Ocular Motor System Research Articles

An algorithm as a diagnostic tool for central ocular motor disorders, also to diagnose rare disorders

BackgroundRecently an increasing number of digital tools to aid clinical work have been published. This study’s aim was to create an algorithm which can assist physicians as a “digital expert” with the differential diagnosis of central ocular motor disorders, in particular in rare diseases.ResultsThe algorithm’s input consists of a maximum of 60 neurological and oculomotor signs and symptoms. The output is a list of the most probable diagnoses out of 14 alternatives and the most likely topographical anatomical localizations out of eight alternatives. Positive points are given for disease-associated symptoms, negative points for symptoms unlikely to occur with a disease. The accuracy of the algorithm was evaluated using the two diagnoses and two brain zones with the highest scores. In a first step, a dataset of 102 patients (56 males, 48.0 ± 22 yrs) with various central ocular motor disorders and underlying diseases, with a particular focus on rare diseases, was used as the basis for developing the algorithm iteratively. In a second step, the algorithm was validated with a dataset of 104 patients (59 males, 46.0 ± 23 yrs). For 12/14 diseases, the algorithm showed a sensitivity of between 80 and 100% and the specificity of 9/14 diseases was between 82 and 95% (e.g., 100% sensitivity and 75.5% specificity for Niemann Pick type C, and 80% specificity and 91.5% sensitivity for Gaucher’s disease). In terms of a topographic anatomical diagnosis, the sensitivity was between 77 and 100% for 4/8 brain zones, and the specificity of 5/8 zones ranged between 79 and 99%.ConclusionThis algorithm using our knowledge of the functional anatomy of the ocular motor system and possible underlying diseases is a useful tool, in particular for the diagnosis of rare diseases associated with typical central ocular motor disorders, which are often overlooked.

Ex Vivo Oculomotor Slice Culture from Embryonic GFP-Expressing Mice for Time-Lapse Imaging of Oculomotor Nerve Outgrowth.

Accurate eye movements are crucial for vision, but the development of the ocular motor system, especially the molecular pathways controlling axon guidance, has not been fully elucidated. This is partly due to technical limitations of traditional axon guidance assays. To identify additional axon guidance cues influencing the oculomotor nerve, an ex vivo slice assay to image the oculomotor nerve in real-time as it grows towards the eye was developed. E10.5 IslMN-GFP embryos are used to generate ex vivo slices by embedding them in agarose, slicing on a vibratome, then growing them in a microscope stage-top incubator with time-lapse photomicroscopy for 24-72 h. Control slices recapitulate the in vivo timing of outgrowth of axons from the nucleus to the orbit. Small molecule inhibitors or recombinant proteins can be added to the culture media to assess the role of different axon guidance pathways. This method has the advantages of maintaining more of the local microenvironment through which axons traverse, not axotomizing the growing axons, and assessing the axons at multiple points along their trajectory. It can also identify effects on specific subsets of axons. For example, inhibition of CXCR4 causes axons still within the midbrain to grow dorsally rather than ventrally, but axons that have already exited ventrally are not affected.

Bedside examination of the vestibular and ocular motor system in patients with acute vertigo or dizziness

In the initial assessment of the patient with acute vertigo or dizziness, both structured history-taking and a targeted bedside neuro-otological examination are essential for distinguishing potentially life-threatening central vestibular causes from those of benign, self-limited peripheral labyrinthine origin and thus for deciding on further diagnostic testing. In this article, the key elements of the vestibular and ocular motor examination, which should be obtained at the bedside in these acutely dizzy patients, will be discussed. Specifically, this will include the following five domains: ocular stability for (I) nystagmus and for (II) eye position (skew deviation), (III) the head-impulse test (HIT), (IV) postural stability, and (V) ocular motor deficits of saccades, smooth pursuit eye movements, and optokinetic nystagmus. We will also discuss the diagnostic accuracy of specific combinations of these bedside tests (i.e. HIT, testing for nystagmus and vertical divergence, referred to as the H.I.N.T.S. three-step examination), emphasizing that the targeted neuro-otological bedside examination is more sensitive for identifying central causes in acute prolonged vertigo and dizziness than early MRI of the brain.

