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Amblyopia is the leading cause of unilateral visual loss in children. Fortunately, amblyopia is both preventable by screening for risk factors and treatable, especially if identified at an early age. Amblyopia is classified by etiology into strabismic, refractive, and deprivational. A significant amount of research has been dedicated to further understand the underlying mechanisms of amblyopia and to optimize its treatment. The Pediatric Eye Disease Investigator Group [PEDIG] has been instrumental in spearheading current studies that guide evidence-based management.

Purpose A subset of children with high ametropia and neurobehavioral disorders have chronic difficulties with spectacle or contact lens wear. We report the results of refractive surgery in a series of these children treated using bilateral or unilateral phakic intraocular lenses (IOLs) for ametropia >10 D. Methods Clinical course and outcome data were collated prospectively in a group of 12 children (mean age, 10.1 years; range, 4-17 years) with neurobehavioral disorders exacerbated by poor compliance with spectacles. Myopia in 18 eyes ranged from −10.0 to −22.75 D (mean, −15.2 D) and in 2 hyperopic eyes from +10.25 to +10.75 (mean, +10.5 D). Goal refraction was approximately 0 to +1 D. Correction was achieved by implantation of an iris-enclaved phakic IOL under general anesthesia. Mean follow-up was 9.1 months (range, 3-15 months). Results Myopia correction averaged 14.5 D and hyperopia correction 9.4 D. Eighty-six percent of eyes (17/20 eyes) were corrected to within ± 1 D of emmetropia and the remaining 14% (3 eyes) to within ± 2 D. Uncorrected visual acuity improved substantially in all 20 eyes (60-fold; from a mean of 20/3400 to a mean of 20/57). Ocular comorbidities in each child accounted for residual postoperative, subnormal visual acuity (eg, amblyopia, nystagmus, albinism, regressed retinopathy of prematurity). Visual functions (measured using a 23-item validated survey) improved. One eye required IOL exchange; no other clinically significant complications have been encountered. Conclusions Phakic IOL implantation improves visual function substantially in neurobehaviorally impaired children who have high ametropia and difficulties wearing glasses.

Purpose To quantitatively characterize eye and head oscillations in patients with infantile nystagmus syndrome (INS). Methods Vertical and horizontal eye and head position in INS patients were measured simultaneously at a sampling frequency of 500 Hz. Eye and head movements were measured continuously for 180 seconds. The data was calibrated and converted to angular vectors, which were further analyzed with custom software. Results A total of 10 patients with INS were included: 3 with pseudo-jerk, 3 with pure-jerk, 2 with pseudo-pendular with foveating saccade form of jerk, 1 with bidirectional jerk, and 1 with asymmetric pendular nystagmus waveforms. None of the patients had periodic, aperiodic, or a superimposed latent nystagmus component. Two types of head oscillations were observed: one with a frequency of 1–3 Hz, present in all patients; and another with a frequency range of 5–8 Hz, present in only 7 patients. High-frequency oscillations were episodic, whereas low-frequency oscillations were constantly present. Peak velocity of the high-frequency head oscillations and eye velocity of nystagmus were not correlated, suggesting that these oscillations did not influence foveation. Conclusions Two types of head oscillations were found in INS patients: a constant, low-frequency and an episodic, high–frequency. Lack of correlation between the foveation period of nystagmus and peak head velocity during high-frequency oscillations suggests a coexisting pathological phenomenon rather than a compensatory mechanism used to improve the visual acuity.

Fixational eye movements such as microsaccades are important to prevent fading. These miniature eye movements are also necessary to redirect gaze to the target after a drift. Generation of saccades and microsaccades utilizes common neural substrates. We, therefore, hypothesized that physiological modulators of saccades should also affect microsaccades. Test of this hypothesis will also provide support for the models of a microsaccade generation. We performed two experiments. In the first experiment, complete darkness led to a decrease in the frequency and velocity, but increased the amplitude of microsaccades. In the second experiment, active eyelid closure further reduced the velocity and frequency of microsaccades, but increased their amplitude. Darkness reduces the superior colliculus activity leading to a reduction in the velocity and frequency of microsaccades. Eye closure might cause sustained inhibition of the omnipause neurons. Subsequent disinhibition of the burst neurons might cause a reduction in the post-inhibitory rebound firing resulting in a decreased velocity of microsaccades. Sustained inhibition of the omnipause neurons could also reduce the inhibitory drive that would otherwise abort microsaccades. Hence, by inhibiting the activity of omnipause neurons, the eye closure could increase the amplitude of microsaccades.

