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Show The Neural Mechanism for Latent (Fusion Maldevelopment) Nystagmus Lawrence Tychsen, MD, Michael Richards, MD, Agnes Wong, MD, PhD, Paul Foeller, MS, Dolores Bradley, PhD, Andreas Burkhalter, PhD Abstract: Latent nystagmus (LN) is the by-product of fusion maldevelopment in infancy. Because fusion maldevelopment-in the form of strabismus and am-blyopia- is common, LN is a prevalent form of pathologic nystagmus encountered in clinical practice. It originates as an afferent visual pathway disorder. To unravel the mechanism for LN, we studied patients and nonhuman primates with maldeveloped fusion. These experiments have revealed that loss of binocular connections within striate cortex (area V1) in the first months of life is the necessary and sufficient cause of LN. The severity of LN increases systematically with longer durations of binoc-ular decorrelation and greater losses of V1 connections. Decorrelation durations that exceed the equivalent of 2-3 months in human development result in an LN prevalence of 100%. No manipulation of brain stem motor pathways is required. The binocular maldevelopment originating in area V1 is passed on to downstream extrastriate regions of cerebral cortex that drive conjugate gaze, notably MSTd. Conjugate gaze is stable when MSTd neurons of the right and left cerebral hemispheres have balanced binocular activity. Fusion maldevelopment in infancy causes unbalanced monocular activity. If input from one eye dominates and the other is suppressed, MSTd in one hemisphere becomes more active. Acting through down-stream projections to the ipsilateral nucleus of the optic tract, the eyes are driven conjugately to that side. The unbalanced MSTd drive is evident as the nasalward gaze-holding bias of LN when viewing with either eye. Journal of Neuro-Ophthalmology 2010;30:276-283 doi: 10.1097/WNO.0b013e3181dfa9ca 2010 by North American Neuro-Ophthalmology Society Latent nystagmus (LN) is a common subtype of path-ologic nystagmus observed in human and nonhuman primates (1). It is linked strongly to binocular maldevel-opment in infancy, from either strabismus or deprivation of monocular spatial vision (amblyopia). LN is characterized by a conjugate horizontal slow-phase drift of eye position that is directed nasalward with respect to the viewing eye (2,3). When viewing switches from eye to eye, the direction of the slow-phases reverses instantan-eously: leftward when the right eye (RE) is fixating and rightward when the left eye (LE) is fixating (Fig. 1). The severity of the nystagmus (and its conspicuity during clinical examination) increases when one eye is covered, hence the term latent. When the nystagmus is evident with both eyes open, it is called manifest LN. LN is distinguished easily during clinical examination from congenital nystagmus, also called the infantile nys-tagmus syndrome (INS), by the fact that LN has instantaneous reversal of direction with alternating fixa-tion. By eye movement recording, it is distinguished also in waveform. The waveform of LN is always that of de-creasing velocity and linear trajectory, whereas that of INS is of increasing velocity and pendular trajectory (2). Eye movement recordings or high magnification clinical inspection with a slit-lamp biomicroscope or ophthal-moscope frequently reveals a superimposed small tor-sional movement. Seminal contributions to our understanding of the clinical features of LN have been made by Dell'Osso et al (2,4), who have also clarified the historical origins of LN's various terms. In 1872, Faucon (5) first described what we now appreciate as manifest LN. In 1912, Fromaget and Fromaget (6) introduced the term nystagmus latent. These early reports of LN were reviewed by Sorsby (7) in 1931. From the Departments of Ophthalmology and Visual Sciences (LT, AW, PF) and Anatomy and Neurobiology (LT, AB), Washington University School of Medicine, St Louis, Missouri; Department of Ophthalmology and Vision Sciences (MR, AW), University of Tor-onto, Ontario, Canada; and the Yerkes Regional Primate Research Center (DB), Atlanta, Georgia. Supported by a Grant EY10214 (L.T.) from the National Institutes of Health, AWalt and Lilly Disney Award for Amblyopia Research from Research to Prevent Blindness (L.T.), Summer Student Research Scholarship from the University of Toronto Faculty of Medicine (M.R.), Grant MOP 67104 (A.W.) and a New Investigator Award (A.W.) from the Canadian Institutes of Health Research. Address correspondence to Lawrence Tychsen, MD, Room 2 South 89, St Louis Children's Hospital, Washington University School of Medicine, One Children's Place, St Louis, MO 63110; E-mail: tychsen @vision.wustl.edu. 276 Tychsen et al: J Neuro-Ophthalmol 2010; 30: 276-283 State-of-the-Art Review Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. The oxymoron manifested latent nystagmus was introduced by Kestenbaum (8) in 1947, who emphasized that LN is often observed in patients with strabismus when they view with both eyes open. Although