Compartmentalization of extraocular muscle function.

Ocular motor diversity exceeds capabilities of only six extraocular muscles (EOMs), but this deficiency is overcome by the plethora of fibers within individual EOMs surpassing requirements of homogeneous actuators. This paper reviews emerging evidence that regions of individual EOMs can be differentially innervated to exert independent oculorotary torques, broadening the oculomotor repertoire, and potentially explaining diverse strabismus pathophysiology. Parallel structure characterizes EOM and tendon fibers, with little transverse coupling of experimentally imposed or actively generated tension. This arrangement enables arbitrary groupings of tendon and muscle fibers to act relatively independently. Coordinated force generation among EOM fibers occurs only upon potentially mutable coordination of innervational commands, whose central basis is suggested by preliminary findings of apparent compartmental segregation of abducens motor neuron pools. Humans, monkeys, and other mammals demonstrate separate, nonoverlapping intramuscular nerve arborizations in the superior vs inferior compartments of the medial rectus (MR) and lateral rectus (LR) EOMs that could apply force at the superior vs inferior portions of scleral insertions, and in the medial vs lateral compartments of the superior oblique that act at the equatorial vs posterior scleral insertions that might preferentially implement incycloduction vs infraduction. Magnetic resonance imaging of the MR during several physiological ocular motor behaviors indicates differential compartmental function. Differential compartmental pathology can influence clinical strabismus. Partial abducens palsy commonly affects the superior LR compartment more than the inferior, inducing vertical strabismus that might erroneously be attributed to cyclovertical EOM pathology. Surgery may selectively manipulate EOM compartments.

Diffusion tensor MRI shows abnormal brainstem crossing fibers associated with ROBO3 mutations.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is caused by mutations in the ROBO3 gene, critical for the crossing of long ascending medial lemniscal and descending corticospinal tracts in the medulla. Diffusion tensor imaging in a patient with HGGPS revealed the absence of major pontine crossing fiber tracts and no decussation of the superior cerebellar peduncles. Mutations in the ROBO3 gene lead to a widespread lack of crossing fibers throughout the brainstem.

Otolith function in cerebellar ataxia due to mutations in the calcium channel gene CACNA1A.

The vestibulo-ocular reflexes stabilize retinal images during head movements. While there is a wealth of information about the interaction between the cerebellum and vestibulo-ocular reflexes mediated by the semicircular canals, little is known about the role of the cerebellum in the generation of the otolith-mediated linear vestibulo-ocular reflex (LVOR). By means of transient linear acceleration of the whole body along the interaural axis, we examined the LVOR in six patients with hereditary cerebellar ataxia due to mutations of the calcium channel gene CACNA1A, five with spinocerebellar ataxia type 6 (SCA6) and one with episodic ataxia type 2 (EA-2). Six age-matched normal subjects served as controls. Using a peak acceleration of 0.5 g in combination with recording by the binocular scleral magnetic search coil method, it was possible to study the latency and sensitivity of the LVOR in the first 150 ms after motion onset. The normal LVOR showed a significant dependence on viewing distance and covaried with vergence angle, and could be enhanced by the presence of a visible target. In contrast, the LVOR of ataxic patients had normal latency but significantly decreased sensitivity that was not enhanced with visible or nearer targets despite normal vergence. Substituting for the normal smooth LVOR slow phase, ataxic patients employed catch-up saccades 150-250 ms after motion onset. These findings suggest a critical role of the cerebellum in the modulation of otolith-ocular signals that is independent of motor vergence.

New tests of vestibular function.

