Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

Teprotumumab for Thyroid Eye Disease-related Strabismus.

PURPOSE: To assess and quantify teprotumumab's effect on thyroid eye disease-related strabismus by change in measured horizontal and vertical deviations and change in extraocular motility. METHODS: We reviewed a series of patients with thyroid eye disease-related strabismus treated with teprotumumab. Exclusion criteria included age under 18 years, strabismus of alternate etiology, or thyroid eye disease-related reconstructive surgery during the treatment course. Primary outcomes were absolute (prism diopters) and relative (%) differences in horizontal and vertical deviations in primary position at distance, as well as change in ductions of the more affected eye. Secondary outcomes included incidence and timing of strabismus surgery postteprotumumab. RESULTS: Thirty-one patients were included, with mean age 63 years and thyroid eye disease duration 10 months. After teprotumumab, there was 6 prism diopters (39%) mean reduction in vertical deviation ( p < 0.001), without significant change in mean horizontal deviation ( p = 0.75). Supraduction, abduction, adduction, and infraduction significantly improved in the more restricted eye ( p < 0.01, p < 0.01, p = 0.04, and p = 0.01, respectively). Thirty-five percent of patients underwent strabismus surgery posttreatment, at an average 10 months after last infusion. CONCLUSIONS: Teprotumumab produced a statistically significant reduction in vertical but not horizontal strabismus angles in primary position at distance. Extraocular motility in all 4 ductions also improved. A substantial minority of patients still required strabismus surgery following teprotumumab.

Teprotumumab for Thyroid Eye Disease-related Strabismus.

PURPOSE: To assess and quantify teprotumumab's effect on thyroid eye disease-related strabismus by change in measured horizontal and vertical deviations and change in extraocular motility. METHODS: We reviewed a series of patients with thyroid eye disease-related strabismus treated with teprotumumab. Exclusion criteria included age under 18 years, strabismus of alternate etiology, or thyroid eye disease-related reconstructive surgery during the treatment course. Primary outcomes were absolute (prism diopters) and relative (%) differences in horizontal and vertical deviations in primary position at distance, as well as change in ductions of the more affected eye. Secondary outcomes included incidence and timing of strabismus surgery postteprotumumab. RESULTS: Thirty-one patients were included, with mean age 63 years and thyroid eye disease duration 10 months. After teprotumumab, there was 6 prism diopters (39%) mean reduction in vertical deviation ( p < 0.001), without significant change in mean horizontal deviation ( p = 0.75). Supraduction, abduction, adduction, and infraduction significantly improved in the more restricted eye ( p < 0.01, p < 0.01, p = 0.04, and p = 0.01, respectively). Thirty-five percent of patients underwent strabismus surgery posttreatment, at an average 10 months after last infusion. CONCLUSIONS: Teprotumumab produced a statistically significant reduction in vertical but not horizontal strabismus angles in primary position at distance. Extraocular motility in all 4 ductions also improved. A substantial minority of patients still required strabismus surgery following teprotumumab.

Vertical Comitance of Hypertropia in Congenital and Acquired Superior Oblique Palsy.

