Professional Documents
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Evolutionary Basis
of Strabismus and
Nystagmus in Children
Michael C. Brodsky
123
The Evolutionary Basis of Strabismus
and Nystagmus in Children
Michael C. Brodsky
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To the winds of fate that charted my course
on this unexpected scientific journey through
our collective past.
Foreword
Let me congratulate you for picking up this book. Stay with it. You will be in for a
fantastic journey.
In ancient times, physicians, scientists, and philosophers were asking the same
questions: What is the human experience; why are we here? Recall that Socrates is
considered by some to be the father of Western medicine. As well as a great philoso-
pher. Think also of Galileo Galilei, Sir Isaac Newton, or Charles Darwin. But some-
where along the path of the human experience, perhaps culminating in Descarte’s
famous “I think, therefore I am,” physicians became increasingly focused on smaller
and smaller parts of the whole. This is not all bad. Think of how a powerful tele-
scope will allow study and observation of the smallest and most distant star. But
when viewed through that lens, one loses perspective of the great surround. Literally,
one cannot see the galaxy through all the stars. But if one looks through the “wrong
end” of the telescope, although the view is minified, the surrounding celestial bodies
can be seen and put in perspective. The greatest thinkers over time had the ability
and desire to focus on both views, the detailed and the wide. It is exactly this type
of original, broad-brush, and breakthrough thinking that characterizes Dr. Brodsky’s
writings. They cross-correlate studies from a number of different disciplines. His
ideas are bold and initially may seem iconoclastic, but they gradually weave a web
that consolidates much of what we see in our strabismic patients.
If one looks at strabismus through a telescope, we perhaps see crossed eyes,
DVD, or an overacting inferior oblique muscle. But if we step back as Dr Brodsky
has and look at the big picture through the other end of the telescope, through the
wide angle lens of evolutionary biology, we see that many strabismic disorders are
often the result of exaptations (a term describing a trait that has been co-opted for a
use other than the one for which natural selection has built it), and atavisms (a reap-
pearance of an ancestral trait that has been lost through evolutionary change over
successive generations). Evolution is not the underpinning of perfect design. As Dr.
Brodsky quotes R.W. Rodieck, “Evolution is not engineering-it is more like tinker-
ing-it is not design. The visual system never had an opportunity to be designed-or
redesigned from scratch; instead, both form and function reflect its long, particular,
and capricious history.”
This is book truly sui generus—unlike any I have read. It is unique in format. The
book consists of a collection of 20 articles (editorials, opinion pieces, and studies)
that the author has previously published over the arc of his career. Each chapter is
vii
viii Foreword
followed by a postscript written in 2020. These postscripts give insight into how the
author’s views may have changed since the articles’ publication. They view each
article through an ongoing evolution of understanding. As Brodsky states, “Anyone
who tells you that they have the final answer is not a scientist. In science, models
evolve with new and better data.”
Although I had read each of these articles when initially published, I see the util-
ity this book provides for reading them as parts of a piece. Each movement in a
symphony may seem complete in and of itself. But when experienced in sequence,
the full artistic message of the symphony can be more fully enjoyed. Similarly, each
of these 20 chapters can stand alone shedding light on its given subject. But when
read as parts of a whole thesis, we come to realize the author’s underlying message,
“Our past is always with us.”
Burton J. Kushner, MD
Professor Emeritus, Department of Ophthalmology and
Visual Sciences, University of Wisconsin,
Wisconsin, MD, USA
Preface
ix
x Preface
Michael C. Brodsky
Rochester, MN, USA
Acknowledgement
I am grateful to the Mayo Clinic for providing me with the research time to envi-
sion, assemble, and curate this unique collection. I am also indebted to the Knights
Templar Eye Foundation, which generously provided research funding for the time
and resources needed to prepare this book. Finally, I wish to thank Asja Rehse, my
editor extraordinaire at Springer, who made it easy.
xi
Contents
xiii
xiv Contents
What Is DVD?
Fig. 1.1 Dissociated vertical divergence. (a) Absence of hyperdeviation with binocular fixation.
(b) Right hyperdeviation and extorsion evoked by occlusion. (c) Left hyperdeviation and extorsion
evoked by occlusion. (d) Absence of hyperdeviation during binocular occlusion (as viewed through
translucent occluders)
esotropia but is also observed in association with congenital exotropia and after
surgical realignment of the hypotropic eye in congenital “double elevator palsy” [6].
As succinctly stated by Helveston [3], “… DVD is a reflex type of event that is pro-
grammed to occur if the appropriate mechanisms for nullifying its expression are
not functional.”
What Is a Dorsal Light Reflex? 3
In 1935, von Holst [15, 16] reported that a fish tends to orient its dorsal surface
toward the direction of maximal light intensity (Fig. 1.2). A fish restrained in an
upright position and illuminated from one side will move the eye that is ipsilateral
to the light source downward and the contralateral eye upward (Fig. 1.2) [15–17].
These postural and ocular responses to asymmetrical illumination are righting
reflexes that function to reorient the body and eyes with respect to the apparent
visual vertical, as judged by the direction of maximal light. Either reflex is only
partly compensatory, with its gain determined by the interplay of visual and vestibu-
lar drives [17].
von Holst [15, 16] discovered that visual and otolithic signals are yoked within
the central vestibular system to establish postural orientation in the roll plane. In the
restrained, labyrinthectomized fish, labyrinthine input can no longer curb this visu-
ally induced postural reflex, and the vertical divergence response to a lateral light
stimulus is approximately doubled [17]. The enhancement of this visual righting
reflex in the absence of vestibular input demonstrates that the dorsal light reflex is a
visually mediated ocular tilt reaction that is counterbalanced by the otoliths [14]. If
the dorsal light reflex in fish resulted from otolithic imbalance, ablation of the
a
13• 22• 27•
30• 60•
Direction
of Light
90•
b
30• 60•
Direction
of Light
5• 4• 3•
6• 10• 12• 90•
Fig. 1.2 Dorsal light response in goldfish. (a) In the unrestrained goldfish, the degree of body tilt
in the roll plane increases with increasing angles of illumination. (b) In the restrained goldfish,
vertical divergence of the eyes increases with increasing angles of illumination. (Reprinted with
permission from reference [18])
What Is a Dorsal Light Reflex? 5
otoliths would abolish it rather than increase it. When the right labyrinth is removed
and the left eye is blinded, visual and utricular tone summate and the fish will com-
mence permanent rolling to the right (Fig. 1.3) [14, 16]. When the left labyrinth and
left eye are left intact, utricular and visual innervation oppose each other and normal
postural responses are again observed [14, 16]. Thus, left utricular activation has an
effect similar to that of unilateral illumination of the right eye, and it counteracts the
effect of unilateral illumination of the left eye (Fig. 1.3). Visual information pertain-
ing to light asymmetry converges with utricular input pertaining to gravitational
asymmetry to modulate postural reflexes at the level of the vestibular nuclei [18].
The dorsal light reflex bears a profound resemblance to DVD (Table 1.1). (For
purposes of comparison, dorsal can be conceptualized as the direction from which
vertical sunlight illuminates the labyrinths in upright fish and humans.) In fish, the
amplitude of the dorsal light response increases with the intensity of illumination.
In DVD, the finding of variable vertical amplitudes in the 2 eyes must also be a
Table 1.1 Similarities Between Dorsal Light Reflex in Goldfish and Dissociated Vertical
Divergence in Humans
Dorsal Light Reflex Dissociated Vertical Divergence
Evoked by asymmetrical light input to the eyes Evoked by asymmetrical visual input to the eyes
Visually deprived eye shifts dorsally Visually deprived eye shifts dorsally
Tropotactic response* Probably tropotactic
Magnitude of response dependent on strength Magnitude of response dependent on degree
of light stimulus of binocular visual disparity
Magnitude of response dependent on “mood” Vertical amplitude variable
and external factors
Long latency of vertical reequilibration after Slow reversal of hyperdeviation after
prolonged lateral illumination cessation of monocular occlusion
Decreasing exponential waveform Decreasing exponential waveform
Body tilts in roll plane toward light (ie, toward Presence and direction of head tilt variable
the side of the preferred eye)
Right utricular output counteracts right eye Undetermined
illumination
*Functions to reestablish binocular equilibrium rather than to directionally orient the eyes toward
incoming light
6 1 Dissociated Vertical Divergence
How would a dorsal light reflex manifest in humans, who have frontally placed
eyes, predominantly binocular visual fields, and stereopsis? Binocular vision must
function to suppress this reflex, since a vertical divergence of the eyes would effec-
tively abolish binocularity and stereopsis. When binocularity is poorly developed,
however, this primitive reflex can reemerge if binocular visual input fluctuates. If
reduced visual input to 1 eye is interpreted by the brain as visual tilt, then the dorsal
light reflex should serve to equilibrate visual input between the 2 eyes. For this to be
the case, the central vestibular system must interpret decreased visual input to 1 eye
as being equivalent to a hypotropia, and respond with a vertical vergence signal. In
humans, the oblique muscles have been found to play the predominant role in pro-
ducing visual vertical divergence movements (Fig. 1.4), as elegantly demonstrated
by Enright [29] and elaborated on by others [30, 31]. Clinical observation [2, 8] and
scleral search coil recordings [30–32] in individuals with DVD have confirmed that
extorsion and elevation of the deviating eye are accompanied by a reciprocal intor-
sion and depression of the fixating eye, which conforms to the visual vertical diver-
gence response in humans [20]. The prominent role of the oblique muscles in
restoring vertical fusion is evidenced by the dynamic extorsion of the rising eye that
accompanies DVD, as well as the horizontal divergence of the non-fixating eye,
which reflects the tertiary abducting function of these muscles [31].
In the case of DVD, reduced visual input in the left eye would activate the left
inferior oblique and right superior oblique muscles to produce a cyclovertical diver-
gence movement (Fig. 1.5) [31]. Contraction of these muscles produces a clockwise
torsional movement of both eyes, together with infraduction of the right eye and
supraduction of the left eye. Maintenance of fixation with the right eye would
require simultaneous innervation to the elevators (superior rectus and inferior
Fig. 1.4 Vertical
divergence of the eyes in a
DVD. Vertical divergence
produced by decreased
visual input to the right eye
(a) and left eye (b) show
opposite vertical and
torsional components.
These divergence
b
movements enable normal
individuals to fuse small
vertical image disparities
8 1 Dissociated Vertical Divergence
a Visuo-vestibular Innervation
Fig. 1.5 Visuo-vestibular and fixational innervation in dissociated vertical divergence with hyper-
deviation of the left eye. In accord with the dorsal light reflex, decreased visual input in the left eye
is equivalent to a hypotropia, which activates a vertical vergence mechanism to equilibrate the 2
eyes. (Arrow size denotes relative magnitudes of innervation.) (a) In humans, vertical vergence is
mediated primarily by the oblique muscles, causing contraction of the inferior oblique muscle on
the left and the superior oblique muscle on the right. Visuo-vestibular innervation, if unaffected by
fixational innervation, would cause simultaneous elevation and extorsion of the left eye and depres-
sion and intorsion of the right eye. (b) Compensatory fixational innervation to the elevators is
necessary to maintain a steady vertical position of the right eye. By Hering law, fixational innerva-
tion to the right eye will augment the effects of vestibular innervation to the inferior oblique and
superior rectus muscles of the left eye, actively driving the hyperdeviation. Compensatory fixa-
tional innervation negates infraduction of the right eye but leaves it with a small intorsional
predominance
oblique muscles) of the right eye to counteract the infraducting action of the supe-
rior oblique muscle. By Hering law, compensatory fixational innervation to the
elevators of the fixating eye recruits the same muscles contralaterally, which would
augment vestibular innervation to the superior rectus and inferior oblique muscles
of the higher eye and actively drive the vertical component of the deviation (Fig. 1.5).
Thus, the observed hyperdeviation in DVD is the composite of 2 visual righting
reflexes: a visuo-vestibular reflex that activates a torsional divergence of the eyes
and a compensatory fixational reflex that maintains fixation with the visually advan-
taged eye and produces an upward movement of the other eye. The pivotal role of
the monocular fixation in DVD explains the nonexistence of simultaneous bilateral
DVD and dictates that an upward movement of 1 eye never begins while the other
eye is higher. It is only after the higher eye has completed its descent to the midposi-
tion that the other eye may start to ascend.
The interplay between visuo-vestibular and fixational innervation explains the
perplexing observation that, after removal of a cover from an eye of a patient with
DVD, the higher eye will sometimes descend below the neutral position before
resuming fixation [2–4]. A similar phenomenon is observed when occlusion of the
Is DVD a Skew Deviation? 9
fixating eye induces a downward refixation movement in the hyperdeviated eye, and
the covered eye makes a simultaneous downward movement below midposition
before ascending and extorting [2–4, 33, 34]. In both instances, a fixation shift pro-
vides a momentary glimpse into an underlying bias in central vestibular tone.
a b c
Fig. 1.6 Utricular ocular tilt reaction in humans. When the eyes are frontally placed, a torsional
component becomes necessary to neutralize a tilt in the roll plane. (a) Physiologic ocular tilt reac-
tion. A rightward body tilt activates right utricular and inhibits left utricular pathways subserving
graviceptive tone in the roll plane, resulting in vertical divergence with conjugate torsion of the
eyes and head tilt toward the lowermost eye. (b) Normal eye position with head upright. (c)
Pathologic ocular tilt reaction. A leftward ocular tilt reaction can be caused by an inhibitory lesion
of the left utricular pathways or an excitatory lesion of the right utricular pathways
10 1 Dissociated Vertical Divergence
central nervous system erroneously computes as being vertical [40–45]. The head
tilt is not compensatory for the ocular misalignment or torsion. Rather, the vertical
divergence, ocular torsion, and head tilt are all compensatory adjustments to the
new subjective vertical [41]. Under physiological conditions, this ocular tilt reaction
functions as a righting reflex that enables an organism to maintain gravitational
orientation during tilt in the roll plane (as occurs when skiing or motorcycle riding).
Tilting in the roll plane evokes a physiological skew deviation in lower animals and,
to a lesser degree, in humans (Fig. 1.6) [42]. However, the purely vertical skew
deviation in lower animals is supplanted by a torsional divergence movement in
humans, since the eyes are frontally placed.
No physiological position of body tilt evokes DVD, and no neurologic lesion has
produced it [46]. The intermittent forms of acquired skew deviation that have been
documented in patients with midbrain lesions have not been associated with extor-
sion of the ascending eye or intorsion of the descending eye, as occurs in DVD [36,
47–49]. Vertical divergence of the eyes with the “inverse” torsional characteristics
of DVD is a signature of abnormal binocular vision. Evolutionary conservation of
the dorsal light reflex as the visual counterpart of the utricular ocular tilt reaction
(Fig. 1.3) would explain the acquisition of these inverse torsional movements in
frontal-eyed animals.
In humans, both ocular tilt reactions are conserved as complementary “mirror-
image” righting reflexes, as evidenced by the observed extorsion of the rising eye in
DVD and the intorsion of the rising eye in the utricular ocular tilt reaction (Table 1.2).
In this context, DVD can be conceptualized as an inverse skew deviation. It is the
visual counterpart of neurologic skew deviation; the former is a visuo-vestibular
ocular tilt reaction, while the latter is a utricular ocular tilt reaction. An imbalance
of visual input from the 2 eyes modulates the afferent limb of DVD, while an imbal-
ance in graviceptive input from the utricles modulates the afferent limb of neuro-
logic skew deviation. If the utricular ocular tilt reaction and the dorsal light reflex
Conclusions
Dissociated vertical divergence is a dorsal light reflex that utilizes binocular visual
input to calibrate central vestibular tone. In lower animals, this human dorsal light
reflex functions to equilibrate visual input by simultaneously increasing dorsal light
input to one eye and decreasing it to the other. When binocular control mechanisms
are poorly developed in humans, this dorsal light reflex evokes a phylogenetically
newer vertical vergence movement of the eyes to produce an inappropriate vertical
divergence with torsional characteristics opposite to those required to neutralize a
body tilt (a righting reflex gone wrong).
In the upright human, the observed ocular movement is upward because the eye
with greater visual input is generally used for fixation and the movement of the visu-
ally disadvantaged eye is dorsally directed. The absence of a corresponding hypode-
viation on alternate cover testing reflects the instantaneous shift in visual advantage
to the uncovered eye that occurs with monocular occlusion. This hypothesis explains
the reciprocal nature of the observed hyperdeviation, the dynamic torsion that dis-
tinguishes DVD from other forms of skew deviation, and the tight link between
DVD and visual fixation.
The existence of DVD provides testimony to the duality of the ocular tilt mecha-
nism in humans, to the interplay between visual feedback and vestibular modulation
of extraocular muscle tone, and to the evolutionary role of binocular vision in the
suppression of this visuo-vestibular response.
References
1. Nathan P. The nervous system. 2nd ed. Oxford, UK: Oxford University Press;
1982. p. 84–103.
2. Bielschowsky A. Disturbances of the vertical motor muscles of the eyes. Arch
Ophthalmol. 1938;20:190–6.
3. Helveston EM. Dissociated vertical deviation: a clinical and laboratory study.
Trans Am Ophthalmol Soc. 1980;78:734–79.
4. von Noorden GK. Binocular vision and ocular motility. In: Theory and manage-
ment of strabismus. 4th ed. St Louis: CV Mosby; 1990. p. 341–5.
5. Flynn JT. Strabismus: a neurodevelopmental approach. New York: Springer-
Verlag NY Inc; 1991. p. 71–4.
6. Olsen RJ, Scott WE. Dissociative phenomena in congenital monocular eleva-
tion deficiency. J AAPOS. 1998;2:72–8.
12 1 Dissociated Vertical Divergence
46. Brandt T, Dieterich M. Central vestibular syndromes in roll, pitch, and yaw
planes. J Neuroophthalmol. 1995;15:291–303.
47. Mitchell JM, Smith JL, Quencer RM. Periodic alternating skew deviation. J
Clin Neuroophthalmol. 1981;1:5–8.
48. Greenberg HS, DeWitt LD. Periodic nonalternating ocular skew deviation
accompanied by head tilt and pathologic lid retraction. J Clin Neuroophthalmol.
1983;3:181–4.
49. Corbett JJ, Schatz NJ, Shults WT, et al. Slowly alternating skew deviation:
description of a pretectal syndrome in three patients. Ann Neurol. 1981;10:540–6.
50. van Rijn LJ, ten Tusscher MPM, de Jong I, Hendrikse F. Asymmetrical vertical
phorias indicating dissociated vertical deviation in subjects with normal bin-
ocular vision. Vis Res. 1998;38:2973–8.
Postscript
Although this article was dedicated to dissociated vertical divergence (DVD), which
is considered to be a tertiary phenomenon in infantile strabismus, it was revelatory
for me in that it “cracked the code” of infantile strabismus by showing DVD to be
an atavistic visual reflex. Accordingly, it provided compelling evidence that titrat-
able binocular deviations can arise from unbalanced binocular input through the
subcortical visuo-vestibular pathways.
Many who disagreed with this analysis fundamentally misunderstood it. Some
pointed out that there is no vestibular imbalance in infantile strabismus. This is, of
course, true, as it is the visual rather than the otolithic input that is fluctuating in
DVD. More adamantly, they noted that the visual cortex is integral to DVD, as corti-
cal suppression of one eye can activate it, suggesting to them that DVD must be a
cortical phenomenon. However, our cortical visual motion pathways are reconfig-
ured to the older subcortical pathways in infantile strabismus, so that cortical sup-
pression can produce the same outcome as unequal luminance input in lateral eyed
animals. This also explains how DVD can occur spontaneously when both eyes are
open (and therefore receiving equal luminance input). As fixation has a stronger
effect on DVD than luminance disparity, it is likely that conscious fixation evokes
cortical suppression of one eye in patients with strabismus. So DVD can be acti-
vated both by an exteroceptive stimulus (covering one eye) or an interoceptive stim-
ulus (cortical suppression). The unanswered question is whether covering one eye
evokes DVD through subcortical pathways, whether it evokes cortical suppression
and thereby evokes DVD, or whether both mechanisms can be operative to varying
degrees.
Some have questioned the existence of this subcortical mechanism by pointing
out that there no subcortical photometer in humans. This is untrue. The melanopsin
pathways that project from intrinsically sensitive retinal ganglion cells to the supra-
chiasmatic nucleus to entrain circadian rhythms. I once considered the melanopsin
to be a good candidate system for DVD. This evolutionarily ancient opsin is selec-
tively sensitive to blue light, which comes from the sky. However, preliminary lumi-
nance studies with my colleagues, Drs. Scott Larson and Randy Kardon at the
Postscript 15
University of Iowa, have not shown a selective effect of blue light binocular dispar-
ity in generating DVD. In retrospect, this could have been predicted since the
Bagolini bar, a red filter bar, is often placed over one eye to titrate DVD and thereby
confirm the diagnosis.
Whereas volitional body movements are controlled by the cerebral cortex, indi-
vidual muscles are innervated by subcortical centers. Only within the vestibular
system, where visual motion is encoded in canal referenced planes, can torsional
eye movements be generated. To my mind, the fact that DVD is linked to cortical
suppression (through fixation, occlusion, diffusion, or suffusion with light), is what
distinguishes DVD as a human dorsal light reflex.
DVD Remains a Moving Target!
2
The variable torsional component of DVD can be explained by considering the base-
line torsional position of the eyes. von Noorden [7] has observed that when DVD is
accompanied by “true” inferior oblique muscle overaction, the dynamic intorsion of
the deviated eye is absent as it returns to primary position. Conversely, I have
observed that patients with DVD and superior oblique muscle overaction often have
a prominent torsional component that may exceed the vertical component of the
deviation [8]. These observations suggest that the torsional amplitude of DVD is
defined by the disparity between the extorsional position of the hyperdeviated eye
during inferior oblique muscle activation, and the baseline torsional position of the
globe. When the baseline position is one of extorsion (as occurs with inferior oblique
muscle overaction) [9], this torsional disparity is minimal and the corresponding
torsional movement is small as the extorted eye ascends and descends to an extorted
position. When the baseline position of the globes is one of intorsion (as occurs with
superior oblique muscle overaction), there is a large torsional disparity that is mani-
fested as a prominent torsional movement as the eye ascends and descends.
DVD can manifest in adduction and thereby simulate inferior oblique muscle overac-
tion. This finding is classically attributed to occlusion of the adducting eye by the nose
[7, 10]. However, the notion that the child’s nose acts as an occluder is dubious,
because young children have a poorly formed nasal bridge. Furthermore, alternate
cover testing in lateral gaze (which can only be obtained when no occlusion is present)
confirms that the adducting eye is elevated when the abducting eye is fixating in
DVD. It has been my observation that spontaneous hyperdeviation of the adducting
eye in DVD begins as the eye rotates into the vertical field of action of the inferior
oblique muscle, suggesting that paroxysmal activation of the inferior oblique muscle
can excessively elevate the adducted eye. As the eye moves into adduction, the increas-
ing vertical action of the inferior oblique muscle explains how DVD can manifest
primarily in adduction in the absence of true inferior oblique muscle overaction (ie,
without hypotropia of the abducting eye, a V pattern, or fundus extorsion) [10, 11].
In children with early-onset esotropia, DVD often coexists with oblique muscle
overaction [7, 10–12]. Whereas DVD is caused by paroxysmal activation of the
oblique muscles (with secondary fixational activation of the vertical rectus
Association with Torticollis 19
DVD is often associated with an anomalous head tilt that may be directed toward or
away from the side of the hyperdeviated eye [13–18]. In some patients, head tilting
may be a compensatory means of controlling the hyperdeviation. Jampolsky [15,
16] has characterized the head tilt pattern in DVD in which a hyperdeviation of
either eye increases or becomes manifest when the head is tilted to the opposite side.
This observation is now understandable (and indeed predictable) on the basis of the
torsional kinematics of DVD. For example, DVD with hyperdeviation of the left eye
occurs when the right superior oblique and left inferior oblique muscles receive
simultaneous innervation and a secondary fixational innervation is recruited to
maintain monocular fixation with the lower (and visually preferred) right eye [5]. A
head tilt to the right activates otolithic innervation to the right superior oblique and
the left inferior oblique muscles and thereby increases the left hyperdeviation,
whereas a head tilt to the left would recruit otolithic innervation to neutralize this
cyclovertical divergence [19]. This reasoning suggests that a head tilt to the side of
the hyperdeviating eye can serve as a compensatory means of recruiting otolithic
innervation to control the hyperdeviation.
Other patients with DVD have a head tilt pattern characterized by a hyperde-
viation that becomes manifest or increases when the head is tilted to the same side
[15–18]. According to Jampolsky [16], when fixation with 1 eye predominates in
DVD, tonic fixational innervation to the contralateral superior rectus muscle can
eventually lead to a contracture. If this contracture occurs, it can alter the head tilt
response to one characteristic of superior rectus muscle contracture, with an
increase in the vertical deviation on head tilt to the side of the hyperdeviating eye
[16–18]. When superior rectus muscle contracture develops, a compensatory head
tilt to the opposite side is presumably used to minimize otolithic innervation to the
tight superior rectus muscle, and a head tilt to the side of the higher eye will make
manifest or increase a hyperdeviation [16–18]. In this setting, surgical recession
of a tight superior rectus muscle can reduce or eliminate the compensatory head
tilt [18].
Some head tilts in children with DVD are accompanied by a manifest hyperde-
viation [13, 14]. A dorsal light reflex in humans would produce a head tilt away
from the side of the hyperdeviating eye. Such a tilt would reflect a central vision-
dependent tonus asymmetry [19] and would potentiate the DVD. This head tilt does
not exist to realign the eyes, and surgical treatment of the associated hyperdeviation
should not eliminate it.
20 2 DVD Remains a Moving Target!
Most children with congenital esotropia and DVD also have latent nystagmus [5, 7,
12, 14, 20]. Guyton et al5 have proposed that DVD is a compensatory movement
that damps the cyclovertical component of latent nystagmus. von Noorden has
argued that this variable damping of latent nystagmus could be an effect rather than
the cause of DVD [5]. Pritchard [21] recently found DVD in 47% of patients with
intermittent exotropia, most of whom had no latent nystagmus.
Latent nystagmus, like DVD, is linked to unequal visual input to the extent that
occlusion, suppression, or amblyopia makes it manifest and alternate occlusion
reverses its direction. In describing DVD, Bielschowsky [22] noted that “. . . while this
eye maintains constant fixation, the other eye, which is deviated upward behind the
screen, will make at irregular intervals vertical movements of different extent. . . .”
This observation correlates with eye movement recordings that show that DVD can be
associated with a vertical latent nystagmus in the hyperdeviating eye [23, 24]. If latent
nystagmus occurs because asymmetric visual input resets central vestibular tone in the
yaw plane (ie, plane of rotation about an earth-vertical axis), then DVD might incor-
porate a similar oscillation. Alternatively, the cyclovertical divergence that occurs in
DVD could translate a component of the latent nystagmus into the vertical plane,
which could reduce the horizontal component and cause it to appear on eye movement
recording as a vertical latent nystagmus.
Ironically, these complex ocular kinematics ultimately raise basic diagnostic
questions. Although the torsional component of DVD is not cosmetically problem-
atic, what is its significance for the patient? When does it begin? Is it synonymous
with the torsional nystagmus seen in uncorrected congenital esotropia? Is it associ-
ated with a shift in the subjective visual vertical? When DVD improves spontane-
ously, does it merely revert to a torsional component that is subclinical?
Our fundamental treatment goals for DVD are also called into question. Is the
goal of strabismus surgery simply to eliminate the vertical component of DVD?
Does oblique muscle weakening selectively alter the torsional component? Can ver-
tical rectus muscle surgery selectively reduce the vertical component of DVD at the
expense of worsening the torsional component? Answers to these questions will
inevitably redirect our approach to surgical treatment of DVD.
In its essence, DVD is a balancing movement that uses binocular visual input to
calibrate ocular motor and postural tone in the roll plane. As we undertake to recog-
nize its subjective correlates and define its adaptational functions, we are reminded
that DVD remains a moving target.
References
1. Brodsky MC. Dissociated vertical divergence: a righting reflex gone wrong.
Arch Ophthalmol. 1999;117:1216–22.
2. von Holst E. Über den Lichtrückenreflex bei Fische. Pubbl Staz Zool (Napoli).
1935;15:143–8.
Relationship to latent nystagmus 21
Postscript
Congenital Esotropia
Binocutarity
with Fixation
Equal Preference or Amblyopia
Vision Superimposed
Hypertropia
Fig. 2.1 Clinical algorithm for the differential diagnosis of dissociated vertical divergence
(DVD)-associated head tilts. (Used with permission from Brodsky MC, Jenkins R, Nucci
P. Unexplained head tilt following surgical treatment of congenital esotropia: a postural manifesta-
tion of dissociated vertical divergence. Br J Ophthalmol. 2004;88:264-272, British Medical
Association)
Postscript 23
Light
Fixation
(Normal light)
Fig. 2.2 Video-oculography in a patient with bilateral DVD and latent nystagmus (upper panel)
showing a brief true vertical divergence of the eyes, causing them to initially rotate in opposite
directions when either eye is occluded (lower panel). Note that the latent nystagmus intensifies as
the DVD develops. OD, right eye; OS, left eye. (With permission from Christoff A, Raab EL,
Guyton DL, et al: DVD-A conceptual, clinical, and surgical overview. J AAPOS 2014;18:378-384.
Elsevier Press)
For any number of reasons, I consider it implausible that DVD occurs to damp
latent nystagmus. To accept this notion one would have to ignore all of the evolu-
tionary evidence that both DVD and latent nystagmus are subcortical reflexes aris-
ing from unequal visual input from the two eyes. Many patients without latent
nystagmus get DVD and, in most patients with both conditions, DVD does not
appear to reduce the amplitude of latent nystagmus. In fact, most patients with DVD
show an intensification of latent nystagmus when either eye is covered (Fig. 2.2).
The presence of DVD in some patients with intermittent exotropia and no latent
nystagmus dispels the notion that latent nystagmus must be the driving force for
DVD to develop. No controlled studies have examined patients with latent nystag-
mus without DVD to see if these patients also show nystagmus damping. Importantly,
latent nystagmus is of greater intensity when the poorer-seeing eye is fixating. If
DVD were occurring to damp latent nystagmus, one would necessarily expect to see
a greater DVD amplitude when the patient was attempting to fixate with the poorer
eye. However, the opposite is often the case. Latent nystagmus and DVD occur
together but neither arises from the other. It is easy to confuse links and correlations
with cause and effect.
Primary Oblique Muscle Overaction
The Brain Throws a Wild Pitch
3
The term tonus was originally coined by Ewald [11] to describe the state of excita-
tion of a living muscle during rest. In 1977, Meyer and Bullock [12] advanced their
tonus hypothesis, which states that neuronal tonus pools within the central nervous
system receive multisensory input and that tonus asymmetries between antagonistic
pools can produce tonic motor responses. According to this hypothesis, the eyes are
not merely sensory organs but components of a multimodally driven tonus pool that
calibrates baseline muscle tone (ie, tonus-inducing organs) [12, 13]. This hypothesis
explains how sensory information collected by the eyes can help to govern extra-
ocular muscle tonus. The bilateral positioning of the eyes and ears permits them to
function as balance organs. Visual and graviceptive input are yoked together within
the central vestibular system to determine optimal postural orientation.
