visual acuity deficit (0.41 logMAR [SD 0.20]; P ¼ .0112) (Figure 2). In the cohort of children with Down syndrome and infantile nystagmus, those with poorer fixation stability (lower NOFF value) tended to show larger visual acuity deficits than those with better fixation stability (higher
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FIGURE 3. Scatterplot showing the binocular visual acuity deficit (from mean normal) in children with Down syndrome and nystagmus as a function of the nystagmus optimal fixation function (NOFF). Symbols correspond to the nystagmus waveform types: infantile nystagmus (solid circles); manifest latent nystagmus (solid triangles). The solid and dotted lines denote the best fit and the 95% predictive interval, respectively, of a model14 fit to the unassociated infantile nystagmus data; this model shows an exponential decrease of visual acuity deficit with increasing foveation. The scale at the top gives the corresponding foveation fraction (ie, the fraction of points within the optimal portion of data meeting simultaneous position and velocity criteria).
NOFF value), as shown in Figure 3 (solid circles), where the visual acuity deficit is plotted as a function of the NOFF value. Also shown in Figure 3 are the data from the comparison group of patients with unassociated infantile nystagmus together with the best fit of the exponential model previously proposed for unassociated infantile nystagmus.14 Compared to the model fit, the 14 Down syndrome patients with infantile nystagmus showed a 0.17 logMAR (SD 0.20) larger visual acuity deficit for any given NOFF value (P ¼ .005, paired t test). Nonetheless, 11 of the 14 children (79%) fell within the 95% predictive limits of the exponential model (dotted lines in Figure 3). The data from the 2 Down syndrome children with manifest latent nystagmus are indicated by solid triangles in Figure 3. A similar relationship between visual acuity deficit and fixation stability appears to hold for these patients.
DISCUSSION USING A BEHAVIORAL TESTING METHOD THAT POSES ONLY
limited demands on the child’s cognitive and motor skills,7,8 we found mild to moderate visual acuity deficits in this group of children with Down syndrome and nystagmus averaging approximately 4 lines below ageVOL. 157, NO. 2
adjusted mean normal; all but 3 scored outside of the normal limits for their age. The number of participants in this sudy was small but spanned a wide age range throughout childhood, thus providing cross-sectional evidence of visual acuity failing to mature with age, as can be seen in Figure 1. Recordings of fixational eye movements showed waveforms typical of infantile nystagmus as well as waveforms typical of fusion maldevelopment nystagmus (traditionally known as ‘‘manifest latent nystagmus’’). In general, nystagmus in early childhood is not always accompanied by visual acuity deficits. The nystagmus optimal fixation function is a meaningful metric to quantify nystagmus severity, as its association with age-corrected visual acuity has been shown.14,23 NOFF values in this group of children with Down syndrome and nystagmus did not differ from those found in the larger group of patients with unassociated infantile nystagmus (Figure 2). The relationship between the NOFF values and the agecorrected visual acuity deficit in these 2 disease groups showed similarities: greater (better) NOFF values corresponding to smaller deficits in visual acuity (Figure 3). In fact, the data from all but 2 of the children with Down syndrome and nystagmus fell within the 95% predictive interval of the exponential model fitted to the data from the larger group of patients with unassociated infantile nystagmus (area between the dotted lines in Figure 3). However, Figure 3 also clearly shows a (small) systematic difference between the Down syndrome data and the model prediction: The children with Down syndrome and nystagmus on average showed a 0.15 logMAR (1.5 lines) larger visual acuity deficit than predicted based on the model. Therefore we conclude that of the 4-line overall visual acuity deficit in these children, all but 1.5 lines could be ‘‘explained’’ by nystagmus. It is typically not clear in children with nystagmus to what extent visual acuity deficits are caused by the reduced fixation stability or vice versa, although it seems plausible in the case of Down syndrome that the underlying cause is in reduced motor control. Interestingly, in a study of accommodation and bifocal spectacles in children with Down syndrome, Nandakumar and Leat24 reported a difference of approximately 1.5 lines in near visual acuity between test conditions with singlevision and bifocal