BACKGROUND: Ivanir and Trobe have claimed that hypertropia (HT) that is greater in upgaze than downgaze, or equal to it, is characteristic of decompensated congenital superior oblique (SO) palsy and never present in ischemic, traumatic, or tumorous SO palsy. The reliability of this claim was tested in patients with SO palsy confirmed by MRI demonstration of subnormal ipsilesional SO size. METHODS: Quasi-coronal, surface coil MRI was performed in target-controlled central gaze to identify patients with a unilateral reduction in SO cross section indicative of palsy. Nine patients gave an unequivocal history or had markedly increased vertical fusional amplitudes indicative of congenital onset (mean age 38 ± 16 years, SD). Seven patients had unequivocal acquired onset (age 47 ± 14 years and symptom duration 5.4 ± 4.8 years), including 2 with demonstrated trochlear Schwannoma and 5 with onset after severe head trauma. Fifteen patients had gradually progressive onset unequivocally not congenital yet not associated with any identifiable precipitating event (age 52 ± 20 years and symptom duration 13 ± 14 years). RESULTS: Maximum SO cross section averaged 8.6 ± 3.9 mm2 in congenital palsy, not significantly different from 11.3 ± 3.5 mm2 in acquired palsy (P = 0.08) either unequivocally or progressively acquired, but significantly less than about 19 mm2 contralesionally in SO palsy (P < 10-4). Although mean central gaze HT was greater at 20.6 ± 8.0Δ in 9 cases of congenital than that in 22 acquired cases at 11.4 ± 6.8Δ (P = 0.002), HT was 8.4 ± 16.3Δ less in upgaze than downgaze in congenital SO palsy and 3.7 ± 11.2Δ less in acquired SO palsy. In congenital palsy, 33% of patients had HT greater in upgaze than downgaze while in 67% HT was greater in downgaze (by up to 42Δ). In acquired SO palsy, HT was greater in upgaze than downgaze or equal to it in 8 cases (36%, P = 0.87, X2). In acquired SO palsy, HT was greater in upgaze than downgaze in 37% and greater in downgaze than upgaze in 59% of cases. The HT was equal in upgaze and centralgaze in no congenital and 3 acquired cases of SO palsy. Trends were similar in unequivocal acquired and progressive acquired (noncongenital) SO palsy (P > 0.4). CONCLUSIONS: Hypertropia is not characteristically greater in upgaze than downgaze in congenital SO palsy proven by SO atrophy on MRI. In fact, average HT is greater in downgaze than upgaze in both acquired and congenital palsy, sometimes strikingly so in the latter. The finding of HT greater in upgaze than downgaze, or equal to it, does not reliably indicate that SO palsy is congenital, nor does maximum SO cross section.

Disorders of the Fourth Cranial Nerve.

ABSTRACT: This review of disorders of the fourth cranial nerve includes discussion on anatomy, examination techniques, congenital and acquired etiologies, differential diagnosis, and management options. The findings of the superior oblique muscle on orbital MRI in patients with fourth nerve palsy have had a major impact on our understanding of this cranial neuropathy. In addition, briefly reviewed are rare disorders of the fourth nerve: superior oblique myokymia, Brown syndrome, and ocular neuromyotonia. It behooves the clinician to have a clear understanding of the role that the fourth cranial nerve plays in a variety of neuro-ophthalmic conditions.

The Adnexal Phenotype of Sagging Eye Syndrome.

PURPOSE: The sagging eye syndrome (SES) describes a condition that presents with age-related distance esotropia, alone or in combination with cyclovertical strabismus. It has a high prevalence in those aged over age 40 years presenting with binocular diplopia. The authors aim to characterize the adnexal phenotype of those who have been diagnosed with SES. METHODS: In this case-control study, patients were recruited from a prospectively maintained clinical and imaging database. The inclusion criteria required that subjects be above the age of 18 years and have a diagnosis of age-related distance esotropia or cyclovertical strabismus due to SES. Age-matched controls were selected from a validated database of normal faces that were not affected by any medical or surgical conditions. The margin to reflex distance from the upper eyelid, margin to reflex distance to the lower eyelid, the tarsal platform show, intracanthal distance, and inferior scleral bow were measured. Differences in the measurements between patients and controls were analyzed using a 2-tailed Student t tests. RESULTS: Twenty-two patients and 22 age-matched controls (11 males and 11 females per group) were included for study. Females with SES had a significantly greater margin to reflex distance to the lower eyelid and inferior scleral bow, with a lower tarsal platform show and margin to reflex distance from the upper eyelid than controls. Male patients with SES had a significantly greater margin to reflex distance to the lower eyelid and inferior scleral bow with a significantly lower margin to reflex distance from the upper eyelid and tarsal platform show than controls. DISCUSSION: This study supports the growing body of evidence which suggests that the SES represents age-related mechanical changes in the orbit that manifest as a specific adnexal phenotype.

Functional anatomy of extraocular muscles during human vergence compensation of horizontal heterophoria.