In his early pioneering studies of vision-dependent tonus responses in fish, von
Holst [14] found that a posterior shift of a dorsal light source induces a pitch-up move-
ment of the body, whereas an anterior shift induces a pitch-down movement, as if the
animal is programmed to position the body so that the light source retains a dorsal
orientation (Fig. 3.1). With the body stabilized in the upright position, an overhead light
moving fore-and-aft evokes a wheel-turning movement of both eyes, which rotate to
maintain torsional alignment with the light source (Fig. 3.1) [14–16]. Since light nor-
mally comes from overhead when a fish is upright, a posterior movement of the light is
registered as a pitch forward movement of the body (ie, a movement of the body away
from the light). This change in visual input evokes increased tonus to the inferior
oblique muscles, which extort the eyes (Fig. 3.1). The observation that visual and ves-
tibular input can alter postural and extraocular muscle tonus to produce a physiologic
bilateral oblique muscle overaction in lower animals suggests that similar excitatory
stimuli may be operative in strabismic humans with primary oblique muscle overaction.
a b
c d
e f
Fig. 3.1 Physiologic effects of gravistatic (postural) and visual input to the oblique muscle tonus
in fish. These bilateral torsional eye movements function to align the eyes with the perceived visual
vertical by modulating oblique muscle tonus. (a) A pitch-down body movement evokes increased
inferior oblique muscle tonus and extorsion of the eyes. (b) A pitch-up movement evokes increased
superior oblique muscle tonus and intorsion of the eyes. (c) In the unrestrained fish, an anterior
light source evokes a pitch-down body movement. (d) In the unrestrained fish, a posterior light
source evokes a pitch-up body movement. (e) In the restrained fish, anterior movement of overhead
light evokes increased superior oblique muscle tonus and intorsion of both eyes. (f) In the restrained
fish, posterior movement of overhead light evokes increased inferior oblique muscle tonus and
extorsion of both eyes
28 3 Primary Oblique Muscle Overaction
is to maintain eye position and stabilize fixation during head movements [16].
Vestibuloocular movements are the most primitive of all extraocular movements. As
expounded by Walls,
. . . the primitive function of the eye muscles was not to aim the eyes at all. Their original
actions were all reflex and involuntary, and were designed to give the eyeball the attributes
of a gyroscopically-stabilized ship, for the purpose of maintaining a constancy of the visual
field despite chance buffetings and twistings of the animals body by water currents.
[9] (p303)
In the rabbit, for example, a rightward body tilt along its long axis causes the
right eye to be lower in space than the left eye. This tilt elicits a compensatory verti-
cal divergence of the eyes to elevate the right eye and depress the left eye, thereby
stabilizing the eyes in space [17–19]. A pitch forward of the body would produce a
compensatory extorsional movement of both eyes [14, 15, 20].
Now consider the same pitch-down body movement in a rabbit that is fixating
with the right eye maximally abducted and the left eye maximally adducted
(Fig. 3.2). Since the eyes are laterally placed in the rabbit, this position of gaze
Fig. 3.2 Overhead view of a rabbit fixating an object in the right posterior visual field. Solid lines
correspond to the visual axis of the abducted right eye and the adducted left eye. When the rabbit
pitches forward (as when starting to run down a hill), the head rotates downward and the tail rotates
upward. Although both eyes move downward in space, the left visual axis (which is directed
toward the nose) rotates downward, while the right visual axis (which is directed toward the tail)
rotates upward (curved arrows). This divergence of the visual axes corresponds to a right hypertro-
pia that must be neutralized by vestibular innervation to elevate the lower left eye and depress the
higher right eye. The compensatory vertical divergence for a pitch-forward position corresponds to
primary inferior oblique muscle overaction
Vestibular Interactions with the Ocular Motor System 29
would direct the left visual axis anterior to its neutral position and the right visual
axis posterior to its neutral position. A forward pitch in the body plane with the eyes
in this position would tilt the left visual axis to a lower position in space than the
right visual axis (Fig. 3.2). This tilt would necessitate compensatory vestibuloocular
innervation to increase upward tonus in the left eye and increase downward tonus in
the right eye, while extorting both eyes in response to the body pitch. Conversely, if
the body were pitched back during dextroversion, the higher visual axis of the
adducted left eye would necessitate increased downward tonus in the left eye and
increased upward tonus in the right eye to stabilize the position of the eyes in space.
The necessary vestibulo-ocular movements, which correspond to the vertical diver-
gence in lateral gaze seen in humans with primary oblique muscle overaction, are
programmed at an early evolutionary stage to assure stability of the visual field in
all fields of gaze. In 1996, Zee [18] formulated this hypothesis to explain how the
alternating skew deviation in lateral gaze that occurs in humans could be a reversion
to a phylogenically old otolith-mediated righting reflex in lateral-eyed animals.
Zee’s hypothesis also explains how superior oblique muscle overaction with alter-
nating hypotropia of the adducting eye reflects a pitch-up otolithic bias and a down-
ward tonus bias to the extraocular muscle plant, whereas inferior oblique muscle
overaction with alternating hypertropia of the adducting eye would result from a
pitch-down otolithic bias and an upward tonus bias to the extraocular muscle plant.
In lateral-eyed animals and in humans, the semicircular canals are roughly
aligned with the extraocular muscles (Fig. 3.3) [17]. When the head is rotated in a
particular plane, a semicircular canal within the labyrinth detects acceleration and
sends excitatory innervation to the extraocular muscle(s). Within the brainstem and
Superior Rectus
23°
Anterior
41°
Semicircular Canals
56°
Posterior
Top View
30 3 Primary Oblique Muscle Overaction
SR
LR
MR
IO
III
IV
MLF
AC
PC
HC
VI
LVN
MVN
Fig. 3.4 Neuroanatomical projections from the labyrinths to the extraocular muscles. The orienta-
tion of the anterior semicircular canal corresponds to that of the ipsilateral superior rectus and
contralateral inferior oblique muscles. The orientation of the posterior semicircular canals corre-
sponds to that of the ipsilateral superior oblique and contralateral inferior rectus muscles. The
orientation of each horizontal canal corresponds to that of the horizontal rectus muscles. Turning
the head to the right stimulates the right horizontal canal to increase excitatory innervation to the
right medial rectus muscle and left lateral rectus muscle so that the eyes rotate equally and opposite
to the direction of head rotation. HC indicates horizontal canal; AC, anterior canal; PC, posterior
canal; LVN, lateral vestibular nucleus; MVN, medial vestibular nucleus; VI, abducens nucleus;
MLF, medial longitudinal fasciculus; IV, trochlear nucleus; III, oculomotor nucleus; SR, superior
rectus muscle; MR, medial rectus muscle: LR, lateral rectus muscle; and IO, inferior oblique mus-
cle. (Data modified with permission from Tusa [21])
Superior Oblique Muscle Overaction and A-Pattern Strabismus in Neurologic Disorders 31
pitch-up movement that excites both posterior canals also inhibits both anterior
semicircular canals, which send inhibitory innervation to the ocular elevators. The
result is an equal contraversive movement of both eyes to adjust for the pitch-up
head movement. Injury to or inhibition of anterior canal pathways subserving
upward eye movements causes a functional activation of the posterior canal down-
gaze pathways and produces downward eye movements [22].
In addition to the semicircular canals, each labyrinth contains otolithic sensors
consisting of the utricle and the saccule [19]. While the semicircular canals respond
to angular acceleration and produce dynamic vestibuloocular movements, the paral-
lel otolithic system responds to linear acceleration and is sensitive to changes in
static head position [19]. Damage to the semicircular canal pathways produces pha-
sic ocular deviations and nystagmus, while damage to the otolithic projections cor-
responding to the semicircular canal pathways causes tonic ocular deviations
(strabismus) [19, 23–25]. The otolithic pathways are not as well studied, but are
believed to have similar projections to the corresponding canal pathways [19]. For
the sake of simplicity, we refer to the otolithic pathways corresponding to a particu-
lar canal pathway simply as the anterior canal or posterior canal system, recogniz-
ing the similarity in projections between the otoliths and semicircular canals.
Likewise, we also use the term anterior (or posterior) canal predominance to mean
“predominance of the otolithic pathways corresponding to those of the anterior (or
posterior) semicircular canals.”
The otolithic pathways corresponding to the anterior and posterior semicircular
canals are under different inhibitory control (Fig. 3.5) [19, 21, 22, 26, 27]. The ante-
rior canals receive inhibitory connections from the cerebellar flocculi, while the
posterior canals do not. Thus, a structural lesion or metabolic abnormality that
inhibits output from the cerebellar flocculi can also disinhibit the anterior canals,
resulting in an upward deviation of the eyes [21]. Conversely, bilateral lesions of the
ventral tegmental tract or brachium conjunctivum can injure central pathways from
the anterior semicircular canals and produce a posterior canal predominance, result-
ing in tonic downgaze. Maturation of cerebellar floccular inhibition to anterior canal
pathways may be dependent on normal visual experience early in life. Ocular stabi-
lization is normally modulated by visual and vestibular input. When binocular
visual input is pre-empted, this multisensory mechanism may fall under greater
weight of labyrinthine control, allowing excitatory anterior canal output to predomi-
nate [28].
A bilateral lesion that injures both anterior canal pathways or disinhibits both pos-
terior canal pathways will increase prenuclear innervation to the superior oblique
and inferior rectus subnuclei, resulting in a posterior canal predominance and
increased downward tonus to both eyes. This downward tonus must be overcome by
fixational innervation (Fig. 3.6). Since the inferior rectus muscles retain their
32 3 Primary Oblique Muscle Overaction
SR
IR
III N
I S
O
MLF
BC BC
BC VTT
MLF
SVN
SVN
MVN
VTT
AC AC
HC HC
Cerebellum PC
PC
Fig. 3.5 Segregation of pathways controlling anterior and posterior canal tone. Only the anterior
canal pathways receive inhibitory innervation by the cerebellar flocculus. A loss of modulation
from the cerebellar flocculi could disinhibit the anterior canals and produce an upward tonus
imbalance, leading to bilateral inferior oblique muscle overaction, bilateral extorsion, and V-pattern
strabismus. FLO indicates flocculus; NOD, nodulus; AC, anterior canal; PC, posterior canal; HC,
horizontal canal; SVN, superior vestibular nucleus; VTT, ventral tegmental tract; MVN, medial
vestibular nucleus; MLF, medial longitudinal fasciculus; BC, brachium conjunctivum; III N, ocu-
lomotor nucleus (S, I, O, and M represent the oculomotor subnuclei); SR, superior rectus muscle;
and IR, inferior rectus muscle. (Data modified with permission from Tusa [21])
vertical field of action in adduction while the superior oblique muscles have mini-
mal vertical action in abduction, this downgaze predominance would produce a
relative overdepression of the adducting eye in lateral gaze (Fig. 3.7). Activation of
both superior oblique muscles produces bilateral intorsion in the primary position
and an A pattern due to the tertiary abducting action of the superior oblique muscles
in downgaze. In addition, binocular intorsion rotates the inferior rectus insertions
laterally and reduces the adducting action of the inferior rectus muscles in downgaze.
The vestibuloocular pathways pass through the posterior fossa and are suscepti-
ble to injury when structural abnormalities involve the brainstem or the cerebellum.
In children with hydrocephalus and myelomeningocele, the constellation of
Superior Oblique Muscle Overaction and A-Pattern Strabismus in Neurologic Disorders 33
AC AC
AC AC
Fig. 3.6 Superior oblique muscle overaction. (a) Vestibular innervation. A central vestibular tonus
imbalance corresponding to bilateral posterior canal predominance would produce tonic down-
gaze, divergence, and intorsion of the eyes if unopposed by fixational innervation. (b) Vestibular
plus fixational innervation. Fixational innervation, which conforms to the Hering law, recruits
bilateral innervation to the superior rectus and inferior oblique muscles to negate the vertical com-
ponent of the downward tonus bias. Fixational innervation allows a disconjugate intorsional bias
to persist. PC indicates posterior canal; HC, horizontal canal; and AC, anterior canal
Fig. 3.7 Superior oblique muscle overaction. The observed eye movements in different fields of
gaze are a summation of fixational innervation that conforms to Hering’s law, and an underlying
central vestibular imbalance that does not. All 4 depressors are receiving excessive vestibular
innervation. Since the vertical action of the superior oblique muscles is maximal in adduction, the
adducting eye exhibits a downshoot in adduction relative to the abducting eye. The tertiary abduct-
ing effects of the overacting superior oblique muscles are maximized by vestibular innervation in
downgaze and minimized by fixational intervation in upgaze, producing an A pattern
inhibitory pathways from the cerebellar flocculi to the anterior canals. The resulting
anterior canal predominance would increase upward tonus in the extraocular mus-
cles and predispose to bilateral inferior oblique muscle overaction (Fig. 3.8).
Prolonged occlusion of one eye can also induce inferior oblique muscle overac-
tion in nonstrabismic humans with normal stereopsis [54, 55], suggesting that either
prolonged interruption or early loss of single binocular vision may also be regis-
tered as forward pitch (ie, away from the light). The retention of this primitive
vision-dependent tonus mechanism in humans would explain why poor sensory
fusion leads to inferior oblique muscle overaction rather than superior oblique mus-
cle overaction. The “neurologic lesion” that induces this central vestibular imbal-
ance is loss of binocular visual input.
Primary oblique muscle overaction appears to defy Hering’s law [56], which dic-
tates that, in any volitional conjugate movement, both eyes receive equal innerva-
tion. As summarized by Bielschowsky, “all of the muscles of both eyes always
participate in each movement; one half experiences an increase in tonus and the
other half a decrease” [57] (p178). This control system optimizes binocular vision
in all positions of gaze [56–58]. Although Hering’s law requires that the ocular
PC A PC
HC HC
AC AC
HC HC
AC AC
Fig. 3.8 Primary inferior oblique muscle overaction. (a) Visuovestibular innervation. Failure to
develop normal binocular vision is associated with increased upward tonus to the eyes, perhaps
through reduced anterior canal inhibition from the cerebellar flocculi. A central vestibular tonus
imbalance corresponding to bilateral anterior canal predominance would produce tonic upgaze,
horizontal divergence, and extorsion of the eyes if unopposed by fixational innervation. (b)
Visuovestibular plus fixational innervation. Fixational innervation recruits equal innervation from
the inferior rectus and superior oblique muscles to negate the vertical component of the upgaze
bias, and allows the disconjugate extorsional bias to persist. PC indicates posterior canal; HC, hori-
zontal canal; and AC, anterior canal
36 3 Primary Oblique Muscle Overaction
motor system synthesize a conjugate signal to the motor neurons involved in the
execution of any ocular movement, it should be evident from the previous discus-
sion that equal innervation to any set of vertical yoke muscles would produce dis-
sociated movements of the 2 eyes. To execute conjugate vertical eye movements, the
extraocular muscles of both eyes must receive appropriate innervation to move the
eyes equally rather than receiving equal innervation.
Hering [56] made reference only to voluntary eye movements as conforming to
his law of equal innervation. Since the semicircular canals and their corresponding
otolithic pathways segregate innervation to each set of yoke muscles, it is not sur-
prising that dissociated eye movements of central origin are generally associated
with vestibular disease. Paradoxically, these dissociated movements may reflect the
fact that the vertical yoked muscles receive roughly equal innervation rather than
the necessary innervation to rotate the eyes equally in one plane.
Our model of primary oblique muscle overaction as a pitch plane imbalance
predicts that oblique muscles overact bilaterally in conjunction with rather than
relative to their yoke vertical rectus muscles. In primary gaze, the torsional action
of the overacting oblique muscles predominates in both eyes, producing the bilat-
eral extorsion observed in primary inferior oblique muscle overaction and the bilat-
eral intorsion observed in primary superior oblique muscle overaction. When both
sets of elevators or depressors receive excessive central vestibular innervation,
adduction of either eye produces excessive vertical excursion of the adducting eye
as it moves into the vertical field of action of the overacting oblique muscle
(Fig. 3.7). In this context, an upward tonus imbalance to both eyes manifests as
bilateral overelevation of the adducting eye, and a downward tonus imbalance mani-
fests as bilateral overdepression of the adducting eye. Volitional gaze out of the
vertical field of action of the overacting yoke muscles recruits physiologic innerva-
tion to counterbalance the vertical tonus imbalance, while gaze into the vertical field
of action of the overacting yoke muscles allows this underlying tonus imbalance to
predominate, producing the A and V patterns observed clinically (Fig. 3.7). The
ocular torsion produced by primary oblique muscle overaction also initiates a cas-
cade of secondary mechanical events, including rotational displacement of the rec-
tus muscle insertions, oblique muscle length adaptation, and mechanical tightening
of the oblique muscles, as detailed elegantly by Guyton and Weingarten [5]. These
peripheral responses augment the overelevation or overdepression of the adducting
eye and the corresponding A and V pattern observed clinically.
This neurologic model would also explain why primary oblique muscle overac-
tion is usually associated with a negative Bielschowsky head-tilt test [1, 59]. A head
tilt to either side recruits ipsilateral otolithic innervation to stimulate 1 of the 2
overacting vertical muscles in each eye while inhibiting the other. The net result for
each eye is a minimal change in vertical tonus in the primary position. However, this
model would predict that pitching the head forward and backward (ie, a vertical
head-tilt test) would superimpose a physiologic tonus imbalance on the underlying
central vestibular tonus imbalance in the pitch plane and thereby alter the ampli-
tudes of an existing A or V pattern and the amplitudes of the associated hyperdevia-
tions in lateral gaze. Accordingly, the clinical practice of pitching the patient’s head
Nonneurologic Causes of Oblique Muscle Overaction 37
Dissociated vertical divergence may coexist with primary oblique muscle overac-
tion [60]. Dissociated vertical divergence has been attributed to a central vestibular
tonus imbalance in the roll plane induced by fluctuations of binocular visual input
[60, 61]. This hypothesis is based on physiologic studies [60, 61] in fish that show
that unequal visual input to the 2 eyes induces a reflex body tilt in the roll (frontal)
plane toward the side with greater visual input. This dorsal light reflex is a balancing
movement that uses light from the sky as a visual reference to maintain vertical
orientation by equalizing luminance input to the 2 laterally placed eyes. In a verti-
cally restrained fish, unequal visual input induces a vertical divergence of the eyes,
with depression of the eye that has greater visual input and elevation of the eye that
has lesser visual input. This vertical divergence of the eyes corresponds to the dis-
sociated vertical divergence seen in humans who fail to develop single binocular
vision secondary to early-onset strabismus.
In humans with dissociated vertical divergence, suppression or mechanical
occlusion of one eye increases upward tonus to the extraocular muscles of that eye
and downward tonus to the extraocular muscles of the opposite eye [60, 61].
Simultaneous recruitment of central vestibular innervation to both elevators in the
visually deprived eye has been invoked to explain the spontaneous overelevation in
adduction that can be observed with dissociated vertical divergence, when no V pat-
tern or baseline extorsion is present [60]. The observation that decreased visual
input increases upward tonus to one eye (in the case of dissociated vertical diver-
gence) and to both eyes (in the case of inferior oblique muscle overaction) attests to
the retention of primitive vision-induced tonus mechanisms [62, 63] in humans, and
to the atavistic resurgence of these primitive subcortical reflexes when strabismus
precludes the development of binocular vision. Our neurologic model of primary
oblique muscle overaction as a central vestibular tonus imbalance in the pitch plane
complements the recently proposed theory of dissociated vertical divergence as a
central vestibular tonus imbalance in the roll (frontal) plane, and begs the question
of whether latent nystagmus might be similarly driven by a central vestibular tonus
imbalance in the yaw (axial) plane.
Most of the mechanisms invoked to explain the existence of A and V patterns with
oblique muscle overaction have described orbital anatomical abnormalities that
could account for the abnormal movements on a biomechanical basis [64–75]. It is
beyond the scope of this article to review and critique all of them. In some patients,
38 3 Primary Oblique Muscle Overaction
Conclusions
Lower lateral-eyed animals use light from the sky above and gravity from the earth
below as major sources of sensory input to neuronal tonus pools within the central
vestibular system. These neuronal tonus pools calibrate extraocular muscle and pos-
tural tonus to maintain vertical orientation. In lower animals, oblique muscle tonus
is determined by luminance and gravitational input in the pitch plane. In humans,
the brain leverages visual and gravistatic sensory input to calibrate extraocular mus-
cle tonus in the pitch plane. Early loss of single binocular vision is treated by the
central vestibular system as forward pitch, necessitating increased upward tonus to
the extraocular muscles and manifesting as primary oblique muscle overaction.
Neurologic lesions within the posterior fossa can produce the opposite central ves-
tibular imbalance, in which a backward pitch evokes increased downward tonus to
the extraocular muscles and produces primary superior oblique muscle overaction.
This duality reflects an ancestral bimodal tuning of central vestibular output to the
extraocular muscles that is subordinate to binocular vision in humans.
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42 3 Primary Oblique Muscle Overaction
Postscript
The human extraocular muscles have evolved to meet the needs of a dynamic,
3-dimensional visual world. Under normal conditions, the extraocular muscles are
choreographed to an ensemble of visual tracking, refixation movements, and ver-
gence modulation that assures stable binocular fixation [1]. But a fundamental
dichotomy defines the central programming of the human ocular motor plant. While
the rectus muscles produce large ocular rotations into secondary and tertiary posi-
tions of gaze, the oblique muscles evoke very limited torsional excursions of the
eyes [1]. With rare exceptions [2], large torsional eye movements cannot be gener-
ated by normal individuals in the absence of a head movement [3–7]. This disparity
is also seen with vestibular eye movements in which a horizontal or vertical head
rotation induces an ocular counterrotation that effectively stabilizes the position of
the eyes in space, but a head tilt in the roll plane evokes a static ocular counterroll
of only 10% [8]. This negligible static counterroll led Jampel [9] to conclude that
the primary role of the oblique muscles in humans is to prevent torsion. So the ques-
tion is whether the human oblique muscles retain only a vestigial function in which
they are consigned to make a nominal contribution to vertical gaze, or whether the
primary function of the human oblique muscles is to modulate torsional eye position
and to maintain perceptual stability of the visual world.
To address this basic question, one must first examine the role of the oblique mus-
cles in lower animals. The extraocular muscles originally functioned to stabilize the
eyes in space during body movements and corresponding rotations of the visual
environment. In lateral-eyed vertebrates such as fish and rabbits, the oblique mus-
cles produce torsional movements of the eyes in response to pitch movements of the
body [10, 11]. When the animal pitches forward or backward, the oblique muscles
produce a partial wheel-like counterrotation of both eyes that helps to stabilize the
torsional position of the eyes in space [10, 11]. In fish, a directional shift in overhead
luminance in the sagittal plane also produces an ipsidirectional pitch movement of
the body (ie, a dorsal light reflex in the pitch plane) [11–13]. When the animal’s
body is restrained during this stimulus, this dorsal light reflex causes both eyes to
rotate torsionally so that their upper poles move in the same direction as the light
source [12, 13]. Torsional optokinetic nystagmus has also been recorded in the rab-
bit, indicating that environmental rotation in the pitch plane can directly activate the
oblique muscles [14].
The oblique muscles also contribute to ocular movements during roll (ie, rota-
tions about the head-tail axis of the animal) [15]. A body tilt evokes utricular inner-
vation to the ipsilateral superior rectus and superior oblique muscles (which are
elevators in fish and rabbits) and the contralateral inferior rectus and inferior
oblique muscles (which are depressors in fish and rabbits) [16]. The resulting
supraduction of the lower eye and infraduction of the higher eye helps to stabilize
the vertical position of the eyes during body roll. The magnitude of the ocular
counterroll relative to a body roll is only approximately 50% in lateral-eyed ani-
mals such as rabbits [17]. A similar vertical divergence can also be induced by a
rotating optokinetic cylinder rotating around the long axis of the fish [10] or by
providing unequal visual input to the 2 eyes [11, 14]. For example, increasing
visual input to the left eye of a fish by shining a light at an angle onto the top of a
fish tank produces a body tilt toward the left in the freely swimming fish (a dorsal
light reflex in the roll plane). When body roll is restrained, the same stimulus
evokes a vertical divergence of the eyes (supraduction of the right eye and infra-
duction of the left) that tends to equalize visual input to the 2 eyes [18]. These
primitive adaptations use visual and graviceptive input to set postural and extra-
ocular muscle tonus during pitch and roll [19].
Human ocular torsion can be subdivided into cyclovergence (a disconjugate
torsional rotation of the globes producing extorsion or intorsion of both eyes)
and cycloversion [1, 7] (a conjugate torsional rotation of both globes producing
intorsion of one eye and extorsion of the other eye). These 2 torsional eye move-
ments in humans correspond to the torsional eye movements in lower animals
induced by pitch and roll. Since pitch evokes a disconjugate torsional rotation
(ie, either intorsion or extorsion of both eyes) in lateral-eyed animals, phyloge-
netic retention of this primitive adaptation in humans would mean that a pitch
stimulus (a slant of the visual environment around the interaural axis) would
evoke a cyclovergence response (a disconjugate torsional movement of both
eyes) in humans, whereas a roll stimulus (a tilt of the head or the visual environ-
ment around the nasooccipital axis) would evoke a cycloversion response in
humans. These primitive adaptations are indeed measurable in the laboratory as
the small cyclovergence movements that are induced artificially by haploscopy or
optically induced cyclodisparity [6, 20–24] and in the small cycloversion move-
ments that are evoked by head tilt (ie, the human ocular counterroll to a gravicep-
tive stimulus) [16], by torsional optokinetic stimuli [25–27], or by static-tilted
visual stimuli [28, 29].
Oblique Muscle Exaptations 47
Although we retain our primitive adaptations, the function of the human oblique
muscles has evolved to meet the needs of single binocular vision. In the course of
evolution, primitive adaptations give way to exaptations. An adaptation is some-
thing fit (aptus) by construction for (ad) its usage [30]. Exaptation is a relatively
new evolutionary concept advanced by Gould [30] to describe a feature, now useful
to an organism, that did not arise as an adaptation for its present role, but that was
subsequently co-opted for its current function. Such structures are fit (aptus) not by
explicit molding for (ad) current use, but as a consequence of (ex) properties built
for other reasons [30]. According to this definition, a mechanism must have a func-
tion and must enhance the fitness of its bearer to qualify as an exaptation [30, 31].
For example, the feathers of birds may have originally evolved for thermal insula-
tion (an adaptation), only to be subsequently co-opted for flight (an exaptation)
[31, 32].
According to Blakemore et al [32], binocular animals have abandoned the enor-
mous biologic advantage of panoramic vision in order to have their eyes pointing
forward, the most obvious advantage of which is stereopsis. Frontal repositioning of
the eyes seems to have exapted the oblique muscles to subserve stereopsis. Evolution
has grafted a new torsional control system that is subordinate to binocular vision on
top of the “primitive” dynamic torsional programming of the oblique muscles.
Although the brain programs eye torsional position by regulating the tonus of all
extraocular muscles, the oblique muscles have the predominant effect on ocular tor-
sion. It is therefore instructive to examine torsional eye position as a function of
oblique muscle innervation.
How do the human oblique muscles subserve stereopsis? Under conditions of
binocular fixation, an object closer in space than the fixation point will produce an
image on the temporal retinas, while an object farther in space than the fixation
point will produce an image on the nasal retinas [6]. This horizontal disparity forms
the basis for stereoscopic perception. If one examines the circles that appear ele-
vated on a Titmus stereoacuity test under binocular conditions, examination with
each eye will show a nasal displacement of the circle in space, indicating that the
image falls on the temporal retina in each eye when the circle is viewed binocularly.
When the Titmus test is turned upside down so that the monocular image falls on the
nasal retinas of each eye, the circles appear to lie behind the plane of the page.
Now consider a binocular individual with normal stereopsis who is fixating on
the center of a vertical object that is slanted so that its inferior aspect is closer than
the superior aspect (Fig. 4.1). As the individual fixates the center of the slanted
object, the visual image of the upper pole is postfixational, which means that it falls
48 4 Do You Really Need Your Oblique Muscles?
onto the nasal retina of each eye, whereas the visual image of the lower pole is pre-
fixational, falling onto the temporal retina of each eye. The reader can appreciate
this slant illusion by holding a pencil in the midsagittal plane with the upper pole
slanted away from the body and the lower pole tilted toward the body. On occlusion
of either eye, the upper pole of the pencil will appear to be tilted, with the upper pole
leaning toward the side of the uncovered eye (Fig. 4.1) [33]. So under monocular
conditions, the person perceives a disconjugate image torsion that is analogous to
how the image would be seen if there were intorsion of each eye.
If a vertical cyclodisparity in the 2 eyes is translated by the visual cortex into a
binocular sensation of depth in the pitch plane (ie, slant), can retinal image torsion
cause a vertical binocular image to be perceived as slanted in the pitch plane? The
Fig. 4.1 Tilt is the monocular correlate of stereoscopic slant. (a) An individual binocularly view-
ing a vertical object that is slanted in the pitch plane. (b) The monocular images corresponding to
the object are extorted when viewed with each eye
Oblique Muscle Exaptations 49
answer is yes. The reader can appreciate this phenomenon by placing a white
Maddox Rods over each of the 2 eyes in a trial frame, and looking toward a bright
focal light source with the grids oriented horizontally to produce a vertical line
(Fig. 4.2). Now counterrotate the lenses so that their upper pole of each line moves
nasally and their lower pole moves temporally until the image of the binocular verti-
cal line breaks into 2 tilted lines (Fig. 4.2). If the rotation is stopped at the break
point, the torsional diplopia can be overcome and the 2 lines can be fused. When
cyclofusion occurs, which is almost purely on a sensory (as opposed to a motor)
Fig. 4.2 Binocular cyclodisparity of vertical lines is perceived stereoscopically as slant. (a)
Rotation of horizontal double Maddox Rods to produce binocular image intorsion (as would be
seen if both eyes were extorted). (b) Sensory cyclofusion causes the patient to stereoscopically
perceive a vertical line (solid line) as slanted in the pitch (ie, sagittal) plane (dashed line)
50 4 Do You Really Need Your Oblique Muscles?
basis, the single line will suddenly appear to be stereoscopically slanted in the pitch
plane, with the upper pole inclined toward the observer and the lower pole inclined
away from the observer. The opposite inclination is seen when the upper poles of the
Maddox Rods are rotated temporally. The original treatise by Wheatstone [34]
describing his invention of the stereoscope in 1838 provided the first example of
pitch stereopsis produced by dichoptic lines that are tilted in different directions.
This stereoscopic effect shows us something remarkable about the normal bin-
ocular visual system. It tells us that when an isolated vertical image cyclodisparity
falls within the physiologic range of sensory fusion, it is misregistered stereoscopi-
cally as a slant of the vertical object in the pitch plane [7, 21, 22, 32–38]. In a real
world setting, however, perceived pitch is not solely a function of retinal cyclodis-
parity, but it depends both on the brain’s computation of registered eye rotation and
on retinal cyclodisparity. So to create an accurate stereoscopic representation of
vertical objects in the pitch plane, cyclovergence should not occur and the eyes must
be locked into a well-defined static orientation relative to a given gaze position (ie,
conforming to Donder’s law) [1, 7, 21, 22]. The innervational patterns of oblique
muscle recruitment, which counteract the torsional actions of the rectus muscles in
different positions of gaze, must also be subordinate to this goal.
That binocular torsional control represents an active function of the human
oblique muscles rather than an evolutionary loss of contractile function is seen in
the kinematics of human convergence [39]. It has long been recognized that both
eyes extort during convergence and that this extorsion increases in downgaze and
decreases in upgaze [40, 41]. (Extorsion is even considered by some to be a compo-
nent of the synkinetic near reflex [42].) While the existence of these cyclovergence
movements were once thought to constitute a violation of Listing’s law, they can be
reconciled with Listing’s law if it is assumed that convergence is associated with a
temporal rotation of Listing’s plane in each eye (Fig. 4.3) [43]. Vertical rotation of
the eyes around these temporally rotated axes produces incyclovergence of the eyes
in upgaze and excyclovergence in downgaze [44–46]. Several lines of evidence sug-
gest a neural and biomechanical basis for these cyclovergence movements. In mon-
keys, Mays et al [47] measured single cell recordings within the trochlear nucleus
and found decreased unit activity during convergence. This decrease in firing rate
was greater when the monkey converged in downgaze than in upgaze, a finding that
corresponds to the observed convergence-associated torsional movements in
humans. More recently, dynamic magnetic resonance imaging by Demer et al [48,
49] have found that downward rotation of the lateral rectus muscle pulley and
medial rotation of the inferior rectus pulley during convergence, indicating that the
inferior oblique muscle may also play a role in convergence-associated torsion, pre-
sumably via its collagenous attachments to the lateral rectus and inferior rectus
muscles.