infantile esotropia is the leading association with LN, any disorder that perturbs development of bin-ocular fusion in infancy, such as monocular or severe binocular deprivation, will produce LN and manifest LN (9,10). The National Institutes of Health Committee on Eye Movement and Strabismus classification (11) has therefore recommended that the terms LN/manifest LN be replaced by the etiologic descriptor fusion maldevelopment nystagmus. DEVELOPMENT OF FUSION ELIMINATES NASALWARD VISUAL CORTEX BIASES Behavioral studies have shown that the postnatal de-velopment of binocular sensory and motor functions in normal infant monkeys parallels that of normal infant humans but on a compressed time scale: one week of monkey development approximates 1 month of human (12-15). Binocular disparity sensitivity and binocular fu-sion are absent in human and monkey neonates. Stereopsis emerges abruptly in humans during the first 3-5 months of postnatal life (16-20) and in monkeys, during the first 3-5 weeks (14), achieving adult-like levels of sensitivity. V1 horizontal axonal connections are key components of fusion development and maldevelopment (Fig. 2). Binoc-ularity in primates begins with horizontal connections be-tween V1 ocular dominance columns (ODCs) of opposite ocularity (21-23). These connections are immature in the first weeks of life, conveying crude weak binocular responses (24-26). Maturation of binocular connections requires correlated (synchronous) activity between right eye and left eye geniculostriate inputs (27,28). Decorrelation of inputs (Fig. 3), produced by binocular noncorrespondence, causes loss of horizontal connections over a period of days in V1 of kittens (27,29). The inference from our experimental results and clinical studies is that similar losses occur over a period of weeks in V1 of monkeys and over a period of months in V1 of children. Binocular decorrelation also promotes in-terocular suppression (Fig. 4) as a further hindrance to fusion (1). In the first months of life in humans and weeks of life in monkeys, monocular motion visual evoked potentials reveal a nasotemporal asymmetry (30-33). Monocular preferential looking testing reveals greater perceptual sensitivity to na-salward motion (34). Monocular pursuit and optokinetic tracking reveal biases favoring nasalward target motion (12,35-38). These nasalward motion biases are pronounced before onset of sensorial fusion and stereopsis but system-atically diminish thereafter. They are retained in subtle form in normal adult humans and can be unmasked using FIG. 1. Nasalward gaze asymmetries in strabismic human and monkey. A. Latent nystagmus in gaze holding. When the subject views with the right eye, both eyes have a nasalward slow-phase drift, followed by temporalward refoveating fast-phase microsaccades. The direction of the nystagmus reverses instantaneously when the left eye fixates so that the slow phase is nasalward with respect to the fixating eye. B. Pursuit. Horizontal smooth pursuit is asymmetric during monocular viewing. Pursuit is smooth (normal) when target motion is nasalward in the VF. Pursuit is cogwheel (low gain) when the target moves temporalward. The movements of the 2 eyes are conju-gate, and the direction of the asymmetry reverses in-stantaneously with a change of fixating eye so that the direction of robust pursuit is always for nasalward motion in the visual field (likewise for OKN). FIG. 2. Neuroanatomic basis for binocular vision. Mon-ocular retinogeniculate projections from left eye (tem-poral retina, nasal visual hemifiled) and right eye (nasal retina, temporal hemifield) remain segregated up to and within the input layer of ocular dominance columns (ODCs) in V1, layer 4C (striate visual cortex). Binocular vision is made possible by horizontal connections be-tween ODCs of opposite ocularity in upper layers 4B and 2/3 (as well as lower layers 5/6, not shown). RE inputs = red; LE inputs = blue. State-of-the-Art Review Tychsen et al: J Neuro-Ophthalmol 2010; 30: 276-283 277 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. contrived monocular stimuli (39,40). If normal maturation of binocularity is impeded by eye misalignment or monoc-ular deprivation, the nasalward biases persist and become pronounced (34,41-47). The nasalward gaze bias is the key feature of the fusion maldevelopment syndrome. Other common findings are loss of stereopsis, interocular sup-pression, strabismus, and smaller amplitude torsional/vertical oscillations of the eyes. BINOCULAR DECORRELATION FROM VARIOUS CAUSES BEGINS THE LN CASCADE Clinical studies of children (43) and adults (2,4,44,48) with LN have inspired a series of behavioral, physiological, and neuroanatomic studies in nonhuman primates (NHPs) who had LN associated with naturally occurring (22,23,49-55) or experimentally induced (1,10,56-65) infantile strabismus. The common finding of these experiments is that the prev-alence and severity of LN correlate systematically with the age of onset and duration of binocular decorrelation in