We employed magnetic resonance imaging to quantify human extraocular muscle (EOM) contractility during intermittent convergent and divergent strabismus with each eye viewing monocularly at 20 cm compared with centered target fusion. Contractility, indicated by posterior partial volume change, was analyzed in transverse rectus and in medial and lateral superior oblique (SO) muscle compartments. In five subjects with intermittent esotropia, abduction of the deviated eye to monocular target fixation was associated with significant whole lateral rectus (LR) contraction, but with medial rectus (MR) relaxation that was significantly greater in the superior than inferior compartment. Esotropic eye abduction to binocular fusion was associated with similar relaxation in the two MR compartments, but with greater contraction in the LR's superior than inferior compartment. The whole diverging eye SO muscle relaxed. In three subjects with intermittent exotropia, converging eye fusional adduction was associated with significant whole LR relaxation and with MR contraction attributable to significantly greater contraction in the superior than inferior compartment. In adduction of the exotropic eye to monocular target fixation but not fusional adduction, the whole SO exhibited significant relaxation. Rectus pulley positions were not significantly altered by fusion of either form of intermittent strabismus. Globe rotational axis was eccentric in intermittent strabismus, rolling the eye so that rectus EOM lever arms facilitated vergence. These results confirm, and extend to fusion of intermittent horizontal strabismus, differential compartmental function in horizontal rectus EOMs and suggest a novel role for the SO in compensation of both intermittent esotropia and exotropia. NEW & NOTEWORTHY Disjunctive eye movements normally permit binocular fixation in near visual space but also compensate for mechanical imbalances in binocular alignment developing over the life span. Magnetic resonance imaging of the extraocular muscles demonstrates important differential function in muscle compartments during compensation of large-angle intermittent convergent and divergent strabismus in humans. Eye translation during rotation also enhances vergence compensation of intermittent strabismus.

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.

The Globe's Eccentric Rotational Axis: Why Medial Rectus Surgery Is More Potent than Lateral Rectus Surgery.

PURPOSE: Tables typically recommend greater lateral rectus (LR) than medial rectus (MR) surgical doses for horizontal strabismus of any given magnitude, a difference unexplained by mechanical models that assume globe rotation about its center. We tested this assumption during horizontal ductions. DESIGN: Prospective observational study. PARTICIPANTS: Eighteen adult subjects with normal binocular vision. METHODS: Surface coil magnetic resonance imaging at 390 or 430 µm resolution was obtained using 2-mm-thick contiguous axial planes while subjects fixated targets in central, right, and left gaze. Angular displacements of lines connecting the corneal apex through the minor lens axis to the retina were measured to approximate clinical ductions. Globe centers were calculated from their area centroids. Apparent lens and globe-optic nerve (ON) junction rotations around the globe center were then compared with clinical ductions. MAIN OUTCOME MEASURES: Apparent angular rotations of lenses and globe-ON junctions during horizontal ductions. RESULTS: Globe-ON junctions appeared to rotate significantly less around globe centers than did lenses for abduction (20.6°±4.7° vs. 27.4°±7.4°, ± standard deviation (SD), P < 0.001) and adduction (25.3°±6.7° vs. 31.9°±8.3°, P < 0.001). Both rotations differed significantly from clinical adduction (27.9°±8.3°, P < 0.007), but only in abduction was globe-ON junction rotation significantly less than clinical abduction (28.6°±9.4°, P < 0.001). The true geometric globe rotational center was 2.2±0.5 mm medial and 0.8±1.0 mm posterior to the geometric globe center and was displaced farther medially and posteriorly during adduction. This eccentricity imbues each millimeter of MR recession with approximately 30% more trigonometric rotational effect than equivalent LR recession. CONCLUSIONS: The medial and posterior eccentricities of the normal ocular rotational axis profoundly influence horizontal rectus action. The proximity of the globe's rotational axis to the MR shortens its lever arm relative to the LR, explaining why mechanical effects of smaller MR recessions are equivalent to larger LR recessions.