lenses. A limitation of our study is that it did not control for under-accommodation, to which children with Down syndrome are prone,24,25 although it is debatable whether under-accommodation is the cause or a result of the visual acuity deficit.25 Other studies of visual function in children with Down syndrome have reported visual acuity levels similar to those presented here.6–8 Those studies typically included children with Down syndrome regardless of whether they also had nystagmus. Courage and associates6 provided separate results for the subset of their Down syndrome patients without nystagmus. Using behavioral test conditions apparently similar to ours, they found visual acuity deficits from normal in the same range as our results from children with
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Down syndrome with nystagmus. It should be noted, however, that nystagmus was diagnosed by clinical observation rather than by eye-movement recordings in the Courage paper.6 It is therefore conceivable that some small nystagmus cases went undetected. However, we must conclude that although nystagmus may ‘‘explain’’ a significant portion of the visual acuity deficits in our data, this portion may nonetheless be relatively small and of the same order of magnitude as the variations observed in visual acuity deficit between studies. Ten to 30 percent of patients with Down syndrome have nystagmus.1,5–7,11,12,26 These reported numbers, however, are based on patients’ medical records or on direct observation in the test setting, not on eye-movement recordings. Therefore, fine nystagmus may have gone
undetected, and the actual incidence of nystagmus among individuals with Down syndrome may be higher. The nystagmus waveforms encountered in this study were predominantly of the infantile nystagmus types and a few fusion maldevelopment types. In contrast, AverbuchHeller and associates27 reported almost exclusively fusion maldevelopment–type nystagmus in their small group of Down syndrome adults. Although it is most likely that other factors also contribute to visual acuity loss in Down syndrome (cortical abnormalities, residual refractive error, cognitive limitations), nystagmus alone could account for a substantial extent of the visual acuity deficit in these children. Therefore, nystagmus treatment may potentially result in improved visual acuity in children with Down syndrome.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. The following disclosure was reported: J. Felius also received funding from the Vision of Children Foundation, San Diego, California, for a related project. This research was funded in part by a grant from the Communities Foundation of Texas, Dallas, Texas (J.F.). Contributions of authors: study design (J.F., C.L.B., D.R.S.); conduct of the study (J.F., C.L.B., D.R.S.); collection and management of the data (J.F., C.L.B., D.R.S.); data analysis (J.F.); preparation of the manuscript (J.F.); manuscript review and approval (J.F., C.L.B., D.R.S.).
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22. Dell’Osso LF, Daroff RB. Congenital nystagmus waveforms and foveation strategy. Doc Ophthalmol 1975;39(1):155–182. 23. Felius J. Measuring nystagmus in infants and young children. In: Harris C, Gottlob I, Sanders J, eds. The Challenge of Nystagmus. Cardiff: Nystagmus Network; 2012:295–306. 24. Nandakumar K, Leat SJ. Bifocals in children with Down syndrome (BiDS) - visual acuity, accommodation and early literacy skills. Acta Ophthalmol 2010;88(6):e196–e204.
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John Keats (1795-1821): Physician and Surgeon
S
oon after his mother died in 1810, John Keats at the age of 14 was apprenticed to a local physician. In 1815, he then registered as a medical student at Guy’s Hospital in London and was soon promoted to the equivalent of a junior resident, assisting surgeons there. In 1816 he received his license to practice as a physician and seemed headed for a medical career. Poetry had the stronger attraction for him but his memories of his hospital experience did
not leave him. They show up in the third stanza of his 1818 ‘‘Ode to a Nightingale’’ where he remembers ‘‘.the weariness, the fever, and the fret, Here, where men sit and hear each other groan; Where palsy shakes a few, sad, last grey hairs. Where but to think is to be full of sorrow And leaden-eye despairs..’’ The hospital also doubtless exposed him to the tuberculosis that killed him a few years later, a tragic end that was not unique to physicians of that era.
Submitted by Ron Fishman MD of the Cogan Ophthalmic History Society.
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