Diagnosis and Differential Diagnosis of Peripheral and Central Vestibular Disorders

The diagnosis of the various peripheral and central vestibular disorders is mainly based on the patient history (time course, type of symptoms, modulating factors, and accompanying symptoms) and a systematic clinical examination of the vestibular, ocular motor, and cerebellar systems (examination for nystagmus, head impulse test, positional maneuvers, Romberg test and examination for central ocular motor signs). The two most important laboratory tests are the "video-head impulse test" and caloric irrigation. Fortunately, the diagnosis of vestibular disorders has become easier and more precise as a result of the very clinically oriented diagnostic criteria of the Bárány Society (www.jvr-web.org/ICVD.html).

Ocular Motor System Control Models and the Cerebellum: Hypothetical Mechanisms.

To review our studies and "top-down" models of saccadic intrusions and infantile nystagmus syndrome with the aim of hypothesizing areas of cerebellar connections controlling parts of the ocular motor subsystems involved in both types of function and dysfunction. The methods of eye-movement recording and modeling are described in detail in the cited references. Saccadic intrusions, such as square-wave jerks and square-wave oscillations, can be simulated by a single malfunction, whereas staircase saccadic intrusions required two independent malfunctions. The major infantile nystagmus syndrome waveforms are traceable to a failure to calibrate the damping ratio of the smooth pursuit system. The use of a behavioral ocular motor system model demonstrated how putative cerebellar dysfunctions could accurately simulate both the oscillations and the ocular motor responses seen in patients with both saccadic and pursuit disorders.

Eye-hand re-coordination: A pilot investigation of gaze and reach biofeedback in chronic stroke.

Within the domain of motor performance, eye-hand coordination centers on close relationships between visuo-perceptual, ocular and appendicular motor systems. This coordination is critically dependent on a cycle of feedforward predictions and feedback-based corrective mechanisms. While intrinsic feedback harnesses naturally available movement-dependent sensory channels to modify movement errors, extrinsic feedback may be provided synthetically by a third party for further supplementation. Extrinsic feedback has been robustly explored in hand-focused, motor control studies, such as through computer-based visual displays, highlighting the spatial errors of reaches. Similar attempts have never been tested for spatial errors related to eye movements, despite the potential to alter ocular motor performance. Stroke creates motor planning deficits, resulting in the inability to generate predictions of motor performance. In this study involving visually guided pointing, we use an interactive computer display to provide extrinsic feedback of hand endpoint errors in an initial baseline experiment (pre-) and then feedback of both eye and hand errors in a second experiment (post-) to chronic stroke participants following each reach trial. We tested the hypothesis that extrinsic feedback of eye and hand would improve predictions and therefore feedforward control. We noted this improvement through gains in the spatial and temporal aspects of eye-hand coordination or an improvement in the decoupling noted as incoordination post-stroke in previous studies, returning performance toward healthy, control behavior. More specifically, results show that stroke participants, following the interventional feedback for eye and hand, improved both their accuracy and timing. This was evident through a temporal re-synchronization between eyes and hands, improving correlations between movement timing, as well as reducing the overall time interval (delay) between effectors. These experiments provide a strong indication that an extrinsic feedback intervention at appropriate therapeutic doses may improve eye-hand coordination during stroke rehabilitation.

Keep Your Eye on the Ball; the Impact of an Anticipatory Fixation During Successful and Unsuccessful Soccer Penalty Kicks.

The success of a sporting task requiring an object to be kicked or hit toward a target (e.g., kicking a ball into a goal) is impacted by the length of the Quiet Eye (QE). Limitations in the ocular motor system mean that after impact, these fast moving objects are not tracked using smooth pursuit eye movements. Rather, anticipatory fixations are used to re-fixate ahead of the moving object.Using a soccer penalty kick, the current study investigated whether striking a stationary object to generate high ball velocity results in an anticipatory fixation prior to ball contact and if this occurs at detriment to the QE period and task success.Facing a goalkeeper, 12 participants produced a successful (scored) and unsuccessful (saved) penalty whilst wearing a mobile eye tracker.QE was longer in the successful compared to unsuccessful penalty (p = 0.036) and was due to QE offset ending later in the successful compared to unsuccessful penalty (p = 0.008). An anticipatory fixation occurred later (p = 0.025) and was shorter (p = 0.005) in successful compared to unsuccessful penalties. The football was kicked wider (more accurately) within the goal during the successful compared to unsuccessful penalty (p < 0.001). Results highlight the importance of the QE period in successfully executing a soccer penalty kick. Unsuccessful penalties were associated with shorter QE length and earlier QE offset, which was due to initiating an anticipatory fixation in prediction of tracking the fast moving football, resulting in kicking the ball more centrally in the goal, making it easier for the goalkeeper to save.