Accuracy of Diagnostic Imaging Modalities for Classifying Pediatric Eyes as Papilledema Versus Pseudopapilledema.

PURPOSE: To identify the most accurate diagnostic imaging modality for classifying pediatric eyes as papilledema (PE) or pseudopapilledema (PPE). DESIGN: Prospective observational study. SUBJECTS: Nineteen children between the ages of 5 and 18 years were recruited. Five children (10 eyes) with PE, 11 children (19 eyes) with PPE owing to suspected buried optic disc drusen (ODD), and 3 children (6 eyes) with PPE owing to superficial ODD were included. METHODS: All subjects underwent imaging with B-scan ultrasonography, fundus photography, autofluorescence, fluorescein angiography (FA), optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL), and volumetric OCT scans through the optic nerve head with standard spectral-domain (SD OCT) and enhanced depth imaging (EDI OCT) settings. Images were read by 3 masked neuro-ophthalmologists, and the final image interpretation was based on 2 of 3 reads. Image interpretations were compared with clinical diagnosis to calculate accuracy and misinterpretation rates of each imaging modality. MAIN OUTCOME MEASURES: Accuracy of each imaging technique for classifying eyes as PE or PPE, and misinterpretation rates of each imaging modality for PE and PPE. RESULTS: Fluorescein angiography had the highest accuracy (97%, 34 of 35 eyes, 95% confidence interval 92%-100%) for classifying an eye as PE or PPE. FA of eyes with PE showed leakage of the optic nerve, whereas eyes with suspected buried ODD demonstrated no hyperfluorescence, and eyes with superficial ODD showed nodular staining. Other modalities had substantial likelihood (30%-70%) of misinterpretation of PE as PPE. CONCLUSIONS: The best imaging technique for correctly classifying pediatric eyes as PPE or PE is FA. Other imaging modalities, if used in isolation, are more likely to lead to misinterpretation of PE as PPE, which could potentially result in failure to identify a life-threatening disorder causing elevated intracranial pressure and papilledema.

Surgical interventions for vertical strabismus in superior oblique palsy.