From an evolutionary perspective, it is worth examining whether these torsional
movements during convergence simply represent primitive adaptations that have
been phylogenetically retained, like the small ocular counterroll which has no
known function in humans [17]. In the lateral-eyed animal, upgaze corresponds to
an intorsional movement of both eyes when the rotation is viewed from the frontal
Oblique Muscle Exaptations 51
D D
LP LP
U U
D D
U U
D D
LP LP
U U
Fig. 4.3 View of both eyes from above demonstrating orientation of Listing’s plane (LP) during
distance fixation (a) and convergence (b). Curved arrows denote cyclovergence movements of the
eyes associated with vertical rotation about horizontal visual axes in Listing’s plane. A “saloon
door” rotation of Listing’s plane, which is opposite in direction to the ocular rotation, can be used
to reconcile the convergence-associated extorsion of the eyes in downgaze (D) and intorsion of the
eyes in upgaze (U) with Listing’s law
52 4 Do You Really Need Your Oblique Muscles?
torsionally anchor the eyes to produce a stable motor substrate for slant perception
of vertical objects.
Psychophysical experiments have shown that horizontal visual landmarks are
selectively used in humans to lock in torsional eye position, although the neural
feedback loops for this process are unknown. As early as 1861, Nagel [35] observed
that the rotation of horizontal fusion contours produced cyclovergence, while the
rotation of vertical contours produced only a stereoscopic effect [28]. Ogle and
Ellerbrock [37] noted that cyclofusion of torsionally disparate horizontal lines that
were presented dichoptically with no visual background caused a previously fused
vertical line to pitch in the sagittal plane. According to Bradshaw and Rogers [57],
cyclovergence is not well driven by disparities along vertical meridians even when
these are created by a real inclined surface. By inducing cyclodisparity of horizon-
tal lines to the 2 eyes dichoptically, small cyclofusional eye movements can be
elicited in humans under experimental conditions [7, 20, 23, 24, 37, 38, 56]. The
small size of these cyclofusional movements suggests that the human cyclover-
gence system is equipped to provide a fine-motor modulation to a system that is
designed primarily for stability rather than movement [7]. The greater stereoscopic
value of vertically compared than horizontally tilted images explains why verti-
cally oriented gratings evoke smaller cyclovergence movements than horizontally
oriented gratings [23].
Humans inhabit a terrestrial environment composed of primarily vertical and
horizontal landmarks that serve as reference points for vertical orientation [21, 22].
In a terrestrial setting, the most prominent horizontal contour is the horizon, which
may be the main visual reference for stabilizing the eyes relative to the outside
world [21]. While cyclodisparities of vertical contours may be caused by slant of the
observed objects, cyclodisparities of horizontal contours indicate cyclovergence
errors that need correction [20, 21]. As summarized by Howard and Rogers [33]:
An orientation disparity between the images of lines in the horizontal plane of regard can
be due only to eye misalignment, whereas an orientation disparity from a vertical line may
be due to inclination of the line in depth. It would therefore be adaptive if cyclovergence
were evoked only by disparities in horizontal elements, leaving residual disparities in verti-
cal elements intact as clues for inclination.
Fig. 4.4 Right superior oblique palsy. (a) Examiner’s view of patient’s retinas showing extorsion
of the right eye. (b) Under binocular conditions, the patient perceives a vertical object (solid line)
as stereoscopically slanted in the pitch plane (dashed line)
way, exaptations of the neural circuitry that steers our cyclovergence and cyclover-
sion movements seem to override our primitive adaptations to promote stereopsis
[39, 50].
While the human oblique muscles function under static conditions to constrain
torsional rotation of the eyes, it is not the physiologic role of any muscle to simply
constrain movement (check ligaments and muscle pulleys are better suited to this
function). To the surprise of many, Tweed et al [63] have recently found that the
human oblique muscles execute large cycloversional saccades immediately
56 4 Do You Really Need Your Oblique Muscles?
preceding head movements in the roll plane. The 3-dimensional scleral search coil
recordings were performed as normal study participants observed a laser spot while
their eyes were directed 20° downward. The subjects then made combined eye-head
movements to refixate the laser spot as it jumped 20° (from right head tilt and right
gaze to left head tilt and left gaze). Eye movement recordings showed that these
subjects generated ipsiversive torsional saccades that ranged in size from 11° to 17°
and averaged 14.5°. These cycloversional eye movements preceded the head move-
ments by 20 to 60 milliseconds, indicating that these movements were not vestibular
in origin. The eyes arrived at the target first and locked on, hanging in space as the
head rotated around them (Fig. 4.5). When the head came to a halt, the ocular tor-
sion relative to the head had stabilized near zero, and the eyes were poised for the
swiftest possible response to further movement of the target. These torsional eye
movements, which occur at the initiation of a head tilt and are not visible on gross
inspection, may reveal another exaptation of our torsional control system. The
human oblique muscles may have been exapted to generate saccadic torsional eye
movements to reestablish roll plane orientation in anticipation of a postural rotation
in the roll plane. These anticipatory saccades instantaneously recalibrate torsional
eye position to provide a stable visual representation of tilt in the roll (frontal) plane.
The evolution of frontally positioned eyes for stereopsis may have created a survival
advantage for the grafting of this new torsional control system on top of the ances-
tral control system that produces the ocular counterroll (Table 4.1). Similar tor-
sional saccades have not been observed in lateraleyed animals (although studies
involving eye-head or eye-body coordination in animals are extremely difficult to
perform).
Since ocular torsion within the realm of fusion can produce a stereoscopic tilt in
the pitch plane, it seems reasonable to ask whether strabismus or other neuro-
logic disease, which can be associated with a pathologic tilt in the internal
1 2 3 4 1
Fig. 4.5 Depiction of torsional eye position during head tilt from side to side. (1) Initial torsional
position during right head tilt. (2) During head tilt to the left, the eyes lead the head and quickly
assume their final torsional position corresponding to the left head tilt. (3) The eyes “hang in
space” until the head catches up. (4) Head tilt to the right produces the reverse sequence of tor-
sional eye movements. (Reprinted with permission from The American Association for the
Advancement of Science, copyright 1999 [63].)
Oblique Muscle Exaptations 57
In the pitch plane, these same primitive adaptations are operative. Donahue and
I [65] have proposed that primary oblique muscle overaction is associated with a
slant of the internal representation of the visual vertical in the pitch plane. A sub-
jective inclination of the superior portion of the visual environment toward the
individual would produce a corresponding extorsion of both globes and lead to
inferior oblique muscle overaction [65]. Conversely, structural neurologic disease
within the brain stem or cerebellum would produce the intorsion and superior
oblique muscle overaction so commonly seen in children with Chiari malforma-
tions, meningomyelocele, or hydrocephalus [65]. The alternating skew deviation
on lateral gaze with bilateral abducting hypertropia that is associated with cranio-
cervical disease may represent another central vestibular disturbance in the pitch
plane [71, 72].
Under pathological conditions, the oblique muscles still function to keep the
eyes in binocular torsional register with the perceived visual environment, and an
altered torsional position of the eyes constitutes an ocular motor recalibration to the
tilted or slanted internal representation of the visual world that characterizes central
vestibular disease. By recognizing that a subjective tilt of the visual environment
evokes a corrective torsional repositioning of both eyes, we can begin to place the
horse before the cart in understanding congenital strabismus.
Conclusions
To understand why you really need your oblique muscles, it is necessary to distin-
guish primitive adaptations, which originally evolved to stabilize laterally placed
eyes during body pitch and roll, from exaptations, which subsequently evolved to
meet the needs of frontal binocular vision. The human oblique muscles have been
exapted to override primitive torsional adaptations with newer mechanisms that
subserve stereopsis. These exaptations govern the relative torsional alignment of the
eyes in different positions of gaze. Since perception of stereoscopic slant is a func-
tion of torsional eye position, the human oblique muscles modulate cyclovergence
to establish a stable stereoscopic pitch representation of the visual world. In the roll
plane, the human oblique muscles generate a cycloversion movement of the eyes
just prior to volitional head movement to lock in a stable visual perception of tilt.
These exaptations provide spatial accuracy and temporal continuity to our stereo-
scopic visual perception of slant and our nonstereoscopic visual perception of tilt.
In a larger sense, they furnish us with a multifaceted torsional control system that
provides 3-dimensional stability to the visual world and thereby improves fitness.
Exaptations in human oblique muscle function do not completely erase more
primitive adaptations. These primitive adaptations produce the small vestigial tor-
sional eye movements that can be measured experimentally by inducing pitch or tilt
of the external visual environment. They manifest clinically when congenital stra-
bismus or other central vestibular disease alters our internal representation of the
visual vertical. One may conclude that only our primitive adaptations are vestigial;
our oblique muscles are not.
Conclusions 59
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Postscript
Vestibular disease holds little interest for the ophthalmologist. Although patients
with vestibular disease can develop nystagmus, diplopia, and oscillopsia, these
symptoms can be treated empirically. Peripheral vestibular disease is caused by
injury to the labyrinth rather than to the eye, whereas central vestibular disease is
caused by brainstem or cerebellar disorders involving the central vestibular path-
ways along their course to the ocular motor nuclei [1, 2]. But the ophthalmologist
encounters a unique form of vestibular nystagmus that is caused by unbalanced
input from the two eyes rather than from the two labyrinths. This visuo-vestibular
nystagmus is known as “latent nystagmus.”
Congenital esotropia is associated with a clinical triad of latent nystagmus, infe-
rior oblique muscle overaction, and dissociated vertical divergence [3]. These
unique eye movements conform to primitive vision-dependent tonus mechanisms
that are reactivated by congenital strabismus or early abnormal visual experience
[4–7]. Evolutionary analogues of primary oblique muscle overaction and dissoci-
ated vertical divergence have been identified in lower vertebrates [5, 6]. In fish,
these are physiologic extraocular movements that use weighted binocular visual
input to modulate extraocular muscle tonus and to maintain visual orientation dur-
ing body movements [5, 6]. The stimulus for bilateral inferior oblique muscle over-
action corresponds to a visuo-vestibular imbalance in the sagittal (pitch) plane,
while dissociated vertical divergence corresponds to a similar imbalance in the
coronal (roll) plane [5–7]. We propose that latent nystagmus results from a similar
visuo-vestibular tonus imbalance in the horizontal turning (yaw) plane.
in direction and in waveform to the nasalward slow-phase drift of the fixating eye in
latent nystagmus [21, 29]. To our knowledge, Roelofs [30] first observed horizontal
optokinetic asymmetry in patients with latent nystagmus in 1928. Fifty years later,
experiments by van Hof–van Duin [31] and Wood et al [32] suggested that reduced
binocularity in strabismus can lead to nasotemporal asymmetry. In 1977, Kommerell
[33] suggested that latent nystagmus could be regarded as the consequence of hori-
zontal optokinetic asymmetry. In 1982, Hoffman [34] developed a model to explain
nasotemporal asymmetry based on combined cortical and subcortical input to the
nucleus of the optic tract in the cat. In 1983, Schor [21] proposed that latent nystag-
mus and nasotemporal optokinetic asymmetry are mediated by the nucleus of the
optic tract.
Human nasotemporal asymmetry has received considerable attention because it
persists throughout life in humans with congenital strabismus [15, 21, 25, 34–36].
Even after surgical realignment, nasotemporal asymmetry remains as a “footprint in
the snow” of abnormal visual development [36]. Nasotemporal asymmetry is seen
in rabbits, kittens, monkey infants, and human infants within the first 6 months of
life [36]. The evolutionary retention of this primitive nasotemporal asymmetry in
human infancy shows how ontogeny recapitulates phylogeny during human visual
development [37, 38].
In ordinary life, large parts of the visual field move together during self-motion
[39]. Optic flow occurs during translation (which is signaled by the otoliths and
linear optic flow) and rotation (which is signaled by the semicircular canals and
rotational optic flow) [39]. The low sensitivity to nasal to temporal optic flow in
afoveate, lateraleyed animals is commonly assigned the function of preventing the
locomoting animal from responding to the image motion of stationary contours dur-
ing forward motion, while permitting full compensation for rotational input during
turning movements [39–41]. The absence of nasotemporal optokinetic responses in
lateral-eyed animals assures that during forward movements, ineffective temporal-
ward eye movements do not destabilize images of objects that are directly ahead of
the animal [39–41]. The optokinetic responses of both eyes are controlled by which-
ever eye is stimulated by temporal-to-nasal movement of the visual world [40].
Latent nystagmus recapitulates this monocularly driven horizontal optokinetic
movement.
Vestibular eye movements are reflex contraversive rotations of the eyes that occur
during involuntary head movements, acting to stabilize the position of the eyes in
space and thereby maintain visual orientation [1, 2, 42, 43]. According to Walls,
“ … vestibularly-controlled reflex eye movements are historically the oldest of all,
with all other kinds of eye-muscle controls and operations accreted to them above
the primitive fish level of evolution” [44] (p71). During head movements, input to
the semicircular canals within the 2 labyrinths provides the afferent stimulus for the
vestibulo-ocular reflex [1, 2, 43, 45]. The semicircular canals respond to angular
68 5 Latent Nystagmus
Studies in subhuman primates have shown that latent nystagmus arises as a result of
incomplete development of visual input from occipitotemporal cortex to subcortical
vestibular pathways [50, 51]. In monkeys with latent nystagmus, there is a loss of
binocularity in the nucleus of the optic tract (NOT), the subcortical structure that
feeds into the vestibular system, with most cells driven by the contralateral eye [50,
51]. The areas that normally provide binocular input to the NOT are the middle tem-
poral (MT) visual area and the medial superior temporal (MST) visual area in occipi-
totemporal cortex. When strabismus is surgically induced in infant monkeys during
the first 2 weeks of life, these monkeys also develop latent nystagmus and visual area
MT/MST loses binocularity. If either eye is covered during infancy, visual area MT/
MST and NOT develop normal binocularity, but the striate cortex still shows loss of
binocularity and these monkeys do not develop latent nystagmus [52]. This finding
suggests that the initial cause of latent nystagmus is loss of binocularity in visual area
MT/MST from the misaligned eye during the first few weeks of life [52].
Is Latent Nystagmus a Vestibular Nystagmus? 69
Neuroanatomical experiments have confirmed the Schor hypothesis [21] that the
NOT is the generator of latent nystagmus [21, 34, 50–52]. A latent nystagmus
occurs in monkeys following artificial induction of esotropia within the first 2 weeks
of life [53]. Unilateral electrical stimulation of the NOT in binocularly deprived
monkeys induces a conjugate nystagmus with the slow phases directed toward the
side of stimulation [54, 55]. Latent nystagmus can be abolished by direct injection
of muscimol, a potent γ-aminobutyric acid A agonist into the NOT in monkeys [50].
Simultaneous bilateral blockage of the NOT virtually abolishes latent nystagmus for
the duration of the blockade [50].
Subcortical optokinetic responses are also mediated by the pretectal NOT [15,
21, 34–36]. The monocular pathways subserving nasotemporal asymmetry and its
neutralization by binocularly driven pathways from the visual cortex were first elu-
cidated by Hoffman in the cat [34, 35]. The cat NOT is a diffuse cell aggregation in
the pretectum that is optimally located to integrate direct retinal and diffuse cortical
projections [34]. These nuclei have high levels of spontaneous activity and operate
in a push-pull fashion such that the sum of their opponent innervation determines
the optokinetic response [21, 34].
The NOT contains neurons that are sensitive to visual motion [54]. Many units in
the primate NOT have large receptive fields that are appropriate for encoding full-
field visual motion to support optokinetic eye movements [54]. Stimulation of the
right and left NOT results in optokinetic nystagmus with slow phases to the right
and left, respectively [21]. Output from the NOT is maximal for horizontal move-
ments but 0 for vertical movements [34].
This phylogenetically ancient subcortical system is depicted in Fig. 5.1. Crossed
connections from each eye to the contralateral NOT transmit horizontal visual
motion information to the vestibular nucleus before impinging on the ocular motor
nuclei [40, 56]. Pretectal neurons in the left NOT receive only crossed input from
the right eye and respond only to leftward motion, while those in the right NOT
receive only crossed input from the left eye and respond only to rightward motion
[15, 21, 36]. In the first 6 months of infancy, this subcortical system predominates
in humans, so that temporally directed monocular optokinetic responses are poor in
early infancy compared with nasally directed optokinetic responses [36]. By 6
months of age, cortical binocular pathways, which are responsive to temporally
directed motion, provide a route whereby the NOT, with its specialized directional
responses, can be accessed from either eye [37, 38]. In animals with well-developed
foveae and frontal, stereoscopic vision, the visual inputs feeding directly to the pre-
tectum are supplemented by inputs routed through the visual cortex that selectively
respond to moving images with no positional disparity in the 2 eyes [57]. This cou-
pling between optokinetic nystagmus and stereopsis allows frontal-eyed animals to
selectively stabilize the moving images of those parts of the scene within a selected
depth plane, while disregarding induced image motion of the visual world at other
distances [40, 57]. In humans with congenital strabismus, binocularly driven corti-
copretectal pathways never become established, allowing the primitive monocular
nasotemporal asymmetry to predominate.
70 5 Latent Nystagmus
LR MR MR LR
NOT NOT
III III
AC AC
PC VI VI
PC
HC HC
VN VN
Labyrinth Labyrinth
R L R L
R L CC R L
Cortex Cortex
Fig. 5.1 Schematic diagram depicting cortical and optokinetic pathways. Cortical input to tempo-
rally directed movement, which is present only in frontal-eyed animals, requires the establishment
of normal binocular cortical connections. This input is absent in humans with congenital strabis-
mus. Direct crossed pathways from the eye to the nucleus of the optic tract provide nasalward
subcortical optokinetic responses even when binocular cortical connections are absent (R and L
represent monocular cortical cells corresponding to the right and left eyes, respectively). Note that
the nucleus of the optic tract (NOT) relays horizontal visuo-vestibular information to the vestibular
nucleus (VN), where it is integrated with horizontal vestibular input from the labyrinths to estab-
lish horizontal extraocular muscle tonus. LGN indicates lateral geniculate nucleus; CC, corpus
callosum; V1, abducens nucleus; III, oculomotor nucleus; LR, lateral rectus muscle; MR, medial
rectus muscle; AC, anterior canal; PC, posterior canal; and HC, horizontal canal
Bilateral positioning of the eyes and ears promotes survival by enabling the organ-
ism to crosslink input from different sense organs to impart balance. Each eye and
its ipsilateral semicircular canals share the same directional bias to movement. For
example, the right horizontal semicircular canal is activated by head rotation to the
right (which induces a rotation of the visual world to the left) and inhibited by head
rotation to the left (which induces a rotation of the visual world to the right) [2, 43,
Is Latent Nystagmus a Vestibular Nystagmus? 71
45, 58, 59]. The monaural and monocular directional biases summate, so that activa-
tion of the right horizontal semicircular canal during rightward head rotation is rein-
forced by the physiologic activation of the right eye by the induced nasal rotation of
the visual world. The close geometrical relationship between the semicircular canals
and the extraocular muscles presumably facilitates the integration of head motion
and visual movement and their orderly summation to produce transformation to an
appropriate ocular motor response [46, 60].
Latent nystagmus usually conforms to Alexander’s law, which states that the
intensity of a peripheral vestibular nystagmus increases when the eyes are moved in
the direction of the fast phase and decreases when the eyes are moved in the direction
of the slow phase [2, 21, 60–63]. Latent nystagmus damps when the fixating eye is
turned toward the nose (which is also the direction of the slow phase) and increases
in intensity when the fixating eye is turned toward the ipsilateral ear (which is in the
direction of the fast phase) [14, 15, 62, 63]. A similar damping of horizontal nystag-
mus is seen in peripheral horizontal vestibular nystagmus after disease or injury to 1
horizontal semicircular canal. By contrast, Alexander’s law does not apply to con-
genital nystagmus, which reverses direction in different positions of gaze. The con-
traversive head turn in latent nystagmus (ie, a head turn opposite in direction to the
deviation of the fixating eye) also characterizes vestibular eye movements [2].
Additional evidence for the duality of optic and vestibular innervation can be elic-
ited by occluding 1 eye in the patient with latent nystagmus, spinning the patient,
suddenly stopping the spin, then immediately observing the effect of the postrota-
tional nystagmus on the latent nystagmus when either eye is occluded. A horizontal
nystagmus induced by body spinning nullifies or accentuates latent nystagmus
depending on the direction of spin relative to the fixating eye (Fig. 5.2). For example,
spinning the patient to the right excites the right horizontal canal and inhibits the left
horizontal semicircular canal to induce a nystagmus with a slow-phase rotation to the
left and a fast-phase rotation to the right. If the spin is suddenly stopped (after approxi-
mately 10 rotations), a shift in endolymph deflects the cupula in the opposite direc-
tion, causing transient excitation of the left horizontal semicircular canal and transient
inhibition of the right horizontal semicircular canal and inducing a left-beating nys-
tagmus (termed “postrotational nystagmus”). If the left eye is occluded to induce
latent nystagmus prior to this maneuver, the latent nystagmus will diminish or disap-
pear immediately following cessation of the spin. If the occluder is quickly moved to
cover the right eye, the intensity of the latent nystagmus with the left eye viewing will
be correspondingly increased relative to that observed with the left eye fixating before
the spin. In this way, the clinician can observe how visual input is summated with
vestibular input to establish central vestibular tone in the horizontal plane.
The more visual input is dominated by 1 eye in latent nystagmus, the higher the
velocity of the slow-phase rotations in the direction toward the opposite eye [22].
Simonsz and Kommerell [63] performed eye movement recordings before and after
occlusion therapy for amblyopia in patients with latent nystagmus. After prolonged
occlusion, the slow-phase velocity of the nystagmus in the amblyopic eye decreased
to the same extent that the slow-phase velocity of the nystagmus in the preferred eye
increased. The sum of the 2 slow-phase velocities remained the same in
72 5 Latent Nystagmus
a b
V V
O O O O
++ ––
c d
V V V V
O O O O
–– ++ –– ++
Fig. 5.2 Visual and vestibular interaction in latent nystagmus. Latent nystagmus decreases with
spinning toward the fixating eye and increases with spinning toward the occluded eye. O represents
direction of ocular (visuo-vestibular) tonus; V, direction of horizontal vestibular tonus. Both O and
V correspond to the slow phase of the induced nystagmus. ++ Indicates stimulated horizontal
semicircular canal; --, inhibited horizontal semicircular canal; (a) Occlusion of the left eye
increases visuo-vestibular tonus to the left. (b) The patient with latent nystagmus is spun to the
right to stimulate the right horizontal semicircular canal, which increases leftward horizontal ves-
tibular tonus and causes a slow conjugate drift of both eyes to the left. At this point, the latent
nystagmus would be enhanced by vestibular input (if the examiner could observe it). (c) When the
spinning is suddenly stopped, the opposite vestibular stimulus is exerted, causing the left semicir-
cular canal to drive the eyes to the right. This rightward vestibular tonus imbalance nullifies the
leftward visual tonus imbalance induced by monocular fixation with the right eye, thereby reduc-
ing the intensity of the latent nystagmus. (d) When the occluder is quickly switched to the right
eye, the visual tonus imbalance is augmented by an ipsidirectional visual tonus imbalance, increas-
ing the intensity of the latent nystagmus
Is Latent Nystagmus a Vestibular Nystagmus? 73
straight-ahead gaze, demonstrating that visual input to the 2 eyes (just like rota-
tional input to the 2 horizontal canals) maintains a push-pull relationship [21, 63].
This observation lends further support to a vestibular underpinning for latent nys-
tagmus. The clinical similarities between latent nystagmus and peripheral vestibular
nystagmus are summarized in Table 5.1.
side of the open eye appears” [72]. Kestenbaum [10] emphasized that latent nystag-
mus could not be attributed to luminance per se, since shining a bright light in the
right eye worked like occlusion of the right eye and caused a left-beating nystag-
mus. He noted that the presence of a sharper visual image on the retina of one eye
than the other appeared to be the decisive stimulus for inducing latent nystagmus.
Predominance of a primitive visuo-vestibular imbalance provides an evolution-
ary basis for the shift in egocenter that has been invoked to explain latent nystagmus
[14]. According to this hypothesis, the egocenter is localized to the median body
plane under normal binocular conditions, but shifts to the side of the fixating eye
under monocular conditions. Dell’Osso et al [14] hypothesized that humans with
latent nystagmus retain an abnormal egocenter in the median plane even under mon-
ocular conditions, causing the fixating eye to drift toward midline. In the lateral-
eyed animal, fixation with the right eye would instantaneously shift the egocenter to
the left of the object of regard, necessitating a body turn to frontalize the object and
a contraversive eye rotation to maintain fixation [14]. As neatly summarized by
Dichgans and Brandt: … the results of visual and vestibular stimulation on egocen-
tric localization indicate the close similarity in the perceptual consequences of stim-
ulation of the two organs. The assumption of a unitary central representation of
egocentric space, based on visual and vestibular (as well as acoustic and somatosen-
sory) afferents is perceptually obvious [42] (pp763–764).
It remains to be determined whether a higher order egocentric shift could cause
the visuo-vestibular imbalance which generates the linear slow phase of latent
nystagmus.
This underlying vestibular response to both visual motion and body rotational stim-
uli may explain the overlapping nystagmus response that characterizes latent, opto-
kinetic, and peripheral vestibular nystagmus [2, 19, 21, 62, 71]. This overlap may
reflect the fact that all 3 movements subserve a similar physiologic function (ie,
detection of rotation of the body and visual environment).
Latent nystagmus, optokinetic nystagmus, and the vestibuloocular reflex also
show velocity storage, a phenomenon in which constant vestibular input or visual
flow in the same direction is stored for up to 20 seconds in the brainstem, even when
the stimulus is terminated (Table 5.2) [50, 51]. The presence of velocity storage
serves to enhance the slow-tracking eye movements to vestibular stimulation and
optic flow response at low frequencies of rotation [2, 74]. Although latent nystag-
mus has variously been attributed to anomalous cortical motion processing [25, 26],
or a cortical pursuit asymmetry [53, 75], the absence of velocity storage mechanism
within the pursuit system implicates the vestibular system as the generator of latent
nystagmus.
Conclusions
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80 5 Latent Nystagmus
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Postscript
prominent torsional ocular rotations that accompany latent nystagmus further attest
to their visuo-vestibular origin. Again, the unanswered question is whether covering
one eye evokes DVD directly via the subcortical circuitry, indirectly via the cortex,
or both.
What accounts for the jump from optokinesis as the stimulus for monocular
nasotemporal asymmetry (MNTA) to fixation as the stimulus for latent nystagmus?
Evolutionarily, motion gives way to fixation. Things have to move for fixation to
occur. The modulation of latent nystagmus by fixation occurs because cortical
reflexes are retrofitted to subcortical ones. One concern with the subcortical hypoth-
esis for MNTA and latent nystagmus has been that directionally-selective horizontal
retinal ganglion cells have been found in rats, rabbits, and cats, but not in primates.
Some believe that the sweep of nasalward motion across consecutive ganglion cells
could encode the equivalent directional signal. Alternatively, it could be that these
directional ganglion cells have not yet been found in primates, as they are probably
relatively rare so it would not be an easy task to find them in tissue as densely
packed as the primate retina.
This analysis calls into question the misguided classification of latent nystagmus
as “fusion maldevelopment nystagmus.” This designation, proposed by a self-
appointed NIH-sponsored committee, implies that the primary cause of essential
infantile esotropia and latent nystagmus is a primary defect in cortical fusional
development. There is no evidence that this is the case. It is more plausible that
fusion maldevelopment and latent nystagmus are both inevitable outcomes of an
early binocular misalignment that eventuates in infantile esotropia. Chap. 17 dem-
onstrates how prolonged subcortical neuroplasticity could allow subcortical MNTA
to generate both essential infantile esotropia and latent nystagmus, with the observed
reconfiguration of cortical motion pathways occurring as a secondary phenomenon.
Dissociated Vertical Divergence
Perceptual Correlates of the Human Dorsal Light Reflex
6
In living organisms, light from the sky above and gravity from the earth below have
led to the evolution of sensory organs for vision and balance. The bright sky serves
as a hemispheric light source that provides a stable visual reference for which way
is up. In lower animals, the central vestibular system integrates visual input from the
2 eyes and graviceptive output from the 2 labyrinths to modulate postural and extra-
ocular muscle tonus and maintain vertical orientation [1–3]. Although visual input
is usually subordinate to vestibular input in establishing postural orientation, some
lateral-eyed animals also maintain vertical orientation by equalizing visual input to
the 2 eyes [4]. Many fish and insects exhibit a dorsal light reflex in which illumina-
tion from one side evokes a reflex body tilt toward the light [4–7]. When a light is
shined down from the right side, for example, the right eye receives greater visual
input than the left eye (Fig. 6.1). This binocular disparity would only exist in nature
if the animal were tilted with its right side toward the sky. This visual imbalance
causes the central vestibular system to register a leftward body tilt relative to the
body position that would be necessary for the 2 eyes to receive equal binocular
visual input, and to reflexively alter postural tonus to correct the tilt [1–4] (Fig. 6.1).
In a vertically stabilized fish, the same stimulus evokes a vertical divergence of the
eyes to reorient the interpupillary axis relative to the new light source, causing the
eye with lesser visual input to shift dorsally, and the eye with greater visual input to
shift ventrally [3] (Fig. 6.1).
The term dorsal pertains to the back or upper aspect of an animal. The dorsal
aspect of the head in fish, quadrupeds, and bipeds corresponds to the top of the head.
In bipeds such as humans, the back retains its phylogenetic dorsal orientation,
although it is no longer the upper aspect in the upright position. Humans with con-
genital strabismus who never develop single binocular vision exhibit an atavistic
resurgence of the dorsal light reflex in the form of dissociated vertical divergence
(DVD) [8]. When these strabismic humans fixate monocularly, the nonfixating eye
exhibits a slow dorsal rotation termed dissociated vertical deviation. This dorsal
a b
Fig. 6.1 In the fish, increasing luminance to the right eye by shining a light from the 1-o’clock
position (as seen by the animal) shifts subjective vertical clockwise toward the 1-o’clock position
(as seen by the animal). Visual objects aligned with the gravitational vertical are therefore misreg-
istered as being tilted counterclockwise toward the 11-o’clock position relative to the animal’s
subjective vertical. (a) Vertical objects and the animal’s body are subjectively misregistered as
being tilted counterclockwise, necessitating a clockwise body tilt toward the body position that is
necessary for equal binocularvisual input. (b) When a corrective body tilt is prevented, the ocular
component of this righting reflex evokes a vertical divergence of the eyes to rotate the interpupil-
lary axis toward a position that is perpendicular to the altered subjective vertical
DVD, but a perceived visual tilt should be present after the DVD has occurred. To
elucidate the perceptual correlates of DVD, I examined visual tilt perception in 9
patients with DVD and 9 normal control subjects.
Patients and Methods
Nine patients with bilateral DVD were examined prospectively and consecutively.
Children who had been treated with previous cyclovertical muscle surgery were
excluded from the study since the resulting fundus torsion could influence the per-
ception of tilt. Dissociated vertical divergence was diagnosed when occlusion of
either eye evoked a dorsal rotation of the occluded eye. The amplitude of the DVD
was measured in both eyes using the vertical prism under cover test. Visual acuity
was measured in each eye, versions were examined, field measurements were
obtained, and a dilated retinal examination was performed to look for static torsion.
To determine whether patients experienced a perceived visual tilt (ie, a perceived
tilt of the visual environment without any sensation of body tilt) or subjective tilt (ie,
a perceived tilt of the body) under monocular conditions, each patient was instructed
to view a pencil held vertically in the sagittal plane midway between the 2 eyes dur-
ing occlusion of each eye and during alternate occlusion of the eyes. The patient’s
head was maintained in the upright position before and during testing. Care was
taken to assure that the pencil was not slanted forward or backward in the sagittal
plane, as a slant would optically induce a monocular image tilt. Each patient was
instructed to hold up his or her index finger and to move this finger to demonstrate
any perceived movement of the pencil as each eye was occluded. The cover test and
alternate cover test were repeated 3 to 4 times in each patient to assure that percep-
tual responses were consistent from one trial to the next. When a perceived motion
was noted, the patient was specifically asked whether the pencil appeared to move
sideways or to tilt. The patient was then asked, “does it look like the pencil is mov-
ing, or does it feel like you are moving?” A labyrinthine imbalance such as that
brought on by spinning or by disease of the semicircular canals, is generally per-
ceived as a sensation of body movement in space. Thus, a perceived sensation of
body movement in space would suggest that unequal visual input is inducing a laby-
rinthine imbalance, while perceived visual tilt with no sensation of body movement
would suggest that the neural pathways activated by unequal visual input do not
directly alter the relative output of the 2 labyrinths. This test was also performed in
9 control subjects who had normal stereopsis and no history of strabismus.