Loss of CXCR4/CXCL12 Signaling Causes Oculomotor Nerve Misrouting and Development of Motor Trigeminal to Oculomotor Synkinesis.

PurposeProper control of eye movements is critical to vision, but relatively little is known about the molecular mechanisms that regulate development and axon guidance in the ocular motor system or cause the abnormal innervation patterns (oculomotor synkinesis) seen in developmental disorders and after oculomotor nerve palsy. We developed an ex vivo slice assay that allows for live imaging and molecular manipulation of the growing oculomotor nerve, which we used to identify axon guidance cues that affect the oculomotor nerve.MethodsEx vivo slices were generated from E10.5 IslMN-GFP embryos and grown for 24 to 72 hours. To assess for CXCR4 function, the specific inhibitor AMD3100 was added to the culture media. Cxcr4cko/cko:Isl-Cre:ISLMN-GFP and Cxcl12KO/KO:ISLMN-GFP embryos were cleared and imaged on a confocal microscope.ResultsWhen AMD3100 was added to the slice cultures, oculomotor axons grew dorsally (away from the eye) rather than ventrally (toward the eye). Axons that had already exited the midbrain continued toward the eye. Loss of Cxcr4 or Cxcl12 in vivo caused misrouting of the oculomotor nerve dorsally and motor axons from the trigeminal motor nerve, which normally innervate the muscles of mastication, aberrantly innervated extraocular muscles in the orbit. This represents the first mouse model of trigeminal-oculomotor synkinesis.ConclusionsCXCR4/CXCL12 signaling is critical for the initial pathfinding decisions of oculomotor axons and their proper exit from the midbrain. Failure of the oculomotor nerve to innervate its extraocular muscle targets leads to aberrant innervation by other motor neurons, indicating that muscles lacking innervation may secrete cues that attract motor axons.

Functional anatomy of human extraocular muscles during fusional divergence.

We employed magnetic resonance imaging to quantify human extraocular muscle contractility during centered target fusion and fusional divergence repeated with each eye viewing monocularly at 20 cm through 8Δ and at 400 cm through 4Δ base in prism. Contractility, indicated by posterior partial volume (PPV) change, was analyzed in transverse rectus and in medial and lateral superior oblique (SO) muscle compartments and by cross-sectional area change in the inferior oblique (IO). At 20 cm, 3.1 ± 0.5° (SE) diverging eye abduction in 10 subjects was associated with 4.2 ± 1.5% whole lateral rectus (LR) PPV increase ( P < 0.05) and 1.7 ± 1.1% overall medial rectus (MR) PPV decrease attributable to 3.1 ± 1.8% reduction in the superior compartment ( P < 0.025), without change in its inferior compartment or in muscles of the aligned eye. At 400 cm, 2.2 ± 0.5° diverging eye abduction in nine subjects was associated with 6.1 ± 1.3% whole LR PPV increase ( P < 10-5) but no change in MR, with compartmentally similar relaxation in the LR and MR of the aligned eye. Unlike convergence, there were no IO or SO contractile changes for divergence to either target nor any change in rectus pulley positions. Results confirm and extend to proximal divergence the unique role of the superior MR compartment, yet no MR role for far divergence. Corelaxation of aligned eye LR and MR combined with failure of MR relaxation during divergence is consistent with the limited behavioral range of divergence. NEW & NOTEWORTHY Magnetic resonance imaging shows that the lateral rectus muscle must overcome continued contraction by its opponent the medial rectus when humans diverge their visual axes to achieve single, binocular vision. While the upper but not lower compartment of the medial rectus assists by relaxing for near targets, it does not do so when targets are far away. This behavior violates Sherrington's law of reciprocal action of antagonists and conventional assumptions about the ocular motor system.