BACKGROUND: Superior oblique palsy is a common cause of vertical strabismus in adults and children. Patients may be symptomatic from binocular vertical diplopia or compensatory head tilt required to maintain single vision. Most patients who are symptomatic elect to undergo strabismus surgery, but the optimal surgical treatment for vertical strabismus in people with superior oblique palsy is unknown. OBJECTIVES: To assess the relative effects of surgical treatments compared with another surgical intervention, non-surgical intervention, or observation for vertical strabismus in people with superior oblique palsy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 12), MEDLINE Ovid (1946 to 13 December 2016), Embase Ovid (1947 to 13 December 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to 13 December 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 13 December 2016, ClinicalTrials.gov (www.clinicaltrials.gov); searched 13 December 2016, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 13 December 2016. We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We included randomized trials that compared at least one type of surgical intervention to another surgical or non-surgical intervention or observation. DATA COLLECTION AND ANALYSIS: Two review authors independently completed eligibility screening, data abstraction, 'Risk of bias' assessment, and grading of the evidence. MAIN RESULTS: We identified two randomized trials comparing four different surgical treatments for this condition, two methods in each trial. The studies included a total of 45 children and adults. The surgical treatments were all procedures to weaken the ipsilateral inferior oblique muscle. One study compared inferior oblique myectomy to recession of 10 mm; the other study compared inferior oblique disinsertion to anterior transposition (2 mm anterior to the temporal border of the inferior rectus insertion).We judged both studies to be at unclear risk of bias due to incomplete reporting of methods and other methodological deficiencies.Neither study reported data on the primary outcome of this review, which was the proportion of participants with postoperative surgical success, defined as hypertropia less than 3 prism diopters (PD) in primary gaze. However, both studies reported the average reduction in hypertropia in primary gaze. One study found that at 12 months' postoperatively the average decrease in hypertropia was higher in participants who underwent inferior oblique myectomy than in those who underwent recession, however data were not available for statistical comparison. The other trial found that after at least six months of follow-up, the mean decrease in primary position hypertropia was lower in participants who underwent inferior oblique disinsertion than in those who underwent anterior transposition (mean difference (MD) -5.20 PD, 95% confidence interval (CI) -7.76 to -2.64; moderate-quality evidence).Both trials also reported the average postoperative reduction in vertical deviation in adduction. One study reported that the average reduction in hypertropia in adduction was greater in participants who underwent inferior oblique myectomy than in those who underwent recession, but data were not available for statistical comparison. The other study found a lower decrease in hypertropia in contralateral gaze in participants who underwent inferior oblique disinsertion than in those who underwent anterior transposition (MD -7.10 PD, 95% CI -13.85 to -0.35; moderate-quality evidence).Secondary outcomes with sufficient data for analysis included proportion of participants with preoperative head tilt that resolved postoperatively and proportion of participants who underwent a second surgery. These outcomes were assessed in the trial comparing inferior oblique anterior transposition to disinsertion; both outcomes favored anterior transposition (risk ratio 7.00, 95% CI 0.40 to 121.39 for both outcomes; very low-quality evidence). None of the participants who underwent inferior oblique anterior transposition or disinsertion developed postoperative hypotropia or reversal of the vertical deviation. All participants who underwent inferior oblique anterior transposition developed elevation deficiency, which the authors deemed to be clinically insignificant in all cases, whereas no participants who underwent inferior oblique disinsertion experienced this complication. Additionally, the trial comparing inferior oblique myectomy to recession reported that no participant in either group required another strabismus surgery during the postoperative period. AUTHORS' CONCLUSIONS: The two trials included in this review evaluated four inferior oblique weakening procedures for surgical treatment of superior oblique palsy. We found no trials comparing other types of surgical procedures for this disorder. Both studies had enrolled a small number of participants and provided low-quality evidence due to limitations in completeness and applicability. We therefore found no high-quality evidence to support recommendations for optimal surgical treatment of superior oblique palsy. Rigorously designed, conducted, and reported randomized trials are needed to identify the optimal surgical treatment for vertical strabismus in this disorder.

Finite Element Biomechanics of Optic Nerve Sheath Traction in Adduction.

Historical emphasis on increased intraocular pressure (IOP) in the pathogenesis of glaucoma has been challenged by the recognition that many patients lack abnormally elevated IOP. We employed finite element analysis (FEA) to infer contribution to optic neuropathy from tractional deformation of the optic nerve head (ONH) and lamina cribrosa (LC) by extraocular muscle (EOM) counterforce exerted when optic nerve (ON) redundancy becomes exhausted in adduction. We characterized assumed isotropic Young's modulus of fresh adult bovine ON, ON sheath, and peripapillary and peripheral sclera by tensile elongation in arbitrary orientations of five specimens of each tissue to failure under physiological temperature and humidity. Physical dimensions of the FEA were scaled to human histological and magnetic resonance imaging (MRI) data and used to predict stress and strain during adduction 6 deg beyond ON straightening at multiple levels of IOP. Young's modulus of ON sheath of 44.6 ± 5.6 MPa (standard error of mean) greatly exceeded that of ON at 5.2 ± 0.4 MPa, peripapillary sclera at 5.5 ± 0.8 MPa, and peripheral sclera at 14.0 ± 2.3 MPa. FEA indicated that adduction induced maximum stress and strain in the temporal ONH. In the temporal LC, the maximum stress was 180 kPa, and the maximum strain was ninefold larger than produced by IOP elevation to 45 mm Hg. The simulation suggests that ON sheath traction by adduction concentrates far greater mechanical stress and strain in the ONH region than does elevated IOP, supporting the novel concept that glaucomatous optic neuropathy may result at least partly from external traction on the ON, rather than exclusively on pressure on the ON exerted from within the eye.

Functional morphometry demonstrates extraocular muscle compartmental contraction during vertical gaze changes.