PURPOSE Optokinetic eye movements stabilize gaze by tracking motion of the visual scene during sustained movement of a creature's body. The purpose of this study was to describe vertical and horizontal optokinetic nystagmus (OKN) in nonhuman primates (NHPs) with normal binocular vision, and to compare their responses to NHPs with binocular maldevelopment induced by prism-rearing. METHODS Optical strabismus was created in infant macaques (n = 6) by fitting them with prism goggles. The goggles were removed after 3, 6, 9, or 12 weeks to determine the effects of increasing durations of binocular noncorrespondence. Infant NHPs (n = 2) reared wearing plano goggles served as controls. OKN was evoked by horizontal or vertical stripe motion. Eye movements were recorded by using binocular search coils. RESULTS NHPs reared in early infancy under conditions of binocular noncorrespondence for durations of 6 weeks or longer had horizontal OKN responses biased directionally in favor of nasalward motion. NHPs reared with prisms for any duration had vertical OKN responses more biased than normal NHPs in favor of upward motion. Diagonal "crosstalk" during horizontal or vertical OKN (vertical slow phases during horizontal stimulus motion, and vice versa) was present to some degree in all NHPs. However, crosstalk-upward during horizontal OKN and nasalward during vertical OKN-was most pronounced in NHPs reared with prism for durations long enough to induce a permanent esotropic strabismus (longer than 3 weeks). CONCLUSIONS With fusion maldevelopment, the OKN pathways retain a nasalward and upward bias. During forward locomotion, optic flow excites temporalward and downward visual motion in each eye. The OKN biases would act in counterbalance. The biases attenuate with emergence of fusion, but may persist and crosstalk when fusion is impeded.

Most common eye movements, oblique saccades, feature rapid velocity, precise amplitude, but curved trajectory that is variable from trial-to-trial. In addition to curvature and inter-trial variability, the oblique saccade trajectory also features high-frequency oscillations. A number of studies proposed the physiological basis of the curvature and inter-trial variability of the oblique saccade trajectory, but kinematic characteristics of high-frequency oscillations are yet to be examined. We measured such oscillations and compared their properties with orthogonal pure horizontal and pure vertical oscillations generated during pure vertical and pure horizontal saccades, respectively. We found that the frequency of oscillations during oblique saccades ranged between 15 and 40 Hz, consistent with the frequency of orthogonal saccadic oscillations during pure horizontal or pure vertical saccades. We also found that the amplitude of oblique saccade oscillations was larger than pure horizontal and pure vertical saccadic oscillations. These results suggest that the superimposed high-frequency sinusoidal oscillations upon the oblique saccade trajectory represent reverberations of disinhibited circuit of reciprocally innervated horizontal and vertical burst generators.

Saccadic eye movements rapidly shift gaze to the target of interest. Once the eyes reach a given target, the brainstem ocular motor integrator utilizes feedback from various sources to assure steady gaze. One of such sources is cerebellum whose lesion can impair neural integration leading to gaze-evoked nystagmus. The gaze evoked nystagmus is characterized by drifts moving the eyes away from the target and a null position where the drifts are absent. The extent of impairment in the neural integration for two opposite eccentricities might determine the location of the null position. Eye in the orbit position might also determine the location of the null. We report this phenomenon in a patient with Arnold Chiari type 1 malformation who had intermittent esotropia and horizontal gaze-evoked nystagmus with a shift in the null position. During binocular viewing, the null was shifted to the right. During monocular viewing, when the eye under cover drifted nasally (secondary to the esotropia), the null of the gaze-evoked nystagmus reorganized toward the center. We speculate that the output of the neural integrator is altered from the bilateral conflicting eye in the orbit position secondary to the strabismus. This could possibly explain the reorganization of the location of the null position.