infancy. The most common clinical cause of binocular decorre-lation is strabismus, which in human infants is over-whelmingly esotropic (convergent) (66). Early onset esotropia exceeds exotropia by a ratio of 9:1. Esotropia is also the most common form of naturally occurring stra-bismus in NHPs (67,68). It may therefore be considered the paradigmatic form of strabismus in primates. However, any prolonged deprivation of normal binocular experience in early infancy can cause binocular decorrelation (e.g., monocular congenital cataract, uniocular high ametropia in hyperopia or myopia, uniocular neonatal vitreous hemor-rhage, uniocular corneal clouding, dense bilateral cataracts). In NHP models, monocular deprivation (uniocular am-blyopia) or severe binocular deprivation (bilateral ambly-opia) (10,57,63) produced by eyelid suturing (the thin translucent eyelid of NHPs mimics a congenital cataract, allowing diffuse luminance to the retina but blocking spatial vision) is also used to generate LN. But an important fact to note is that loss of spatial vision is not required; the majority of human and NHP infants with strabismus alternate fix-ation initially and have no amblyopia (69). The necessary and sufficient factor is binocular decorrelation, not lack of sharp visual acuity. Decorrelation durations that exceed the equivalent of 3 months in human infant development result in an LN prevalence of 100% (1,65,70). Perturbing these inputs from the first week of life causes LN, but delaying the pertur-bation to the time of onset of normal fusion and stereopsis (the equivalent of age 2-4 months in human) is equally effective (71). The severity of the resultant LN corresponds FIG. 3. Horizontal connections for binocular vision to layer 2-4B of V1 in normal (correlated activity) primates (A) and strabismic (decorrelated) primates (B). V1 of normal primates is characterized by equal numbers of monocular and binocular connections. In strabismic pri-mates, the connections are predominantly monocular. RE inputs = red; LE = blue; binocular = violet. FIG. 4. Metabolic activity in neighboring ocular domi-nance columns (ODCs) within V1 of normal primates (A) and strabismic primates (B). In normal primates, layer 4C stains uniformly for the metabolic enzyme cytochrome oxidase (brown), indicating equal activity in right eye and left eye columns. In strabismic primates, a narrow mon-ocular zone within the dominant ODCs (shown here as left eye) shows normal metabolic activity (brown), but ODCs belonging to the suppressed eye (shown as right eye) and binocular border zones between ODCs are pale, connoting abnormally low (suppressed) activity. State-of-the-Art Review 278 Tychsen et al: J Neuro-Ophthalmol 2010; 30: 276-283 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. to the severity of loss of binocular connections between ODCs of opposite ocularity in visual area V1 and the se-verity of interocular suppression (1,72). Area V1 feeds forward to extrastriate areas MT/MST known to be im-portant for gaze holding and gaze tracking, such as smooth pursuit, optokinetic nystagmus (OKN), and the short-latency ocular following response (73-76). MALDEVELOPMENT IN V1 IS PASSED ON TO MEDIAL TEMPORAL AND MEDIAL SUPERIOR TEMPORAL AREAS Visual areas V1, V2 (prestriate cortex), medial temporal (MT), and medial superior temporal (MST) of the cerebral cortex are major components of the conjugate gaze pathway (77). Each of these areas in normal primates contains di-rectionally selective binocular neurons (78-81). MST in each cerebral hemisphere encodes ipsiversive gaze (74,82-84). MST in turn projects downstream to the brain stem vi-suomotor nuclei that generate eye movements, including the nucleus of the optic tract (NOT), medial vestibular nucleus, and interconnected abducens and ocular motor nuclei (77,85). In primates, subcortical inputs to NOT may play a minor role (for reviews of the physiology of NOT and its role in LN see the work of Mustari and colleagues, as well as Hoffmann) (9,10,86). But the dominant pathway is from MST to brain stem. The dominant role of the cortical pathway, and the minimal role of a subcortical pathway, is reinforced by studies of children. Neuroimaging of visual cortex, combined with eye movement recordings, has shown absence of visually driven pursuit or OKN in cerebrally blind infants (87,88). One mechanism for the gaze-holding asymmetry would be overrepresentation of nasalward neurons within visual areas V1 through MT in the immature/strabismic cortex. However, directional and binocular responses of neurons in V1, V2, and MT have been investigated in infant monkeys, as well as in monkeys with early onset strabismus, and no overrepresentation of neurons selective for nasalward mo-tion has been found (26,61,89,90). Rather than over-representation of nasalward neurons, the mechanism appears to be lack of connectivity of and suppression of temporalward neurons. In strabismic animals, binocular (excitatory) responses are reduced and interocular sup-pression is increased (89-91). These