Protocadherin-Mediated Cell Repulsion Controls the Central Topography and Efferent Projections of the Abducens Nucleus

Cranial motor nuclei in the brainstem innervate diverse types of head and neck muscles. Failure inestablishing these neuromuscular connections causes congenital cranial dysinnervation disorders (CCDDs) characterized by abnormal craniofacial movements. However, mechanisms that link cranial motor nuclei to target muscles are poorly understood at the molecular level. Here, we report that protocadherin-mediated repulsion mediates neuromuscular connection in the ocular motor system in zebrafish. We identify pools of abducens motor neurons that are topographically arranged according to soma size and convergently innervate a single muscle. Disruptions of Duane retraction syndrome-associated transcription factors reveal that these neurons require Mafba/MAFB, but not Sall4/SALL4, for differentiation. Furthermore, genetic perturbations of Pcdh17/protocadherin-17 result in defective axon growth and soma clumping, thereby abolishing neuromuscular connectivity. Our results suggest that protocadherin-mediated repulsion forms the central topography and efferent projection pattern of the abducens nucleus following Mafba-dependent specification and imply potential involvement of protocadherins in CCDD etiology.

Why acute unilateral vestibular midbrain lesions rarely manifest with rotational vertigo: a clinical and modelling approach to head direction cell function

A retrospective clinical study focused on the frequency of rotational vertigo in 63 patients with acute unilateral midbrain strokes involving the vestibular and ocular motor systems. In contrast to unilateral pontomedullary brainstem lesions, rotational vertigo in midbrain lesions occurred with a low frequency (14%) and transient (< 1 day) course. Swaying vertigo or unspecific dizziness (22%) and postural imbalance (31%) were more frequent. Midbrain strokes with transient rotational vertigo manifested with lesions chiefly in the caudal midbrain tegmentum, while manifestations with swaying, unspecific, or no vertigo chiefly occurred in rostral mesencephalic or meso-diencephalic lesions. We hypothesize that these different manifestations can be explained by the distribution of two separate cell systems based on semicircular canal function: the angular head-velocity cells and the head direction cells, both of which code for head rotation. Animal experiments have shown that angular head-velocity cells are located mainly in the lower brainstem up to the midbrain, whereas the head direction cells are found from the midbrain and thalamic level up to cortical regions. Due to the differences in coding, unilateral dysfunction of the angular velocity cell system should result in the sensation of rotation, while unilateral dysfunction of the head direction cell system should result in dizziness and unsteadiness. We simulated the different manifestations of vestibular dysfunction using a mathematical neural network model of the head direction cell system. This model predicted and confirmed our clinical findings that unilateral caudal and rostral brainstem lesions have different effects on vestibular function.

The Intersection between Ocular and Manual Motor Control: Eye-Hand Coordination in Acquired Brain Injury.

Acute and chronic disease processes that lead to cerebral injury can often be clinically challenging diagnostically, prognostically, and therapeutically. Neurodegenerative processes are one such elusive diagnostic group, given their often diffuse and indolent nature, creating difficulties in pinpointing specific structural abnormalities that relate to functional limitations. A number of studies in recent years have focused on eye–hand coordination (EHC) in the setting of acquired brain injury (ABI), highlighting the important set of interconnected functions of the eye and hand and their relevance in neurological conditions. These experiments, which have concentrated on focal lesion-based models, have significantly improved our understanding of neurophysiology and underscored the sensitivity of biomarkers in acute and chronic neurological disease processes, especially when such biomarkers are combined synergistically. To better understand EHC and its connection with ABI, there is a need to clarify its definition and to delineate its neuroanatomical and computational underpinnings. Successful EHC relies on the complex feedback- and prediction-mediated relationship between the visual, ocular motor, and manual motor systems and takes advantage of finely orchestrated synergies between these systems in both the spatial and temporal domains. Interactions of this type are representative of functional sensorimotor control, and their disruption constitutes one of the most frequent deficits secondary to brain injury. The present review describes the visually mediated planning and control of eye movements, hand movements, and their coordination, with a particular focus on deficits that occur following neurovascular, neurotraumatic, and neurodegenerative conditions. Following this review, we also discuss potential future research directions, highlighting objective EHC as a sensitive biomarker complement within acute and chronic neurological disease processes.

Axons get ahead: Insights into axon guidance and congenital cranial dysinnervation disorders.