The vestibulo-ocular reflex (VOR) is the only drive for short-latency eye movements stabilizing the retina during externally imposed, sudden, high-head accelerations. New strategies can exploit this unique VOR feature to study it under conditions relevant to the daily lives of patients, and to exclude the contributions from confounding nonvestibular mechanisms. Testing of the yaw vestibulo-ocular reflex (VOR) during random, whole-body rotational transients at < or = 2800 degrees/s2 delivered about centered and eccentric axes enables measurement of gains and millisecond latencies of the canal and otolith VORs in humans. Repeated measurements in acute unilateral deafferentation show sequential recovery of canal and otolith VORs to contralesional rotation, but severe and permanent deficits to ipsilesional rotation. Patients with bilateral loss of caloric responses show severe bilateral loss of VORs to transient rotation, suggesting that the apparent preservation of their VORs during sinusoidal rotations at moderate frequencies may be due instead to somatosensory inputs. Since visual acuity is degraded by retinal image motion, dynamic visual acuity (DVA) measured during imposed head-on-body or whole-body transient motion can correlate closely with VOR performance only if optotypes are presented during directionally and temporally unpredictable, high-acceleration head motion. Prediction and efference copy are relentlessly employed by vestibulopathic patients to enable good DVA during predictable or low-acceleration head motion. The linear VOR to transient lateral acceleration is strongly dependent upon viewing distance. The latency of this otolith VOR is slightly longer and more variable than the canal VOR. Unlike the canal VOR, the otolith VOR does not develop a strong directional asymmetry in unilateral deafferentation. The otolith VOR is bilaterally attenuated in bilateral vestibulopathy, and loses target distance dependence in cerebellar degeneration.

Orbital wall approach with preoperative orbital imaging for identification and retrieval of lost or transected extraocular muscles.

PURPOSE: To report the results of an anterior approach along the orbital wall to recover a lost or transected extraocular muscle. METHODS: This is a retrospective review of lost or transected muscles retrieved by an anterior orbitotomy approach to the adjacent orbital wall because they were unable to be recovered by a standard conjunctival approach. Magnetic resonance imaging or computed tomography was performed on all subjects before surgery. RESULTS: Six patients underwent anterior orbitotomy via an orbital wall approach; all had undergone an attempted retrieval from a standard transconjunctival approach that failed. Five muscles had been lost from surgical or traumatic transection, and 1 muscle had been lost during strabismus surgery. The muscle location at retrieval ranged from 20 to 25 mm (mean, 23 mm) posterior to the limbus. The duration that these muscles were disinserted ranged from 7 days to 7.5 years (mean, 24 months). Preoperative deviation in primary gaze ranged from 15 to 50 PD, whereas first day postretrieval deviations all measured less than 8 PD. After a mean follow-up of 162 weeks, the mean deviation in primary gaze was 2 PD (range, orthotropia to 7 PD of esotropia). CONCLUSIONS: Anterior orbitotomy along the orbital wall with preoperative orbital imaging of extraocular muscle anatomy and function combine to create a valuable approach for retrieval of a lost or transected muscle. This technique may successfully retrieve lost or transected muscles that previously were irretrievable when using a standard transconjunctival approach.

Vestibular function in severe bilateral vestibulopathy.

OBJECTIVES: To assess residual vestibular function in patients with severe bilateral vestibulopathy comparing low frequency sinusoidal rotation with the novel technique of random, high acceleration rotation of the whole body. METHODS: Eye movements were recorded by electro-oculography in darkness during passive, whole body sinusoidal yaw rotations at frequencies between 0.05 and 1.6 Hz in four patients who had absent caloric vestibular responses. These were compared with recordings using magnetic search coils during the first 100 ms after onset of whole body yaw rotation at peak accelerations of 2800 degrees /s(2). Off centre rotations added novel information about otolithic function. RESULTS: Sinusoidal yaw rotations at 0.05 Hz, peak velocity 240 degrees/s yielded minimal responses, with gain (eye velocity/head velocity)<0.02, but gain increased and phase decreased at frequencies between 0.2 and 1.6 Hz in a manner resembling the vestibulo-ocular reflex. By contrast, the patients had profoundly attenuated responses to both centred and eccentric high acceleration transients, representing virtually absent responses to this powerful vestibular stimulus. CONCLUSION: The analysis of the early ocular response to random, high acceleration rotation of the whole body disclosed a profound deficit of semicircular canal and otolith function in patients for whom higher frequency sinusoidal testing was only modestly abnormal. This suggests that the high frequency responses during sinusoidal rotation were of extravestibular origin. Contributions from the somatosensory or central predictor mechanisms, might account for the generation of these responses. Random, transient rotation is better suited than steady state rotation for quantifying vestibular function in vestibulopathic patients.

Impairments in the initial horizontal vestibulo-ocular reflex of older humans.

