Oculomotor System Plasticity After Sustained Unilateral Brain- Derived Neurotrophic Factor Treatment of the Extraocular Muscles: A Novel Treatment for Strabismus

Program Number: 2570 Poster Board Number: C0274 Presentation Time: 3:45 PM–5:30 PM Oculomotor System Plasticity After Sustained Unilateral BrainDerived Neurotrophic Factor Treatment of the Extraocular Muscles: A Novel Treatment for Strabismus Christy Willoughby1, Linda K. McLoon1, 2, Michael J. Mustari3. 1Neuroscience, University of Minnesota, Minneapolis, MN; 2Opthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN; 3Opthalmology, University of Washington, Seattle, WA. Purpose: Conjugate gaze and stereopsis are established and finetuned in early life by visual experience. Strabismus is an oculomotor disorder where eye position is misaligned. If left untreated, strabismus persists through adulthood and is the leading cause in the United States of amblyopia. A common strabismus treatment, surgery, has high failure rates, possibly because strabismus only alters the highly adaptable extraocular muscle. Neurotrophic factors present a potential alternative treatment approach because of their actions both on muscle and motor neurons that direct eye position and movement. We assessed if unilateral sustained delivery of brain-derived neurotrophic factor (BDNF) to an extraocular muscle could alter the eye position of infant non-human primates. Methods: Sustained-release pellets of BDNF were implanted unilaterally on the lateral rectus muscle of two normal infant nonhuman primates. After three months of treatment, eye position was assessed with corneal light reflex testing. Extraocular muscle specimens were collected for histological analysis of changes in muscle morphology and innervation density from BDNF treatment. Muscle specimens were compared to two control infant non-human primates. Results: Unilateral sustained release of BDNF for three months to the lateral rectus muscle in infant non-human primates resulted in strabismus for both treated infant monkeys. Analysis of muscle specimens showed that neuromuscular junction density substantially increased in the treated extraocular muscle, suggesting that BDNF altered eye alignment by increasing motor neuronal control over extraocular muscle. Conclusions: Our results demonstrate that unilateral sustained neurotrophic factor treatment in infant monkeys alters normal eye position. Our results suggest that altered signaling in the extraocular muscles can perturb the development of normal eye alignment, and may provide insight into causes of childhood strabismus. Our results also strongly support BDNF as a promising novel candidate treatment for strabismus. Future work will treat non-human primates with strabismus to determine the dosage of BDNF and duration necessary to improve/restore normal eye alignment. Commercial Relationships: Christy Willoughby, None; Linda K. McLoon, None; Michael J. Mustari, None Support: NEI Grants R01EY153, P30EY11375 (LKM), University of Washington National Primate Research Centers/NIH/Division of Research Resources Grants RR000165 and RR000166 (MJM), Minnesota Lions and Lionesses, Research to Prevent Blindness, Doctoral Dissertation Fellowship (CLW) Program Number: 2571 Poster Board Number: C0275 Presentation Time: 3:45 PM–5:30 PM Mechanisms of Pattern Strabismus: role of supra-nuclear neural circuits versus peripheral eye plant Fatema Ghasia1, 2, Aasef Shaikh4, Mark Walker2, 3. 1Ophthalmology, Cleveland Clinic, Cleveland, OH; 2Neurology, Cleveland VAMC -Daroff Dell’Oss Ocular Motility Lab, Cleveland, OH; 3Neurology, Case Western Reserve University, Cleveland, OH; 4Neurology, Emory University, Atlanta, GA. Purpose: The purpose of this study was to quantitatively study eye movement and vestibular function in patients with pattern strabismus. Our goal was to delineate the role of impaired central processing in supra-nuclear motion circuits versus abnormal static torsion resulting in altered direction of recti muscle pull. Methods: Eye movements were measured using high-precision video-oculography (VOG) (Eyelink 1000, SR research) in subjects with infantile pattern strabismus (IPS n=3), late onset pattern strabismus (LPS n=2), infantile comitant strabismus (IS n=1), late onset comitant strabismus (LS n=4) and from healthy controls (C n=15). Horizontal and vertical eye positions were simultaneously recorded during fixation, saccades, step-ramp pursuit and vestibuloocular reflex (VOR). Static torsion was measuring with fundus photography. Results: Oculomotor responses in the plane orthogonal to desired movements (cross-coupled responses) were seen in patients with pattern strabismus. The cross-coupled response was larger in IPS than LPS. The cross-coupled responses were evident during saccades more than smooth pursuit but not during VOR. There was a greater amount of static torsion as measured by fundus photos in IPS compared to LPS. The amount of cross coupled responses in human pattern strabismics was smaller compared to non-human primates reared by alternate monocular occlusion. Conclusions: Cross coupled responses were seen in pattern strabismics and its amplitude varied with different class of eye movements. Infantile onset pattern strabismus could be due to abnormal neural connections whereas late onset pattern strabismus or pattern strabismus in patients with craniofacial anomalies could be due to orbital pulley instability. Commercial Relationships: Fatema Ghasia, None; Aasef Shaikh, None; Mark Walker, None Support: Knights Templar Pediatric Eye Research Award, Fight for Sight Grant in Aid