The Optokinetic Uncover Test: a New Insight Into Infantile Esotropia

CLINICAL SCIENCES The Optokinetic Uncover Test A New Insight Into Infantile Esotropia

Michael C. Brodsky, MD; Lindsay Klaehn, COT

Importance: We devised the optokinetic uncover test patients with infantile esotropia syndrome associated to examine the role of peripheral retinal motion input with mild neurological disease. in generating horizontal optokinetic responses in patients with infantile strabismus. Results: All patients showed poor temporally directed optokinetic responses that instantaneously improved Objective: To ascertain whether subcortical visual when the occluded esodeviated eye was uncovered, ex- input contributes to the asymmetrical monocular posing it to nasally directed optokinetic motion. This im- optokinetic responses that characterize infantile provement in optokinetic responses did not necessitate esotropia. a fixation shift to the contralateral eye.

Design and Setting: Observational study in an aca- Conclusions and Relevance: Nasally directed opto- demic research setting. kinetic input to the esodeviated eye can supplement temporal monocular optokinetic responses in the fixating eye Participants: Ten patients with infantile under binocular conditions. This nonfoveal optokinetic esotropia. contribution suggests that monocular nasotemporal optokinetic asymmetry is partly attributable to subcortical Intervention: Optokinetic uncover test. visuovestibular responses mediated by nonfoveal retina.

Main Outcome Measures: Optokinetic testing was JAMA Ophthalmol. 2013;131(6):759-765. performed in 7 patients with isolated infantile esotro- Published online February 14, 2013. pia (5 untreated and 2 previously treated) and in 3 doi:10.1001/jamaophthalmol.2013.2348

NFANTILE ESOTROPIA IS CHARAC- from each eye.10-21 Accordingly, the per- terized by the idiopathic onset of sistence of MNTA in infantile strabismus crossed eyes within the first 6 has been attributed to a cortical pursuit months of life.1 It is often accom- deficit caused by early failure of cortical panied by crossed fixation, pri- binocular vision to develop.22-24 maryI oblique muscle overaction, latent nystagmus, and dissociated vertical diver- CME available online at gence.2 This constellation of findings is also jamanetworkcme.com seen in the setting of prematurity and other and questions on page 713 neurological disorders.3 Patients with infantile esotropia re- Video available online at tain a monocular nasotemporal optoki- www.jamaophth.com netic asymmetry (MNTA) characterized by brisk monocular optokinetic responses to Neonates show poor pursuit re- nasally moving optokinetic targets and sponses to focal moving stimuli but dem- poor monocular optokinetic responses to onstrate strong optokinetic responses to temporally moving optokinetic targets.4-8 large full-field rotating stimuli.19-21 These The phenomenon of MNTA is believed to full-field responses are attributed to the ac- underlie latent nystagmus.4,7-10 In pri- tivation of subcortical optokinetic path- mates and humans, MNTA is normally ways that modulate full-field rotational op- Author Affiliations: seen during the first several months of tokinetic responses and remain active until Author Aff Departments of Ophthalmology life.10-22 Its spontaneous resolution coin- maturation of binocular cortical pursuit Departmen (Dr Brodsky and Ms Klaehn) (Dr Brodsk and Neurology (Dr Brodsky), cides with maturation of binocular corti- pathways within the first 6 months of and Neurol 19-21 Mayo Clinic, Rochester, cal pursuit pathways that provide the tem- life. This MNTA is seen in lateral- Mayo Clini Minnesota. poral component for the optokinetic reflex eyed afoveate animals during turning Minnesota.

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Cover Reverse OKN Right eye left eye direction Left eye Uncover right eye Cover Uncover Cover left eye left eye Right eye 25 20 15 10 5 0 – 5 – 10 – 15 Left Right – 20 – 25 – 30

Right eye fixing Left eye fixing Left eye fixing Right eye fixing

Figure 1. Video-oculography tracing of horizontal optokinetic responses to full-field stripes (patient 4 in the video; http://www.jamaophth.com). Red line corresponds to the right eye horizontal position. Blue line corresponds to the left eye horizontal position. The first 3 beats show a poor optokinetic response when the right (amblyopic) eye is fixing a rightward (temporalward) optokinetic target. When the left eye is uncovered, the tracing improves, and fixation shifts to the left (nonamblyopic) eye. The right eye is then covered, while maintaining a rightward (nasalward) monocular stimulus to the left eye, resulting in a strong optokinetic response. The drum direction is then reversed to leftward, creating a monocular temporalward stimulus to the left eye, which produces a poor optokinetic response. When the right eye is uncovered, allowing it to receive a nasalward stimulus, the optokinetic response improves even though the left eye maintains fixation. Covering the left eye to induce a rightward (nasalward) monocular optokinetic stimulus leads to further improvement in the optokinetic waveform. OKN indicates optokinetic nystagmus.