Cranial nerves innervate head muscles in a well-characterized and highly conserved pattern. Identification of genes responsible for human congenital disorders of these nerves, combined with the analysis of their role in axonal development in animal models, has advanced understanding of how neuromuscular connectivity is established. Here, we focus on the ocular motor system, as an instructive example of the success of this approach in unravelling the aetiology of human strabismus. The discovery that ocular motility disorders can arise from mutations in transcription factors, including HoxA1, HoxB1, MafB, Phox2A, and Sall4, has revealed gene regulatory networks that pattern the brainstem and/or govern the differentiation of cranial motor neurons. Mutations in genes involved in axon growth and guidance disrupt specific stages of the extension and pathfinding of ocular motor nerves, and have been implicated in human strabismus. These genes encompass varied classes of molecule, from receptor complexes to dynamic effectors to cytoskeletal components, including Robo3/Rig1, Alpha2-chimaerin, Kif21A, TUBB2, and TUBB3. A current challenge is to understand the protein regulatory networks that link the cell surface to the cytoskeleton and to dissect the co-ordinated signalling cascades and motile responses that underpin axonal navigation. Here we review recent insights derived from basic and clinical science approaches, to show how, by capitalising on the strengths of each, a more complete picture of the aetiology of human congenital cranial dysinnervation disorders can be achieved. This elucidation of these principles illustrates the success of clinical genetic studies working in tandem with molecular and cellular models to enhance our understanding of human disease. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 861-875, 2017.

Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance.

Unraveling the genetics of the paralytic strabismus syndromes known as congenital cranial dysinnervation disorders (CCDDs) is both informing physicians and their patients and broadening our understanding of development of the ocular motor system. Genetic mutations underlying ocular CCDDs alter either motor neuron specification or motor nerve development, and highlight the importance of modulations of cell signaling, cytoskeletal transport, and microtubule dynamics for axon growth and guidance. Here we review recent advances in our understanding of two CCDDs, congenital fibrosis of the extraocular muscles (CFEOM) and Duane retraction syndrome (DRS), and discuss what they have taught us about mechanisms of axon guidance and selective vulnerability. CFEOM presents with congenital ptosis and restricted eye movements, and can be caused by heterozygous missense mutations in the kinesin motor protein KIF21A or in the β-tubulin isotypes TUBB3 or TUBB2B. CFEOM-causing mutations in these genes alter protein function and result in axon growth and guidance defects. DRS presents with inability to abduct one or both eyes. It can be caused by decreased function of several transcription factors critical for abducens motor neuron identity, including MAFB, or by heterozygous missense mutations in CHN1, which encodes α2-chimaerin, a Rac-GAP GTPase that affects cytoskeletal dynamics. Examination of the orbital innervation in mice lacking Mafb has established that the stereotypical misinnervation of the lateral rectus by fibers of the oculomotor nerve in DRS is secondary to absence of the abducens nerve. Studies of a CHN1 mouse model have begun to elucidate mechanisms of selective vulnerability in the nervous system.

Inaccurate Saccades and Enhanced Vestibulo-Ocular Reflex Suppression during Combined Eye-Head Movements in Patients with Chronic Neck Pain: Possible Implications for Cervical Vertigo.

The primate ocular motor system is designed to acquire peripheral targets of interest by coordinating visual, vestibular, and neck muscle activation signals. The vestibulo-ocular reflex (VOR) is greatly reduced at the onset of large eye-head (gaze) saccades and resumes before the end of the saccades to stabilize eye-in-orbit and ensure accurate target acquisition. Previous studies have relied on manipulating head movements in normal individuals to study VOR suppression and gaze kinematics. We sought to determine if reduced head-on-trunk movement alters VOR suppression and gaze accuracy similar to experiments involving normal subjects and if intentionally increasing head and neck movement affects these dynamics. We measured head and gaze movements using magnetic search coil oculography in eight patients with cervical soft tissue disorders and seven healthy subjects. All participants made horizontal head-free saccades to acquire a laser dot target that stepped pseudorandomly 30-65° to either side of orbital mid-position, first using typical head and eye movements and again after being instructed to increase head amplitudes as much as possible. Compared to healthy subjects, patients made smaller head movements that contributed only 6% to total gaze saccade amplitudes. Head movements were also slowed, prolonged, and delayed. VOR suppression was increased and prolonged. Gaze saccades were inaccurate and delayed with long durations and decreased peak velocities. In patients with chronic neck pain, the internal commands issued for combined eye-head movements have large enough amplitudes to create accurate gaze saccades; however, because of increased neck stiffness and viscosity, the head movements produced are smaller, slower, longer, and more delayed than they should be. VOR suppression is disproportionate to the size of the actual gaze saccades because sensory feedback signals from neck proprioceptors are non-veridical, likely due to prolonged coactivation of cervical muscles. The outcome of these changes in eye-head kinematics is head-on-trunk stability at the expense of gaze accuracy. In the absence of vestibular loss, the practical consequences may be dizziness (cervical vertigo) in the short term and imbalance and falls in the long term.