INTRODUCTION: Foveation is the fundamental requirement for clear vision. Saccades rapidly shift the gaze to the interesting target while gaze holding ensures foveation of the desired object. PURPOSE: We will review the pertinent physiology of saccades and gaze holding and their pathophysiology leading to saccadic oscillations, slow saccades, saccadic dysmetria, and nystagmus. SUMMARY: Motor commands for saccades are generated at multiple levels of the neuraxis. The frontal and parietal eye field send saccadic commands to the superior colliculus. Latter then projects to the brain-stem saccadic burst generator. The brain-stem burst generators guarantee optimum signal to ensure rapid saccadic velocity, while the neural integrator, by mathematically integrating the saccadic pulse, facilitates stable gaze holding. Reciprocal innervations that ensure rapid saccadic velocity are prone to inherent instability leading to saccadic oscillations. In contrast, suboptimal function of the burst generators causes slow saccades. Impaired error correction, either at the cerebellum or the inferior olive, leads to impaired saccade adaptation and ultimately saccadic dysmetria and oculopalatal tremor. Impairment in the function of neural integrator causes nystagmus. CONCLUSION: Neurophysiology of saccades, gaze holding, and their deficits are well recognized. These principles can be implemented to define novel therapeutic and rehabilitation approaches. Language: en

Two patients were assessed for acute onset of diplopia. Clinical examination revealed upbeat nystagmus, exotropia, and internuclear ophthalmoplegia (INO). Both patients had vascular risk factors; acute ischemic stroke affecting ponto-mesencephalic junction was suspected. Magnetic resonance imaging confirmed strategic location of the acute infarct affecting the medial longitudinal fasciculus, adjacent occulomotor nuclei, and paramedian tract. We propose that constellation of acute onset of upbeat nystagmus, INO, and exotropia in patients with vascular risk factors might be unequivocal manifestation of the ponto-mesencephalic stroke.

Vertically incomitant pattern strabismus comprises 50% of infantile horizontal strabismus. The oblique muscle dysfunction has been associated with pattern strabismus. High-resolution orbit imaging and contemporary neurophysiology studies in non-human primate models of strabismus have shed light into the mechanisms of pattern strabismus. In this review, we will examine our current understanding of etiologies of pattern strabismus. Speculated pathophysiology includes oblique muscle dysfunction, loss of fusion with altered recti muscle pull, displacements and instability in connective tissue pulleys of the recti muscles, vestibular hypofunction, and abnormal neural connections. Orbital mechanical factors, such as abnormal pulleys, were reported as a cause of pattern strabismus in patients with craniofacial anomalies, connective tissue disorders, and late-onset strabismus. In contrast, abnormal neural connections could be responsible for the development of a pattern in infantile-onset strabismus. Pattern strabismus is likely multifactorial. Understanding the mechanisms of pattern strabismus is pivotal to determine an appropriate surgical treatment strategy for these patients.

Purpose Fixational saccades shift the foveal image to counteract visual fading related to neural adaptation. Drifts are slow eye movements between two adjacent fixational saccades. We quantified fixational saccades and asked whether their changes could be attributed to pathologic drifts seen in amblyopia, one of the most common causes of blindness in childhood. Methods Thirty-six pediatric subjects with varying severity of amblyopia and eleven healthy age-matched controls held their gaze on a visual target. Eye movements were measured with high-resolution video-oculography during fellow eye-viewing and amblyopic eye-viewing conditions. Fixational saccades and drifts were analyzed in the amblyopic and fellow eye and compared with controls. Results We found an increase in the amplitude with decreased frequency of fixational saccades in children with amblyopia. These alterations in fixational eye movements correlated with the severity of their amblyopia. There was also an increase in eye position variance during drifts in amblyopes. There was no correlation between the eye position variance or the eye velocity during ocular drifts and the amplitude of subsequent fixational saccade. Our findings suggest that abnormalities in fixational saccades in amblyopia are independent of the ocular drift. Discussion This investigation of amblyopia in pediatric age group quantitatively characterizes the fixation instability. Impaired properties of fixational saccades could be the consequence of abnormal processing and reorganization of the visual system in amblyopia. Paucity in the visual feedback during amblyopic eye-viewing condition can attribute to the increased eye position variance and drift velocity.