Anatomical studies demonstrate selective compartmental innervation of most human extraocular muscles (EOMs), suggesting the potential for differential compartmental control. This was supported by magnetic resonance imaging (MRI) demonstrating differential lateral rectus (LR) compartmental contraction during ocular counterrolling, differential medial rectus (MR) compartmental contraction during asymmetric convergence, and differential LR, inferior rectus (IR), and superior oblique (SO) compartmental contraction during vertical vergence. To ascertain possible differential compartmental EOM contraction during vertical ductions, surface coil MRI was performed over a range of target-controlled vertical gaze positions in 25 orbits of 13 normal volunteers. Cross-sectional areas and partial volumes of EOMs were analyzed in contiguous, quasi-coronal 2-mm image planes spanning origins to globe equator to determine morphometric features correlating best with contractility. Confirming and extending prior findings for horizontal EOMs during horizontal ductions, the percent change in posterior partial volume (PPV) of vertical EOMs from 8 to 14 mm posterior to the globe correlated best with vertical duction. EOMs were then divided into equal transverse compartments to evaluate the effect of vertical gaze on changes in PPV. Differential contractile changes were detected in the two compartments of the same EOM during infraduction for the IR medial vs. lateral (+4.4%, P = 0.03), LR inferior vs. superior (+4.0%, P = 0.0002), MR superior vs. inferior (-6.0%, P = 0.001), and SO lateral vs. medial (+9.7%, P = 0.007) compartments, with no differential contractile changes in the superior rectus. These findings suggest that differential compartmental activity occurs during normal vertical ductions. Thus all EOMs may contribute to cyclovertical actions.

Rectus Extraocular Muscle Size and Pulley Location in Concomitant and Pattern Exotropia.

PURPOSE: To determine whether rectus extraocular muscle (EOM) sizes and pulley locations contribute to exotropia, we used magnetic resonance imaging (MRI) to measure these factors in normal control participants and in patients with concomitant and pattern exotropia. DESIGN: Prospective case-control study. PARTICIPANTS: Nine patients with concomitant exotropia, 6 patients with pattern exotropia, and 21 orthotropic normal control participants. METHODS: High-resolution surface-coil MRI scans were obtained in contiguous, quasicoronal planes. Rectus pulley locations were determined in oculocentric coordinates for central gaze, supraduction, and infraduction. Cross sections in 4 contiguous image planes were summed and multiplied by the 2-mm slice thickness to obtain horizontal rectus posterior partial volumes (PPVs). MAIN OUTCOME MEASURES: Rectus pulley locations and horizontal rectus PPVs. RESULTS: Rectus pulleys were located differently in patients with A-pattern, versus V- and Y-pattern, exotropia. The lateral rectus (LR) pulleys were displaced significantly superiorly, the medial rectus (MR) pulleys were displaced inferiorly, and the inferior rectus pulleys were displaced laterally in A-pattern exotropia. However, the array of all rectus pulleys was excyclorotated in V- and Y-pattern exotropia. The PPV of the medial rectus muscle was statistically subnormal by approximately 29% in concomitant, but not pattern, exotropia (P < 0.05). The ratio of the PPV of the LR relative to the MR muscles in concomitant exotropia was significantly greater than in control participants and those with pattern exotropia (P < 0.05). CONCLUSIONS: Abnormalities of EOMs and pulleys contribute differently in pattern versus concomitant exotropia. Abnormal rectus pulley locations derange EOM pulling directions that contribute to pattern exotropia, but in concomitant exotropia, pulley locations are normal, and relatively small medial rectus size reduces relative adducting force.

Rectus Pulley Displacements without Abnormal Oblique Contractility Explain Strabismus in Superior Oblique Palsy.