physiological abnor-malities have neuroanatomic correlates. In V1 of strabismic monkeys, binocular connections are deficient (22,23) and interocular metabolic activity is suppressed (53,92,93). BINOCULAR DECORRELATION UNMASKS AN INNATE NASALWARDMONOCULAR BIAS LN is always linked to abnormal binocular development in infancy. This important clinical observation motivated the studies of NHPs, which have provided the functional-structural correlations needed to explain the pathophysi-ology. The translational value of NHP studies cannot be overstated. The NHP studies have provided the pivotal facts necessary to explain one of the most common clinical ocular motor disorders. The NHP studies have also motivated repair of fusion earlier in infancy (94), thereby preventing LN or reducing its severity. LN is caused by an afferent binocular visual pathway defect. The binocular defect unmasks a directional bias encoded in the cerebral gaze pathways. Normal binocular development (fusion) in the first months of life eliminates the directional bias; abnormal development (maldeveloped fusion) exaggerates the bias. If fusion goes unrepaired in infancy, the directional bias persists permanently through-out adult life (1,95). A key implication emerging from the NHP studies is that the visual cortex in each cerebral hemisphere is wired innately for nasalward motion. The innate wiring is mon-ocular. To generate temporalward gaze holding, signals must traverse binocular connections, unimpeded by inter-ocular suppression. If normal binocularity fails to develop, the system remains predominantly monocular and asym-metric, incapable of driving temporalward gaze holding or robust temporalward pursuit/OKN (10,43,44,61,66,90). LN is an abnormal monocular bias added on to a normal ipsiversive hemispheric gaze bias. HYPOTHETICAL SIGNAL FLOW FOR LN Figure 5 illustrates the mechanism for LN, showing the circuit mediating gaze holding in primates and the role of binocular connections. Shaded structures indicate less active visual and motor neurons caused by occlusion of one eye or interocular suppression. The circuit on the right depicts the pathways and visuomotor component structures in a pri-mate with LN. The flow is from top to bottom, starting from the monocular visual field (VF) of the fixating (or viewing) RE. The nasal and temporal VFs in primates are unequal in area, with a bias favoring the larger temporal hemifield. Retinal ganglion cell fibers (RGC) from the nasal and temporal retinas decussate at the optic chiasm, synapse at the lateral geniculate nucleus (LGN), and project to alternating monocular RE and LE ODCs in V1. During development, RGCs from the nasal retina outnumber and establish connections earlier than those from the temporal retina. The LGN laminas corresponding to the nasal retina (laminas 1, 3, and 5) contain more neurons and develop earlier than those from the temporal hemiretina (laminas 2, 4, and 6). Within the LGN, the neurons remain monocular, with no binocular interlaminar interaction. The monocular bias, favoring nasal hemiretinal inputs, is passed on to the ODCs of area V1. In each V1, ODCs representing the nasal hemiretina (temporal visual hemi-field) occupy slightly more cortical territory than those State-of-the-Art Review Tychsen et al: J Neuro-Ophthalmol 2010; 30: 276-283 279 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. representing the temporal hemiretinas (nasal hemifield), but each ODC contains neurons sensitive to nasalward (left-ward) versus temporalward (rightward) visual motion. Receptive field neurons in V1 and MT are simplified here as half circles to match their corresponding hemifields. The arrows indicate the directional preference of the neurons. The visual area neurons (including those beyond V1 in area MT) are sensitive to both nasalward and temporalward motion (26,61,89), but only those encoding nasalward motion are wired innately through monocular connections to gaze (eye motion) neurons in the MST area (congregated in the dorsal-medial portion or MSTd). MSTd in each cerebral hemisphere encodes ipsiversive gaze (74,82-84), which is nasalward gaze in relation to the contralateral eye (leftward for MST in the left cerebral hemisphere and rightward for MST in the right hemisphere) (90). The only difference between the LN primate's visual cortex and the normal primate's visual cortex is a paucity of binocular horizontal connections (23,72) (compounded by interocular suppression (53,92,93)). The paucity is depicted as a lack of diagonal RE ODC to LE ODC connections, absent in the LN cortex (right side of figure), and present in the normal cortex (left side of figure). In the cortex of normal primates, access to MSTd for temporalward gaze requires binocular connections to homoversive neurons within neighboring ODCs that have opposite ocularity (LE ODC neurons when viewing with the RE). The pathway from V1/MT to MSTd requires efferent projections through the splenium of the corpus callosum (96,97). MSTd efferents project to the ipsilateral