Disrupted Saccade Control in Chronic Cerebral Injury: Upper Motor Neuron-Like Disinhibition in the Ocular Motor System.

Saccades rapidly direct the line of sight to targets of interest to make use of the high acuity foveal region of the retina. These fast eye movements are instrumental for scanning visual scenes, foveating targets, and, ultimately, serve to guide manual motor control, including eye–hand coordination. Cerebral injury has long been known to impair ocular motor control. Recently, it has been suggested that alterations in control may be useful as a marker for recovery. We measured eye movement control in a saccade task in subjects with chronic middle cerebral artery stroke with both cortical and substantial basal ganglia involvement and in healthy controls. Saccade latency distributions were bimodal, with an early peak at 60 ms (anticipatory saccades) and a later peak at 250 ms (regular saccades). Although the latencies corresponding to these peaks were the same in the two groups, there were clear differences in the size of the peaks. Classifying saccade latencies relative to the saccade “go signal” into anticipatory (latencies up to 80 ms), “early” (latencies between 80 and 160 ms), and “regular” types (latencies longer than 160 ms), stroke subjects displayed a disproportionate number of anticipatory saccades, whereas control subjects produced the majority of their saccades in the regular range. We suggest that this increase in the number of anticipatory saccade events may result from a disinhibition phenomenon that manifests as an impairment in the endogenous control of ocular motor events (saccades) and interleaved fixations. These preliminary findings may help shed light on the ocular motor deficits of neurodegenerative conditions, results that may be subclinical to an examiner, but clinically significant secondary to their functional implications.

What Causes Nystagmus?

ABSTRACTBackground and Purpose: Nystagmus is a commonly encountered clinical finding both in children and adults. Despite its complexities, a fundamental understanding of the basic etiology and underlying pathophysiology of nystagmus is critical to manage these patients appropriately.Patients and Method: The subset of ocular motility disorders that constitutes true nystagmus is identified and delineated from saccadic intrusions. Once defined, we explore the causes of commonly encountered forms of nystagmus and their clinical features.Results: Three separate mechanisms work to integrate sensory input and calibrate ocular movements: the afferent visual pathway, the neural integrator, and the vestibular system. Specific neuroanatomical pathways and corresponding pathologic changes are reviewed.Conclusion: A basic understanding of the underlying pathophysiology of nystagmus is essential to clinical practice. Three main mechanisms utilize multifactorial sensory input to produce a normally functioning ocular motor system. Both congenital and acquired forms of nystagmus result from pathology within these systems causing insufficient or asymmetric input to the central nervous system.

Isolated Infarction of Anterior Cerebellar Vermis

The anterior cerebellar vermis has been known to act in coordination of gait and postural adjustment of the trunk and legs. However, oculomotor abnormalities in an isolated anterior vermian lesion have not been described in the literature. A 59-year-old man presented with acute non-rotatory dizziness and disequilibrium. Neuro-ophthalmologic examination found impaired smooth pursuit and hypometric saccades in the contralesional direction, and disconjugate ipsiversive ocular torsion, but without spontaneous or gaze-evoked nystagmus. Imaging study showed an infarction restricted to the rostral end of right cerebellar vermis involving the lingual and central lobules. The anterior cerebellar vermis participates in the maintenance of axial posture and gait, and also in the control of ocular motor and vestibular systems. Keywords: Cerebellum; Cerebellar vermis; Gait; Smooth pursuit; Saccades; Ocular torsion 중심 단어: 소뇌, 소뇌충부, 보행, ì›í™œì¶”ì¢ ì•ˆêµ¬ìš´ë™, ì‹ ì†ì•ˆêµ¬ìš´ë™, 안구회ì„

Improvement of Eye Alignment in Adult Strabismic Monkeys by Sustained IGF-1 Treatment.