To determine age-related changes, the initial horizontal vestibulo-ocular reflex (VOR) of 11 younger normal subjects (aged 20-32 years) was compared with that of 12 older subjects (aged 58-69 years) in response to random transients of whole-body acceleration of 1,000 and 2,800 degrees/s2 delivered around eccentric vertical axes ranging from 10 cm anterior to 20 cm posterior to the eyes. Eye and head positions were sampled at 1,200 Hz using magnetic search coils. Subjects fixed targets 500 cm or 15 cm distant immediately before the unpredictable onset of rotation in darkness. For all testing conditions, younger subjects exhibited compensatory VOR slow phases with early gain (eye velocity/head velocity, interval 35-45 ms from onset of rotation) of 0.90 +/- 0.02 (mean +/- SEM) for the higher head acceleration, and 0.79 +/- 0.02 for the lower acceleration. Older subjects had significantly (P < 0.0001) lower early gain of 0.77 +/- 0.04 for the higher head acceleration and 0.70 +/- 0.02 for the lower acceleration. Late gain (125-135 ms from onset of rotation) was similar for the higher and lower head accelerations in younger subjects. Older subjects had significantly lower late gain at the higher head acceleration, but gain similar to the younger subjects at the lower acceleration. All younger subjects maintained slow-phase VOR eye velocity to values > or = 200 degrees/s throughout the 250-ms rotation, but, after an average of 120 ms rotation (mean eccentricity 13 degrees), 8 older subjects consistently had abrupt declines (ADs) in slow-phase VOR velocity to 0 degree/s or even the anticompensatory direction. These ADs were failures of the VOR slow phase rather than saccades and were more frequent with the near target at the higher acceleration. Slow-phase latencies were 14.4 +/- 0.4 ms and 16.8 +/- 0.4 ms for older subjects at the higher and lower accelerations, significantly longer than comparable latencies of 10.0 +/- 0.5 ms and 12.0 +/- 0.6 ms for younger subjects. Late VOR gain modulation with target distance was significantly attenuated in older subjects only for the higher head acceleration.

Dynamic visual acuity during transient and sinusoidal yaw rotation in normal and unilaterally vestibulopathic humans.

The vestibulo-ocular reflex (VOR) stabilizes gaze to permit clear vision during head movements. It has been supposed that VOR function might be inferred from dynamic visual acuity (DVA), the acuity during imposed head motion. We sought to determine effectiveness of DVA for detection and lateralization of unilateral vestibulopathy, using rigorous psychophysical methods. Seventeen normal and 11 unilaterally vestibulopathic subjects underwent measurement of optically best corrected DVA during head motion. A variable size letter "E" 6 m distant was displayed in oblique random orientations to determine binocular DVA by a computer controlled, forced choice method. Three types of whole-body yaw rotation were delivered by a servo-controlled chair synchronized with optotype presentation. Two types of motion were predictable: (1) steady-state 2.0-Hz rotation at 10-130 degrees/s peak velocity with repetitive optotype presentation only during head velocity exceeding 80% of peak; and (2) directionally predictable transients at peak accelerations of 1000, 1600 and 2800 degrees/s2 with optotype presentation for 300 ms. For neither of these predictable motions did DVA in vestibulopathic subjects significantly differ from normal, with suggestions from search coil recordings that this was due to predictive slow and saccadic eye movements. Unilaterally vestibulopathic subjects experienced a significant decrease in DVA from the static condition during ipsilesional rotation for all three peak head accelerations. Only during directionally unpredictable transients with 75 ms or 300 ms optotype presentation was the sensitivity of DVA in unilaterally vestibulopathic subjects significantly abnormal during ipsilesional rotation. The ipsilesional decrease in DVA with head motion was greater for 75 ms than 300 ms optotype presentation. Search coil recordings confirmed hypometric compensatory eye movements during DVA testing with unpredictable, ipsilesional rotation. Receiver-operator characteristic analysis indicated ideal detection and lateralization of unilateral vestibulopathy by DVA tested with a 75-ms optotype exposure for unpredictable transient rotations to a peak acceleration of 2800 degrees/s. DVA can reliably detect unilateral deafferentation only if precautions are taken to prevent compensation by predictive slow eye movements and saccades.

Quantitative analysis of rectus extraocular muscle layers in monkey and humans.