Results
Patient ages ranged from 4½ to 51 years. All but 1 patient was younger than 15
years. Seven patients had a history of congenital strabismus that had been treated
with only horizontal muscle surgery. One child with prominent DVD had a history
of perinatal bruising of both eyelids, but had never developed congenital esotropia,
86 6 Dissociated Vertical Divergence
Comment
Fig. 6.2 Visual tilt evoked by monocular occlusion in the strabismic human with dissociated verti-
cal divergence. Gray image of the pencil denotes perceived visual tilt immediately following
occlusion of one eye. Curved arrows denote the perceived rotation of the tilted visual image back
to vertical, coinciding with the appearance of dissociated vertical divergence. On occlusion of
either eye, the vertical pencil positioned in the sagittal plane is perceived as instantaneously tilted,
with its upper pole tipped toward the side of the covered eye. This subjective visual tilt is quickly
followed by a perceived rotation back to vertical that coincides with the cyclovertical divergence
of the eyes
correct a perceived tilt and to thereby reestablish vertical orientation under condi-
tions of monocular fixation. In this discussion, I adhere to the convention in vestibu-
lar research of describing subjective visual tilt from the point of view of the subject
rather than the examiner, although figures are shown from the perspective of the
examiner to facilitate clinical application. According to this convention, when a
patient looks “to the right,” it is to the patient’s right rather than the examiner’s right,
and so a clockwise rotation of visual environment or a torsional rotation of the
patient’s eyes must also be defined as clockwise from the patient’s perspective.
True vertical corresponds to the gravitational vertical. Our perception of true verti-
cal is influenced by graviceptive input to the 2 labyrinths and visual input to the 2
eyes. Subjective vertical applies to an individual’s internal vertical orientation relative
to true earth coordinates. When the subjective vertical is altered by neurologic disease
or abnormal binocular vision input, the patient will experience a subjective visual tilt,
which is a percieved tilt of the visual environment relative to the subjective vertical
[8]. As shown in Fig. 6.1, increased luminance input to the right eye of a fish tilts the
88 6 Dissociated Vertical Divergence
subjective vertical clockwise (as viewed by the animal), so that a vertical visual stimu-
lus would then appear to be tilted counterclockwise relative to the subjective vertical.
The direction of perceived visual tilt in DVD corresponds to the postural responses of
lateral-eyed animals that exhibit a dorsal light reflex. The same perceptual shift is
reported by strabismic humans with DVD when a binocular visual imbalance is
induced by occlusion of one eye (Fig. 6.2). Thus, with occlusion of the left eye, a right
eye predominance would shift the subjective vertical clockwise (as seen by the
patient), so that true vertical then appears to be rotated counterclockwise relative to
the patient’s altered subjective vertical (Fig. 6.3). This counterclockwise tilt of the
SV SV
Fig. 6.3 Depiction of perceived visual tilt following monocular occlusion in patients with dissoci-
ated vertical divergence. SV indicates the subjective vertical (the patient’s internal representation
of vertical). A perceived tilt of the visual environment (a tilt of the subjective visual vertical) is
determined by the position of vertical objects in the visual world relative to the internal representa-
tion of vertical (ie, relative to the subjective vertical). Left, Occlusion of the left eye evokes a
monocular tilt in the subjective vertical. Since the visual environment is perceived in relation to the
tilted subjective vertical, which the patient perceives as vertical, the monocular visual environ-
ment, as viewed with the right eye, is now perceived as tilted counterclockwise relative to the
patient’s subjective vertical. Right, The human dorsal light reflex is a twofold movement consisting
of a primitive vertical divergence, which realigns the interpupillary axis with the tilted subjective
vertical (as in fish), and a newer cycloversional movement that rotates both eyes torsionally in the
direction of the tilted visual environment. This counterclockwise cycloversional movement (ie,
intorsion of the right eye and extorsion of the left eye) produces a clockwise rotation in the sub-
ject’s tilted visual environment to realign it with the tilted subjective vertical (which the subject
perceives as vertical), thereby annulling the subjective visual tilt
Comment 89
visual world, which is seen monocularly with the uncovered right eye, evokes a cyclo-
vertical divergence movement of the eyes to erase the perceived tilt (Fig. 6.3).
I have proposed that DVD is an atavistic resurgence of the dorsal light reflex that
is evoked by a binocular visual disparity in humans with early-onset strabismus [8].
Since the eyes retain some of their primitive function as balance organs in humans,
unequal visual input induces a central vestibular imbalance in which the internal
sense of vertical no longer corresponds to the gravitational vertical (Fig. 6.3) [8].
Some patients with DVD also have a head tilt away from the side of the hyperdevi-
ated eye [12, 13], which corresponds to the postural component of the dorsal light
reflex in fish [14]. This head tilt, which is not compensatory for binocular vision
[12, 13], may serve to align the head to the tilted internal vertical representation (ie,
the subjective vertical) [14].
Under monocular viewing conditions, patients with DVD may experience a
“schizophrenic” perceptual situation in which the eyes tell the brain that the external
world and the body are tilted relative to the altered internal representation of verti-
cal, while the otoliths tell the brain that the head is upright [8]. A similar sensory
conflict is induced when humans view a tilted visual world under experimental con-
ditions [15]. Under the latter circumstances, the brain strikes a compromise, and the
subjective visual vertical is tilted to an intermediate position between what the eyes
and labyrinths are telling the brain [15].
In DVD, the dorsal rotation of the visually deprived eye corresponds to the ver-
tical divergence induced by the primitive dorsal light reflex. Although the deviating
eye is said to drift “upward” in humans with DVD, the direction of rotation is not
necessarily upward in space but always dorsal relative to the head, regardless of
whether the patient is positioned in the upright, supine, or head-hanging position
[16]. Humans with DVD also display a phylogenetically newer cycloversional
movement that corrects the perceived tilt of the visual environment [17]. This ipsi-
directional cycloversional movement can also be evoked by viewing torsional
optokinetic stimuli or by inducing a static visual tilt of the visual environment
[18–22]. All of these visual stimuli evoke a reflex cycloversional movement, which
serves to align the tilted visual environment with the tilted internal representation
of vertical [22].
Thus, the human dorsal light reflex comprises a twofold movement—a vertical
divergence to realign the interpupillary axis of the eyes relative to the altered inter-
nal representation of the vertical, and a cycloversional movement that torsionally
rotates the eyes in the direction of the tilted visual world to correct the perceived
visual tilt (Fig. 6.3). The vertical component of the human dorsal light reflex is a
primitive adaptation that corresponds to the purely vertical divergence in fish. The
phylogenetically newer cycloversional component conforms to Stephen Jay Gould’s
definition of an exaptation, which is a feature that did not arise as a primary adapta-
tion, but one that was subsequently co-opted or grafted on to meet the newer
demands of evolution (in this case, frontally placed eyes) [23]. According to Gould,
exaptations are features that were not originally built by natural selection for their
current role, but that now enhance fitness (in this case, by restoring vertical orienta-
tion under monocular viewing conditions in the frontal-eyed human) [23].
90 6 Dissociated Vertical Divergence
The human dorsal light reflex demonstrates how the central vestibular system
can uncouple the vertical and torsional components of a cycloversional movement
to allow each component to subserve its corrective function relative to specific con-
ditions of a perceived tilt. During head or body tilt in humans, altered otolithic tone
(ie, unbalanced input from the 2 labyrinths rather than from the 2 eyes) stimulates
elevation and intorsion of the lower eye in space, and depression and extorsion of
the higher eye in space [24]. This stimulus forms the basis of the Bielschowsky
Head Tilt Test [25]. In DVD, however, the elevating eye extorts, and the depressing
eye intorts, producing a cyclovertical divergence in which the torsional eye move-
ments are opposite to those evoked by head tilt [8]. This dissociation could occur
only if the central vestibular system separately processes visual disparity input and
graviceptive input from the trunk and otoliths, then integrates them to establish
subjective vertical orientation as it does in fish [1, 8]. The central ocular motor com-
mand centers must be at liberty to implement separate commands for vertical diver-
gence and cycloversion in humans, although the 2 signals produce a single integrated
extraocular movement.
This study needs to be viewed in light of its inherent limitations. First, it is a
qualitative and subjective study that was performed in a clinic setting. The advan-
tage of this simple method is that it enables the practicing ophthalmologist to
confirm or refute these results without the need for special instrumentation. This
disadvantage is that, because eye movement recordings were not obtained, a pre-
cise and quantitative temporal relationship between the appearance of DVD and
the resolution of the subjective visual tilt could not be confirmed. Second, it is
well recognized that both eyes normally extort in convergence [26]. One could
therefore question whether the perceived image intorsion when the dominant eye
is uncovered might result from each eye being in an extorted convergent position
relative to the vertical object. If this were the case, however, one would expect
the control group to have experienced the same perceptual changes since their
eyes would also extort during convergence. However, this did not occur. Third,
von Helmholtz [27] determined that the subjective vertical retinal meridian is
tilted approximately 1° in each eye, with its top tipped temporally [27]. This
subjective tilt could cause the top of a vertical line to appear to be tipped nasally
(ie, tilted toward the side of the covered eye, as shown in Fig. 6.2) [28]. As such,
it could be argued that this small degree of extorsional tilt in the subjective verti-
cal retinal meridians of each eye could potentially contribute to the perception
that the monocular image appears instanteously intorted when either eye is
uncovered. If this were the case; however, one would again expect the control
group to have perceived a similar visual tilt. Yet, only patients with DVD per-
ceived a visual tilt under monocular conditions, suggesting that this effect did not
influence the results of this study. Furthermore, the original von Helmholtz mea-
surements of the subjective retinal vertical, like standard horopter measurements,
were obtained using isolated visual stimuli in the absence of any surrounding
contextual cues. In this study, normal background contextual cues were present,
so one would not expect patients in either group to detect this small vertical bias.
Comment 91
Fourth, it is not clear why the group of patients with DVD were less likely than
the control group to report a perceived lateral movement of the pencil when the
cover was switched from one eye to the other. It could be that the perception of
tilt overrides the perception of lateral movement in these patients; that surgically
corrected congenital esotropia is associated with an altered perception of visual
space under monocular conditions; or that I was more attuned to elucidating the
direction and sequential changes of the perceived tilt in patients with DVD, and
that verbal or nonverbal cues could have influenced patient responses. Last, one
could argue that if DVD is not a human dorsal light reflex, this cyclovertical
divergence could be the cause rather than the result of the observed perceptual
changes. In other words, extorsion of the covered eye in DVD could cause the
vertical pencil to appear momentarily intorted when the either eye is uncovered.
As the eye intorts to fixate, the image would extort, producing a similar sequence
of perceptions as observed. If this were the case, one would expect patients with
DVD to report that the image of the pencil shifted from an initial position of
intorsion to a final position of extorsion. However, all patients with DVD stated
that the tilted image of the pencil appeared vertical following its rotation, which
would only occur if this reflex cycloversional movement served to correct the
monocular visual tilt. This perceptual response suggests that this complex cyclo-
vertical movement must function to reestablish vertical visual orientation when
binocular vision is preempted.
In conclusion, DVD is associated with a subjective tilt of the visual environment
and a reflex cyclovertical divergence of the eyes. This subjective visual tilt appears
to drive both components of the resulting cyclovertical divergence. These percep-
tual correlates add to the accumulating body of evidence that DVD is a human
dorsal light reflex, which serves to restore vertical visual orientation under mon-
ocular conditions. In DVD, a subjective sensation of visual tilt under monocular
viewing conditions evokes 2 compensatory eye movements—a phylogenetically
older vertical divergence movement (ie, a primitive adaptation) to realign the eyes
relative to the altered internal representation of vertical, and an exaptive cyclover-
sion movement that torsionally rotates the eyes in the direction of the tilted visual
environment to restore vertical visual orientation by neutralizing the perceived
visual tilt. The vertical component of this movement corresponds to the ancestral
dorsal light reflex in fish, while the cycloversional component of the human dorsal
light reflex appears to be an exaptation that functions to annul the subjective visual
tilt under monocular conditions when the eyes are frontally placed. This twofold
reflex movement corresponds both in theory and in actuality to the ocular motor
response that would result from a tilted internal representation of the visual verti-
cal. In the human dorsal light reflex, the direction of the cycloversion movement
relative to the vertical divergence is opposite to that observed during a head tilt in
space, demonstrating that the vertical divergence and the cycloversional compo-
nent of visual tilt are independently programmed, and that these 2 extraocular
movements can be dissociated by unequal visual input to the 2 eyes in humans with
congenital strabismus.
92 6 Dissociated Vertical Divergence
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Postscript 93
Postscript
This article deals with the complex issue of why the torsional eye movements in
DVD are opposite in direction to those produced by the vestibular pathways. In my
original analysis of DVD, I had explained this phenomenon teleologically by stating
that the torsional directions between vestibular and visual pathways had to be oppo-
site in direction to summate to zero under conditions of normal functioning. In this
analysis, I demonstrate that monocular occlusion is associated with a subjective
sensation of tilt, which is rapidly corrected by the DVD. The absence of any subjec-
tive tilt after a DVD torsional movement occurs suggests that these movements are
corrective in nature (i.e. that DVD is indeed a righting reflex).
From there, I use the direction of the perceived visual tilt to deconstruct the
vertical component of DVD, which rotates the eyes back to the altered internal
orientation for true vertical (i.e. toward the subjective vertical) from torsional
component (which is directed toward and thereby corrects the perceived tilt of the
visual world (termed the subjective visual vertical). Whereas the perceived true
vertical and the position of the world rotate in the same direction during body tilt,
in visual tilts they scissor apart, necessitating torsional movements that are oppo-
site in direction to those produced by body tilt. The neurologic pathways by which
these visual torsional movements are separately mediated in humans remain
unknown.
94 6 Dissociated Vertical Divergence
In its essence, DVD is a tilt rather than a hyperdeviation. If the reader tilts his or
her head to the left and looks in the mirror, they will find that the right eye is higher
than the left in space. Do they suddenly have a large right hypertropia? No, they
have a tilt with no true hypertropia. The true hypertropia is actually the magnitude
of the total vertical deviation in space minus the tilt. That is why you can have a true
hypertropia superimposed upon a DVD. The vertical component of DVD is there-
fore a tilt in physical space to realign the eyes with internal orientation of the indi-
vidual. On top of this, the gyroscopic torsional component of DVD creates a roll
movement to restore restore vertical orientation of the outside world. Despite its
atavistic origin, DVD reflects complex computational processing at many levels
within the visual system.
The Reversed Fixation Test
A Diagnostic Test for Dissociated Horizontal Deviation
7
The adjective “Dissociated” was first used to describe binocular eye movements by
Bielschowsky; he applied the term “dissociated vertical divergence” to the alternat-
ing hyperdeviation that accompanies congenital strabismus [1–3]. In 1976, Raab [4]
described the slow unilateral abduction of the deviating eye as a horizontal variant
of dissociated vertical divergence. In 1990, Spielmann [5] assigned the name “dis-
sociated horizontal deviation” to patients with infantile strabismus with intermittent
esodeviation of either eye. Spielmann noted that some esodeviations are smaller
when the child is visually inattentive than when the child is fixating or during cover
testing. This finding suggested that monocular fixation can increase esotonus in
some patients with infantile strabismus [5].
Beginning also in 1990, several clinical reports applied the term “dissociated
horizontal deviation” to intermittent exodeviations that were larger in 1 eye or
confined to 1 eye on alternate cover testing, ie, dissociated [6–11]. Affected
patients manifested an exodeviation of variable amplitude [6–11]. Associated
findings such as dissociated vertical divergence, latent nystagmus, and sensorial
suppression of 1 eye (even when the eyes were aligned) also distinguished this
form of dissociated horizontal deviation from intermittent exotropia [6–8]. The
exodeviation was noted to be larger during periods of visual inattention [9]. The
authors of these reports advocated limiting surgery to a single lateral rectus mus-
cle in the exodeviating eye (recession with or without a posterior fixation suture)
for unilateral cases of dissociated horizontal deviation, while reserving bilateral
lateral rectus muscle recession for cases of so-called bilateral dissociated horizon-
tal deviation or unilateral dissociated horizontal deviation combined with exotro-
pia [6–11].
Consider a patient who has had surgery for infantile esotropia and subsequently
developed an intermittent exodeviation of the left eye. Alternate cover testing shows
that only the left eye drifts out under the cover. The reversed fixation test is now
necessary to confirm or rule out the presence of a dissociated deviation.
Scenario 2 97
Scenario 1
Step 1: A base-in prism is placed before the left eye to neutralize the exodevia-
tion. The left eye is covered for about 5 seconds. The cover is then switched briefly
to the right eye then immediately back to the left eye to confirm that the exodevia-
tion is neutralized. If not, the prism is changed and the procedure repeated until the
exodeviation of the left eye is neutralized, eg, by 25 prism diopters. With the prism
held before the left eye, the occluder is moved to cover the right eye. No movement
of the left eye is seen (Fig. 7.1, top).
Step 2: (Reversed fixation test): After about 5 seconds, the occluder again is
briefly switched from the right eye to the left eye (with the prism still held in place
in front of the left eye). No movement of the right eye is observed (Fig. 7.1, bot-
tom). This means that the 25 prism diopters are also corrective for left eye fixation.
Interpretation: The absence of right eye movement in the reversed fixation test
demonstrates that the exotropia is not dissociated. Rather, this patient may have an
adduction deficit of the right eye due to postoperative slippage of the right medial
rectus muscle.
Scenario 2
Step 1: A 25 prism diopter base-in prism placed before the left eye is found to
neutralize the exodeviation. With the 25 prism diopter base-in prism still in front of
the left eye, the right eye is covered for several seconds (Fig. 7.2, top). No move-
ment of the left eye is seen.
Step 2: (Reversed fixation test): With the prism still in front of the left eye, after
several seconds the occluder is switched from the right eye to the left eye. An abduc-
tion saccade of the right eye is observed, corresponding to an adducted position of
the right eye under the cover (Fig. 7.2, bottom). This adducted position can be mea-
sured by having a second observer (or the patient) place a base-out prism in front of
the right eye while keeping the right eye occluded. Then the cover is for a short
moment switched to the left eye and immediately back to the right eye to observe
whether the adducted position of the right eye is neutralized. If not, the prism is
changed and the procedure repeated until the adducted position is neutralized, eg,
by a 25 prism diopter base-out prism.
Interpretation: In this situation, there is less esotonus when the right eye is fixat-
ing than when the left eye is fixating. Thus, when the left eye is made to fixate in its
unchanged, abducted position (through the prism), the right eye assumes an adducted
position of the same size behind the cover, ie, there is no squint angle. This patient
has a dissociated component of 25 prism diopters which equals the entire exodevia-
tion of the left eye (provided that unequal accommodative convergence is excluded
by dynamic retinoscopy or by maximum visual acuity at distance with the patient in
his or her corrected cycloplegic refraction). If there is no horizontal incomitance,
the patient will also be orthotropic in straight gaze as long as the left eye is fixating.
98 7 The Reversed Fixation Test
25∆
25∆
Fig. 7.1 Intermittent exotropia. Top: Following neutralization with a 25 prism diopter base-in
prism, no change in esotonus occurs when the occluder is shifted to the right eye. Bottom:
Therefore, no movement of the right eye is seen when the occluder is again shifted to the left eye,
demonstrating that the exotropia is not dissociated
Scenario 2 99
25∆
25∆ 25∆
Fig. 7.2 Dissociated horizontal deviation. Top: Following neutralization with a 25 prism diopter
base-in prism, the esotonus increases when the occluder is shifted to the right eye. Bottom:
Reversed fixation test. When the occluder is again shifted to the left eye, a 25 prism diopter abduc-
tion saccade of the right eye is seen, demonstrating the dissociated nature of the exodeviation
100 7 The Reversed Fixation Test
Scenario 3
Step 1: A 25 prism diopter base-in prism is placed before the left eye to neutral-
ize the exodeviation. With the prism held before the left eye, the occluder is moved
to cover the right eye. No movement of the left eye is seen (Fig. 7.3, top).
Step 2: (Reversed fixation test): With the prism still in front of the left eye, the
occluder is briefly switched from the right eye to the left eye, then immediately back
to the right eye. An abduction saccade of the right eye is observed, corresponding to
an adducted position of the right eye under the cover (Fig. 7.3, bottom). When mea-
sured with a second observer (or the patient) placing a base-out prism in front of the
right eye, the size of the abduction saccade is 10 prism diopters.
Interpretation: Assuming that unequal accommodative convergence has been
ruled out, this patient has 10 prism diopters of dissociated horizontal component
superimposed on 25 prism diopters of underlying exotropia. The patient who spon-
taneously alternates fixation, will alternately manifest an exodeviation of 15 prism
diopters in the right eye and an exodeviation of 25 prism diopters in the left eye.
Scenario 4
Consider the patient with the same history who manifests a large exodeviation dur-
ing periods of visual inattention. Alternate cover testing shows a large exodeviation
of the left eye and a small esodeviation of the right eye.
Step 1: A 25 prism diopter base-in prism is placed before the left eye to neutral-
ize the exodeviation. With the prism held before the left eye, the occluder is moved
to cover the right eye. No movement of the left eye is seen (Fig. 7.4, top).
Step 2: (Reversed fixation test): With the prism still in front of the left eye, the
occluder is switched from the right eye to the left eye. An abduction saccade of the
right eye is observed, corresponding to an adducted position of the right eye under
the cover. When measured with a second observer (or the patient) placing a base-out
prism in front of the right eye, the size of the abduction saccade is 30 prism diopters
(Fig. 7.4, bottom).
Interpretation: Assuming that unequal accommodative convergence has been
ruled out, this patient alternately manifests an exotropia of 25 prism diopters in the
left eye and an esotropia of 5 prism diopters in the right eye, attributable to a dis-
sociated component of 30 prism diopters.
Comment
25∆
25∆ 10∆
Fig. 7.3 Dissociated horizontal deviation. Top: Following neutralization with a 25 prism diopter
base-in prism, the esotonus increases when the occluder is shifted to the right eye. Bottom:
Reversed fixation test. When the occluder is again shifted to the left eye, a 10 prism diopter abduc-
tion saccade of the right eye is seen, demonstrating the partially dissociated nature of the
exodeviation
102 7 The Reversed Fixation Test
25∆
25∆ 30∆
Fig. 7.4 Dissociated horizontal deviation with coexistent exodeviation and esodeviation. Top:
Following neutralization with a 25 prism diopter base-in prism, the esotonus significantly increases
when the occluder is shifted to the right eye. Bottom: Reversed fixation test. When the occluder is
again shifted to the left eye, a 30 prism diopter abduction saccade of the right eye is seen, demon-
strating that this patient has 25 prism diopters of exotropia (causing the exodeviation of the left
eye) with an additional dissociated component of 30 prism diopters (causing the 5 prism diopter
esodeviation of the right eye during left eye fixation as shown in the top figure)
Comment 103
from the nondissociated vertical divergence caused, for example, by primary oblique
muscle overaction [17].
In the horizontal plane, a major advantage of the reversed fixation test is that an
incomitant horizontal deviation will not be misdiagnosed as “dissociated.” This test
allows the examiner to measure a dissociated component as the difference between
the squint angle when the right eye is fixating and the angle when the left eye is
fixating, without any change of the horizontal gaze direction. If the reversed fixation
test shows that the angle is the same on right and left eye fixation, a dissociated
component of the deviation has been ruled out. Since fixation per se (with either
eye) can evoke differing degrees of esotonus, the degree of exodeviation that is
apparent with visual inattention (eg, when the patient is asked to remember an event
24 hours ago or to solve a mathematical task) can be larger than that measured when
either eye is used to fixate [11, 14].
The reversed fixation test shows that dissociated horizontal deviation exists in a
minority of patients with unilateral exodeviation [13, 14]. While this disorder is
referred to as dissociated horizontal deviation in the left or the right eye, it is well to
remember that the dissociated component results from a change in vergence tonus
on a supranuclear level when the fixating eye is switched, and that it actually
involves both eyes.
In conclusion, dissociated horizontal deviation is a unique clinical disorder that
can be diagnosed only after a variety of other simulating conditions have been
excluded. The reversed fixation test is a decisive test for the diagnosis of dissociated
horizontal deviation. With the reversed fixation test, keeping the neutralizing prism
in its position in front of the same eye, a change in the fixation from one eye to the
other normally does not alter the strabismus angle. With corrected cycloplegic
refraction, when prism alternate cover testing discloses a movement of the eye not
viewing through the prism, a dissociated component of the strabismus is established.
References
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2. Bielschowsky A. Die einseitigen und gegensinnigen (“dissoziierten”)
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(DHD). Rev Mex Oftalmol. 1990;64:169–73.
104 7 The Reversed Fixation Test
Postscript
This paper documented the reversed fixation test (RFT) as a determinative test for
dissociated horizontal deviation (DHD), as first articulated by Michael Gräf in
2001. Note that an equal amount of esotonus exerted by fixation with each of the
two eyes would yield a negative reversed fixation test in the presence with
DHD. Such cases would have equal exodeviations with each eye fixing. Thus, some
cases of DHD will inevitably fly under our radar.
After further study, it became clear to me that the diagrams in this article incor-
rectly depict large shifts in eye position corresponding to the reversed fixation test
(RFT). In point of fact, they are tiny, on the order of 2–8 PD. This tiny shift occurs
because the reversed fixation test measures only the difference in dissociated esoto-
nus that is exerted when each of the two eyes are fixating. Since fixation with one
eye is already exerting considerable esotonus, and the deviation has been corrected
Postscript 105
by a base in prism, the switch to fixation with the eye that exerts greater or lesser
esotonus would show a movement that reflects the difference. Thus, even a small
shift is still significant for DHD.
By inference, when intermittent exotropia is accompanied by a positive reversed
fixation test, one can probably conclude that its onset was within the first six months
of life. However, other cases of intermittent exotropia are accompanied by DVD
(either manifest or measurable on prism and alternate cover testing). This associa-
tion may reflect that fact that DVD is a primitive visual reflex that is present all of
us, so if intermittent exotropia begins early in life, DVD can be coexpressed as well.
Does Infantile Esotropia Arise
From a Dissociated Deviation? 8
Tonus refers to the effects of baseline innervation on musculature in the awake, alert
state [1]. Since the normal anatomical resting position of the eyes is one of exode-
viation, extraocular muscle tonus plays a vital physiologic role in establishing ocu-
lar alignment. Under normal conditions, binocular esotonus is superimposed on the
baseline anatomical position of rest to maintain approximate ocular alignment, save
for a minimal exophoria that is easily overcome by active convergence. When bin-
ocular visual input is preempted early in life, monocular fixation may give rise to a
larger dissociated esotonus that gradually drives the 2 eyes into a “convergent” posi-
tion, resulting in infantile esotropia [2].
In our companion article [2], we examine clinical and evolutionary evidence for
the proposition that dissociated horizontal deviation is a clinical expression of dis-
sociated esotonus. When superimposed on a baseline orthoposition, dissociated
esotonus manifests as an intermittent esotropia that is asymmetrical or unilateral
[3]. More commonly, dissociated esotonus is superimposed on a baseline exodevia-
tion, producing an intermittent exodeviation that is asymmetrical, unilateral, or
associated with a paradoxical esodeviation when the nonpreferred eye is used for
fixation [4–11].
Although the term dissociated has historically been restricted to the description
of vergence eye movements [12–14], in a more general sense it describes any ocular
movements that result from a change in the relative balance of visual input from the
2 eyes [15]. These movements arise almost exclusively in the setting of infantile
strabismus [16], which has a strong predilection for esotropia over exotropia. It is
held that infantile esotropia disrupts binocular control mechanisms and thereby
engenders these dissociated eye movements [16]. This time-honored notion assumes
a distinct and unrelated pathogenesis for infantile esotropia.
The purpose of this analysis is to raise an unexamined question regarding the
pathogenesis of infantile esotropia. Since dissociated deviations almost uniquely
accompany infantile strabismus, could infantile esotropia arise from a dissociated
deviation? Our findings raise the possibility that dissociated esotonus could be the
proximate cause of infantile esotropia.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 107
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_8
108 8 Does Infantile Esotropia Arise From a Dissociated Deviation?
In conclusion, our findings raise the intriguing possibility that dissociated esoto-
nus, an unrecognized dissociated eye movement, may be the cause, rather than the
effect, of infantile esotropia. If this proves to be the case, then the prevailing concept
of infantile esotropia as the proximate cause of dissociated deviations may need to
be revised.
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2. Brodsky MC, Fray KJ. Dissociated horizontal deviation after surgery for infan-
tile esotropia: clinical characteristics and proposed pathophysiologic mecha-
nisms. Arch Ophthalmol. 2007;125(12):1683–92.
3. Spielmann A. Déséquilibres verticauxet torsionnels dans le strabisme précoce.
Bull Soc Ophtalmol Fr. 1990;4:373–84.
4. Romero-Apis D, Castellanos-Bracamontes A. Desviacion horizontal disociada
(DHD). Rev Mex Oftalmol. 1990;64:169–73.
5. Wilson ME, McClatchey SK. Dissociated horizontal deviation. J Pediatr
Ophthalmol Strabismus. 1991;28(2):90–5.
6. Romero-Apis D, Castellanos-Bracamontes A. Dissociated horizontal deviation:
clinical findings and surgical results in 20 patients. Binocul Vis Strabismus
Q. 1992;7:173–8.
7. Quintana-Pali L. Desviacion horizontal disociada. Bol Hosp Oftalmol.
1990;42:91–4.
8. Zabalo S, Girett C, Domínguez D, Ciancia A. Exotropia intermitente con des-
viación vertical discodiada. Arch Oftalmol B Aires. 1993;68:11–20.
9. Wilson ME. The dissociated strabismus complex. Binocul Vis Strabismus
Q. 1993;8:45–6.
10. Wilson ME, Hutchinson AK, Saunders RA. Outcomes from surgical treatment
for dissociated horizontal deviation. J AAPOS. 2000;4(2):94–101.
11. Spielmann AC, Spielmann A. Antinomic deviations: esodeviation associated
with exodeviation. In: Faber TJ, editor. Transactions 28th Meeting European
Strabismological Association, Bergen, Norway, June, vol. 2003. London:
Taylor & Francis; 2004. p. 173–6.
12. Bielschowsky A. Über die Genese einseitiger Vertikalbewegungen der Augen.
Z Augenheilkd. 1904;12:545–57.
13. Bielschowsky A. Die einseitigen und gegensinnigen (“dissoziierten”)
Vertikalbewegungen der Augen. Albrecht Von Graefes Arch Ophthalmol.
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14. Bielschowsky A. Disturbances of the vertical motor muscles of the eye. Arch
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15. Lyle TK. Worth and Chavasse’s Squint. The binocular reflexes and treatment of
strabismus. Philadelphia: Blakiston; 1950. p. 40–1.
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Postscript 113
Postscript
This editorial elaborates on the previous chapter and further expands on from my
AOS thesis on dissociated horizontal deviation (DHD), which proposed that we
have been thinking about DHD the wrong way. Rather than being a dissociated
exodeviation, DHD actually arises when monocular fixation causes dissociated
esotonus to be superimposed on baseline exodeviation (usually following strabis-
mus surgery for infantile esotropia). In this setting, fixation with the poorer eye
generates a greater degree of dissociated esotonus, sometimes causing the baseline
esotropia to convert to an esotropia. Therefore, when patients become inattentive, a
much larger exodeviation becomes evident.