PURPOSE. Children with cerebral palsy (CP) tend to be either excluded from studies of strabismus repair or pooled with children who have other neurologic disorders. The authors limited this study to children with defined CP to determine the success or failure of restoring eye alignment and fusion. METHODS. An observational, cross-sectional, prospective study was conducted on a representative cohort of 50 children. CP severity ranged from Gross Motor Function Classification System (GMFCS) level 1 (least severe) to 5 (most severe). Mean age at entrance and surgery was 3.5 years, and mean follow-up was 4.1 years (minimum 1 year). RESULTS. The predominant form of strabismus was infantileonset: esotropia in 54%, exotropia in 26%, and dyskinesia in 10%. Sixty-six percent of esotropic children and 61% of exotropic children achieved optimal (microtropic) alignment after an average of 2 and 1.8 surgical procedures, respectively. The likelihood of optimal alignment was similar in children with mild (GMFCS level 1‐2) versus severe (GMFCS level 3‐5) CP (P 0.7; 2 ). Irrespective of GMFCS severity, 46% of children gained binocular fusion/stereopsis, but the quality of fusion gained was greater in children with mild CP (P 0.05). Earlier surgery was more likely to be successful (P 0.05). CONCLUSIONS. Restoration of binocular alignment and a degree of fusion is a realistic goal in the majority of strabismic CP children. Repair may be achieved in children at both the mild and the severe ends of the GMFCS spectrum, without undue concern about treatment futility or excessive reoperation. (Invest Ophthalmol Vis Sci. 2011;52:7664‐7671) DOI:10.1167/ iovs.10-6906

Background/aims: Measurement of visual acuity can be difficult in children with cerebral palsy (CP). The purpose of this study was to determine the probability of obtaining quantitative (logMAR) visual acuities in CP children with different severities of motor dysfunction. Methods: An observational, cross-sectional design study was conducted in 76 children (mean age 5.9 years) who had CP severity graded using the Gross Motor Function Classification Scale (GMFCS). Visual testing was performed using optotypes, spatial-sweep (SSVEP) or flash (FVEP) visually evoked potentials. Results: LogMAR acuity was obtainable in 88% of CP children, using either optotypes or SSVEPs. The success rate decreased with increasing severity of GMFCS Levels 1–5; nevertheless, logMAR acuities were obtainable in more than one-half (56%) of children with the most severe disease: Level 5. Similar results were obtained for CP severity assessed using physiological-anatomical subtype (hemiplegic; diplegic; quadriplegic) rather than GMFCS. The mean logMAR acuity (0.37; 20/48) in the CP cohort as a whole was ∼2 Snellen-equivalent lines worse than that recorded in age-matched, normal children (0.22; 20/33). Conclusion: Quantitative visual acuities can be obtained in the majority of CP children, including those with severe motor dysfunction. Difficulties in testing CP children lead often to the misconception that the children have immeasurably low vision.

Inverse and forward dynamic models have been conceptually important in computational motor control. In particular, inverse models are thought to convert desired action into appropriate motor commands. In parallel, forward models predict the consequences of the motor command on behavior by constructing an efference copy of the actual movement. Despite theoretical appeal, their neural representation has remained elusive. Here, we provide evidence supporting the notion that a group of premotor neurons called burst-tonic (BT) cells represent the output of the inverse model for eye movements. We show that BT neurons, like extraocular motoneurons but different from the evoked eye movement, do not carry signals appropriate for the half-angle rule of ocular kinematics during smooth-pursuit eye movements from eccentric positions. Along with findings of identical response dynamics as motoneurons, these results strongly suggest that BT cells carry a replica of the motor command. In contrast, eye-head (EH) neurons, a premotor cell type that is the target of Purkinje cell inhibition from the cerebellar flocculus/ventral paraflocculus, exhibit properties that could be consistent with the half-angle rule. Therefore, EH cells may be functionally related to the output of a forward internal model thought to construct an efference copy of the actual eye movement.