movements, in which the full-field velocity of the nasal- lays, as well as 1 patient with Down syndrome, were included ward optokinetic stimulus to one eye determines opto- because their clinical findings otherwise conformed to those kinetic rotation of both eyes. Because MNTA antedates of infantile esotropia. development of the visual cortex both phylogenetically and ontogenetically, debate has been waged as to whether RESULTS the persistent MNTA in humans with strabismus is caused by a cortical pursuit defect, a persistent activation of sub- On optokinetic testing, all patients showed brisk re- cortical optokinetic pathways, or a combination of 3,8,10,19,25 sponses to nasally directed monocular optokinetic tar- both. gets and poor responses to temporally directed optoki- Cortical pursuit movements in foveate animals re- netic targets with each eye. During attempted pursuit of quire foveal (or perifoveal) stimulation, while subcorti- temporally directed optokinetic targets, removal of the cal optokinetic movements in afoveate animals are gen- occluder from the contralateral eye produced an imme- erated by full-field optic flow detected by peripheral 26 diate improvement in optokinetic responses (video; http: retina. If the persistence of MNTA in humans with in- //www.jamaophth.com). In 3 patients with alternating fantile strabismus is caused solely by defective cortical fixation, this improved optokinetic response produced pursuit, its activation should necessitate foveal (or para- a fixation shift to the contralateral eye, allowing the op- foveal) fixation. We devised the optokinetic uncover test tokinetic response to be foveally driven by the eye re- to examine the role of peripheral retinal motion input ceiving the nasally directed stimulus. In 7 patients with in generating horizontal optokinetic responses in pa- a fixation preference for one eye, this improved optoki- tients with infantile strabismus. netic response was accompanied by an immediate or de- layed fixation shift when the preferred eye was uncov- METHODS ered and by maintenance of fixation when the nonpreferred eye was uncovered. In 3 patients, 3-dimen- Ten patients had a history of infantile esotropia confirmed by sional video-oculography (Sensorimotoric Instru- MNTA on optokinetic testing using a handheld rotating drum ments) was performed using a full-field optokinetic stimu- (Figure 1). Patients ranged in age from 1 to 38 years, and all lus projected on a flat surface (stripe width of 2.2Њ and underwent full ophthalmological examinations with special at- velocity of 15Њ per second with the patient viewing at 3 tention to signs of crossed fixation, latent nystagmus, primary m). These recordings confirmed that uncovering the con- oblique muscle overaction, and amblyopia assessed by the in- tralateral eye produced improvement in the optokinetic ability to maintain fixation with one eye (Table). Seven of 10 patients had no history of neurological disease, developmen- waveform regardless of whether a change in fixation oc- tal delay, or prematurity. Two of these patients had under- curred (Figure 1). In 3 patients with mild neurological gone previous strabismus surgery and had residual esotropia. disease or prematurity, the optokinetic uncover test pro- Three of 10 patients had mild neurological disease. Two pa- duced results identical to those in 7 patients with idio- tients with mild prematurity and speech and fine-motor de- pathic infantile esotropia. Six of the untreated patients

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Dissociated Systemic or Patient No./ Latent Vertical Fixation Angle Neurological Sex/Age, y Nystagmus Divergence Preference Amblyopia at Neara Disease 1/M/4 No No Right eye Yes 30 No 2/M/4 Yes Yes Left eye Yes 20 Speech and fine-motor delay 3/M/2 No No Left eye Yes 25 No 4/F/27 Yes Yes Left eye Yes 10 No 5/F/5 No No None No 40 Mild speech and motor delay 6/F/38 Yes Yes Left eye No 18 No 7/M/6 Yes Yes Left eye Yes 20 No 8/M/2 No No None No 50 No 9/F/1 No No None No 45 No 10/M/4 No No None No 45 Trisomy 21

a Prism diopter esotropia unless otherwise indicated.

subsequently underwent strabismus surgery to correct their infantile esotropia. Other clinical findings are sum- marized in the Table.