It was Michael Gräf at the University of Giessen who first recognized that mon-
ocular fixation evokes convergence in DHD. He has since devised the “17 x 13” test
to elicit this phenomenon. Just ask the patient to multiply 17 x 13 and you will see
the large baseline exodeviation appear. I referred to this particular quality of DHD
as the “Heisenberg Uncertainty Principle” of clinical strabismus measurement,
wherein the act of measuring a horizontal deviation by occluding either eye inevita-
bly changes the measurement you obtain (in this case by evoking monocular fixa-
tion with its commensurate esotonus). Strabismus surgery based on the measured
deviation (using prism and alternate cover testing), will correct the measurements
but leave a large residual exodeviation during periods of inattention.
My early interest in DHD was directed at the establishing utility of the reversed
fixation test in identifying dissociated esotonus (Chap 7). This quick clinical test
works well except when the dissociated esotonus happens to be equal in the two
eyes. In this essay, I propose that the dissociated esotonus that characterizes DHD
could be the underlying cause of essential infantile esotropia. Accordingly, what we
recognize as essential infantile esotropia may be the end-stage phenotype of disso-
ciated esotonus.
In patients with infantile or consecutive exotropia, the innervational effects of
dissociated esotonus are easily visualized. In infantile esotropia, however, the dis-
sociated esotonus is fully expressed, rendering it impossible to visualize DHD dur-
ing monocular fixation. This mechanism also explains why we occasionally see
DHD manifesting as an intermittent esotropia of varying amplitude depending on
which eye is fixating. (Fig. 8.1).
114 8 Does Infantile Esotropia Arise From a Dissociated Deviation?
Fig. 8.1 Preoperative photos of DHD showing eye position during (a) period of inattention, (b)
left eye fixation at near, (c) right eye fixation at near. (Reprinted with permission from Brodsky
MC: Intermittent esotropia in an adult. JAMA Ophthalmol 2021, with permission from the
American Medical Association)
The Accessory Optic System
The Fugitive Visual Control System in Infantile Strabismus
9
What Is the AOS?
The AOS consists of 3 nuclei at the mesodiencephalic border that receive direct reti-
nal input from the accessory optic tract (AOT) [6–9] (Fig. 9.1). The AOT comprises
an inferior and a superior fasciculus, with its superior fasciculus divided into a pos-
terior branch, a middle branch, and an anterior branch that is identical to the original
transpeduncular tract (tractus peduncularis transversus) discovered in 1870 by
Gudden [10, 11]. The number of accessory optic fibers is small [7]. In almost all
mammalian species, most optic fibers reach the accessory optic nuclei via the
transpeduncular tract, which is visible as it courses over the brachium of the supe-
rior colliculus [12].
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 115
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_9
116 9 The Accessory Optic System
Fig. 9.1 Neuroanatomical connections of the accessory optic system. The brainstem is depicted
from the front (with the left-hand side of the animal on the right-hand side of the drawing). Accessory
terminal nuclei include the dorsoterminal nucleus (DTN), which lies adjacent to the nucleus of the
optic tract (NOT); medial terminal nucleus (MTN); lateral terminal nucleus (LTN); and principal
part of the inferior olive (IOp). Optokinetic input from the right retina crosses to the left accessory
optic nuclei (depicted), which send ipsilateral projections to the left dorsal cap (DC) of the inferior
olive and then back to the right flocculus (not shown), resulting in a double decussation of motion
pathways from each eye. (Adapted with permission from Simpson et al. [12]) CP indicates posterior
commissure; D, nucleus of Darkschewitsch; DMNm, deep mesencephalic nucleus, pars medialis;
EW, nucleus of Edinger-Westphal; INC, interstitial nucleus of Cajal; inSFp, intersitial nucleus of the
superior fasciculus, posterior fibers; MAO, medial accessory nucleus, inferior olivary complex; ML,
medial lemniscus; MLF, medial longitudinal fasciculus; PAGm, periaqueductal gray, medial part;
pdl, dorsolateral division, basal pontine complex; pm, medial division, basal pontine complex; pv,
ventral division, basal pontine complex; PVG, periventricular gray; RN, red nucleus; rpc, pontine
reticular nucleus, pars caudalis; rpo, pontine reticular nucleus, pars oralis; vl, lateral vestibular
nucleus; VLO, ventrolateral outgrowth, inferior olivary complex; vm, medial vestibular nucleus; vs,
superior vestibular nucleus; vsp, spinal vestibular nucleus; VTRZ, visual tegmental relay zone; β,
nucleus β of the inferior olive; 3n, oculomotor nerve; 4n, trochlear nerve; and 6n, abducens nerve
What Is the AOS? 117
Paired
vertical recti
148°
Paired
obliques
43°
∗ ∗
∗ 143°
47° 90°
0°
Paired 45° Paired
vertical canals vertical canals
41° 139°
Fig. 9.2 Spatial orientation of preferred axes of 3-dimensional rotation for dorsal cap neurons in
the right inferior olive recorded during optokinetic stimulation in a spherical enclosure. (Adapted
with permission from Van der Steen et al. [27] VA indicates vertical axis)
The rabbit flocculus ipsilateral to the seeing eye is optimally sensitive to optoki-
netic stimulation about a 135° axis, while the flocculus contralateral to the seeing
eye is optimally sensitive to optokinetic stimulation around a horizontal 45° axis
(Fig. 9.3) [26–29]. For horizontal stimulation, the DTN and its adjacent NOT are
selectively sensitive to nasally directed optokinetic stimulation presented to the con-
tralateral eye [7, 8, 12, 13]. Conversely, electrical microstimulation in the alert rab-
bit’s flocculus produces abduction of the ipsilateral eye [27, 29, 30] or dissociated
torsional and vertical rotations of the 2 eyes, corresponding to the plane of 1 semi-
circular canal [26–30]. Because floccular motion detection for each eye is not fully
represented on its own side of the body, monocular optokinetic responses must be
derived from the synthesis of bilateral floccular representations [28]. Therefore, the
flocculus provides a subcortical binocular visual system that generates asymmetri-
cal torsional eye movements under dissociated conditions of optokinetic stimula-
tion [28].
Studies using decortication have revealed contributions from the visual cortex to
the AOS. Disruption of contributions from the visual cortex to the AOS by strabis-
mus may alter the inherent biases of the accessory optic nuclei [31–33]. The
What Is the AOS? 119
45°
1.5
90°
1.0
135° 0.5
Top view
0.0
Spikes/s
0° 0.5
Mean Firing Frequency, Spikes/s
22.5°
0.0
45°
67.5°
0.5
90°
112.5° 0.0
135°
Top view157.5°
0.5
0.6°/s
Spikes/s
5.3 0.0
2.6 CW CCW 15 Repetitions 0 45 90 135 180
Spontaneous 5s 100 ms Bin width
activity Planetarium Axis Angle, °
Fig. 9.3 Sensitivity to monocular optokinetic stimulation in a spherical enclosure. (a) Responses
of posterior axis climbing fiber Purkinje cells to stimulation presented to the ipsilateral left eye. (b)
Responses of anterior axis climbing fiber Purkinje cells to stimulation presented to the contralat-
eral eye. CCW indicates counterclockwise optokinetic rotation; CW, clockwise optokinetic rota-
tion. (Adapted with permission from Van der Steen et al. [27])
120 9 The Accessory Optic System
ipsilateral visual cortex is necessary for several response properties that distinguish
DTN and LTN neurons in the cat from those in the rabbit. Following decortication,
cat DTN and LTN neurons lose their binocularity and become almost totally domi-
nated by the contralateral eye [33]. For example, LTN neurons excited by upward
movement, which in the cat are equal in number to those excited by downward
movement, become less numerous so that the cat LTN becomes like that of the rab-
bit, consisting of neurons excited by slow downward movements to the contralateral
eye [33]. Unlike the LTN and DTN, neurons in the cat MTN are largely monocular
and similar to those in the rabbit [12]. The monocular nasotemporal optokinetic
asymmetry that characterizes infantile strabismus is known to result from monocu-
lar cortical input to the NOT and DTN [34], unmasking a subcortical visuovestibu-
lar bias that generates latent nystagmus [35]. The AOS provides a neuroanatomical
substrate whereby vertical monocular subcortical motion biases could generate the
canal-based torsional eye movements that characterize primary oblique muscle
overaction and dissociated vertical divergence [2, 4]. Although we observe and ana-
lyze these eye movements in yaw, pitch, and roll [2], they are encoded in a canal-
oriented push-pull bilateral coordinate system that detects optokinetic flow in every
direction [36].
Photic stimulation can activate the AOT in the rabbit [4, 37]. The AOS neurons
show the same responses to retinal illumination as ON-type direction-sensitive reti-
nal ganglion cells, being excited only at the onset of retinal stimulation [23], and
generate a firing response that is related to light intensity [32]. In this way, the AOS
may implement the visuovestibular reflexes that characterize infantile strabismus
[1, 2]. However, because the AOS is primarily a motion detector, central modulation
of the primitive luminance reflexes that characterize infantile strabismus may
require input from additional subcortical visual pathways. It is possible that other
primitive luminance pathways may provide parallel subcortical luminance input to
the visuovestibular system [38]. Like the AOS, luminance input that modulates the
dorsal light reflex in fish (which corresponds to dissociated vertical divergence and
primary oblique muscle overaction in humans with infantile strabismus) [1, 2] is
transmitted to the central pretectal nucleus in the contralateral midbrain and then
down to the vestibulocerebellum, which integrates visual and vestibular input [39].
These luminance and motion pathways may constitute the subcortical equivalents of
the “what” and “where” visual streams within the association visual cortex. How
these subcortical visual streams intercommunicate to consolidate spatial and tempo-
ral summation of visual information at the subcortical levels remains a mystery. But
the likelihood that they provide the innervational substrate for the atavistic eye
movements that characterize infantile strabismus should not be ignored.
Conclusions
The AOS provides a critical piece of the puzzle for infantile strabismus by serving
as a neuroanatomic substrate for visuovestibular eye movements. The AOS is atavis-
tic, present in humans, subcortical, crossed, and sensitive to optokinetic motion. It
Conclusions 121
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sis, evolutionary underpinnings, diagnosis, treatment, and potential role in the
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4. Brodsky MC, Donahue SP. Primary oblique muscle overaction: the brain throws
a wild pitch. Arch Ophthalmol. 2001;119(9):1307–14.
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11. Gudden B. Ueber den Tractus peduncularis transversus. Arch Psychiatry.
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12. Simpson JI, Giolli RA, Blanks RH. The pretectal nuclear complex and the
accessory optic system. Rev Oculomot Res. 1988;2:335–64.
13. Giolli RA, Blanks RHI, Lui F. The accessory optic system: basic organization
with an update on connectivity, neurochemistry, and function. Prog Brain Res.
2006;151:407–40.
14. Takeda T, Maekawa K. The origin of the pretectoolivary tract: a study using the
horseradish peroxidase method. Brain Res. 1976;117(2):319–25.
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17. Maekawa K, Simpson JI. Climbing fiber responses evoked in vestibulocerebel-
lum of rabbit from visual system. J Neurophysiol. 1973;36(4):649–66.
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Postscript
The accessory optic system (AOS) provides a critical piece of the puzzle in infantile
strabismus by explaining how visual motion can be processed in a vestibular coor-
dinate system. The existence of this subcortical system explains how torsional eye
movements can be generated in response to unequal binocular visual input, and how
individual extraocular muscles can be driven to overact when binocular visual
development is comprised. The clear implication is that this atavistic system some-
how remains functional in infantile strabismus and infantile nystagmus. This propo-
sition is not so bold when one considers that our extraocular muscles are oriented in
a semicircular canal-based planar coordinate system. The AOS subserves optokine-
sis, however, so it remains unclear whether primitive luminance pathways are
encoded in a similar coordinate system, or whether luminance disparity generates
correlative input the AOS.
The reader would be remiss in not asking why humans retain primitive neuro-
logic systems such as the AOS after newer cortical systems develop. A satisfying
answer can be found in John Allman’s 1999 book Evolving Brains. In one section,
during a visit to a power generation plant in the 1970s, he noted that several
124 9 The Accessory Optic System
different control systems, some ancient, others new, were situated adjacent to each
other. Some contained pneumatic controls and a system of controls based on vac-
uum tube technology, while the newer control systems relied upon computer-driven
control systems. Yet, these systems were all used together to control the generation
of electricity at the plant. When he asked why the archaic systems had not been
superseded by the new ones, he was told that the demand for power had always been
too great for the plant to ever be shut down. He concluded that “The brain has
evolved in the same manner as the control systems in this power plant. The brain,
like the power plant, can never be shut down and fundamentally reconfigured, even
between generations. All the old control systems must remain in place, and new
ones with additional capacities are added and integrated in such a way as to enhance
survival.”
The subcortical visual pathways are old school. They are concerned with side
vision, while the visual cortex is more concerned with central vision (as evidenced
by its generous macular representation). Yet the human AOS remains functional
within the first 2–3 months of life of infancy. The implication of this article is that
direct retinotectal input to the AOS may perpetuate its function and thereby generate
the unique eye movements that characterize (and possibly generate) infantile stra-
bismus. Accordingly, infantile strabismus may be generated primarily by the AOS,
or be perpetuated secondarily by the AOS only when cortical binocular vision fails
to develop. It may even be that the secondary reconfiguration of the motion visual
cortex, as first proposed by Hoffman, stimulates the AOS to retain the necessary
neuroplasticity to subserve this function. Long ago, Clifton Schor proposed that
cortical suppression of one eye could momentarily disinhibit the subcortical path-
ways to allow their retinotectal input to predominate. Any combination of these
mechanisms could be operative. Anyone who tells you that they have the final
answer is not a scientist. In science, models evolve with new and better data. Science
is a series of leaps, with new hypotheses leading to ongoing falsifications. So keep
an open mind.
Visuo-Vestibular Eye Movements
Infantile Strabismus in 3 Dimensions
10
Why is symmetry ubiquitous in the animal kingdom? More specifically, what is the
evolutionary origin of the bilateral symmetry that dictates that we have 2 eyes, ears,
arms, and legs situated equidistant from the midline? The problem of symmetry in
biological systems is a complex subject of ongoing study [4–6]. One of the evolu-
tionary functions of biological symmetry is balance. Because of the earth’s gravita-
tional field, survival requires that animals maintain vertical orientation. An animal
that falls tends to get eaten. For living organisms, gravity necessitates balance.
Because physical symmetry promotes balance, biological symmetry is an important
part of nature’s solution to the problem of gravity.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 125
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_10
126 10 Visuo-Vestibular Eye Movements
The evolution of bilaterally symmetrical organs situated equidistant from the sagit-
tal plane promotes balance by virtue of physical weight alone. Our 2 lungs, when
inflated with air, become ballast in water. But many bilateral structures also function
as physiologic balance organs. While it is axiomatic that our 2 labyrinths superin-
tend balance, other bilateral organs modulate balance in different ways. Our 2 cere-
bral hemispheres each control motor tone in the contralateral limbs. Our 2 cerebellar
hemispheres clearly control balance. Even the 2 kidneys have been shown to func-
tion in part as balance organs [7].
Many primitive reflexes that promoted survival in the ancestral setting lose their
beneficial function as evolution proceeds [11, 12]. With progressive encephaliza-
tion, newer cortical reflexes are grafted onto older subcortical reflexes, which persist
in latent form even when they no longer serve a useful function [13, 14]. Abnormal
neurodevelopment in infancy is associated with a persistence of numerous subcorti-
cal reflexes (Table 10.1) [15]. In pediatric neurology, these primitive reflexes are
among the clinical signposts of abnormal neurodevelopment [15]. In pediatric
Ocular Motor Incursions Operate as Visual Balancing Reflexes in Lateral-Eyed Animals 127
Primitive visual reflexes rely on a dissociated form of binocular vision between the
2 laterally placed eyes, which has been superseded by cortical binocular vision in
humans [9]. Humans experience frontal binocular vision with forfeiture of periph-
eral vision in exchange for cortical fusion and stereopsis. Infantile strabismus recre-
ates the dissociated binocular condition that allows lateraleyed animals to process
dissociated luminance and visual input from each eye with little or no binocular
overlap. Infantile strabismus effectively disables the newer cortical binocular sys-
tem and unveils the primitive visual reflexes that have been inscribed into our primi-
tive ocular motor control system [14, 16].
The resurrection of these primitive visual reflexes generates a triad of ocular
movements that have come to define infantile strabismus. This symphony of eye
movements reveals each of the primitive visual reflexes that use dissociated binocu-
lar visual input to maintain physical orientation in 3-dimensional space.
Latent nystagmus corresponds to the optokinetic component of ocular rotation
that is driven monocularly by nasal optic flow during a turning movement of the
body in lateral-eyed animals [16]. When infantile esotropia disrupts the establish-
ment of binocular visual connections, visual input from the fixating eye to the con-
tralateral nucleus of the optic tract evokes a counterrotation of the eyes that
corresponds to a turning movement of the body toward the object of regard. The
clinical expression of this visual reflex is also evident in the monocular
128 10 Visuo-Vestibular Eye Movements
Fixation + Light
Fixation
Fixation + Light
Fig. 10.1 Ohm’s visual balancing metaphor for dissociated vertical divergence [17] as depicted
by Mattheus and Kommerell [18]. Position of the scales corresponds to the relative vertical posi-
tions of the eyes in dissociated vertical divergence as determined by binocular visual input. White
retina indicates light input, dark retina indicates no light input, and x corresponds to the presence
of fixation in light or in darkness. (Reprinted with permission from Aeolus Press, Buren, the
Netherlands)
Latent Nystagmus, Primary Oblique Overaction, and Dissociated Vertical Divergence… 129
overaction that can be induced by altering binocular visual input. In humans, a for-
ward or backward rotation relative to overhead light sends excitatory innervation to
each of the elevators or each of the depressors. Because the vestibular system segre-
gates innervation to its target extraocular muscles, the vertical actions of the human
oblique muscles summate in adduction with those of the rectus muscles to produce
the innervational overelevation of the adducting eye that defines primary inferior
oblique muscle overaction. The fundamental association of primary oblique muscle
overaction with early loss of binocular vision in humans suggests that the brain
registers abnormal binocular visual input as forward rotation [19].
Most patients with infantile esotropia have no neurologic disease. From where do
these involuntary ocular rotations arise? Stereotypical eye movements that do not fit
any paradigm must come from somewhere. As stated by Keiner, “Nothing comes
from nothing”[14] (p151). The source of these dynamic intrusions has eluded us for
the simple reason that they arise from a physiologic imbalance rather than from a
neurologic lesion. They are harmonics of our earlier orchestration that bubble to the
surface when they are not superseded by cortical binocular reflexes.
Just as physiologic vestibular movements reflect the degree of unbalanced laby-
rinthine input, the size of these eye movements are proportional to the degree of
binocular visual imbalance, which can fluctuate depending on momentary cortical
suppression of either eye. Because the eye movements of infantile strabismus are
calibrated by weighted binocular visual input, they increase in proportion to the
disparity of visual input from the 2 eyes [9].
In lateral-eyed animals, visual and labyrinthine input are pooled together within the
central vestibular system to establish central vestibular tone [17–19]. Based on
momentary fluctuations in bilateral input, the central vestibular system constantly
modulates eye position and body position to maintain physical orientation in
3-dimensional space [8]. Vestibular input predominates over visual input, but both
systems are integrated at the level of the vestibular nucleus to maintain balance
[20–22]. In infantile strabismus, binocular visual imbalance alone can alter central
vestibular tone [9]. Because input to the vestibular nucleus can be directly driven by
the balance of visual input from the 2 eyes, this unique form of central vestibular
imbalance does not require that the central nervous system receive an imbalance of
labyrinthine input [9]. It is as if infantile strabismus transforms the 2 eyes into phys-
iologic vestibules. These unique eye movements are visuo-vestibular in origin.
130 10 Visuo-Vestibular Eye Movements
Vestibular eye movements are governed by the anatomical orientation of the laby-
rinths and occur in 3 major head-referenced planes [28]. Yaw rotation occurs around
the z or vertical axis, pitch rotation occurs around the y or interaural axis, and roll
rotation occurs around the x or nasal-occipital axis (Fig. 10.2). While vestibular eye
movements are driven by sensory input from the 2 labyrinths, visuo-vestibular eye
movements are driven by visual input from the 2 eyes. In infantile strabismus, the 2
Fig. 10.2 Cartesian Z
coordinate system for yaw,
pitch, and roll movements
of the head. (Axes differ
from those of the Fick
coordinate system for eye
rotation.) Yaw
Roll Pitch
X Y
Visuo-Vestibular Eye Movements Arise from a Central Vestibular Imbalance th… 131
eyes function as physiologic vestibules that can directly modulate central vestibular
tone in a complementary way to a labyrinthine imbalance. These visuo-vestibular
eye movements generate latent nystagmus in the yaw plane, primary oblique muscle
overaction in the pitch plane, and dissociated vertical divergence in the roll plane
(Table 10.2) [16].
Ultimately, all 3 visuo-vestibular eye movements are clinical expressions of a
visually induced imbalance in central vestibular tone, as evidenced by the fact that
they manifest as rotations in the same head-referenced planes as vestibular eye
movements, which are governed by the orientation of the anatomical components of
the 2 labyrinths [9, 16, 19]. One could geometrically display any variable combina-
tion of these 3 movements as a single vector in 3-dimensional space based on the
size and direction of each movement in its corresponding plane.
Because these visuo-vestibular movements correspond to vector components of
a single central vestibular imbalance in 3-dimensional space, it is not surprising that
their clinical features can overlap. Thus, dissociated vertical divergence incorpo-
rates a vertical latent nystagmus, revealing the shared common origin of these
movements [29]. Clinically, primary oblique muscle overaction and dissociated ver-
tical divergence often summate to produce an admixture of overelevation in adduc-
tion [30]. Similarly, latent nystagmus incorporates vertical and torsional movements
that overlap those of dissociated vertical divergence [31].
Each plane of rotation imparts unique clinical features to its visuo-vestibular
response. The fact that latent nystagmus is a dynamic imbalance while primary
oblique muscle overaction and dissociated vertical divergence are tonic imbalances
probably reflects the natural head and body movements that occur in the 3 orthogo-
nal planes of physical space. During navigation, an animal may turn its head and
body back and forth rapidly, but pitch or tilt movements tend to be slow and sus-
tained. Our evolutionary programming has devised its compensations accordingly.
Thus, the nucleus of the optic tract responds to optokinetic motion in the yaw plane
while subcortical neural pathways that modulate the dorsal light reflex produce a
tonic postural readjustment to a perceived vertical orientation [16]. Accordingly,
horizontal optokinetic input is yoked to horizontal canal input in the yaw plane, but
pitch and roll visual stimuli are yoked to otolithic input. The cerebellar flocculus
may modulate spatially oriented sensorimotor transformations for visuo-vestibular
eye movements [32].
Conclusions
The eye movements of infantile strabismus are harmonics of our earlier orchestra-
tion; echoes of our visual ancestry. Visual analogues of latent nystagmus, dissoci-
ated vertical divergence, and primary oblique muscle overaction are found in the
normal visuo-vestibular eye movements of lateral-eyed animals. These visual
reflexes subserve balance by enabling the animal to leverage fluctuations in binocu-
lar visual input to maintain postural orientation.
By disrupting the development of frontal binocular vision, infantile strabismus
permits our primitive visual reflexes to “bubble to the surface.” The resulting ocu-
lar intrusion movements reflect an imbalance of binocular visual input in 3 planes
of physical space. These overlapping visuo-vestibular eye movements can be
deconstructed clinically into their 3 dimensions, corresponding to yaw, pitch, and
roll. The symphony of binocular movements that accompanies infantile strabis-
mus is a necessary expression of our primitive heritage that impelled them into
being. At a higher level, these movements reveal the wisdom of antiquity by
reminding us how survival in a gravitational world once necessitated the evolution
of a physical symmetry and its co-orchestration at both anatomical and physio-
logic levels.
Infantile strabismus provides a natural experiment to uncover the primitive
visual reflexes that lie buried within us. These visual reflexes are humanity’s
umbilical cord reaching back to a time when the 2 eyes functioned together as
sensory balance organs. In infantile strabismus, dissociated binocular vision
remains the fulcrum on which the visuo-vestibular system teeters. The beauty of
infantile strabismus is that each piece of our visual ancestry is laid out in bold
relief. We see unraveled before us a blazing display of the primitive visual
reflexes that were once necessary to maintain physical orientation in 3- dimen-
sional space.
Conclusions 133
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Postscript
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 137
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_11
138 11 An Expanded View of Infantile Esotropia
esotropia in monkeys using base-out prisms and concluded that abnormal cortical
binocular vision is the cause of infantile esotropia. Such experiments confirm that
cortical binocular alterations following abnormal binocular visual experience can
lead to infantile esotropia.
Second, the conclusion that latent nystagmus arises from a cortical smooth pur-
suit defect [5, 6] ignores the evolutionary record. Latent nystagmus is driven by a
normal monocular nasotemporal optokinetic asymmetry that fails to resolve in chil-
dren with infantile esotropia [5, 10]. This nasal optokinetic preponderance mani-
fests as latent nystagmus when fixation with either eye induces a tonic deviation of
both eyes with nasalward drift of the fixating eye [11–15]. The question is whether
this optokinetic asymmetry is generated at the cortical or the subcortical level, and
there is experimental evidence that can be taken to support either conclusion
[13–15].
What is clear is that the same monocular nasotemporal optokinetic asymmetry is
present in lower vertebrates that do not possess a visual cortex [16, 17]. Hoffmann
[18] has shown in cats that development of binocular corticotectal pathways to the
nucleus of the optic tract (NOT) and the dorsal terminal nucleus is necessary to
cancel this asymmetry within the first year of life. So phylogenetically and ontoge-
netically, the monocular nasotemporal optokinetic asymmetry that drives latent nys-
tagmus antedates development of the binocular visual cortex. The neuroanatomical
substrate of this optokinetic asymmetry has been mapped to normal subcortical
visual pathways that travel first from the retina to the contralateral NOT and dorsal
terminal nucleus (a part of the AOS) in the pretectum and then via the cerebellar
flocculus to the vestibular nuclei [19–22]. These subcortical, visuovestibular path-
ways modulate optokinetic responses to whole-field movement (optic flow) in afo-
veate animals as opposed to cortical pursuit (a foveal function) [21]. Given that the
monocular nasotemporal optokinetic asymmetry that generates latent nystagmus
derives from a subcortical, afoveate, optokinetic pathway, a binocular defect in cor-
tical (foveal) smooth pursuit cannot be the primary cause of latent nystagmus.
The proximate cause of latent nystagmus is that these subcortical optokinetic
pathways remain operational. Since cortical pursuit pathways do not generate tor-
sional eye movements, one simply cannot explain the large torsional movements
that accompany latent nystagmus without invoking activation of these subcortical
visual pathways that project to the vestibular nuclei. In this context, latent nystag-
mus conforms to a visuovestibular nystagmus that is ultimately driven by subcorti-
cal binocular visual input to the vestibular nuclei [10, 23]. Latent nystagmus also
shows the phenomenon of velocity storage [24, 25], which is unique to vestibular
eye movements [26]. As expected, the vestibular ocular reflex remains normal [6]
because labyrinthine input to the vestibular system is unaffected.
Optokinetic eye movements provide the pursuit system for lateral-eyed afoveate
animals [17]. In primates, the subcortical NOT has commissioned the cortex to pro-
vide integrated visual motion information from the 2 hemifields through the middle
temporal area and medial superior temporal area [27]. Efferent signals from the NOT
and dorsal terminal nucleus may transmit velocity error information to the pursuit
system [28]. Pursuit and visuovestibular pathways remain functionally intermingled
within the medial superior temporal area of the primate motion visual cortex [29,
An Expanded View of Infantile Esotropia 139
30]. Therefore, it is not surprising that this visual motion asymmetry is represented
at the cortical level, causing smooth pursuit to be coordinately impaired [31]. So if
one looks for cortical visual motion asymmetry in primates with latent nystagmus,
one will find it and conclude that latent nystagmus must be cortical in origin.
Third, the notion that binocular cortical alterations unmask an innate convergence
bias to produce infantile esotropia is problematic at several levels [32]. Horwood [33,
34] has shown that normal infants display large, fleeting, convergence movements of
the eyes during the first 4 months of life, which are indicative of an emerging ver-
gence system. A greater frequency of these convergence movements between ages 2
and 4 months is predictive of normal binocular development and a lower likelihood
of developing infantile esotropia [33]. If infantile esotropia represents excessive con-
vergence, why would normal infants display more excessive convergence move-
ments than infants who are destined to develop infantile esotropia? It is also
noteworthy that the prevalence of infantile esotropia increases during a period in
which these convergence movements are disappearing in normal infants [34].
Jampolsky [35, 36] has emphasized the importance of distinguishing between
convergence as an active binocular function and esotonus as a passive innervational
output that is centrally driven by unequal visual input to the two eyes. Patients with
accommodative esotropia show excessive convergence, while those with infantile
esotropia do not. Misinterpreting infantile esotropia as a motor outcome of exces-
sive convergence also supports the misconception that dissociated vertical diver-
gence and dissociated horizontal deviation can be dismissed as excessive vergence
damping of latent nystagmus [37], despite the fact that latent nystagmus is not pres-
ent in some patients who have these other dissociated eye movements [32].
Fourth, the claim that early neurologic perturbation of cortical visual input is a high
risk factor for the motor components of infantile strabismus is certainly correct, but
the motor effects are due to a secondary involvement of lower motor circuits. Children
with neurologic disease constitute the minority in those with findings that define
infantile esotropia. There is no substantial evidence that injury to the developing cere-
bral cortex is necessary for infantile esotropia to develop [38]. Indeed, the absence of
neurologic disease is definitional for infantile esotropia. So while neurologic injury is
a risk factor for the development of esotropia in infancy, it should not be inferred from
this association that infantile esotropia is a “soft sign” of neurologic disease.
This leads to a concern about the use of periventricular leukomalacia as a neuro-
logic model for infantile esotropia. It is true that this condition produces preterm
injury to binocular visual input as evidenced by the bilateral focal white matter
injury to the optic radiations that are visible on magnetic resonance imaging [39]. It
is also the case that periventricular leukomalacia is a neurologic disease that can
cause elements of the infantile esotropia syndrome to be expressed. However, chil-
dren with periventricular leukomalacia have a different constellation of clinical
findings (including tonic downgaze, primary superior oblique overaction, optic
nerve hypoplasia, spontaneous conversion of esotropia to exotropia) from those
seen in infantile esotropia [39]. Furthermore, periventricular leukomalacia is now
recognized as a global injury to both cortical and subcortical structures (including
the thalamus, basal ganglia, and cerebellum) [40], making it a poor model for infan-
tile esotropia caused by isolated injury to binocular cortical visual inputs.
140 11 An Expanded View of Infantile Esotropia
This evidence supports the view that dissociated eye movements are generated in
the basement of the brain by primitive visual pathways that are modulated by the
binocular visual cortex. As the AOS modulates full-field optokinetic movements
similar to the NOT and operates in the canal-based coordinate system, it emerges as
an attractive candidate for generating these atavistic torsional movements [1]. In the
evolutionary sense, these are not abnormal eye movements but are normal eye
movements that are resurgent. A comprehensive neuroanatomical model for infan-
tile esotropia must therefore incorporate the cortico-mesencephalic-cerebellar path-
ways (not brainstem) [1], which are known to provide a sensorimotor circuit for the
control and modulation of eye movements in human and nonhuman primates [22].
For these reasons, we should consider that the “cause” of infantile esotropia lies
not only upstairs in the cerebral cortex but also downstairs in the cerebellar cortex.
In humans, neurologic lesions such as midline cerebellar tumors [48] and Chiari
malformations [49] can also cause acquired comitant esotropia. In the rabbit, stimu-
lation of the dorsal cap of the inferior olive (which provides visual climbing fibers
to the cerebellar flocculus) inhibits reflex contractions to the contralateral medial
rectus muscle and the ipsilateral inferior oblique muscle [50–52]. In this context,
bilateral floccular inhibition would provide one mechanism whereby infantile eso-
tropia and bilateral inferior oblique overaction could be generated without
“convergence.”