Pattern strabismus describes horizontal strabismus that is vertically incomitant. Historically, pattern strabismus is attributed to the oblique muscle dysfunction.1 Little is known about the etiology of isolated primary oblique overaction. Clinical observations have suggested that a torsional offset due to loss of fusion might alter the direction of the recti muscle action, hence causing the pattern strabismus.2,3 For example, excyclotorsion of the globe will result in medial rectus becoming a partial elevator leading to overelevation during adduction, and inferior rectus becoming a partial adductor and superior rectus a partial abductor causing a V-pattern. Correlation between the fundus torsion and static eye fixation in patients with pattern strabismus further supported the viewpoint emphasizing altered recti pull.4 Subsequent studies suggested that oblique overaction is a clinical description rather than an actual mechanism of the pattern strabismus.5 Static malposition or dynamic instability of the extraocular muscle pulleys in patients with craniofacial dysmorphism causes pattern strabismus.6 Neurophysiology experiments in nonhuman primates reared with alternate monocular occlusion suggested a neural basis for pattern strabismus.7–9 These animals had cross-axis eye movements; for example, intended horizontal saccades were associated with cross-axis vertical eye movement and vice versa. Neural recordings from ocular motor neurons have shown that horizontal cross-coupled movement corresponds to increased firing rate of horizontal motor neurons, whereas vertical cross-coupled movement corresponds to increased firing rate of vertical motor neurons. The presence of the neural correlate of cross-coupled movements in animal models suggested that abnormal central innervations might cause the pattern strabismus.7–9 These principles describing the pathophysiology of pattern strabismus are based on subjective clinical impression, orbital imaging, and neurophysiology in animal models. There is a paucity of investigations of objective eye movement assessments in human patients with pattern strabismus. We aimed to quantify eye movements and fundus torsion in patients with infantile and late onset pattern strabismus without craniofacial abnormalities. We hypothesized that overaction of the oblique muscles, as previously predicted in pattern strabismus, should be reflected in the static misalignment as well as dynamic disconjugacy of saccades. For example, inferior oblique overaction should cause an upward deviation of the adducting eye during a horizontal saccade, and the oblique upward saccade would have greater amplitude in the adducting than the abducting eye. It is unknown whether patients with pattern strabismus have cross-coupling of the eye movement, as described in the nonhuman primate model. If, indeed, animal models are analogous to the patients with pattern strabismus, we should also see cross-coupled eye movements in these patients. We quantitatively assessed the presence of cross-coupling of saccades in patients with pattern strabismus. There are several possible explanations for cross-coupled responses. Mechanical factors, such as an abnormal fundus torsion or inappropriate innervations, and consequent cross-talk between horizontal and vertical saccade generators, can result in cross-coupling. The torsion hypothesis predicts a correlation between the severity of cross-coupled saccades and the static fundus torsion. According to the torsion hypothesis, patients with greater static torsion will have larger cross-coupling of saccades. The absence of such a correlation would suggest that abnormal static torsion is not the exclusive cause of pattern strabismus.

PURPOSE Human brain generates miniature eye movements, such as microsaccades, to counteract image fading due to visual adaptation. Generation of microsaccade relies on the amount of retinal error or acuity demand for a desired visual task. The goal of this study was to assess the influence of visual blur, induced by uncorrected refractive error on microsaccades and saccades. METHODS Ten subjects with myopia held their gaze on a visual target during two experiment conditions: corrected refractive error and uncorrected refractive error. Eye movements were measured with high-resolution video oculography under binocular viewing conditions during both tasks. Gaze holding function, microsaccades, and visually guided saccades were analyzed and compared during both tasks. RESULTS We found an increase in the amplitude of microsaccades in the presence of uncorrected refractive error, but the microsaccade frequency and velocity remained unchanged. The microsaccade amplitude systematically increased with an increase in uncorrected refractive error. The main sequence relationship relating the saccade amplitude with respective peak velocity was not significantly different between two conditions. The onset latency, peak velocities, and accuracy of visually guided saccades also were unchanged between the two conditions. CONCLUSIONS These results suggest that visual blur, hence the precision of an image on the fovea, has an important role in calibrating the amplitude of fixational eye movements, such as microsaccades.

SummaryOur inner ear is equipped with a set of linear accelerometers, the otolith organs, that sense the inertial accelerations experienced during self-motion [1, 2]. However, as Einstein pointed out nearly a century ago [3], this signal would by itself be insufficient to detect our real movement, because gravity, another form of linear acceleration, and self-motion are sensed identically by otolith afferents. To deal with this ambiguity, it was proposed that neural populations in the pons and midline cerebellum compute an independent, internal estimate of gravity using signals arising from the vestibular rotation sensors, the semicircular canals [4–7]. This hypothesis, regarding a causal relationship between firing rates and postulated sensory contributions to inertial motion estimation, has been directly tested here by recording neural activities before and after inactivation of the semicircular canals. We show that, unlike cells in normal animals, the gravity component of neural responses was nearly absent in canal-inactivated animals. We conclude that, through integration of temporally matched, multimodal information, neurons derive the mathematical signals predicted by the equations describing the physics of the outside world.