PURPOSE: Using high-resolution magnetic resonance imaging (MRI), we investigated whether rectus pulleys are significantly displaced in superior oblique (SO) palsy and whether displacements account for strabismus patterns. DESIGN: Prospective case-control study. PARTICIPANTS: Twenty-four patients diagnosed with SO palsy based on atrophy of the SO muscle on MRI and 19 age-matched orthotropic control subjects. METHODS: High-resolution, surface coil MRI scans were obtained in multiple, contiguous, quasicoronal planes during monocular central gaze fixation. Pulley locations in oculocentric coordinates in the following subgroups of patients with SO palsy were compared with normal results in subgroups of patients with SO palsy: unilateral versus bilateral, congenital versus acquired, and isotropic (round) versus anisotropic (elongated) SO atrophy. Expected effects of pulley displacements were modeled using Orbit 1.8 (Eidactics, San Francisco, CA) computational simulation. MAIN OUTCOME MEASURES: Rectus pulley positions and ocular torsion. RESULTS: Rectus pulleys typically were displaced in SO palsy. In unilateral SO palsy, on average the medial rectus (MR) pulley was displaced 1.1 mm superiorly, the superior rectus (SR) pulley was displaced 0.8 mm temporally, and the inferior rectus (IR) pulley was displaced 0.6 mm superiorly and 0.9 mm nasally from normal. Displacements were similar in bilateral SO palsy, with the SR pulley additionally displaced 0.9 mm superiorly. However, the lateral rectus pulley was not displaced in either unilateral or bilateral SO palsy. The SR and MR pulleys were displaced in congenital SO palsy, whereas the IR and MR pulleys were displaced in acquired palsy. Pulley positions did not differ between isotropic and anisotropic palsy or between patients with cyclotropia of less than 7° versus cyclotropia of 7° or more. Simulations predicted that the observed pulley displacements alone could cause patterns of incomitant strabismus typical of SO palsy, without requiring any abnormality of SO or inferior oblique strength. CONCLUSIONS: Rectus pulley displacements alone, without abnormal oblique muscle contractility, can create the clinical patterns of incomitant strabismus in SO palsy. This finding supports accumulating evidence that clinical binocular misalignment patterns are not reliable indicators of contractile function of the SO muscle. Ocular torsion does not correlate with and thus cannot account for pulley displacements in SO palsy.

Magnetic resonance imaging demonstrates compartmental muscle mechanisms of human vertical fusional vergence.

Vertical fusional vergence (VFV) normally compensates for slight vertical heterophorias. We employed magnetic resonance imaging to clarify extraocular muscle contributions to VFV induced by monocular two-prism diopter (1.15°) base-up prism in 14 normal adults. Fusion during prism viewing requires monocular infraduction. Scans were repeated without prism, and with prism shifted contralaterally. Contractility indicated by morphometric indexes was separately analyzed in medial and lateral vertical rectus and superior oblique (SO) putative compartments, and superior and inferior horizontal rectus extraocular muscle putative compartments, but in the whole inferior oblique (IO). Images confirmed appropriate VFV that was implemented by the inferior rectus (IR) medial compartment contracting ipsilateral and relaxing contralateral to prism. There was no significant contractility in the IR lateral compartment. The superior but not inferior lateral rectus (LR) compartment contracted significantly in the prism viewing eye, but not contralateral to prism. The IO contracted ipsilateral but not contralateral to the prism. In the infraducting eye, the SO medial compartment relaxed significantly, while the lateral compartment was unchanged; contralateral to prism, the SO lateral compartment contracted, while the medial compartment was unchanged. There was no contractility in the superior or medial rectus muscles in either eye. There was no globe retraction. We conclude that the vertical component of VFV is primarily implemented by IR medial compartment contraction. Since appropriate vertical rotation is not directly implemented, or is opposed, by associated differential LR and SO compartmental activity, and IO contraction, these actions probably implement a torsional component of VFV.

Magnetic resonance imaging of bilateral split lateral rectus transposition to the medial globe.