COMMENT

In all patients with infantile esotropia, defective temporalward monocular optokinetic responses in the fixating eye improved when the esotropic nonfixating eye was EOM uncovered, allowing it to receive nasalward optokinetic

input under binocular conditions. From a practical view- NOT-DTN LGN point, this observation shows that the examiner should not test for MNTA when the patient has both eyes open

in the patient and assume that the suppressed eye will NPH not contribute to the optokinetic response in a patient V1 O with infantile esotropia. At a mechanistic level, this ob- M NRTP servation challenges the long-standing assumption that N STS (MT/MST) MNTA in humans with infantile esotropia can be attrib- d.c. uted solely to defective cortical pursuit. In our patients, IO P Cer the modulation of horizontal optokinetic responses by P R the nonfoveal retina of the esotropic eye suggests that sub- F cortical optokinetic pathways must continue to modu- VN late peripheral optic flow in humans with infantile strabismus. This improvement of optokinetic waveform is consistent with the clinical observation that patients with GS manifest latent nystagmus show a visible worsening of 27 their nystagmus when the deviated eye is covered. Figure 2. Neuroanatomical pathways involved in the optokinetic reflex and In a 1936 publication, Ter Braak28 showed that afove- optokinetic nystagmus system of the right half of the brain in the squirrel ate animals, such as the rabbit, generate optokinetic nys- monkey. The connections of the nasal retina of the left eye and the temporal retina of the right eye are shown. Cer indicates cerebellum; d.c. IO, dorsal tagmus in response to movement of large objects, despite cap of inferior olive; EOM, extraocular muscles; GS, Scarpa ganglion of the the fact that they did not track small objects. In the mon- vestibular nerve; LGN, lateral geniculate nucleus; NOT-DTN, nucleus of the key, these full-field optokinetic responses persisted after optic tract–dorsal terminal nucleus; NPH, nucleus prepositus hypoglossus; NRTP, nucleus reticularis tegmenti pontis; OMN, ocular motor nuclei; decortication, suggesting that they were mediated by a sub- PPRF, paramedian pontine reticular formation; STS, movement sensitive 29,30 cortical optokinetic system. In the rabbit, each eye is areas of the middle temporal area (MT) and the medial superior temporal driven by mainly forward (nasalward) optokinetic mo- area (MST) in the cortex around the superotemporal sulcus; V1, primary tion, which provides the stimulus for the optokinetic re- visual cortex; and VN, complex of the brainstem vestibular nuclei. Modified from the chapter by Behrens et al35 with permission. sponses of both eyes.31 These asymmetrical subcortical optokinetic responses are now known to be modulated by the contralateral nucleus of the optic tract (NOT) and dorsal to the vestibular nuclei to modulate visuovestibular re- terminal nucleus (DTN) of the accessory optic system within sponses to full-field optokinetic rotation during turning the mesencephalon, which respond only to ipsilateral op- movements (Figure 2).33-35 tokinetic stimulation (nasalward for the viewing eye).32 In In primates, development of binocular corticopretec- rabbits and in monkeys, these pathways project down to tal pathways to the NOT and the DTN of the accessory the inferior olive and contralateral flocculus and then on optic system, which provide ipsilateral pursuit re-

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R L In V1-only monocular cells

R+L Binocular cells

NOT-DTN NOT-DTN LGN LGN

SCC SCC

MST MST MST MST MT MT MT MT + R+L + + L R L L L R L R L L R R R R V1 V1 V1 V1

Figure 3. Normal cortical and subcortical projections during early human development (based on a model proposed by Hoffmann36). The brain is viewed from the top of the head, so the left eye is on the left. A, In early infancy, a leftward optokinetic stimulus is transmitted contralaterally via a subcortical pathway from the nasal retina of the right eye to the left nucleus of the optic tract–dorsal terminal nucleus (NOT-DTN) (solid red arrow), which is sensitive to leftward motion. Ipsilateral corticofugal input from binocular cells in the left hemisphere to the NOT-DTN (interrupted green arrow) has not yet developed. B, Later in infancy, horizontal optokinetic responses become encephalized by late infancy as binocular cortical pursuit pathways become fully operational (solid green arrow) and subcortical optokinetic pathways regress (interrupted red arrow). At this stage, a leftward optokinetic stimulus to both eyes stimulates corticofugal pathways projecting from binocular cells in V1 to the middle temporal area (MT) and the medial superior temporal area (MST) and on to the ipsilateral NOT-DTN. L indicates left eye monocular cells; LGN, lateral geniculate nucleus; R, right eye monocular cells; R ϩ L, cortical binocular cells (that are absent in early infancy); and SCC, semicircular canals.