The most medial of the deep cerebellar nuclei, the fastigial nucleus (FN), receives sensory vestibular information and direct inhibition from the cerebellar vermis. We investigated the signal processing in the primate FN by recording single-unit activities during translational motion, rotational motion, and eye movements. Firing rate modulation during horizontal plane translation in the absence of eye movements was observed in all non-eye-movement-sensitive cells and 26% of the pursuit eye-movement-sensitive neurons in the caudal FN. Many non-eye-movement-sensitive cells recorded in the rostral FN of three fascicularis monkeys exhibited convergence of signals from both the otolith organs and the semicircular canals. At low frequencies of translation, the majority of these rostral FN cells changed their firing rates in phase with head velocity rather than linear acceleration. As frequency increased, FN vestibular neurons exhibited a wide range of response dynamics with most cells being characterized by increasing phase leads as a function of frequency. Unlike cells in the vestibular nuclei, none of the rostral FN cells responded to rotational motion alone, without simultaneously exhibiting sensitivity to translational motion. Modulation during earth-horizontal axis rotation was observed in more than half (77%) of the neurons, although with smaller gains than during translation. In contrast, only 47% of the cells changed their firing rates during earth-vertical axis rotations in the absence of a dynamic linear acceleration stimulus. These response properties suggest that the rostral FN represents a main processing center of otolith-driven information for inertial motion detection and spatial orientation.

PURPOSE. Cerebral palsy (CP) is a permanent, nonprogressive disorder of movement and posture due to a lesion of the fetal or infant brain. The goal was to determine whether children with different severities of CP, as defined using the Gross Motor Function Classification System (GMFCS), had different degrees or types of visual dysfunction. METHODS. An observational, cross-sectional‐design study was conducted by using neurologic and masked ophthalmic measurements on a representative cohort of 50 children with CP. Mean age was 5.6 years (range, 2‐19.5 years); mean gestational age was 31 weeks. RESULTS. The likelihood of debilitating visual deficits was greater in children with higher GMFCS scores, independent of gestational age. Children with level 5 disease (most severe) were at greatest risk for high myopia, absence of binocular fusion, dyskinetic strabismus, severe gaze dysfunction, and optic neuropathy or cerebral visual impairment (CVI). These deficits were rare or absent in children with the mildest disease, level 1. When categorized by anatomic or physiologic CP subtype, diplegic and spastic children were more often hyperopic and esotropic, but had the highest prevalence of fusion and stereopsis. In contrast, children with quadriplegic and mixed CP (dyskinetic, athetoid, hypotonic, and ataxic) more often had high myopia, CVI, dyskinetic strabismus, and gaze dysfunction. CONCLUSIONS. Visual deficits differ in children who have mild versus severe CP. Children with GMFCS level 1 to 2 have sensorimotor deficits resembling those of neurologically normal children with strabismus and amblyopia; children at level 3 to 5 have more severe deficits, not observed in neurologically normal children. (Invest Ophthalmol Vis Sci. 2008;49: 572‐580) DOI:10.1167/iovs.07-0525

SummaryAs we look around, the orientation of our eyes depends on the order of the rotations that are carried out, a mathematical feature of rotatory motions known as noncommutativity. Theorists and experimentalists continue to debate how biological systems deal with this property when generating kinematically appropriate movements. Some believe that this is always done by neural commands to a simplified eye plant. Others have postulated that noncommutativity is implemented solely by the mechanical properties of the eyeball. Here we directly examined what the brain tells the muscles, by recording motoneuron activities as monkeys made eye movements. We found that vertical recti and superior/inferior oblique motoneurons, which drive sensory-generated torsional eye movements, do not modulate their firing rates according to the noncommutative-driven torsion during pursuit. We conclude that part of the solution for kinematically appropriate eye movements is found in the mechanical properties of the eyeball, although neural computations remain necessary and become increasingly important during head movements.