PURPOSE: Medial transposition of the split or intact lateral rectus (LR) muscle in oculomotor palsy improves extreme exotropia. We studied rectus pulley positions using high-resolution surface coil MRI before and after LR split with medial transposition surgery in a patient with bilateral oculomotor and trochlear nerve palsies. METHODS: This is a report of a 14-year-old girl with 90Δ exotropia due to bilateral oculomotor and trochlear nerve palsies following traumatic midbrain infarction at age 6 years. Surgery comprised longitudinal division of each LR into a superior and inferior, threading of both halves between the inferior rectus (IR) and inferior oblique inferiorly, and inferior to the superior oblique and the superior rectus superiorly, with suturing of each 10 mm posterior to the medial rectus (MR) insertion. RESULTS: Pre-operative MRI of the orbit and extraocular muscles (EOMs) with thin, 2-mm slices revealed bilateral atrophy of all EOMs supplied by the oculomotor and trochlear nerves. Post-operative MRI at 2 months demonstrated no significant changes in rectus EOM pulley positions compared with pre-operative values. CONCLUSIONS: The LR pulley does not change position even after split LR transposition to the MR insertion, confirming the profound constraint of the connective tissue pulley system on the LR path.

Recent advances clarifying the etiologies of strabismus.

BACKGROUND: Strabismus is commonly encountered in neuro-ophthalmology practice. Adult patients may present with symptoms including disabling diplopia and decreased quality of life. Although presentation to the neuro-ophthalmologist often prompts a thorough workup for a neurologic basis of ocular misalignment, advances in orbital imaging and understanding of orbital mechanics have revealed novel mechanical causes. A goal of this review is to clarify mechanical mechanisms of strabismus that were formerly assumed be neurologic in origin. EVIDENCE ACQUISITION: The authors combine their own research and clinical experience with a literature review using PubMed. RESULTS: Aberrant paths of the extraocular muscles can lead to strabismus. The extraocular muscles have connective tissue pulleys that control muscle paths and are, in turn, influenced by the extraocular muscle orbital layers. Orbital connective tissues, including the pulleys, constrain extraocular muscle paths. Abnormalities of these tissues may lead to strabismus that is not due to neurologic pathology. Some extraocular muscles are divided into independent neuromuscular compartments, so that partial motor nerve lesions may manifest as selective denervation of only 1 compartment, complicating the presentation of neuropathic strabismus. CONCLUSIONS: Strabismus in adults due to nonneurologic causes can result from recently described abnormalities of the orbital connective tissue pulley system. Advances in understanding of compartmental extraocular muscle anatomy and innervation can explain cyclovertical strabismus in partial nerve palsies. Recognition of the underlying pathogenesis of the strabismus can lead to improved treatments.

Magnetic resonance imaging of differential compartmental function of horizontal rectus extraocular muscles during conjugate and converged ocular adduction.

Activity in horizontal rectus extraocular muscles (EOMs) was investigated by magnetic resonance imaging (MRI) of humans during asymmetric convergence to a monocularly aligned target at 15-cm distance or monocular fixation of afocal targets placed over a wide range of conjugate abduction through adduction. Cross sections and posterior partial volumes (PPVs) of EOMs were determined from quasi-coronal image planes and were separately analyzed in the inferior vs. superior compartments, defined by lines bisecting their maximum vertical dimensions. Both inferior and superior compartments of medial (MR) and lateral (LR) rectus exhibited contractile changes in PPV and maximum cross section for both asymmetric convergence and a comparable range of conjugate adduction. Both LR compartments, and the inferior MR compartment, exhibited similar decreases in contractility correlating with relaxation during both convergence and conjugate adduction. In contrast, the superior MR compartment exhibited roughly three times the contractility in conjugate adduction as in similar-magnitude convergence. In the aligned eye that did not move during convergence, summed contractility in all compartments of MR and LR exhibited corelaxation consistent with published EOM force measurements in this paradigm (Miller JM, Bockisch CJ, Pavlovski DS. J Neurophysiol 87: 2421-2433, 2002; Miller JM, Davison RC, Gamlin PD. J Neurophysiol 105: 2863-2873, 2011). The superior MR compartment also exhibited significantly greater contractility than the other compartments over the maximum achievable horizontal globe rotation from abduction to adduction. These findings suggest that the superior MR compartment is controlled differentially from the inferior compartment and suggest that its activity is reduced during convergence as a component of generally altered extraocular mechanics.