This body of evidence leads to the conclusion that infantile esotropia may also
incorporate subcortical optokinetic pathways such as the AOS. As genetic studies
provide molecular localization, we could find that lesions anywhere along this
expanded roadmap may provide the ocular motor derangements to derail develop-
ment of cortical binocularity and give rise to infantile strabismus. Depending on
their localization (visual cortex, AOS, cerebellar flocculus), targeted neuropharma-
cologic treatments may become available.
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Postscript
This article challenges the dogmatic position that essential infantile esotropia is
caused by a primary abnormality within the visual cortex. This Worthian concept of
essential infantile esotropia (EIE) arises a priori from the fact that the primary
visual cortex provides a necessary substrate for single binocular vision and stereop-
sis, and empirically from the finding that cortical motion pathways and correlative
pursuit functions are measurably abnormal. The intuitive reasoning has long been
that if the visual cortex subserves binocular vision and stereopsis, and these vital
Postscript 145
functions are disrupted in humans with EIE, then a primary aberration within the
visual cortex must causes the eyes to cross. There is no evidence that this is the case.
This commentary argues that the observed cortical aberrations could be the effect
rather than the cause of EIE. According to this Chavessian hypothesis, the early
binocular misalignment that disrupts cortical visual development can be generated
in the basement of the brain (i.e. within the cerebellar cortex).
As elaborated on in Chap. 17, there is a considerable body of evidence that this
is likely to be the case. Based on the studies of Anna Horwood, the long-held belief
that primary visual cortical aberrations disinhibit convergence is untenable, given
that normal neonates demonstrate large convergence movements, which are predic-
tive of normal binocular alignment. Increased medial rectus and inferior oblique
muscle tonus (the cause) is different from convergence (the effect).
So what is the source of this altered extraocular muscle tonus? The subcortical
accessory optic system, which remains operational in the first 2–3 months of human
infancy, is the only neurologic system that is equipped to cause individual extraocu-
lar muscles to overact and generate the dissociated torsional eye movements that
accompany EIE. As detailed in Chap. 17, extended subcortical neuroplasticity could
generate EIE in the absence of neurologic disease. Alternatively, early binocular
misalignment could perpetuate the function of these subcortical visual motion path-
ways and cause cortical motion pathways to secondarily remodel.
Whether the subcortical/cortical debate represents a dichotomy or a continuum
will soon be solved at the level of genetics. Does a genetic mutation or epigenetic
signal within the subcortical visual pathways turn off a promotor region for normal
inactivation of the AOS, leading to a cascade of secondary cortical changes, or does
failure to produce a functional protein within the binocular visual cortex generate
reversion to an older evolutionary program that secondarily reactivates that atavistic
subcortical system? Or are the subcortical and cortical visual systems both repro-
grammed by a combination of genetic and epigenetic factors? Time will tell.
Ironically, those who advocate for early strabismus surgery in EIE are often
those who attribute it to a primary fusion maldevelopment within the visual cortex
(in which case timing of surgery shouldn’t matter). The occasional finding that very
early strabismus surgery (at 3–4 months of age) can occasionally restore full stere-
opsis further militates against a primary cortical defect in binocular vision as the
underlying cause. Similarly, the association of monofixation syndrome (the inevi-
table outcome of infantile esotropia) with a stable sensory motor situation makes it
difficult to invoke the visual cortex as the underlying cause. You can’t have it both
ways. For how could same visual cortical aberration cause EIE preoperatively only
to fortify binocular vision postoperatively?
The Lizard’s Tail: An Ocular Allegory
12
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 147
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_12
148 12 The Lizard’s Tail: An Ocular Allegory
a b
Fig. 12.1 Conservation of angular momentum. (Modified from Alexander [7], with permission)
from side to side) [7], locking the body into its necessary spatial coordinates. A
similar effect is used by tightrope walkers who carry a long balancing pole (really a
counterbalancing pole). When the tightrope walker starts to tip to the left, he or she
raises the right side of the pole to restore vertical orientation (Fig. 12.1b) [7].
So what does this observation have to do with ophthalmology? The human
oblique muscles have evolved to become the “lizard’s tail” of the oculomotor sys-
tem. The ancestral function of these ocular appendages in lateral-eyed animals was
to gyroscopically stabilize the eyes during pitch rotation of the body [9–11], which
requires generating a movement of sufficient speed and magnitude to minimize full-
field retinal slip and maintain stability of the visual percept. These torsional eye
movements are sensorially driven by a coordinated input to the central vestibular
system from the eyes (luminance and optokinesis) and the labyrinths [12]. In infan-
tile strabismus, the absence of binocular vision recalls this mechanism and unleashes
a primitive torsional bias, leading to primary oblique muscle overaction and correla-
tive torsion [13]. What we call primary oblique muscle overaction may be driven by
a central vestibular imbalance involving the normal gyroscopic orientation of the
pitch plane that results from dissociated binocular visual input [13, 14]. Atavism is
the appearance in an individual of characteristics presumed to have been present in
some remote ancestor, or a reversion to an earlier biological type [15]. One clinical
hallmark of an atavism is that it tends to reappear when higher developmental func-
tions become disabled. In this setting, the primary oblique muscle overaction of
infantile esotropia may be a declaration of atavistic reversion from the cortical bin-
ocular system to its subcortical progenitor that uses the perceived vertical to estab-
lish the torsional coordinates of the eyes [13].
With rare exceptions [16], binocular humans do not have tails and some consider
the function of the human ocular oblique muscles to be largely vestigial. Ask a
patient to twist his or her eyes in one direction or the other, and you will be met with
The Lizard’s Tail: An Ocular Allegory 149
a blank stare. So what good are muscles that do not produce movements and are
inaccessible to volitional drive (except in trained subjects) [17]. Jampel [18, 19]
postulated that the human ocular oblique muscles function to prevent torsion by
counteracting the torsional actions of the vertical rectus muscles when the head or
body inclines. Because conjugate torsion of the eyes creates the perception of tilt
and disconjugate torsion is interpreted as stereoscopic pitch of the visual world [8],
torsional stability simplifies a variety of central computations, equipping the visual
cortex to construct a stable internal representation of visual space as it navigates the
3-dimensional world. The human oblique muscles are the only extraocular muscles
to have contrived functional origins within anterior orbits, directionalizing their
posterior insertions to anchor the primary retinal meridians as the rectus muscles
contract to rotate the eyes. Like the lizard’s swinging tail, the human oblique mus-
cles have been evolutionarily positioned and acrobatically reprogrammed to impose
rotational stability during combined head and eye movements as they coordinately
orchestrate binocular alignment in all fields of gaze. This is a wondrous bal-
ancing act!
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Postscript
Infantile esotropia is characterized by the idiopathic onset of crossed eyes within the
first 6 months of life [1]. It is often accompanied by crossed fixation, primary
oblique muscle overaction, latent nystagmus, and dissociated vertical divergence
[2]. This constellation of findings is also seen in the setting of prematurity and other
neurological disorders [3].
Patients with infantile esotropia retain a monocular nasotemporal optokinetic
asymmetry (MNTA) characterized by brisk monocular optokinetic responses to
nasally moving optokinetic targets and poor monocular optokinetic responses to
temporally moving optokinetic targets [4–8]. The phenomenon of MNTA is
believed to underlie latent nystagmus [4, 7–10]. In primates and humans, MNTA is
normally seen during the first several months of life [10–22]. Its spontaneous reso-
lution coincides with maturation of binocular cortical pursuit pathways that pro-
vide the temporal component for the optokinetic reflex from each eye [10–21].
Accordingly, the persistence of MNTA in infantile strabismus has been attributed
to a cortical pursuit deficit caused by early failure of cortical binocular vision to
develop [22–24].
Neonates show poor pursuit responses to focal moving stimuli but demonstrate
strong optokinetic responses to large full-field rotating stimuli [19–21]. These full-
field responses are attributed to the activation of subcortical optokinetic pathways
that modulate full-field rotational optokinetic responses and remain active until
maturation of binocular cortical pursuit pathways within the first 6 months of life
[19–21]. This MNTA is seen in lateraleyed afoveate animals during turning move-
ments, in which the full-field velocity of the nasalward optokinetic stimulus to one
eye determines optokinetic rotation of both eyes. Because MNTA antedates devel-
opment of the visual cortex both phylogenetically and ontogenetically, debate has
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 151
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_13
152 13 The Optokinetic Uncover Test
been waged as to whether the persistent MNTA in humans with strabismus is caused
by a cortical pursuit defect, a persistent activation of subcortical optokinetic path-
ways, or a combination of both [3, 8, 10, 19, 25].
Cortical pursuit movements in foveate animals require foveal (or perifoveal)
stimulation, while subcortical optokinetic movements in afoveate animals are gen-
erated by full-field optic flow detected by peripheral retina [26]. If the persistence of
MNTA in humans with infantile strabismus is caused solely by defective cortical
pursuit, its activation should necessitate foveal (or parafoveal) fixation. We devised
the optokinetic uncover test to examine the role of peripheral retinal motion input in
generating horizontal optokinetic responses in patients with infantile strabismus.
Methods
Results
On optokinetic testing, all patients showed brisk responses to nasally directed mon-
ocular optokinetic targets and poor responses to temporally directed optokinetic tar-
gets with each eye. During attempted pursuit of temporally directed optokinetic
targets, removal of the occluder from the contralateral eye produced an immediate
improvement in optokinetic responses. In 3 patients with alternating fixation, this
improved optokinetic response produced a fixation shift to the contralateral eye,
allowing the optokinetic response to be foveally driven by the eye receiving the
nasally directed stimulus. In 7 patients with a fixation preference for one eye, this
improved optokinetic response was accompanied by an immediate or delayed fixa-
tion shift when the preferred eye was uncovered and by maintenance of fixation
when the nonpreferred eye was uncovered. In 3 patients, 3-dimensional video-ocu-
lography (Sensorimotoric Instruments) was performed using a full-field optokinetic
stimulus projected on a flat surface (stripe width of 2.2° and velocity of 15° per sec-
ond with the patient viewing at 3 m). These recordings confirmed that uncovering the
contralateral eye produced improvement in the optokinetic waveform regardless of
whether a change in fixation occurred (Fig. 13.1). In 3 patients with mild
Results 153
10
5
0
–5
–10
Left
–15
–20
–25
–30
Right eye fixing Left eye fixing Left eye fixing Right eye fixing
Comment
“encephalized” as they are incorporated into the cortical pursuit system (Fig. 13.3)
[18, 19].
In humans, these same subcortical optokinetic pathways retain their nasalward
directional predominance and are believed to mediate the full-field horizontal opto-
kinetic responses that are observed in early infancy until they are rendered inactive
by the establishment of binocular cortical pursuit pathways (Fig. 13.3) [20, 21].
However, the general notion that they can retain function in the absence of cortical
input has been controversial [25, 40]. For example, it has been suggested that the
relative preservation of responses to nasally directed stimuli in patients with incom-
plete bilateral occipital lobe destruction could be owing to remnants of the subcorti-
cal projection to the NOT-DTN that may have been released from cortical control
[25, 40, 41]. Ter Braak and Schenk [42] described a patient with acquired cortical
blindness who retained some preservation of full-field optokinetic responses, but
subsequent studies [43, 44] have found no evidence of this effect. These findings
suggest that subcortical optokinetic pathways, once “shut off” after the first few
months of life, are incapable of reactivating [21, 22]. However, they do not address
the question of whether specific derangements in binocular cortical development
can act to preserve their function.
Our finding that peripheral retinal optokinetic input can override defective foveal
pursuit suggests that infantile strabismus allows these subcortical optokinetic path-
ways (which rely on peripheral retinal input) to remain operational. Unlike “decor-
tication,” infantile strabismus may maintain the function of the subcortical visual
pathways in a way that prevents them from being shut off. In 1983, Schor [8] pro-
posed that selective maldevelopment of cortical binocular vision could provide a
competitive advantage to reinforce the activation of direct subcortical projections
from the nasal retina of each eye to the contralateral NOT-DTN and thereby potenti-
ate their function. According to Hoffmann and colleagues [11, 17], the Hebbian
mechanism of synaptic formation predicts that only neurons firing in a correlated
manner (in this case, sharing the same direction sensitivity) become consolidated
during development. Through this activity-dependent mechanism, the ipsilateral
direction sensitivity of the NOT-DTN would preferentially allow crossed nasal ret-
inogeniculate pathways that connect monocularly through the visual cortex to
establish corticofugal connections to the ipsilateral NOT-DTN, enabling these latent
subcortical pathways to remain functional in infantile esotropia (Fig. 13.4) [11, 17].
In this way, infantile esotropia could remodel the cortical motion pathways to selec-
tively maintain the nasally biased subcortical gateway through which unbalanced
binocular visual input can turn the gears on these evolutionarily ancient eye move-
ment control systems (Fig. 13.4) [45]. The fact that cortical suppression can elicit
latent nystagmus [46], and that peripheral retinal input can also drive this response,
suggests that selective preservation of crossed corticopretectal connections may
allow these latent subcortical mechanisms to be expressed in infantile esotropia.
This explanation has several implications for the MNTA that characterizes infan-
tile esotropia. First, a selective preservation of crossed monocular nasal retinal pro-
jections from the contralateral eye would eliminate the temporal retinal projections
subserving cortical pursuit from the ipsilateral eye, explaining why the cortical
156 13 The Optokinetic Uncover Test
EOM
NOT-DTN LGN
NPH
V1
O
M NRTP
N STS
(MT/MST)
d.c.
P 10
Cer
P
R
F
VN
Fig. 13.2 Neuroanatomical pathways involved in the optokinetic reflex and optokinetic nystag-
mus system of the right half of the brain in the squirrel 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 cap of inferior olive; EOM, extraocular muscles; GS, Scarpa ganglion of the vestibular
nerve; LGN, lateral geniculate nucleus; NOT-DTN, nucleus of the optic tract–dorsal terminal
nucleus; NPH, nucleus prepositus hypoglossus; NRTP, nucleus reticularis tegmenti pontis; OMN,
ocular motor nuclei; PPRF, paramedian pontine reticular formation; STS, movement sensitive
areas of the middle temporal area (MT) and the medial superior temporal area (MST) in the cortex
around the superotemporal sulcus; V1, primary visual cortex; and VN, complex of the brainstem
vestibular nuclei. (Modified from the chapter by Behrens et al [35] with permission)
Comment 157
NOT-DTN NOT-DTN
LGN LGN
SCC SCC
Fig. 13.3 Normal cortical and subcortical projections during early human development. (Based
on a model proposed by Hoffmann [36]). 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 (inter-
rupted 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 opera-
tional (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 + L, cortical binocular cells (that are absent in
early infancy); and SCC, semicircular canals
can be generated from the visual cortex (top down) or from subcortical pathways
(bottom up). Fourth, as divined by Schor [8] 30 years ago, the associated monocular
corticofugal projections from the motion centers in the middle temporal area and
the medial superior temporal area to the other ipsilateral accessory optic nuclei that
control cyclovertical rotations of the eyes would (by a similar Hebbian mechanism)
explain the torsional optokinetic biases [6] and complex cyclovertical movements
that accompany latent nystagmus but remain conspicuously absent in a hemispheric
(binocular) pursuit defect. Fifth, the ability of subcortical visual pathways (Fig. 13.2)
to be activated bidirectionally via subcortical and cortical visual pathways would
render obsolete the debate about neuroanatomical localization in infantile eso-
tropia [3].
This study has several inherent limitations. First, we did not use a circular full-
field optokinetic apparatus, which produces the sensation of circularvection (the
false sensation of physical rotation) and is believed to be necessary to directly stimu-
late the visuovestibular system [50]. Although this testing paradigm would have for-
tified our conclusions, we were only able to confirm our observation using a flat
full-field optokinetic stimulus, which (like the optokinetic drum) probably elicits
pursuit responses in healthy individuals [50]. However, the enhancement of tempo-
ralward foveal optokinetic responses when peripheral retina of the nonfixating eye
was exposed to nasalward optokinetic motion demonstrates that cortical pursuit can-
not be the only system involved in the generation of MNTA (and latent nystagmus,
by inference). A selective preservation of crossed cortical projections to the NOT-
DTN from the nasal retina of the contralateral eye (Fig. 13.4) would allow nasalward
cortical pursuit pathways to generate subcortical visuovestibular eye movements
(with their associated torsional components), rendering these 2 classes of eye move-
ment indistinguishable in the setting of infantile esotropia. Second, some of the
patients with infantile esotropia had undergone previous strabismus surgery.
Consequently, the angle of the esotropic deviation was smaller than that seen in
infantile esotropia. Therefore, it cannot be assumed that the optokinetic uncover test
would have necessarily shown a positive response in these patients with infantile
esotropia prior to surgery. Nevertheless, all of our patients with unoperated infantile
esotropia showed this effect, and all of our patients had an angle of deviation large
enough to preclude perifoveal fixation, confirming that this binocular optokinetic
mechanism arises from the synthesis of foveal and peripheral retinal input. Third, the
inclusion of some patients with mild neurological disease could potentially challenge
the results of our study. However, given that all patients showed the same pattern of
responses on the optokinetic uncover test, our results suggest that these patients share
a common pathogenesis for their infantile esotropia. Fourth, because optokinetic
motion is known to displace the eyes in the direction of the fast phase [51], it might
be argued that this displacement could have led to the false conclusion that the
uncovered esodeviated eye was not fixating when the eye receiving temporal optoki-
netic stimulation was uncovered. As shown in the video, however, the fixating eye
was clearly evident in all patients, and videooculography confirmed that the nasal
retina of the esotropic eye could drive the optokinetic response.
In conclusion, the results of this study provide evidence that human subcorti-
cal optokinetic pathways may remain active in the presence of infantile
Comment 159
a b
Occluder Occluder
removed
NOT-DTN NOT-DTN
LGN LGN
SCC SCC
Fig. 13.4 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 tempo-
rally directed stimuli cannot be transmitted to the ipsilateral nucleus of the optic tract–dorsal ter-
minal 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 hemi-
sphere 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) opto-
kinetic 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 + L, cortical binocular cells (that are absent in infantile esotropia); and SCC,
semicircular canals
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Postscript
Our consistent observation that the nasalward optokinetic input to the cortically-
suppressed, esodeviated eye can override foveal input to the fixating eye demon-
strates that subcortical optokinesis remains operative in patients with EIE. This
clinical observation has potential implications for children with other visual disor-
ders as well. For example, it has been noted that children with cortical blindness do
not have optokinetic responses, and therefore inferred that the subcortical accessory
optic system (AOS) cannot remain operative. This conclusion should be taken with
a grain of salt for several reasons. First, this reasoning is tautological, as the ones
who do show optokinetic responses are deemed to have incomplete cortical blind-
ness. Second, although the normal accessory optic system remains functional in the
first 2–3 months of life, optokinetic responses have never been tested during this
early time period to see if they are initially present in children with cortical blind-
ness. Finally, we have reported that many infants with seemingly isolated cortical
visual injury have absent vestibulo-ocular reflexes, suggesting that coexistent sub-
cortical injury may not always be evident on neuroimaging studies. To my knowl-
edge, the potential role of the accessory optic system in motion detection in humans
with “blindsight” has not been investigated.
A Unifying Neurologic Mechanism
for Infantile Nystagmus 14
Infantile nystagmus is conjugate oscillation of the eyes that may appear in isolation
but more often appears in conjunction with afferent visual deficits, such as aniridia,
albinism, optic nerve hypoplasia, congenital retinal dystrophies, isolated foveal
hypoplasia, congenital cataracts, and achiasma. Infantile nystagmus is defined by
the following general features [1–3]:
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 165
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_14
166 14 A Unifying Neurologic Mechanism for Infantile Nystagmus
What Is the AOS?
As detailed in a recent publication [16], the AOS is a primary visual system receiv-
ing direct visual information from the retina via one or more accessory optic tracts
[19]. The AOS is responsible for visuovestibular interaction in afoveate animals
[20–22]. Its retinal input is derived from ON-type direction-sensitive ganglion
cells. The AOS neurons have large receptive fields (averaging approximately 40°
vertically and 60° horizontally), are direction selective, and have a preference for
slow-moving stimuli [19, 22–25]. The AOS processes information about the speed
and direction of movement of large textured parts of the visual world [20, 23, 24].
After accounting for an eye movement-generated slip (efference copy), the AOS
signals motion as a function of slip of the visual world over the retinal surface and
generates corrective eye movements to stabilize the retinal image [20, 23, 24]. As
Role of the AOS in Infantile Nystagmus 167
an analyzer of world motion, the AOS subserves visual proprioception in the afove-
ate animal [20, 23, 24]. Ontogenetically, the function of this subcortical optoki-
netic system antedates full maturation of the vestibuloocular reflex in lower
vertebrates [26, 27].
The AOS is involved in determining self-motion and is uniquely organized in a
vestibular coordinate system [20, 23, 24]. Experimental studies by Simpson and
colleagues [20, 23, 25] indicate that visual and vestibular signals that produce com-
pensatory eye movements are organized about a common set of axes derived from
the orientation of the semicircular canals. Because the AOS is directionally sensitive
to low-velocity movements, whereas the vestibular system typically responds to
movements of higher velocity, the AOS and vestibular labyrinths form 2 comple-
mentary systems to detect self-motion and promote image stabilization so that
objects in the visual world can be quickly and accurately analyzed [19, 20, 24, 25].
The AOS exists in all vertebrate classes [20, 28–30], including humans [31]. In
human infancy, the AOS is believed to generate full-field subcortical optokinetic
responses within the first 2 months of life before normal binocular cortical pursuit
pathways supersede this phylogenetically ancient subcortical system (Fig. 14.1)
[32–36].
Full-field optokinetic nystagmus and foveal pursuit are diametrically opposed ocu-
lar motor functions—you have to turn one off to have the other [36]. Failure to do
so produces a discordance wherein activation of one system provides visual feed-
back that reactivates the other system in a positive feedback manner. The following
clinical and experimental evidence support this mechanism as the substrate for the
horizontal oscillations of infantile nystagmus.
Pendularity
The pendular nature of infantile nystagmus may reflect the balanced antagonism of
these hierarchical optokinetic systems. Pendular pursuit oscillations result from
negative feedback and excessive time delay in the internal pursuit feedback loop.
Most of the control systems in nature (as well as those constructed by man) use
negative feedback (part of the output is fed back to subtract from the input). This
system produces a stable, time-invariant control structure. However, when there is
an increased delay in that feedback pathway, the resulting phase shift in the feed-
back signal causes an effective reversal in its sign. For example, a 180° phase delay
in a sine wave results in the positive portion coinciding with the original negative
portion. Because the feedback is negative by design (ie, the feedback signal is mul-
tiplied by −1), that delayed positive portion becomes negative and it sums with the
undelayed negative portion of the original signal. This signal continues to grow with
each cycle. The result is an oscillation similar to that produced in auditorium
168 14 A Unifying Neurologic Mechanism for Infantile Nystagmus
1 1
2 2
2 1
1 2
1 2
SCC SCC
MST MST MST
MT MST
MT MT MT
V1 V1 V1
V1
V1 monocular cells
Binocular cells
Fig. 14.1 Depiction of the Brain, as Viewed From Above, Showing Normal Cortical and
Subcortical Projections During Early Human Development. (a) Early in infancy, horizontal opto-
kinetic stimuli (shown as leftward or rightward motion) from each nasal retina are transmitted via
a subcortical pathway to the contralateral nucleus of the optic tract-dorsal terminal nucleus (NOT-
DTN) of the accessory optic system (solid red arrow), which is directionally sensitive to ipsiversive
motion (ie, nasalward for the contralateral eye). During this early stage of development, the corti-
cal pursuit pathways (shown as corticofugal projection from the middle temporal area-medial
superior temporal area [MT-MST] to the ipsilateral NOT-DTN) have not yet become functional
(interrupted green arrows). (b) Later in infancy, horizontal optokinetic responses become encepha-
lized, binocular cortical pursuit pathways become fully operational (solid green arrows), and sub-
cortical optokinetic pathways regress (interrupted red arrows). L indicates left eye monocular
cells; LGN, lateral geniculate nucleus; R, right eye monocular cells; R+L, cortical binocular cells;
SCC, splenium of the corpus callosum; and VI, primary visual cortex. Based on the model pro-
posed by Hoffmann [32]
microphone and speaker systems when the volume (gain) is too high for the short,
built-in time delay from microphone to speaker In infantile nystagmus, the antago-
nistic pursuit signals produced by coexpression of the cortical pursuit system and
the subcortical AOS (which functions as an afoveate full-field pursuit system) may
provide the substrate for the underlying pendular oscillation. Saccadic refixation
movements get secondarily superimposed to provide the variable waveforms that
have been identified within the oscillation [1].
Role of the AOS in Infantile Nystagmus 169
Directionality
Foveation Periods
Unique to infantile nystagmus is its association with brief foveation periods follow-
ing saccadic refixation [43–45]. These foveation periods utilize the preserved ability
of the fixation and cortical pursuit systems to stabilize the eyes on target until an
incursion of the subcortical optokinetic signal modulated by the AOS succeeds in
derailing these functions. During foveation periods, ocular motor functions, such as
fixation, pursuit, and the optokinetic and vestibuloocular reflexes, continue to func-
tion robustly in infantile nystagmus despite the superimposition of a pendular oscil-
lation [43–45].
Absence of Oscillopsia
The absence of oscillopsia during normal eye movements arises from an effer-
ence copy that reconstructs target and world motion so that the perception of
either is not influenced by the sweeping of the visual world across the retinas
[46–48]. The absence of oscillopsia in infantile nystagmus requires an online
efference copy to correct for a constantly changing (in amplitude and waveform)
oscillation [46–48]. There is some evidence [24] that efference copy may be
embedded within the functioning AOS. This would explain why rare patients
who first express infantile nystagmus in their adolescence do not invariably expe-
rience oscillopsia [49].
170 14 A Unifying Neurologic Mechanism for Infantile Nystagmus
Null Position
Time of Onset
Infantile nystagmus is usually noted between the second and third months of life
[4]. The developmental time course of infantile nystagmus overlaps that of infantile
esotropia in that both conditions first appear during early infancy when binocular
cortical pursuit pathways normally mature sufficiently to overtake the subcortical
optokinetic system. During the first 2 months of human life, cortical pursuit path-
ways have not fully matured, and full-field optokinetic eye movements are attrib-
uted to subcortical visual systems, such as the NOT and the AOS [34, 35]. Ontogeny
recapitulates phylogeny as the emergence of infantile nystagmus coincides with the
developmental maturation of the cortical pursuit pathways, which fail to exert their
predominance over the subcortical optokinetic pathways in the first 2 months of life.
When maturation of these cortical pathways is delayed or deranged, the subcortical
pathways continue to function, with the persistent antagonism between these 2 sys-
tems expressed in the form of infantile nystagmus. The fact that antagonism cannot
be established in children with cortical visual loss demonstrates how an intact visual
cortex is necessary for infantile nystagmus to develop [51–53]. Once the visual
cortex has developed, the subcortical optokinetic pathways normally cease to func-
tion, which explains why infantile nystagmus does not arise when central binocular
visual loss develops after early infancy [53].
This explanation does not account for cases of infantile nystagmus that have
been noted to appear at birth because the cortical pursuit system is not yet opera-
tional [33–35]. Animal models [54–57] suggest that genetic mutations can invert
the directional sensitivity of the subcortical AOS to allow this oscillation to be
expressed. Inversion of the retinal slip, the error signal of the subcortical optoki-
netic feedback loop, has been demonstrated in an albino rabbit [54] and in achias-
matic zebrafish belladonna mutant [55–57], which shows nystagmus in light with
waveform characteristics superficially resembling infantile nystagmus. Inversion
of the subcortical error signal within the AOS could produce an unstable feedback
mechanism that would tend to increase retinal slip [57]. That result would allow
Role of the AOS in Infantile Nystagmus 171
infantile nystagmus to manifest as the cortical pursuit system matures and would
preclude accurate calibration of pursuit damping. When mutational effects are
localized to the subcortical optokinetic system, electrophysiologic symmetry may
be preserved within the visual cortex. Conversely, some infants with normal vision
exhibit a transient nystagmus that disappears as the visual system matures in the
postnatal period [58], perhaps reflecting an atavistic expression of the normal AOS
before it is inactivated as normal connections from cortical pursuit pathways
become established. There is always the alternative that, in cases of isolated infan-
tile nystagmus appearing at birth, pursuit-system damping calibration is precluded
by some other factor (eg, genetic) independent of sensory loss or AOS directional
inversion.
Despite their apparent reversal, the optokinetic responses in infantile nystagmus are
not reversed; affected patients still generate the correct optokinetic responses during
each foveation period. These responses are driven by the (still intact) cortical pur-
suit system [44]. So-called reversed horizontal optokinetic responses in infantile
nystagmus are attributable to a shift in the null zone brought about by viewing hori-
zontal optokinetic targets [62, 63]. Underlying this dynamic null shift may be the
breakthrough responses of the AOS to full-field optokinetic stimuli that are reacti-
vated by the fully functioning pursuit system.
Optokinetic motion is known to displace the resting position of eyes in the direc-
tion of the fast phase [64]. For example, rightward-moving optokinetic targets
would displace the eyes to the right, simulating right gaze and generatinga right-
beating nystagmus. This binocular displacement would produce the appearance of a
reversed optokinetic nystagmus because the shift in gaze position to the right is
equivalent to a displacement of the null position to the left [53]. In this scenario, the
optokinetic shift in gaze position to the right tells the (still active) AOS that the
world has rotated to the left, reinforcing a right-beating nystagmus.
172 14 A Unifying Neurologic Mechanism for Infantile Nystagmus
Infantile nystagmus syndrome and latent nystagmus (also termed fusion maldevel-
opment nystagmus syndrome) [70] exist on a continuum wherein early loss of vision
in both eyes (eg, from bilateral congenital cataracts or bilateral optic nerve hypopla-
sia) precipitates infantile nystagmus, whereas early visual loss in one eye (eg, from
Role of the AOS in Infantile Nystagmus 173
The responses of the AOS are modulated by the flocculus within the vestibulocere-
bellum. Experimental findings from numerous studies [76] implicated an integral
role for the cerebellum in the modulation of infantile nystagmus. High-resolution
magnetic resonance imaging using voxel-based morphometry has found that gray
matter volume increases within cortical area V5/MT, the fusiform gyrus, and the
vestibulocerebellum. These changes may relate to the antagonism between cortical
pursuit and the subcortical AOS, the effort involved in maintaining fixation, or both.
In situ hybridization studies [9, 77, 78] on the embryonic human brain have
shown that the FRMD7 mutation that characterizes X-linked infantile nystagmus is
expressed in the developing forebrain, midbrain, cerebellum, primordium, spinal
cord, and neural retina. Barreiro et al [79] modeled the ocular motor system and
concluded that infantile nystagmus could result from adaptive cerebellar mecha-
nisms. Yoshida et al [80] found that mutant mice deficient in the glutamate receptor
δ2 subunit, which have limited plasticity of synapses onto Purkinje cells, also have
174 14 A Unifying Neurologic Mechanism for Infantile Nystagmus
Optic tract
nucleus
ADS
Vestibular nuclei and group Y NPT Flocculus
NATP
C2 F1 F2 F3 F4
Front
Sag Dentate DC
VLO
Ant C Prep Hyp
Hor C
Fig. 14.2 Diagram of Cortical and Subcortical Optokinetic Pathways Mediating Infantile
Nystagmus. We propose that cortico-mesencephalic-cerebellar pathways involving the middle
temporal area–medial superior temporal area (MT-MST), the accessory optic system (AOS), the
nucleus of the optic tract, and the flocculus of the cerebellum generate this horizontal oscillation.