PurposeThe goal of this study was to determine if continuous application of insulin-like growth factor-1 (IGF-1) could improve eye alignment of adult strabismic nonhuman primates and to assess possible mechanisms of effect.MethodsA continuous release pellet of IGF-1 was placed on one medial rectus muscle in two adult nonhuman primates (M1, M2) rendered exotropic by the alternating monocular occlusion method during the first months of life. Eye alignment and eye movements were recorded for 3 months, after which M1 was euthanized, and the lateral and medial rectus muscles were removed for morphometric analysis of fiber size, nerve, and neuromuscular density.ResultsMonkey 1 showed a 40% reduction in strabismus angle, a reduction of exotropia of approximately 11° to 14° after 3 months. Monkey 2 showed a 15% improvement, with a reduction of its exotropia by approximately 3°. The treated medial rectus muscle of M1 showed increased mean myofiber cross-sectional areas. Increases in myofiber size also were seen in the contralateral medial rectus and lateral rectus muscles. Similarly, nerve density increased in the contralateral medial rectus and yoked lateral rectus.ConclusionsThis study demonstrates that in adult nonhuman primates with a sensory-induced exotropia in infancy, continuous IGF-1 treatment improves eye alignment, resulting in muscle fiber enlargement and altered innervational density that includes the untreated muscles. This supports the view that there is sufficient plasticity in the adult ocular motor system to allow continuous IGF-1 treatment over months to produce improvement in eye alignment in early-onset strabismus.

Association of Football Subconcussive Head Impacts With Ocular Near Point of Convergence.

An increased understanding of the relationship between subconcussive head impacts and near point of convergence (NPC) ocular-motor function may be useful in delineating traumatic brain injury. To investigate whether repetitive subconcussive head impacts during preseason football practice cause changes in NPC. This prospective, observational study of 29 National Collegiate Athletic Association Division I football players included baseline and preseason practices (1 noncontact and 4 contact), and postseason follow-up and outcome measures were obtained for each time. An accelerometer-embedded mouthguard measured head impact kinematics. Based on the sum of head impacts from all 5 practices, players were categorized into lower (n = 7) or higher (n = 22) impact groups. Players participated in regular practices, and all head impacts greater than 10g from the 5 practices were recorded using the i1Biometerics Vector mouthguard (i1 Biometrics Inc). Near point of convergence measures and symptom scores. A total of 1193 head impacts were recorded from 5 training camp practices in the 29 collegiate football players; 22 were categorized into the higher-impact group and 7 into the lower-impact group. There were significant differences in head impact kinematics between lower- and higher-impact groups (number of impacts, 6 vs 41 [lower impact minus higher impact = 35; 95% CI, 21-51; P < .001]; linear acceleration, 99g vs 1112g [lower impact minus higher impact= 1013; 95% CI, 621 - 1578; P < .001]; angular acceleration, 7589 radian/s2 vs 65 016 radian/s2 [lower impact minus higher impact= 57 427; 95% CI , 31 123-80 498; P < .001], respectively). The trajectory and cumulative burden of subconcussive impacts on NPC differed by group (F for group × linear trend1, 238 = 12.14, P < .001 and F for group × quadratic trend1, 238 = 12.97, P < .001). In the higher-impact group, there was a linear increase in NPC over time (B for linear trend, unstandardized coefficient [SE]: 0.76 [0.12], P < .001) that plateaued and resolved by postseason follow-up (B for quadratic trend [SE]: -0.06 [0.008], P < .001). In the lower-impact group, there was no change in NPC over time. Group differences were first observed after the first contact practice and remained until the final full-gear practice. No group differences were observed postseason follow-up. There were no differences in symptom scores between groups over time. Although asymptomatic, these data suggest that repetitive subconcussive head impacts were associated with changes in NPC. The increase in NPC highlights the vulnerability and slow recovery of the ocular-motor system following subconcussive head impacts. Changes in NPC may become a useful clinical tool in deciphering brain injury severity.