sponses (temporalward for the viewing eye), are neces- netic responses that are observed in early infancy until they sary to cancel this optokinetic asymmetry within the first are rendered inactive by the establishment of binocular cor- year of life (Figure 3).11-18,36 These corticopretectal pro- tical pursuit pathways (Figure 3).20,21 However, the gen- jections to the NOT-DTN come predominantly from the eral notion that they can retain function in the absence of middle temporal area and the medial superior temporal cortical input has been controversial.25,40 For example, it area, as well as from V1 and V2,16 while those to acces- has been suggested that the relative preservation of re- sory optic nuclei (lateral terminal nucleus and medial ter- sponses to nasally directed stimuli in patients with incom- minal nucleus) come exclusively from the middle tem- plete bilateral occipital lobe destruction could be owing to poral area and the medial superior temporal area.37 Within remnants of the subcortical projection to the NOT-DTN the superior temporal sulcus, the middle temporal area that may have been released from cortical control.25,40,41 Ter is involved in motion detection and is responsible for pur- Braak and Schenk42 described a patient with acquired cor- suit movements, while the medial superior temporal area tical blindness who retained some preservation of full- modulates pursuit and visuovestibular detection of op- field optokinetic responses, but subsequent studies43,44 have tic flow.38,39 As normal binocular cortical pursuit path- found no evidence of this effect. These findings suggest that ways become established within the first 6 months of hu- subcortical optokinetic pathways, once “shut off” after the man life, visuovestibular responses to full-field optokinetic first few months of life, are incapable of reactivating.21,22 stimulation become “encephalized” as they are incorpo- However, they do not address the question of whether spe- rated into the cortical pursuit system (Figure 3).18,19 cific derangements in binocular cortical development can In humans, these same subcortical optokinetic path- act to preserve their function. ways retain their nasalward directional predominance and Our finding that peripheral retinal optokinetic input are believed to mediate the full-field horizontal optoki- can override defective foveal pursuit suggests that infan-

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A B

Occluder Occluder removed

R L In V1-only monocular cells

R+L Binocular cells

NOT-DTN NOT-DTN LGN LGN

Transmission only from R Not from L

SCC SCC

MST MST MST MST MT MT MT MT L L L L R R R R V1 V1 V1 V1

Figure 4. Optokinetic uncover test in infantile esotropia. A, When the right eye is covered and the left eye receives a leftward (temporal) optokinetic stimulus, the temporal retina is ineffective in generating a response. The absence of binocular cells within the visual cortex means that temporally directed stimuli cannot be transmitted to the ipsilateral nucleus of the optic tract–dorsal terminal nucleus (NOT-DTN) because maturation of this function requires an early directional match between action potentials originating from binocular cortical cells in the middle temporal area (MT) and the medial superior temporal area (MST) with those projecting from the right eye via the ipsidirectional subcortical pathway to the NOT-DTN. B, When the right eye is uncovered, the nasalward optokinetic stimulus to the right retina generates a leftward optokinetic response that could be mediated by crossed subcortical connections to the NOT-DTN (small red arrow) or through the retinogeniculate pathway to the monocular right eye cells within V1 of the left hemisphere to MT-MST, where corticofugal projections can establish connections with cells in the left NOT-DTN that share the same leftward direction preference (large red arrow). The fact that this nasalward response can be driven by peripheral retina suggests that subcortical (bottom up) optokinetic pathways rather than cortical foveal pursuit (top down) pathways have a predominant role in this response. L indicates left eye monocular cells; LGN, lateral geniculate nucleus; R, right eye monocular cells; R ϩ L, cortical binocular cells (that are absent in infantile esotropia); and SCC, semicircular canals.

tile strabismus allows these subcortical optokinetic path- latent subcortical pathways to remain functional in in- ways (which rely on peripheral retinal input) to remain fantile esotropia (Figure 4).11,17 In this way, infantile eso- operational. Unlike “decortication,” infantile strabis- tropia could remodel the cortical motion pathways to se- mus may maintain the function of the subcortical visual lectively maintain the nasally biased subcortical gateway pathways in a way that prevents them from being shut through which unbalanced binocular visual input can turn off. In 1983, Schor8 proposed that selective maldevelop- the gears on these evolutionarily ancient eye movement ment of cortical binocular vision could provide a com- control systems (Figure 4).45 The fact that cortical sup- petitive advantage to reinforce the activation of direct sub- pression can elicit latent nystagmus,46 and that periph- cortical projections from the nasal retina of each eye to eral retinal input can also drive this response, suggests the contralateral NOT-DTN and thereby potentiate their that selective preservation of crossed corticopretectal con- function. According to Hoffmann and colleagues,11,17 the nections may allow these latent subcortical mecha- Hebbian mechanism of synaptic formation predicts that nisms to be expressed in infantile esotropia. only neurons firing in a correlated manner (in this case, This explanation has several implications for the MNTA sharing the same direction sensitivity) become consoli- that characterizes infantile esotropia. First, a selective pres- dated during development. Through this activity- ervation of crossed monocular nasal retinal projections dependent mechanism, the ipsilateral direction sensitiv- from the contralateral eye would eliminate the temporal ity of the NOT-DTN would preferentially allow crossed retinal projections subserving cortical pursuit from the nasal retinogeniculate pathways that connect monocu- ipsilateral eye, explaining why the cortical component larly through the visual cortex to establish corticofugal of the optokinetic asymmetry can be monocularly driven connections to the ipsilateral NOT-DTN, enabling these in infantile esotropia and binocularly driven with a hemi-