PURPOSE: Rectus extraocular muscles (EOMs) consist of orbital (OL) and global (GL) layers. This study enumerated the fibers in both layers along the length of each EOM. METHODS: Four human (ages 17 months-93 years) and three monkey (ages 5-7 years) orbits were serially sectioned in the coronal plane and stained with Masson's trichrome. All fibers of the rectus EOMs were counted using light microscopy at midorbit in all specimens and regular intervals throughout the orbits for one human and one monkey. RESULTS: In the GL, human EOMs in midorbit contained 8000 to 16,400 fibers, and monkey EOMs contained 3600 to 6600 fibers, varying little among the four rectus EOMs. In humans and monkeys, the number of OL fibers in midorbit varied widely according to specific EOM, being most numerous for the medial rectus (human: 7400-14,600; monkey: 3700-7000). The GL existed over the entire extent of each EOM from origin in the orbital apex into continuity with the tendon inserting on the globe. The OL was absent in the most anterior portion of each EOM, because OL fibers inserted on the respective EOM pulley. CONCLUSIONS: Primate EOMs contain substantial numbers of OL fibers. Numerical similarity of GL fibers is consistent with similar mechanical loading on each of the four rectus EOMs, as required to rotate the globe. Numerical dissimilarity of OL fibers correlates with varying mechanical loading because of varying elasticities of connective tissues onto which these fibers insert.

Structure-function correlation of laminar vascularity in human rectus extraocular muscles.

PURPOSE: Orbital and global layers of rectus extraocular muscles (EOMs) are believed to serve different functions. This study sought anatomic and functional evidence of differing blood flow in the two layers of rectus EOMs. METHODS: Four human orbits ranging in age from 17 months to 93 years were serially sectioned and stained for muscle fibers with Masson's trichrome and for vascular smooth muscle with monoclonal antibody to smooth muscle alpha-actin. Digitally assisted microscopy was used to obtain measurements of luminal cross sections and counts of muscular blood vessels, as well as measurements of muscle fiber number and cross-sectional areas of the two layers. Findings were correlated with first-pass gadodiamide contrast magnetic resonance imaging (MRI) in two living humans to demonstrate relative perfusion of EOMs. RESULTS: In all rectus EOMs, the orbital layer had significantly more vessels per unit area, more vessels per fiber, and more total vascular luminal area, than the global layer (P: < 0.05). Vascularity of EOMs was greatest in the youngest specimen. First-pass contrast MRI was consistent with perfusion of the orbital layer earlier than the global layer of living human rectus EOMs. CONCLUSIONS: Orbital layers of human rectus EOMs have significantly more muscular vessels than the global layers and stain earlier after intravenous bolus injection of paramagnetic MRI contrast. These findings suggest higher and even more rapid blood flow in the orbital layers that may correlate with greater metabolic activity. Greater blood flow is consistent with more sustained mechanical loading of the orbital than the global layer.

Three-dimensional location of human rectus pulleys by path inflections in secondary gaze positions.

PURPOSE: Connective tissue pulleys serve as the functional mechanical origins of the extraocular muscles (EOMs). Anterior to these pulleys, EOM paths shift with gaze to follow the scleral insertions, whereas posterior EOM paths are stable in the orbit. Inflections in EOM paths produced by gaze shifts can be used to define the functional location of pulleys in three dimensions (3-D). METHODS: Contiguous magnetic resonance images in planes perpendicular to the orbital axis spanned the anteroposterior extents of 22 orbits of 11 normal adults with the eyes in central gaze, elevation, depression, abduction, and adduction. Mean EOM cross-sectional area centroids represented in a normalized, oculocentric coordinate system were plotted over the length of each EOM to determine paths. Path inflections were identified to define pulley locations in 3-D. RESULTS: All rectus EOM paths exhibited in secondary gaze positions distinct inflections 3 to 9 mm posterior to globe center, which were consistent across subjects. The globe center and the lateral rectus pulley translated systematically in the orbit with lateral gaze, whereas other pulleys remained stable relative to the orbit. CONCLUSIONS: Distinct inflections in rectus EOM paths in secondary gaze positions confirm the existence of pulleys and define their locations in 3-D. The globe and lateral rectus pulley translate systematically with gaze position. The EOM pulleys may simplify neural control of eye movements by implementing a commutative ocular motor plant in which commands for 3-D eye velocity are effectively independent of eye position.