brain stem NOT (85,98) and to ipsiversive-related brain stem struc-tures (medial vestibular nucleus, dorsolateral pontine nu-cleus, and ocular motor nuclei of cranial nerves 3 and 6). RECONCILING CURRENT KNOWLEDGE WITH PREVIOUS LN HYPOTHESES IN HUMANS Based on clinical observations and eye movement record-ings in humans, several mechanisms have been proposed as the cause of LN. Ishikawa (99) thought that LN could be explained as a hyperactive stretch reflex of the medial rectus muscles, which drove the viewing eye nasalward. Although the muscular basis is untenable, he drew further attention to the linkage of LN with other nasalward visuomotor biases, notably infantile esotropia. Dell'Osso et al (2,4) hypothesized that LN arose from a confusion of egocentric direction caused by strabismus. Patients with unilateral or alternating strabismus view at any given moment with one eye predominantly. The viewing eye is displaced laterally with respect to the midline of the head. This displacement is not present with binocular fu-sion. With fusion, the perceptual center (cyclopean eye) coincides with midline. The incongruity between the body midline and the laterally displaced monocular view was FIG. 5. Neural network diagrams showing visual signal flow for pursuit and gaze holding in strabismic and nor-mal primates. A paucity of mature binocular connections explains behavioral asymmetries evident as asymmetric pursuit/optokinetic nystagmus and latent fixation nys-tagmus. In all primates, pursuit area neurons in each hemisphere encode ipsilaterally directed pursuit. Signal flow is initiated by a moving stimulus in the monocular visual field (VF), which evokes a response in visual area neurons V1 and MT. Each eye at birth has access, through innate monocular connections, to the pursuit area neurons in MSTd of the contralateral hemisphere. Access to pursuit neurons of the ipsilateral hemisphere requires mature binocular connections. In fusion mal-development (right column), retinal ganglion cell fibers from the nasal and temporal hemiretina (eye) decussate at the optic chiasm (chi), synapse at the lateral genic-ulate nucleus (LGN), and project to alternating rows of ODCs in V1 (visual area rectangles). In each V1, ODCs representing the nasal hemiretina (temporal visual hemifield) occupy slightly more cortical territory than those representing the temporal hemiretina (nasal hemifield), but each ODC contains neurons sensitive to nasally directed and temporally directed motion (half circles shaped like the matching hemifield; arrows in-dicate directional preference). Visual area neurons, in-cluding those beyond V1 in area MT, encoding nasally directed motion are wired innately-through monocular connections-to the pursuit area. In normal primates (left column), binocular connections are present, linking neurons with similar orientation/directional preferences within ODCs of opposite ocularity (diagonal lines be-tween columns). When the subject views with the right eye, visual neurons preferring nasally directed motion project to the left hemisphere pursuit area and visual neurons preferring temporally directed motion project to the right hemisphere pursuit area. Temporally directed visual area neurons gain access to pursuit area neurons only through binocular connections. Call = corpus callosum. Bold lines = active neurons and neuronal projections. State-of-the-Art Review 280 Tychsen et al: J Neuro-Ophthalmol 2010; 30: 276-283 Copyright © North American Neuro-ophthalmology Society.Unauthorized reproduction of this article is prohibited. believed to generate a neural command driving the viewing eye toward midline, that is, nasalward. By revising confusion of egocentric direction to unbalanced, infantile, monocular interhemispheric MSTd drive, the hypothesis of Dell'Osso et al (2,4) can be updated to fit well with current biology. Volitional manipulation of interhemispheric activity can also alter LN direction. Dell'Osso et al (100) reported a monocular patient with LN who could do so by imagining viewing through the lost eye (replaced by an ocular prosthesis). The notion of unbalanced cerebral hemisphere activity as a cause of nystagmus was emphasized by Sharpe et al (101,102). and by Zee (103). They proposed an imbalance of pursuit tone to explain a linear conjugate slow-phase drift of the eyes toward the more active hemisphere in adult patients with unilateral parietooccipital damage and normal binocular vision. Although they did not extrapolate their hypotheses to include a mechanism for LN, their insights may be considered important contributions. vanDalen (39) pointed out that a subtle form of LNcan be evoked in normal adult humans when viewing monocularly by flashing light in a Ganzfeld at high temporal frequencies. A current interpretation would be that by eliminating all gaze-stabilizing and fusional cues, while simultaneously activating visual motion neurons, the Ganzfeld unmasks the vestiges of the infantile nasalward bias. 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