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©2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 spheric lesion involving the cortical pursuit pathways. optokinetic motion is known to displace the eyes in the Second, this neurodevelopmental derangement would direction of the fast phase,51 it might be argued that this help to explain how the cortical motion asymmetry in displacement could have led to the false conclusion that infantile esotropia is dictated the directionality of tne NOT- the uncovered esodeviated eye was not fixating when the DTN.47-49 Third, it suggests that infantile esotropia can eye receiving temporal optokinetic stimulation was un- arrest development of the nascent optokinetic system at covered. As shown in the video, however, the fixating a stage wherein MNTA can be generated from the visual eye was clearly evident in all patients, and video- cortex (top down) or from subcortical pathways (bot- oculography confirmed that the nasal retina of the eso- tom up). Fourth, as divined by Schor8 30 years ago, the tropic eye could drive the optokinetic response. associated monocular corticofugal projections from the In conclusion, the results of this study provide evi- motion centers in the middle temporal area and the me- dence that human subcortical optokinetic pathways dial superior temporal area to the other ipsilateral acces- may remain active in the presence of infantile esotro- sory optic nuclei that control cyclovertical rotations of pia. Selective preservation of corticotectal projections the eyes would (by a similar Hebbian mechanism) ex- from the nasal retina of the contralateral eye would plain the torsional optokinetic biases6 and complex cy- enable these subcortical visual pathways to retain their clovertical movements that accompany latent nystag- original function in the setting of infantile esotropia. mus but remain conspicuously absent in a hemispheric The optokinetic uncover test provides a unique insight (binocular) pursuit defect. Fifth, the ability of subcorti- into the role of peripheral motion detection under bin- cal visual pathways (Figure 2) to be activated bidirec- ocular conditions, allowing us to deconstruct the tionally via subcortical and cortical visual pathways would optokinetic system into its cortical and subcortical render obsolete the debate about neuroanatomical local- components. The intrinsic monocular optokinetic ization in infantile esotropia.3 biases that define these subcortical pathways may be This study has several inherent limitations. First, we the proximate cause of MNTA, while failure of the did not use a circular full-field optokinetic apparatus, binocular cortical pursuit pathways to develop may which produces the sensation of circularvection (the false provide the permissive cause that allows these subcor- sensation of physical rotation) and is believed to be nec- tical pathways to remain functional. essary to directly stimulate the visuovestibular system.50 Although this testing paradigm would have forti- Submitted for Publication: August 30, 2012; final revi- fied our conclusions, we were only able to confirm our sion received November 21, 2012; accepted November observation using a flat full-field optokinetic stimulus, 22, 2012. which (like the optokinetic drum) probably elicits pur- Published Online: February 14, 2013. doi:10.1001 suit responses in healthy individuals.50 However, the en- /jamaophthalmol.2013.2348 hancement of temporalward foveal optokinetic re- Correspondence: Michael C. Brodsky, MD, Depart- sponses when peripheral retina of the nonfixating eye was ment of Ophthalmology, Mayo Clinic, 200 First St, Roch- exposed to nasalward optokinetic motion demonstrates ester, MN 55905 ([email protected]). that cortical pursuit cannot be the only system involved Author Contributions: Dr Brodsky had full access to all in the generation of MNTA (and latent nystagmus, by in- the data in the study and takes responsibility for the in- ference). A selective preservation of crossed cortical pro- tegrity of the data and the accuracy of the data analysis. jections to the NOT-DTN from the nasal retina of the con- Conflict of Interest Disclosures: None reported. tralateral eye (Figure 4) would allow nasalward cortical Funding/Support: This study was supported in part by pursuit pathways to generate subcortical visuovestibu- a grant from Research to Prevent Blindness. lar eye movements (with their associated torsional com- Online-Only Material: A video is available at http://www ponents), rendering these 2 classes of eye movement in- .jamaophth.com. distinguishable in the setting of infantile esotropia. Second, some of the patients with infantile esotropia had under- REFERENCES gone previous strabismus surgery. Consequently, the angle of the esotropic deviation was smaller than that seen in 1. Campos EC. Why do the eyes cross? a review and discussion of the nature and infantile esotropia. 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