Facial asymmetry in superior oblique muscle palsy and pulley heterotopy.

INTRODUCTION: Some observers have considered facial asymmetry as characteristic of congenital superior oblique muscle (SO) palsy. However, recent orbital imaging studies have determined that incomitant vertical strabismus resembling SO palsy can be caused by heterotopic rectus muscle pulleys. This finding suggests that facial asymmetry may predict the presence of abnormal orbital anatomy rather than be secondary to ocular torticollis. METHODS: Subjects who underwent orbital computed tomography or magnetic resonance imaging were divided into 5 groups based on clinical evaluation and previously established imaging criteria: (1) congenital SO palsy; (2) acquired SO palsy; (3) strabismus with pulley heterotopy; (4) strabismus without SO palsy or pulley heterotopy; and (5) orthotropic subjects. Frontal photographs were digitized and the following 3 facial morphometric features recorded: (1) angle of inclination of each orbit; (2) relative facial size; and (3) facial angle. RESULTS: The 79 subjects who underwent imaging were divided into the 5 groups as follows: 6 with congenital SO palsy; 7 with acquired SO palsy; 20 with pulley heterotopy; 26 with strabismus without SO palsy or pulley heterotopy; and 20 control subjects. All subjects with either congenital or acquired SO palsy had torticollis. Multivariate analysis demonstrated no significant differences in any of the 3 facial morphometric features among any of the groups. CONCLUSION: Facial asymmetry as assessed by these 3 morphometric features is not useful in distinguishing between congenital SO palsy or pulley heterotopy and other acquired forms of strabismus. This finding casts doubt on the relationship between ocular torticollis and facial asymmetry.

Effects of vestibular and cerebellar deficits on gaze and torso stability during ambulation.

We measured gaze, head, and torso stability during ambulation to determine how vestibulo-ocular reflex dysfunction caused by unilateral vestibulopathy, bilateral vestibulopathy, and cerebellar dysfunction might affect image stabilization on the retina. Subjects were tested during standing, walking, and running on a treadmill. Gaze velocity, vestibulo-ocular reflex gain, and head velocities were calculated from angular positions of the eye and head, as well as linear positions of the head and trunk. Mean gaze velocity with a visible, distant target was below 4 degrees /second for all measurement conditions in control and vestibulopathic subjects. The performance of unilaterally vestibulopathic subjects was indistinguishable from that of control subjects except that the former had less vertical translation during walking. Bilaterally vestibulopathic subjects demonstrated less head translation than control subjects but had higher gaze velocity. In subjects with cerebellar dysfunction, gaze velocity was elevated by pathologic nystagmus, but head movements were similar to those of control subjects.

Evidence for active control of rectus extraocular muscle pulleys.

PURPOSE: Connective tissue structures constrain paths of the rectus extraocular muscles (EOMs), acting as pulleys and serving as functional EOM origins. This study was conducted to investigate the relationship of orbital and global EOM layers to pulleys and kinematic implications of this anatomy. METHODS: High-resolution magnetic resonance imaging (MRI) was used to define the anterior paths of rectus EOMs, as influenced by gaze direction in living subjects. Pulley tissues were examined at cadaveric dissections and surgical exposures. Human and monkey orbits were step and serially sectioned for histologic staining to distinguish EOM fiber layers in relationship to pulleys. RESULTS: MRI consistently demonstrated gaze-related shifts in the anteroposterior locations of human EOM path inflections, as well as shifts in components of the pulleys themselves. Histologic studies of human and monkey orbits confirmed gross examinations and surgical exposures to indicate that the orbital layer of each rectus EOM inserts on its corresponding pulley, rather than on the globe. Only the global layer of the EOM inserts on the sclera. This dual insertion was visualized in vivo by MRI in human horizontal rectus EOMs. CONCLUSIONS: The authors propose the active-pulley hypothesis: By dual insertions the global layer of each rectus EOM rotates the globe while the orbital layer inserts on its pulley to position it linearly and thus influence the EOM's rotational axis. Pulley locations may also be altered in convergence. This overall arrangement is parsimoniously suited to account for numerous aspects of ocular dynamics and kinematics, including Listing's law.