Pathways for horizontal eye movements are shaded blue, pathways for movements around an
oblique horizontal axis are shaded in red, and mossy fiber pathways (unrelated to the climbing fiber
pathways mediating the AOS) are shaded in green. Ant C indicates anterior canal; C2, FI, F2, F3,
and F4, layers within the cerebellar flocculus; DC, dorsal cap; Front, frontal plane; Hor, horizontal
plane; Hor C, horizontal canal; Inf O, inferior oblique muscle; Lat R, lateral rectus muscle; Med
R, medial rectus muscle; MT, middle temporal area; MST, middle superior temporal area; NPT,
nuclei of the paramedian tracts; NRTP, nucleus reticularis tegmenti pontis; Prep Hyp, nucleus
prepositus hypoglossi; Sag, sagittal plane; Sup R, superior rectus muscle; VI, V2, cortical areas;
and VLO, ventrolateral outgrowth. Question marks indicate disputed projection of the nucleus of
the optic tract to the vestibular nuclei and the NRTP. (Modified from Voogd et al. [83])
infantile nystagmus while the cerebellar nodulus and uvula give rise to periodic
alternating nystagmus. These findings do not imply that infantile nystagmus is ana-
tomically localized within the cerebellum but that the vestibulocerebellum actively
participates in generating this oscillation (Fig. 14.2) [83].
Theories of Causation
Other causational theories for infantile nystagmus have invoked atavistic evolu-
tionary mechanisms to explain the oscillation. Yee et al [84] examined the role of
the subcortical AOS in humans and concluded from their optokinetic measure-
ments that infantile nystagmus must be due to an inherent defect in the subcortical
optokinetic system. Dell’Osso [85] rebutted this conclusion and pointed out that
the apparent full-field optokinetic defects could be attributed to the nystagmus
itself rather than to an inherent defect in the subcortical optokinetic system.
Kommerell and Mehdorn [86] ascribed infantile nystagmus to a primary defect in
the optokinetic system, which can no longer maintain retinal slip control.
Kommerell [87] and Kommerell et al [88] inferred that, because patients with
infantile nystagmus can differentiate velocities of optokinetic stimuli, the defect
cannot be in the retinocortical pathway and must be between the cortex and the
ocular motor centers in the brainstem. Optican and Zee [89] reproduced some of
the waveforms of infantile nystagmus by using a computer model to create a rever-
sal in the sign of the velocity pathway to make the neural integrator unstable.
However, the demonstration of simultaneous decelerating (due to a leaky neural
integrator) and accelerating (due to infantile nystagmus) slow eye movements in a
family who had both deficits disproved the hypothetical explanation [90]. Jacobs
and Dell’Osso [17] modeled infantile nystagmus as attributable to an intrinsic
instability in the foveal pursuit system. According to this model, evolution has
necessarily designed the cortical pursuit system to operate on the threshold of
oscillation to provide minimal response time without instability [18]. Given that
the normal horizontal pursuit system is intrinsically underdamped, it is almost
guaranteed that some individuals will fail to achieve the delicate balance between
quasiinstability (underdamped) and total instability (undamped), manifesting as
infantile nystagmus.
Harris and Berry [91, 92] have proposed that contrast sensitivity to low spatial
frequencies is enhanced by motion of an image across the retina and that the best
compromise between moving the image and maintaining the image on the fovea (or
its remnant) is to oscillate the eyes with jerk nystagmus with increasing velocity
waveforms, as is seen empirically in infantile nystagmus. During infancy, “evolu-
tion would need to tread a fine line by programming the development of ocular
motor control in tandem with foveal maturation to maximize visual contrast without
causing nystagmus” [92] (p68). Accordingly, loss of high spatial-frequency infor-
mation (whether caused by foveal, optic nerve, or optical aberrations) could lead to
an atavistic resurgence of low-frequency peripheral retinal visual mechanisms that
enhance their function during oscillation of the eyes [92].
176 14 A Unifying Neurologic Mechanism for Infantile Nystagmus
Conclusions
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Conclusions 181
Postscript
The strength of this analysis is that it explains virtually all components of infantile
nystagmus and affirms that this neurologic oscillation is confined within the visual
system. The recent finding that babies of “methadone moms” have delayed cortical
visual maturation leading to persistent infantile nystagmus also supports this
hypothesis. As summarized in Chap. 20, lines of evidence from several different
studies support an central role for the accessory optic system in that pathogenesis of
infantile nystagmus. How often the genetic mutations leading to idiopathic infantile
nystagmus exert their cellular effects via retinal electrochemical aberrations,
extended subcortical neuroplasticity, delayed visual cortical maturation, or by
enhancing an intrinsic ocular motor instability remains to be determined.
Intermittent Exotropia
and Accommodative Esotropia: Distinct 15
Disorders or Two Ends of a Spectrum?
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 183
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_15
184 15 Intermittent Exotropia and Accommodative Esotropia…
Accomodative Phoria
exotropia – adaptation
+
Accomodation Distance
Diopters Blur +
+ Realignment
CA/C
+ AC/A
Angle Disparity +
Convergence Near
+ Realignment
–
Intermittent Phoria
exotropia adaptation
Fig. 15.1 Systemic model representations of synkinetic interaction between accommodation and
vergence highlights that those two motor systems are cross-linked and produce blur-driven accom-
modation or convergence and disparity-driven convergence or accommodation [40]. Phoria adap-
tation then changes the motor output of the vergence system to adjust binocular alignment at
fixation distances that readily permit binocular fusion. Black lines signify major operational path-
ways, whereas dashed lines signify functional crosslinkages between these pathways. AC/A =
accommodative convergence-to-accommodation ratio; CA/C = convergence accommodation-to-
convergence ratio; + − positive feedback loop; − = negative feedback loop
186 15 Intermittent Exotropia and Accommodative Esotropia…
binocular visual system by the nature of the deviation and refractive error. Long ago,
Jampolsky [36] first presented evidence and maintained that there is no active cen-
trally mediated divergence and that apparent horizontal divergence movements of the
eyes are effectuated by deconvergence. In this way, both the central convergence and
accommodation centers function conjointly as an on-off system rather than a push-
pull system. It may reflect the existence of a central convergence center alone that is,
at its core, the neurologic substrate for intermittent exotropia and accommodative
esotropia, which both involve the modulation of central convergence effort.
But why should intermittent exotropia be more sensitive to disparity and accom-
modative esotropia be more sensitive to blur? Evolutionarily, the crossed nasal ret-
ina is more attuned to blur because there is minimal disparity when each eye sees a
different side, as is the case in fish and rabbits. However, the uncrossed temporal
retina is attuned to binocular disparity in the midline, which may explain in part the
expression of these compensatory responses under pathologic conditions in humans.
These mechanisms fit well with the original evolutionary functions of each hemiret-
ina, which must be retained in humans even after the evolution of crossed chiasm
segregates them into 2 hemispheres. The observation that both conditions are
anchored to the accommodative system (indirectly or directly) may help to explain
their gradual onset, their progressive nature, their occasional clinical overlap
[37–39], and their clinical manifestations.
Does the presence of tenacious proximal fusion in intermittent exotropia and
tenacious distance fusion in some cases of accommodative esotropia reflect an inde-
pendent compensating role of phoria adaptation in resetting horizontal vergence
tone? Although phoria adaptation usually is elicited by introducing prisms before
the eyes to induce a vergence error, this neural adaptation also can function to reset
the measured phoria and thereby negate strabismus. Strabismic patients may retain
the ability to respond to perturbations using this mechanism, perhaps even in
enhanced form. Furthermore, it makes physiologic sense that phoria adaptation
must be confined to the specific range of fixation distance that constrains the devia-
tion to fall within the limits of its compensatory fusional range. For this to be the
case, both intermittent exotropia and accommodative esotropia must invoke a bin-
ocular stabilization mechanism (i.e., phoria adaptation) that conceals the basic pho-
ria measurements that we extract after prolonged occlusion. Perhaps at a sensorimotor
level, near convergence is more robust (because of proximal or other factors), so
that the demands on phoria adaptation are actually less at near than at distance in
intermittent exotropia.
Phoria adaptation would explain how a distance-near disparity in accommoda-
tive esotropia can be managed effectively with medial rectus recessions to target the
near esodeviation without overcorrecting a much smaller distance esodeviation
[23]. This hidden mechanism would signify that some children with distance-near
disparity have a distance esodeviation that “flies under the radar” of our routine
clinical examination by prism and alternate cover testing. One test for this hypoth-
esis would be to repeat prism and alternate cover testing after prolonged occlusion
of one eye in patients with accommodative esotropia who have greater esodevia-
tions at near than distance. If phoria adaptation is operative, one would expect
Intermittent Exotropia and Accommodative Esotropia… 187
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Postscript 189
Postscript
In this piece, we invoke phoria adaptation to explain why strabismus surgery tar-
geted for the greater distance exodeviation does not overcorrect the smaller near
exodeviation in intermittent exotropia, and why strabismus surgery targeted for the
greater near esodeviation does not overcorrect the smaller distance esodeviation in
accommodative esotropia with high AC/A ratio. The selective effects of phoria
adaptation as a function of distance may reflect that fact that near fixation (where
convergence is superimposed upon a baseline exodeviation) brings the eyes closest
to orthotropia in intermittent exotropia whereas distance fixation (i.e. nonaccom-
modation) may bring the eyes close to orthotropia in accommodative esotropia.
Phoria adaptation will selectively compensate where it can.
This analysis led to my subsequent publication invoking phoria adaptation as the
major source of normal binocular tonus and an integral component of these inter-
mittent forms of horizontal strabismus. Thus, while visuo-vestibular tonus predomi-
nates under the dissociated binocular conditions that characterize infantile
strabismus, phoria adaptation provides the major extraocular muscle tonus pool
under most other binocular conditions. The myriad effects of phoria adaptation are
addressed more comprehensively in Chap. 18.
An Optokinetic Clue to the Pathogenesis
of Crossed Fixation in Infantile Esotropia 16
Case Description All 3 children had isolated infantile esotropia. When viewing a
horizontally rotating optokinetic drum under monocular viewing conditions, all dis-
played brisk optokinetic responses to nasalward optokinetic targets and poor opto-
kinetic responses to temporalward optokinetic targets. When viewing a horizontally
rotating optokinetic drum under binocular viewing conditions, all spontaneously
fixated with the eye exposed to nasalward optokinetic motion. When the horizontal
direction of optokinetic rotation was reversed so that the contralateral eye was
receiving nasalward optokinetic input, a spontaneous fixation shift occurred after 5
to 10 seconds.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 191
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_16
192 16 An Optokinetic Clue to the Pathogenesis of Crossed Fixation in Infantile Esotropia
nasal direction of the movement (relative to the nonfixating eye) rather than the
midline position of the fixated object.
During optokinetic stimulation, the spontaneous fixation shift in our 3 patients
was always from the eye with temporally directed optokinetic input to the eye with
nasally directed optokinetic input. Because infantile esotropia necessitates a large
refixation saccade to shift fixation in primary position, this observation challenges
the notion that foveal proximity to a stimulated area of nonsuppressed retina leads
to the phenomenon of crossed fixation. Our findings suggest that this peripheral
monocular nasotemporal asymmetry provides a stronger fixation stimulus than
foveal proximity.
Monocular nasotemporal optokinetic asymmetry arises from a subcortical opto-
kinetic system that is present in lateral-eyed afoveate animals [4], and is detectable
in normal binocular humans within the first several months of life [5]. It is medi-
ated by crossed (nasal) retinal pathways to the accessory optic system and nucleus
of the optic tract within the midbrain [4, 5]. In infantile esotropia, it persists
throughout life and is attributed to a failure of early cortical binocular vision to
develop [5].
The persistence of monocular nasotemporal optokinetic asymmetry in humans
creates the equivalent of a temporalward motion hemianopia during fixation with
either eye. In infantile esotropia, however, both nasal retinas become frontally
directed, raising the intriguing possibility that infantile esotropia provides a posi-
tional reconfiguration to restore bidirectional motion detection under binocular con-
ditions in humans with early binocular misalignment. This mechanism could explain
why the eyes remain crossed even during nonfixation, and why directional optoki-
netic reversal can elicit a fixation switch in humans with infantile esotropia. This
subcortical optokinetic response would remain operative despite cortical suppres-
sion of the esodeviating eye.
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Postscript 193
Postscript
This report demonstrates that patients with essential infantile esotropia (EIE) and
crossed fixation tend to switch fixation to the eye receiving nasalward optokinetic
input, suggesting that monocular nasotemporal optokinetic asymmetry (MNTA)
could underlie the phenomenon of crossed fixation. As MNTA derives from the
nasal retina, EIE can be conceptualized as a condition wherein the nasal retinas are
repositioned to lie within the frontal plane, thereby permitting bidirectional hori-
zontal motion detection (nasalward for each fixing eye). This explanation should not
imply that EIE is generated for the purpose of restoring horizontal motion bidirec-
tionality, but that the preexisting nasalward deviation of both eyes can be exapted
under binocular conditions to promote this critical function. This mechanism dove-
tails with the subcortical hypothesis in the following chapter to suggest that a
dynamic (optokinetic) imbalance could underlie a static deviation (essential infan-
tile esotropia).
Is Infantile Esotropia Subcortical
in Origin? 17
Introduction
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 195
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_17
196 17 Is Infantile Esotropia Subcortical in Origin?
The dissociated binocular rotations that accompany EIE are directionally driven
by unequal binocular visual input to the two eyes [7]. Each of these movements
have precise analogs in lower lateral-eyed animals, and the subcortical neuroana-
tomical pathways for all of these movements are well-established [7]. For example,
MNTA underlies the clinical phenomenon of latent nystagmus in humans [6, 22, 35]
while dissociated vertical divergence conforms to a human dorsal light reflex [7].
The expression of these atavisms suggests that this subcortical visual motion cir-
cuitry is integral to the pathogenesis of EIE [9, 10].
The fundamental evolutionary clue to the pathogenesis of EIE lies in the ubiquitous
finding of monocular nasotemporal asymmetry (MNTA) to horizontal optokinetic
stimuli. Patients with infantile esotropia show brisk nasalward, and absent tempo-
ralward optokinetic responses [6, 22, 35, 40, 42]. This MNTA persists throughout
life after surgical realignment of the eyes. Although it can be measured electro-
physiologically within the visual cortex this horizontal optokinetic asymmetry is
found in most lateral-eyed afoveate animals and used for the detection of full-
field optokinetic flow [27, 28, 36, 41]. It is modulated by the nucleus of the optic
tract and the dorsal terminal nucleus of the accessory optic system (NOT-DTN)
within the midbrain [28, 41]. In lateral-eyed animals, these centers generate visuo-
vestibular eye movements by sending visual motion signals through the vestibu-
locerebellum to the vestibular nucleus, which rotates the eyes at the appropriate
speed and direction to minimize retinal slip [1, 2, 13, 24]. These visuo-vestibular
pathways may continue to remain operational in humans with EIE.
Phylogenetically and ontogenetically, MNTA antedates development of the
visual cortex [9, 27, 36]. In lateral-eyed animals, MNTA may help to prevent tem-
poralward optokinetic stimuli from pinning the eyes back as the animal is moving
forward [28, 31, 41]. Another evolutionary advantage conferred by this reflex may
derive from the fact that the nose and mouth are positioned “nasally” to the eyes,
necessitating accurate nasalward optokinetic tracking as the animal turns toward
Evidence for a Subcortical Pathophysiology in Essential Infantile Esotropia (EIE) 197
potential food substances seen by either eye. During this turning movement, the
opposite eye is subjected to a temporalward full-field optokinetic stimulus that may
be of different velocity (when objects in its field of vision are situated at a different
distance). Having the eye with nasalward optokinetic input dictate the response for
both eyes allows the animal to accurately track the world it is turning toward and
disregard the world from which it is turning away. In normal human infants, this
subcortical full-field optokinetic imbalance is evolutionarily retained and expressed
within the first few months of life. Phylogenetically, this persistence of MNTA in
EIE represents another atavism. Ontogenetically, EIE often develops during the
time period when the subcortical motion pathways are normally turned off (i.e., 3–6
months of age). This time course is often taken as evidence that EIE must be cortical
in origin, but it could also signify that EIE represents a state of extended subcortical
neuroplasticity [7].
EOM
NOT-DTN LGN
NPH
V1
O
M NRTP
N STS
(MT/MST)
d.c.
P 10
P
Cer Cortical
R
F
VN
Subcortical
Fig. 17.2 Schematic diagram depicting the optokinetic system in the right half of the brain during
leftward rotation of the visual world (i.e., nasalward for the left eye). Bold lines depict nasalward
subcortical optokinetic pathways mediated by the nasal retina of each eye. Dashed lines depict
temporalward optokinetic pathways mediated by temporal retina of each eye. Cer, cerebellum;
dclO, dorsal cap of the inferior olive; GS, ganglion Scarpae; LGN, lateral geniculate nucleus, NOT,
nucleus of the optic tract; NPH; nucleus prepositus hypoglossus; NRTP, nucleus reticularis teg-
menti pontis; OMN, ocular motor nuclei; PPRF, paramedian pontine reticular formation; STS,
cortical pursuit areas MT and MST; around the superotemporal sulcus; V1, primary visual cortex;
VN, comlex of the brainstem vestibular nuclei. (Reproduced with permission from Behrens et al.
[2], Springer-Verlag, 1989)
The human subcortical full-field optokinetic system remains operational within the
first few months of human life [4, 5], (when MNTA is normally detectable in
infancy). As cortical binocular vision matures, symmetrical horizontal optokinetic
responses develop [3, 22]. Since subcortical motion pathways normally shut down
as cortical motion pathways develop, one could question whether the persistence of
subcortical reflexes could be a secondary consequence of a primary dysgenesis
within the visual cortex. The fact that the retinotectal pathways normally shut down
at approximately the same time as the binocular cortical pursuit pathways become
established certainly makes it plausible that their corticotectal connections with
NOT-DTN provide a contributory signal to inactivate them.
However, there is evidence that the subcortical pathways do not remain active in
the absence of cortical binocular vision [29]. Infants with homonymous hemianopia
due to early unilateral hemispherectomy, for example, do not continue to express
MNTA to full-field optokinetic input beyond first few months of life [29]. This
observation suggests that subcortical pathways may have a predefined period of
plasticity that causes them to shut down after several months of infant life, regard-
less of whether functioning binocular cortical pursuit pathways can establish corti-
cotectal connections with the NOT-DTN. There is something unique in children
with EIE that permits subcortical motion pathways within the human accessory
optic system to remain operational [8]. A mutation or metabolic perturbation within
200 17 Is Infantile Esotropia Subcortical in Origin?
the subcortical pathways could also enhance their neuroplasticity and preserve their
function throughout life, increasing baseline esotonus and derailing binocular align-
ment to necessitate a secondary remodeling of the visual cortex, which could then
serve to further perpetuate their function. Although corticofugal output can influ-
ence subcortical plasticity in the mature mammalian visual motor system [25], any
direct role of normal corticotectal connections in extinguishing the subcortical
visual motion pathways in human infancy remains to be established.
Conclusion
SUBCORTICAL CORTICAL
Visuovestibular System Nascent Pursuit System
(Full-Field, Afoveate) (Cortical, Foveate)
NOT-DTN MT/MST
AOS
MNTA MNTA
Cortical
MT/MST EIE/LN Disinhibition
of Convergence
Cortical Inhibition
of Convergence
Horizontal Alignment
Single Binocular Vision
Fusion
Stereopsis
Fig. 17.3 Flow chart juxtaposing primary subcortical and cortical mechanisms for development
of EIE. MNTA, monocular nasotemporal asymmetry; AOS, accessory optic system; DTN, dorsal
terminal nucleus of the accessory optic system; EIE, essential infantile esotropia; LN, latent nys-
tagmus; MST, medial superior temporal area; MT, middle temporal area; NOT, nucleus of the
optic tract
202 17 Is Infantile Esotropia Subcortical in Origin?
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loop stimulation on optokinetic nystagmus in squirrel monkeys (Saimiri sciu-
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p. 453–72.
2. Behrens F, Grusser O-J, Roggenkämper P. Open and closed-loop optokinetic
nystagmus in squirrel monkeys (Saimiri sciureus) and in man. In: Allum JHJ,
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sions. Arch Ophthalmol. 2005;123:837–42.
8. Brodsky MC. The accessory optic system: the fugitive visual control system in
infantile strabismus. Arch Ophthalmol. 2012a;130:1055–9.
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Ophthalmol. 2012b;130:1199–202.
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extended subcortical neuroplasticity. Invest Ophthalmol Vis Sci. 2018;59:1964–8.
11. Brodsky MC, Fray KF. Does infantile esotropia arise from a dissociated devia-
tion? Arch Ophthalmol. 2007;125:1703–6.
12. Brodsky MC, Klaehn LD. An optokinetic clue to the pathogenesis of crossed
fixation in infantile esotropia. Ophthalmology. 2017;124:272–3.
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Freund HJ, Buttner U, Cohen B, Noth J, editors. Progress in Brain Research.
Amsterdam: Elsevier; 1986. p. 225–33.
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origin of essential infantile esotropia, microstrabismus, accommodative esotro-
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15. Collewijn H. The oculomotor system of the Rabbit and its plasticity. Berlin/
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16. Hebb DO. The organization of behavior. New York: Wiley and Sons; 1949.
17. Hoffman KP. Neural basis for optokinetic defects in experimental models with
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Conclusion 203
Postscript
Single binocular vision and stereopsis are known to reside within the visual cortex.
By extension, essential infantile esotropia (EIE) has long been considered to be
cortical in origin. This a priori assumption is seemingly corroborated by the finding
of optokinetic asymmetry within cortical motion pathways. This analysis examines
the alternative possibility that extended subcortical neuroplasticity can lead to
EIE. It invokes the argument that persistent binocular optokinetic input at the sub-
cortical level (i.e. monocular nasotemporal asymmetry) can drive the eyes inexora-
bly into an esotropic position despite the presence of alternating cortical suppression.
Accordingly, EIE can be genetic or epigenetic (i.e. arising experientially from early
binocular misalignment) in origin.
This model further invokes the mechanism proposed by Hoffmann hypothesis
wherein the cortical visual motion pathways become secondarily reconfigured to
match the subcortical template. Once this occurs, then cortical suppression of either
eye can actively drive the dissociated eye movements that characterize EIE. Whether
cortical suppression allows the subcortical motion pathways to generate these
movements (Schor C: Subcortical binocular suppression affects the development of
latent and optokinetic nystagmus. Am J Optom Physiol Opt 1983;60:481–502), or
Postscript 205
whether the remodeled cortical pursuit pathways drive the movements through the
NOT-DTN has yet to be determined. Either way, the system eventually reverts to a
subcortical blueprint that can now be funneled in through the visual cortex. And
since the dissociated eye movements conform to the original function of the subcor-
tical pathways, we can begin to understand how and why this cortical reconfigura-
tion must have happened. This mechanism is likely age dependent, with subcortical
pathways known to predominate within the first few months of human life, and the
altered cortical motion pathways predominating later. The dichotomy between cen-
tral and peripheral retina, as described by Marshall Parks (see Binocular Vision in
Duane’s Clinical Ophthalmology, Lippincott, 1991) may have had its evolutionary
origin in the subcortical (extrafoveal) versus cortical (foveal) visual systems. The
primate visual cortex recapitulates this dichotomy in its dorsal (visual motion) and
ventral (visual detail) pathways.
It is critical to distinguish cause and effect in disease pathogenesis. This analysis
raises the possibility that EIE may be subcortical in origin, with the cortical motion
pathways becoming secondarily reconfigured to match their subcortical template.
Accordingly, decreased binocularity and stereopsis that accompany EIE may be
secondary rather than primary. Nevertheless, they may give rise to cortical suppres-
sion which can perpetuate EIE and its dissociated deviations. At the very least, it
seems that aberrations within the subcortical and cortical visual motion pathways
are both integral to the pathogenesis of EIE. Accordingly, the misguided term fusion
maldevelopment syndrome should be discarded, as it connotes a chain of causation
that necessarily originates within the visual cortex, and thereby converts a termino-
logical confusion into a conceptual one.
Phoria Adaptation: The Ghost
in the Machine 18
Introduction
I esteem it a great honor to be invited to give the 50th Scobee Lecture here in my
hometown of San Francisco. Dr. Richard Scobee was revered as a consummate
teacher, clinician, and diagnostician. His teachings permeate our field to such a
degree that we don’t always recognize them in the fabric of what we do. Dr. Scobee
served as a founding member of the American Orthoptic Council and founded the
American Orthoptic Journal, which was first published in 1951, just a year before
his untimely death. His definitive textbook, The Oculorotary Muscles [2], provided
the foundation for the field of orthoptics, and created a cogent framework for what
was to become an emerging field of study. So it was nice that, while preparing this
lecture, so many of Dr. Scobee’s seminal observations seemed to resurface within a
new context. I hope that my choice of topics helps to carry the torch and honor
his memory.
A phoria refers to any deviation of the eyes from one of alignment (orthophoria)
when binocular visual input is preempted [3]. Strabismus occurs when a phoria
persists under binocular conditions, resulting in a manifest deviation (a tropia).
Strabismus surgery is predicated on the notion that alternate occlusion unmasks the
underlying phoria. By targeting surgical dosing to the measured phoria, the resting
position of binocular alignment can be reset to near zero, allowing fusion to actively
maintain binocular alignment. As pointed out by Lancaster, it is tacitly assumed that
the resting deviation when the fusion reflex is preempted (i.e. under conditions of
monocular fixation) is identical to the resting deviation when the fixation reflex is
prevented in both eyes. A recent study has shown this to be the case for humans with
normal binocular vision (Brodsky) [4].
Despite the fact that our eyes stay straight, binocular vision is not a static func-
tion [5]. Maintaining binocular vision is a dynamic force, controlled by both
momentary peripheral fusion (termed motor fusion), tonic vergence, and vergence
adaptation (termed phoria adaptation) that provides the necessary neural integra-
tion to minimize the baseline phoria and thereby stabilize binocular vision. Changes
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 207
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_18
208 18 Phoria Adaptation: The Ghost in the Machine
Phoria adaptation is the slow buildup of tonic vergence innervation to establish and
sustain a new vergence set point following placement of a prism over one or both
eyes [7–10]. Phoria adaptation recalibrates extraocular muscle tonus to realign the
visual axes and thereby meet the demands of binocular alignment [11], and restore
the dynamic range (or fusional reserve) in which fast fusional vergence can function
[12]. Phoria adaptation resets binocular alignment toward orthophoria; thereby
compensating for developmental, environmental, or pathologic alterations in the
binocular mechanism [12]. Because phoria adaptation is stimulated by the effort put
forth by the fast fusional vergence system, repeated tests of fusional amplitude will
increase the limits of fusional movement [13, 14]. After removal of a prism, the rate
of disappearance of this change in tonus is inversely proportional to the length of
time this tonicity is maintained [6, 8, 13, 14].
Clinical investigation into phoria adaptation as a malleable but invisible force
encompasses the history of pediatric ophthalmology, capturing the interest of many
progenitors of our field such as Hering [15], Maddox [16], Hofmann and
Bielschowsky [1, 17], Ogle [18, 19], Reinecke [10], and Guyton [20]. Its slow time
decay was characterized by Hofmann and Bielschowsky over a century ago [1, 6, 9,
20]. Phoria adaptation provides an innervational repository to modulate vergence
tonus to stabilize horizontal, vertical, and torsional binocular alignment [21].
Phoria adaptation serves to establish a new equilibrium as the starting position
for further vergence eye movements and thus decreases the effort for either conver-
gence or divergence eye movements [22]. This resiliency and tenacity means that a
measured phoria can change transiently following active vergence effort [5, 13, 14].
Because of its lingering effects, however, phoria adaptation can alter measurements
of both vergence ranges (which reflect activity of both the fast and the slow ver-
gence system) and also of vergence facility (which examine the patient’s ability to
shift rapidly between divergence and convergence as a function of the fast fusional
vergence system) [7, 23]. For this reason, phorias are routinely measured before
vergence amplitudes are measured [6]. Although phoria adaptation is classically
elicited by introducing prisms before one eye to induce a vergence error, this com-
pensatory mechanism can insinuate itself into many forms of intermittent strabis-
mus. Because phoria adaptation has a memory, its slow dissipation serves to mask
or conceal a large phoria on clinical examination [17].
Phoria adaptation operates independently of the fast vergence system and thereby
minimizes the fixation disparity that results in the need for vergence control [9, 18].
Ogle and Prangen found that an increase in slow fusional vergence was
Measurement of Phoria Adaptation 209
Binocular disparity does not generate phoria adaptation. There is always binocular
disparity in a complex world (in different planes even when the eyes are aligned),
and this binocular disparity is a necessary stimulus for stereopsis. While binocular
retinal image disparity provides the stimulus for the fast fusional vergence system,
it is the motor signal from the fast fusional vergence system that serves as the error
signal for phoria adaptation [5]. The input to the slow neural integrator for phoria
adaptation is generated by the output or effort of fast fusional vergence. Because
there has to be an effort to fuse for phoria adaptation to be recruited, fixation dispar-
ity induced by a conflict in vergence and accommodation may provide a driving
stimulus for prism-induced phoria adaptation [9] (Fig. 18.1). The fast vergence sys-
tem has a neural integrator with a short halflife of 10–15 s [7, 14]. By contrast,
phoria adaptation consists of a more stable neural integrator that leaks with a much
longer time constant (varying from minutes to several days) [5, 9]. The output of the
slow neural integrator allows for a reciprocal reduction of the output of fast fusional
vergence by means of the negative feedback loop in which the system is trying to
adapt until the phoria is controlling the entire response [9]. As the slow fusional
vergence system charges up, the fast fusional vergence system decays to maintain a
constant total output [6, 7]. This feedback loop presumably reduces the fatigue and
eyestrain that would result from the prolonged use of the fast vergence system [7–9].
Phoria adaptation can be estimated but not precisely quantified, due in part to the
fact that it is slower to dissipate after an extended period of fusional demands [6, 9,
13, 17]. Measurement of fusional vergence amplitudes using a prism bar placed
before one eye under binocular conditions and prolonged monocular occlusion are
two examination techniques that help to uncover the degree to which phoria adapta-
tion is operative [9]. Depending on the preexisting level of phoria adaptation, prism
bar testing can serve to induce or dissipate phoria adaptation (a critical distinction
not determinable by the examiner), whereas prolonged occlusion removes the input
of disparity vergence and presumably dissipates any preexisting phoria adaptation.
Although monocular occlusion may dissipate phoria adaptation, it remains unclear
whether prism bars and monocular occlusion operate by equivalent mechanisms
and produce similar endpoints, since monocular occlusion seems to exert other
210 18 Phoria Adaptation: The Ghost in the Machine
Fast
fusional
Ac vergence Tc
Target + Motor output
+
binocular + FD
+ + Vergence
paraliax - + + response
Pc
Phoria
adaptation
Fig. 18.1 Diagram depicting feedback interaction between slow and fast fusional vergence. The
fast fusional vergence system uses binocular retinal image disparity as its input signal. Phoria
adaptation uses the motor output of the fast fusional vergence system as its error signal to reset
tonic vergence and reduce fixation disparity. The output of this slow neural integrator then allows
for reciprocal reduction of fast fusional vergence by means of a negative feedback loop to keep the
final innervational output constant
effects that go beyond disrupting fusional vergence and dissipating phoria adapta-
tion (similar to those of Marlow occlusion) [6, 24]. Monocular occlusion may also
disrupt other adaptive processes that have different time constants.
Phoria adaptation begins to initiate quickly but builds and dissipates more slowly [1,
6, 9]. Even brief presentations of small disparities may be enough to alter phoria
adaptation [14]. Estimates for initiation have ranged from as little as 100 ms to
30 min of binocular visual experience [9, 32, 33]. These wide ranges probably
reflect some degree of immediate initiation followed by a slower buildup period [7].
According to Henson and North, phoria adaptation is substantially complete after
2–3 min of binocular visual experience [33]. An earlier study by Ogle et al. had
found that vertical prism adaptation was complete within 3–7 min and that
Protean Clinical Manifestations 211
adaptation followed a logarithmic curve [18]. A larger prism takes longer to adapt
to but does not increase adaptation time in a linear manner [7].
However, the rate at which phoria adaptation dissipates varies considerably,
ranging from 30 s in some individuals to several days in others [7]. This measured
variability may in part reflect the inherently different time constants for phoria
adaptation between individuals, as well as the inverse correlation between the
degree of phoria adaptation and the duration of the previous vergence effort [7, 13,
34]. Rosenfield et al. found that 20 min of monocular occlusion was sufficient to
estimate the latent deviation [35]. However, a longstanding phoria adaptation may
require hours to fully dissipate [5, 31, 36–38].
Phoria adaptation infuses our binocular alignment with a kind of inertia [13], which
can corrupt or override our clinical measurements. Conversely, when phoria adapta-
tion is fully operational, the phoria that we measure with prism and alternate cover
testing can be spuriously low. Prolonged patching often increases the measured
deviation by breaking down phoria adaptation to reset binocular misalignment
toward its uncompensated value.
Phoria adaptation comes in many guises, with clinical effects that are much more
protean than generally appreciated. What follows are some examples of conditions
in which alternate cover testing of the phoria measurement fails us when the super-
imposed effects of phoria adaptation are not recognized.
1. Stillness: Over a century ago, Sherrington remarked that “The role of muscle as
an executant of movements is so striking that its office in preventing movement
and displacement is somewhat overlooked” [39]. An overlooked but essential
quality of phoria adaptation is the stillness that it confers upon our binocular
alignment. While friction accounts for the stillness of many inanimate objects,
stillness is a formidable task for biological systems. As articulated by Carpenter:
“Why do we take stillness so much for granted? … That while a muscle is main-
taining a constant length and thus doing no work, the actin-myosin bonds
between the sliding filaments are ceaselessly breaking and reforming, consum-
ing ATP and so wastefully turning precious energy into heat rather than work.
To maintain a stationary gaze demands that the brain sends continual com-
mands to the contractile fibers in the ocular muscles and poses as many prob-
lems as moving the eyes fast. Thus, stillness is not an easy task” [40]. In fact,
biological systems are never truly still, as evidenced by the tiny fixational intru-
sions which promote stability of visual perception via the Troxler phenomenon
[41]. Phoria adaptation also explains the recent observation that the brain does
not require visual input to maintain binocular alignment in the dark on a short-
term basis [4].
2. Orthophorization: Despite the baseline divergent anatomical position of the
eyes within the orbits, normal humans have little or no measurable horizontal
phoria on alternate cover testing [10]. Phoria adaptation provides the interstitial
212 18 Phoria Adaptation: The Ghost in the Machine
Accommodative Phoria
esotropia adaptation
–
+ ++
Accommodation Distance
Diopters Blur ++ realignment
CA/C
Target
distance
AC/A
Angle Disparity +
+ Near
+ Convergence
++ realignment
–
Intermittent Phoria
exotropia adaptation
Fig. 18.2 Diagram depicting the general mechanism of phoria adaptation as it influences
vergence-accommodation interaction. Blur-driven accommodation implements a similar neural
integrator as does disparity-driven vergence to program tonicity. Note the cross-linking that gener-
ates accommodation-linked convergence (AC/A) and convergence-linked accommodation (CA/C).
For both convergence and for the accommodative system, the fast system provides the immediate
phasic response to a change in disparity or blur. The tonic adaptation uses the motor output of the
fast system to provide a slower adjustment in the tonic level of accommodation or vergence. In
both systems, phoria adaptation is driven by the motor signal and not by sensory input to the motor
signal. And in some people (like those with accommodative esotropia), accommodation drives
vergence to produce an AC/A ratio while in others like those with intermittent exotropia, conver-
gence drives accommodation to produce a CA/C ratio. Phoria adaptation explains why strabismus
surgery targeted for the distance deviation does not overcorrect the near deviation in intermittent
exotropia, and why strabismus surgery targeted to the near deviation does not overcorrect the dis-
tance deviation in accommodative esotropia. (Reprinted from Ref. [12], with permission)
transitory effects of phoria adaptation, which throws the vergence system into
disarray by causing an esophoria, perhaps contributed to by the secondary
effects of tonic accommodation [49].
5. Intermittent exotropia: Patients with intermittent exotropia display a greater
distance than near exodeviation on initial alternate cover testing. It was Scobee
who noted that the near exodeviation usually increases to approximate the dis-
tance exodeviation after 45 min of monocular occlusion [2]. This “tenacious
proximal fusion” [50] reflects the role of phoria adaptation, which impedes
expression of the full near exodeviation [12]. Although it is generally believed
the presence of large convergence amplitudes are necessary to control intermit-
tent exotropia, it may be that phoria adaptation serves this function [12], which
would explain why correlative fusional convergence amplitudes (i.e. equal to
the amplitude of the exodeviation plus superimposed convergence amplitudes)
are no longer detectable immediately following surgical correction of the exo-
deviation (Fig. 18.2). So phoria adaptation also explains why we can target
surgery for the distance deviation and not overcorrect the near deviation (except
in the rare patients who have a true high AC/A ratio).
214 18 Phoria Adaptation: The Ghost in the Machine
Prism adaptation or prolonged monocular occlusion can also increase the mea-
sured angle in patients with intermittent exotropia and more accurately direct
surgical dosing [51–53]. However, its use as a stand-alone treatment to reduce
hemiretinal suppression and restore binocular control in intermittent exotropia
has never met with success, perhaps owing to the correlative dissipation of pho-
ria adaptation that ensues. While some patients with intermittent exotropia
immediately break down to their full deviation (indicating control by fast ver-
gence), others break down slowly with prism and alternate cover testing, sug-
gesting that phoria adaptation is being used to control the deviation. The
prognosis for relative postoperative control in these two overlapping groups is
unknown.
6. Congenital superior oblique palsy: Patients with congenital superior oblique
palsy are said to have “increased fusional vergence amplitudes,” meaning that
these patients will “eat up prisms” and show a large induced vertical deviation
when a base down prism bar is increased progressively before the paretic eye.
This stepwise dissipation of fusional control to yield a measured deviation far
beyond the normal range of vertical divergence probably reflects the slow dis-
sipation of phoria adaptation [6, 54]. As with intermittent exotropia, these
“increased vertical fusional amplitudes” disappear immediately following suc-
cessful strabismus surgery, signifying that phoria adaptation rather than periph-
eral fusion was masking the true hyperdeviation.
7. Postoperative prism adaptation: When performing strabismus surgery in
adults who have worn prisms to treat diplopia, we admonish them to discon-
tinue their prism glasses postoperatively [6, 8]. We do this not only to prevent
postoperative diplopia, but to prevent a prism-induced recurrence of the devia-
tion. Instructing patients not to wear their prisms after strabismus surgery
betrays an unconscious awareness of phoria adaptation.
8. Physiologic skew deviation: Despite the predicted effects of otolithic input to
the extraocular muscles, normal binocular individuals have no measurable
hyperphoria during head tilt to either side [55]. Phoria adaptation may provide
the “antivestibular” force that maintains orthophoria during head tilt. Despite its
slow decay, it retains a fluidity which allows it to kick in to different degrees in
different fields of gaze. This is not surprising since the vestibular system and the
binocular system each rely upon a central neural integrator with a slow decay
(velocity storage for the vestibular system and phoria adaptation for the eyes) to
produce a perseverative signal that stabilizes balance and perception. This inter-
connection may explain why phoria adaptation can modify vestibulo-ocular
adaptation [56] and vice versa [5, 57]. As pointed out to me by Cameron Parsa,
MD, and Stephen Archer, MD, many patients have tiny amounts of skew devia-
tion (on the order of 1–2 PD) yet they are unable to fuse it, and they do not
prism adapt when a vertical prism is used to eliminate the diplopia. So the cen-
tral vestibular pathways that generate skew deviation may also be integral to the
pathogenesis of phoria adaptation.
9. Fusional vergence amplitudes: As divined long ago by Ogle et al., phoria
adaptation is not a measure of fusional reserves, since the same fusional reserves
Neural Substrate 215
are measurable before and after adaptation [18]. Strong evidence for this mech-
anism for phoria adaptation is evident in patients with intermittent exotropia as
well as those with congenital superior oblique palsy. Phoria adaptation can cre-
ate the false appearance of large fusional vergence amplitudes when it masks a
latent phoria [14]. Phoria adaptation explains why the measured divergence
break and recovery points are lower when tested after convergence [7, 23,
58–60]. It also explains Scobee’s observation that fusional vergence ampli-
tudes, as measured at near, seem to correlate with the horizontal phoria mea-
surement as measured at distance [61]. Scobee found that patients with greater
amounts of exophoria at distance tend to have greater amounts of measured
fusional divergence at near, while patients with esophoria at distance tend to
have smaller amounts of prism divergence at near. Thus, the slow dissipation of
phoria adaptation is indistinguishable from the measurement of fusional diver-
gence amplitudes.
10. Spread of comitance: Although we generally attribute spread of comitance to
extraocular muscle contracture, phoria adaptation can initiate and perpetuate
spread of comitance long before extraocular muscle contracture develops [22,
25, 26, 31]. For example, Kolling et al. found that prolonged occlusion restored
incomitance in patients with superior oblique palsy and spread of comitance
[62]. Similarly, the esodeviation in sixth nerve palsy may become more comi-
tant over time, a phenomenon sometimes attributed to ipsilateral medial rectus
contracture. However, medial rectus contracture should produce a spread of
incomitance. So this paradoxical spread of comitance is more likely attributable
to phoria adaptation, which can vary in different fields of gaze. As emphasized
by Guyton [20], phoria adaptation can eventuate in muscle length adaptation
and secondary anatomical extraocular muscle contracture.
Neural Substrate
Phoria adaptation has been considered by some [10, 63], but not others [64], to be a
cerebellar response, but midbrain vergence-related neurons may also play a role
[65]. Visual adaptations to reversing prisms in the cat are preempted by lesions in
the vestibulocerebellum [66]. In monkeys, removal of the cerebellar vermis (but not
the flocculus) has been shown to disrupt phoria adaptation [67, 68].
When prisms are placed before one eye of an orthotropic patient, the visual
image discordance is interpreted as an error signal. Adaptation and learning to cor-
rect motor error signals is modulated at the level of the vestibulocerebellum [10,
69]. It, therefore, seems likely that phoria adaptation is similarly mediated by both
climbing and mossy fibers within the cerebellum, which implement modifiable,
adaptive, and “plastic” responses [10] (Fig. 18.3) [70]. The cerebellum receives
continuous information via the mossy fiber system. The climbing fiber system origi-
nates from the inferior olivary nucleus and provides a powerful timing and error
signal to Purkinje cells. The inferior olivary nucleus acts as a comparator of motor
commands from the cerebral cortex, brainstem nuclei and receives feedback from
216 18 Phoria Adaptation: The Ghost in the Machine
Inhibitory
interneuron
Parallel fiber
Purkinje
cell
Granule
cell
Deep Climbing
cerebellar fiber
nucleus
Mossy
fiber
Inferior
olive
Phoria
adaptation
Tonic Fast
vergence Binocular vergence motor
innervation alignment error signal
Fig. 18.3 Diagram depicting cerebellar candidate pathways for the modulation of phoria adapta-
tion. Complex spikes from mossy fibers transmit ongoing vergence information from the two eyes
while slow simple spikes from climbing fibers input through inferior olive provide the error signal
to modulate Purkinje cell output to the deep cerebellar nuclei and generate phoria adaptation.
(Modified from Ref. [70], with permission)
receptors via the spinal cord, visual system, or vestibular organs. The inferior olive
senses the error and recalibrates the tonic firing of the Purkinje cells. The increased
frequency of inferior olivary nucleus discharge and complex spikes in the Purkinje
cells triggers long-term depression of the synapse between the parallel fibers and
the Purkinje cells, thereby resetting the single spike discharge rate to produce the
necessary motor learning and adaptation. The Purkinje cell provides profound inhi-
bition via GABA to the cerebellar nuclei, which provide the output of the cerebel-
lum. It is therefore likely that the neural circuitry subserving phoria adaptation is
not localized to a specific area but modulated by cortical, midbrain, and cerebellar
circuitry [10, 65, 66].
Conclusions 217
Future Questions
Is there a critical time period for the development of phoria adaptation? Could
deficient phoria adaptation (due to a leaky neural integrator) engender some com-
mon forms of strabismus? [6, 8, 71, 72] Can hemiretinal suppression impede pho-
ria adaptation to allow intermittent deviations to perpetuate with time? [25] Since
horizontal phoria adaptation is stronger in the convergent direction [6, 9, 73],
could phoria adaptation function as an on-off system rather than a push-pull sys-
tem? Accordingly, could accommodative esotropia reflect a state of augmented
phoria adaptation (driven by the accommodative cross-linkage instead of by ver-
gence input), and intermittent exotropia reflect a state of deficient phoria adapta-
tion? Do measured horizontal fusional divergence amplitudes simply represent
the dissipation of horizontal phoria adaptation rather than the effects of an active
divergence mechanism? Is deficient phoria adaptation associated with specific
symptomatology? [8] Conversely, could some patients grow sensorially accus-
tomed to a high level of phoria adaptation and feel subjectively uncomfortable
when strabismus surgery removes the need for it? Do prism adaptation and pro-
longed monocular occlusion ultimately uncover the effects of phoria adaptation to
the same extent? Should strabismus surgery be calibrated according to the mea-
sured phoria or to the deviation produced by the induced phoria adaptation? Does
phoria adaptation supersede dissociated esotonus following surgical realignment
of the eyes? Are the horizontal, vertical, and torsional components of phoria adap-
tation [25] anatomically segregated but mediated by the same final common path-
ways? Can a focal neurological lesion selectively disable a single component of
phoria adaptation?
Conclusions
Phoria adaptation provides the central tonus mechanism that recalibrates binocular
alignment to minimize the demands on fusional vergence, and thereby promote sen-
sorimotor fusion. It is generated by a central neural integrator, probably within the
cerebellum, that provides inertia, stability, and plasticity to human binocular vision.
Although this shadow control system is often considered synonymous with “tonic
vergence,” phoria adaptation generates a deeper level of perseverative tonicity to
maintain baseline extraocular muscle tonus so that sensorimotor fusion can be
quickly and accurately superimposed. Clinically, its activation cannot readily be
distinguished from its dissipation. Phoria adaptation is deeply entrenched before
most of our prism measurements take place, making its effects virtually invisible to
the clinician. As it so often adulterates our clinical strabismus measurements, it is
truly the ghost in the machine.
As the effects of phoria adaptation may linger even after the largest possible
phoria is measured [74], this analysis begs the question of whether a “true phoria”
can even exist [17], or whether all measured phorias inevitably incorporate some
degree of phoria adaptation. The ubiquity and robustness of this cerebellar learning
218 18 Phoria Adaptation: The Ghost in the Machine
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Postscript
In this Richard G. Scobee lecture, I argue that phoria adaptation is the major source
of binocular tonus. I extrapolate this notion to explain the tenacity of normal bin-
ocular vision. I grapple with the notion that much of what we designate as fusional
vergence amplitudes represents phoria adaptation. Finally, I propose that phoria
adaptation is a normal cerebellar learning process that is driven by a neural integra-
tor that provides plasticity to real world binocular function. Phoria adaptation pro-
vides a unifying explanation for myriad clinical effects that exert themselves in
normal binocular vision and in different disease states.
Postscript 223
As the binocular tonus mechanism for phoria adaptation differs from that which
superintends dissociated eye movements in infantile strabismus, one can conclude
that human binocular vision can be superintended by two distinct tonus pools, each
having a strong contribution from the neural integrators within the cerebellum, with
the operative coordinate system dictated by genetic, neurologic, epigenetic, and
environmental factors as yet undetermined. It is clear, however, that newer this bin-
ocular tonus system can still kick in to maintain binocular alignment after surgical
realignment of the eyes in children with essential infantile esotropia. Perhaps, a
secondary maldevelopment of phoria adaptation could explain the delayed onset of
consecutive exotropia in some surgically-treated patients.
Monocular Nasotemporal Optokinetic
Asymmetry—Unraveling the Mystery 19
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 225
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_19
226 19 Monocular Nasotemporal Optokinetic Asymmetry—Unraveling the Mystery
a b
c d
Fig. 19.1 Monocular nasotemporal optokinetic asymmetry. (A–B) In the human with infantile
strabismus, monocular viewing results in strong nasalward optokinetic responses (solid lines) and
poor temporalward optokinetic responses (dashed lines) relative the viewing eye. (C) In a fish that
is swimming forward, temporalward optokinetic responses (dashed lines) in response optic flow
would rotate the eyes posteriorly and impede visualization of the oncoming visual scene. (D) In a
fish that is turning to the right, nasalward rotation of nearby contours in the right hemifield of
visual space necessitates a strong and accurate optokinetic response in the right eye (solid curved
line). As the fish turns away from the left hemifield of visual space, more distant visual contours
seen by the left eye (dashed curved line) are moving at slower velocities; therefore, the nasalward
visual input to the right eye dictates the optokinetic responses of both eyes
But this is only half the story. When the animal turns to one side, it needs to
track the visual world that is moving nasally, because that is the area it is turning
toward (Fig. 19.1D). Because the nose and mouth are median (ie, nasal) to the
eyes, accurate tracking of nasalward circumferential optic flow may help to stabi-
lize the rapid visual motion of the approaching hemifield, as the animal rotates
toward a salient nearby nutrient [17] to inspect it with the nose and ingest it with
the mouth. At the same time, the opposite eye is seeing an area from which the
animal is turning away, with objects likely at a further distance and therefore pro-
ducing less retinal slip, so that the eye receiving nasalward visual input must dic-
tate the optokinetic response for both eyes. So MNTA provides an ingenious
evolutionary solution to enable the lateral-eyed animal to use optokinetic rotation
to visually navigate both translation and rotation. In the zebrafish pretectum, mon-
ocularly and binocularly driven clusters of directionally selective horizontal motion
detection cells are hierarchically organized to distinguish between translational
and rotational optic flow [19].
Ontegeny recapitulates phylogeny for primitive reflexes within the developing
human visual system. In humans with infantile strabismus, the cortical optokinetic
pathways reconfigure to the monocular subcortical template, so that MNTA can be
modulated through the cortical pursuit centers as they establish ipsilateral connec-
tions to each NOT-DTN [20–23]. The resulting cortical pursuit asymmetry can now
generate MNTA to foveated optokinetic targets [24–26]. In this setting, infantile
esotropia confers the binocular advantage of restoring horizontal optokinetic bidi-
rectionality in the presence of MNTA [24]. Horizontal visual motion can be fol-
lowed in either direction simply by switching fixation to the eye receiving nasalward
input [27]. In infantile esotropia, the human nasal retinas realign in the frontal plane
but continue to function as they originally did in lateral-eyed afoveate animals.
What an evolutionary wonder!
References
1. Atkinson J. Development of optokinetic nystagmus in the human infant and
monkey infant: an analogue to development in kittens. In: Freeman R, editor.
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228 19 Monocular Nasotemporal Optokinetic Asymmetry—Unraveling the Mystery
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Postscript
This article examines the reason why monocular nasotemporal asymmetry (MNTA)
is integral in lateral-eyed afoveate animals, and shows how subcortical visual
reflexes cause the visual cortex to secondarily reconfigure when the substrate for
binocular vision fails to develop within a critical time window. Many pediatric oph-
thalmologists do not routinely check for MNTA, which is surprising, as I have found
it to be a critical determinant of timing of strabismus that often dictates surgical
dosing. MNTA readily distinguishes essential infantile esotropia from accommoda-
tive esotropia, which requires higher surgical dosing to restore binocular alignment.
As clinical overlap can exist (e.g. essential infantile esotropia with an accommoda-
tive component), and a parent’s estimate of onset can be misleading, the absence of
MNTA suggests that you may need to augment the standard recession. However, it
is important to use an optokinetic drum with colored animals rather than stripes to
engage a young child’s attention.
Although the argument that ontology recapitulates phylogeny, first popularized
by Haeckel in 1866, has been refuted as a general neurodevelopmental principle, it
is indisputable that this concept applies to the development of human visual motor
reflexes. The persistence of MNTA in humans with infantile strabismus demon-
strates this principle. The fact that this optokinetic reflex is phylogenetically ancient
(present long before the development of the visual cortex), further shows that its
cortical representation is secondary to a reconfiguration of the visual motion cortex
to the subcortical visual template in binocular humans with early onset strabismus
(actually, fish are also “binocular,” as both eyes see at the same time). Once embed-
ded in patients with strabismus, MNTA persists indefinitely throughout life, making
it a valuable neurodiagnostic sign. MNTA is easy to detect clinically, and it anchors
the examiner to the evolutionary nature of infantile strabismus. So give it a go.
Infantile Nystagmus—Following
the Trail of Evidence 20
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 231
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1_20
232 20 Infantile Nystagmus—Following the Trail of Evidence
the nucleus of the optic tract and the dorsal terminal nucleus of the AOS as the subcorti-
cal visual system permanently ceases to function [15].
In 2014, Lou Dell’Osso and I proposed that this critical period for subcortical
neuroplasticity may be necessary to prevent conflicting optokinetic signals from
arising, since following a foveated object to the right (cortical pursuit) causes the
entire visual world to sweep across the retina to the left, creating a full-field optoki-
netic stimulus that would drive the eyes away from the foveated target [16]. Delayed
cortical visual development, as has been documented in infantile nystagmus [17],
could allow the subcortical optokinetic system to remain operational. If the subcor-
tical AOS failed to become extinguished, both optokinetic systems would trigger
each other in a positive feedback loop. This reverberating circuit would generate an
“optokinetic tug-of-war,” causing the eyes to oscillate horizontally, producing what
we have come to recognize as infantile nystagmus. This mechanism seemed to
explain a number of clinical findings, most notably: (1) infantile nystagmus is iso-
lated to the visual system; (2) infantile nystagmus begins at 2–3 months of age,
when the AOS normally turns off; (3) humans with infantile nystagmus usually have
“reversed” optokinetic responses, consistent with the notion that the still-functional
subcortical optokinetic system overrides foveal pursuit to generate the optokinetic
response; and (4) humans with cortical visual loss don’t have infantile nystagmus,
again showing that the cortical and subcortical visual motion systems both have to
remain operational to produce this palindromic effect on eye position [16].
More recently, Yonehara and colleagues [18] studied the mouse model idiopathic
infantile nystagmus caused by the FRMD7 gene and found that the gene affected a
starburst amacrine cell within the retina, providing asymmetric inhibition to
direction-selective retinal ganglion cells that project to the nucleus of the optic tract
and the dorsal terminal nucleus of the AOS and subserve horizontal optokinesis.
This experimental study was confounded by the finding that FRMD7 mice do not
display infantile nystagmus despite the fact that they have complete loss of horizon-
tal optokinetic responses. Nevertheless, it dovetailed nicely with our proposed
mechanism that a primary retinal abnormality involving the optokinetic system
could lead to infantile nystagmus. More importantly, it suggested, that, if you drill
down deep enough to hone in on the starburst amacrine cell, what we call “idio-
pathic” infantile nystagmus could actually arise from defective electrochemical
transmission at the cellular level, qualifying it nosologically as a sensory disorder
associated with infantile nystagmus.
In a landmark study published last year, Winkelman et al [19] studied 3 patients
with infantile nystagmus associated with an X-linked form of congenital stationary
night blindness due to NYX or CACNA1F mutations, along with a mouse model
that had the same NYX gene mutation and also lacked the functional nyctalopin
protein on bipolar cells at their synapse with the photoreceptors. Both the patients
and the mice showed horizontally oscillating eye movements at a frequency of
4–7 Hz. Impressive was the fact that, in the mouse model, the ON direction-selec-
tive ganglion cells, which detect global motion and project to the AOS, showed
electrical oscillations at the same frequency as the ocular oscillations. The indi-
vidual retinal ganglion cells oscillated asynchronously in the dark, but the oscilla-
tions became synchronous when the retina was stimulated with light and contrast,
Infantile Nystagmus—Following the Trail of Evidence 233
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8. Lee H, Sheth V, Bibi M, et al. Potential of handheld optical coherence tomogra-
phy to determine cause of infantile nystagmus by using foveal morphology.
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234 20 Infantile Nystagmus—Following the Trail of Evidence
Postscript
Many subclinical retinal disorders still fly beneath the radar of our clinical detection
and are therefore diagnosed as “idiopathic” infantile nystagmus. It is not my inten-
tion to state categorically that underlying retinal dysfunction is strictly necessary for
infantile nystagmus to develop. It is certainly possible that some cases of infantile
nystagmus arise spontaneously from an inherent instability of the ocular motor sys-
tem. Most cases of so-called “idiopathic” infantile nystagmus have underlying
genetic mutations. As the downstream effects of these mutations are further eluci-
dated, it will be interesting to see whether the cellular aberrations they produce can
be confined to the ocular motor system, or whether they inevitably perturb the sen-
sory visual system to some degree.
Glossary of Terms
Accessory optic system (AOS) the three terminal midbrain nuclei that receive and
process crossed retinal input related to full-field motion of the visual world
Anterior canal predominance excessive central innervation from the portions of
the otoliths corresponding to the anterior semicircular canals, leading to tonic
upgaze with bilateral inferior oblique muscle overaction.
Atavism a modification of a biological structure whereby an ancestral trait reappears
after having been lost through evolutionary change in successive generations.
Central vestibular imbalance A disruption in input to the vestibular system due
to stimulation or injury to the brainstem or cerebellar neurologic pathways that
transmit information from the labyrinths and eyes.
Cerebellar flocculus a portion of the ancient vestibulocerebellum concerned with
integrating visual and vestibular information to provide ocular stabilization, and
with coordination of the eyes and head during gaze pursuit.
Cortical suppression Inhibition of visual input from one eye within the visual
cortex, usually seen in individuals with strabismus.
Dissociated deviations the tonic deviations and variable binocular movements that
arise from unequal binocular visual input in the setting of infantile strabismus
Dissociated esotonus a differing degree of tonic medial rectus innervation (unre-
lated to convergence) generated by monocular fixation with each of the two eyes
in infantile strabismus.
Dissociated vertical divergence A dorsal drift of either eye evoked by monocular
occlusion or spontaneous cortical suppression of the hyperdeviating eye in indi-
viduals with infantile strabismus.
Dorsal referring to either the back of the organism or the top of the skull
Dorsal light reflex (DLR) a body tilt (or a vertical divergence of the eyes) induced
by unequal luminance input to the two eyes in lateral-eyed animals.
Dorsal terminal nucleus of the accessory optic system (DTN-AOS) the com-
ponent of the midbrain accessory optic system that, together with the nucleus
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 235
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1
236 Glossary of Terms
Chapter 1, Brodsky MC. Dissociated vertical divergence: a righting reflex gone wrong. Arch
Ophthalmol. 1999;117:1216–22.
Chapter 2, Brodsky MC. DVD remains a moving target. J AAPOS. 1999;3:325–7.
Chapter 3, Brodsky MC, Donahue SP. Primary oblique muscle overaction: the brain throws a wild
pitch. Arch Ophthalmol. 2001;119:1307–14.
Chapter 4, Brodsky MC. Do you really need your oblique muscles: adaptations and exaptations.
Arch Ophthalmol. 2001;120:820–8.
Chapter 5, Brodsky MC, Tusa RJ. Latent nystagmus: vestibular nystagmus with a twist. Arch
Ophthalmol. 2004;122:202–9.
Chapter 6, Brodsky MC. Dissociated vertical divergence: perceptual correlates of the human dor-
sal light reflex. Arch Ophthalmol. 2002;120:1174–8.
Chapter 7, Brodsky MC, Gräf MH, Kommerell G. The reversed fixation test: a diagnostic test for
dissociated horizontal deviation. Arch Ophthalmol. 2005;123:1085–7.
Chapter 8, Brodsky MC, Fray KJ. Does infantile esotropia arise from a dissociated deviation? Arch
Ophthalmol. 2007;125:1703–5.
Chapter 9, Brodsky MC. The accessory optic system: the fugitive visual control system in infantile
strabismus. Arch Ophthalmol. 2012;130:1055–9.
Chapter 10, Brodsky MC. Visuo-vestibular eye movements. Arch Ophthalmol. 2005;123:837–42.
Chapter 11, Brodsky MC. An expanded view of infantile esotropia: bottoms up! Arch Ophthalmol.
2012;130:1199–202.
Chapter 12, Brodsky MC. The lizard’s tail: an ocular allegory. Ophthalmology. 2013;120:225–6.
Chapter 13, Brodsky MC, Klaehn L. The optokinetic uncover test: a new insight into infantile
esotropia. Arch Ophthalmol. 2014;131:761–5.
Chapter 14, Brodsky MC, Dell’Osso LF. A unifying neurological mechanism for infantile nystag-
mus. JAMA Ophthalmol. 2014;132:761–8.
Chapter 15, Brodsky MC, Jung J. Infantile exotropia and accommodative esotropia: distinct disor-
ders or two ends of a spectrum? Ophthalmology. 2015;122:1544–6.
Chapter 16, Brodsky MC, Klaehn L. An optokinetic clue to the pathogenesis of infantile esotropia.
Ophthalmology. 2017;124:272–3.
Chapter 17, Brodsky MC. Is infantile esotropia subcortical in origin? Prog Brain Res.
2019;248:183–93.
Chapter 18, Brodsky MC. Phoria adaptation: the ghost in the machine. J Binoc Vis Ocular Motility.
2020;70:1–10.
Chapter 19, Brodsky MC. Monocular nasotemporal optokinetic asymmetry: unravelling the mys-
tery. J AAPOS. 2019;23:219–21.
Chapter 20, Brodsky MC. Infantile nystagmus: following the trail of evidence. J
AAPOS. 2020;24:70–1.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 239
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1
Index
A B
Accessory optic system (AOS), 115, 117, 123, Bagolini bar, 15
135, 137, 163, 166, 167, 231 Balance organs, 26, 66, 68, 76, 89, 126,
canal-based coordinate system, 121 132, 147
decortication, 118 bilaterally symmetrical organs func-
DTN and LTN neurons, 120 tion as, 126
neuroanatomical connections, 116 Balancing movement, 20
photic stimulation, 120 Base-in prism, 97, 99–102
primary visual system, 117 Bidirectional horizontal motion
signals self-motion, 117 detection, 193
spherical enclosure, monocular optokinetic Bielschowsky Head Tilt Test, 90
stimulation, sensitivity, 119 Binocular control mechanisms,
visual system, 117 1, 11, 107, 183
Accessory optic tract (AOT), 115, 166 Binocular deviations, 14, 115, 212
Accommodation-linked convergence (AC/A), Binocular disparity, 6, 15, 83, 185, 186, 209
184, 185, 189, 213 Binocular eye movements, 95
Accommodative esotropia, 183–187, Binocular misalignment, 81, 115, 137, 145,
212–213 192, 201, 204, 211
Adaptation, 36, 45–46, 50, 56–58, 89, 108, Binocular tonus mechanism, 223
183–187, 189 Binocular torsional control, 50
reversion from exaptation to, 56–58 Binocular vertical cyclodisparity, 54
Adler, Alfred, 233 Binocular vision, 7, 10, 11, 26, 34, 35,
Alexander’s law, 71, 73 37, 38, 47, 58, 62, 65, 66, 83, 89,
Amacrine, 232, 233 115, 121, 124, 127, 129, 130, 132,
Angular momentum, 147, 148 138, 144, 145, 148, 151, 155, 166,
Anterior canal or posterior canal 173, 198, 199
system, 30, 31 Binocular visual disturbance, 43
A-pattern strabismus, 25, 31–34, 38, 86 Binocular visual imbalance,
Asymmetrical esodeviation, 96 88, 129, 135, 170
Asymmetry, 5, 6, 19, 66, 86 Binocular visual input
monocular nasotemporal optokinetic, 81, abrupt fluctuations, 85
127, 151, 152, 154, 155, 157–159, physiologic imbalance in, 129
192, 193, 196, 197, 199, 200, 225, Binocular visual system, 62
226, 229 Bipolar cells, 232
nasotemporal, 66, 67, 86 Blur-driven accommodation
Nasotemporal optokinetic, 67 convergence, 175, 176, 213
Atavism, 148, 196, 197 Body tilt, 4, 5, 9, 10, 17, 37, 46, 83, 84, 86,
Atavistic torsional movements, 141 90, 93, 128
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 241
M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in
Children, https://doi.org/10.1007/978-3-030-62720-1
242 Index