Neuro-ophthalmology

Xiao S, Gaier ED, Mazow ML, Stout AU, Travers DA, Angjeli E, Wu HC, Binenbaum G, Hunter DG. Improved adherence and treatment outcomes with an engaging, personalized digital therapeutic in amblyopia. Sci Rep 2020;10(1):8328.Abstract
Given the prevalence of poor adherence to therapy and the biases of self-reporting across healthcare, we hypothesized that an engaging, personalized therapy may improve adherence and treatment outcomes in the home. We tested this hypothesis in the initial indication of amblyopia, a neurodevelopmental disorder for which available treatments are limited by low adherence. We designed a novel digital therapeutic that modifies patient-selected cinematic content in real-time into therapeutic visual input, while objectively monitoring adherence. The therapeutic design integrated a custom-designed headset that delivers precise visual input to each eye, computational algorithms that apply real-time therapeutic modifications to source content, a cloud-based content management system that enables treatment in the home, and a broad library of licensed content. In a proof-of-concept human study on the therapeutic, we found that amblyopic eye vision improved significantly after 12 weeks of treatment, with higher adherence than that of available treatments. These initial results support the utility of personalized therapy in amblyopia and may have broader relevance for improving treatment outcomes in additional indications.
Chauhan MZ, Arcuri J, Park KK, Zafar MK, Fatmi R, Hackam AS, Yin Y, Benowitz L, Goldberg JL, Samarah M, Bhattacharya SK. Multi-Omic Analyses of Growth Cones at Different Developmental Stages Provides Insight into Pathways in Adult Neuroregeneration. iScience 2020;23(2):100836.Abstract
Growth cones (GCs) are structures associated with growing neurons. GC membrane expansion, which necessitates protein-lipid interactions, is critical to axonal elongation in development and in adult neuritogenesis. We present a multi-omic analysis that integrates proteomics and lipidomics data for the identification of GC pathways, cell phenotypes, and lipid-protein interactions, with an analytic platform to facilitate the visualization of these data. We combine lipidomic data from GC and adult axonal regeneration following optic nerve crush. Our results reveal significant molecular variability in GCs across developmental ages that aligns with the upregulation and downregulation of lipid metabolic processes and correlates with distinct changes in the lipid composition of GC plasmalemma. We find that these processes also define the transition into a growth-permissive state in the adult central nervous system. The insight derived from these analyses will aid in promoting adult regeneration and functional innervation in devastating neurodegenerative diseases.
Kang J, Cho SS, Kim HY, Lee BH, Cho HJ, Gwak YS. Regional Hyperexcitability and Chronic Neuropathic Pain Following Spinal Cord Injury. Cell Mol Neurobiol 2020;40(6):861-878.Abstract
Spinal cord injury (SCI) causes maladaptive changes to nociceptive synaptic circuits within the injured spinal cord. Changes also occur at remote regions including the brain stem, limbic system, cortex, and dorsal root ganglia. These maladaptive nociceptive synaptic circuits frequently cause neuronal hyperexcitability in the entire nervous system and enhance nociceptive transmission, resulting in chronic central neuropathic pain following SCI. The underlying mechanism of chronic neuropathic pain depends on the neuroanatomical structures and electrochemical communication between pre- and postsynaptic neuronal membranes, and propagation of synaptic transmission in the ascending pain pathways. In the nervous system, neurons are the only cell type that transmits nociceptive signals from peripheral receptors to supraspinal systems due to their neuroanatomical and electrophysiological properties. However, the entire range of nociceptive signaling is not mediated by any single neuron. Current literature describes regional studies of electrophysiological or neurochemical mechanisms for enhanced nociceptive transmission post-SCI, but few studies report the electrophysiological, neurochemical, and neuroanatomical changes across the entire nervous system following a regional SCI. We, along with others, have continuously described the enhanced nociceptive transmission in the spinal dorsal horn, brain stem, thalamus, and cortex in SCI-induced chronic central neuropathic pain condition, respectively. Thus, this review summarizes the current understanding of SCI-induced neuronal hyperexcitability and maladaptive nociceptive transmission in the entire nervous system that contributes to chronic central neuropathic pain.
Chen CT, Schultz JA, Haven SE, Wilhite B, Liu C-H, Chen J, Hibbeln JR. Loss of RAR-related orphan receptor alpha (RORα) selectively lowers docosahexaenoic acid in developing cerebellum. Prostaglandins Leukot Essent Fatty Acids 2020;152:102036.Abstract
Deficiency in retinoid acid receptor-related orphan receptor alpha (RORα) of staggerer mice results in extensive granule and Purkinje cell loss in the cerebellum as well as in learned motor deficits, cognition impairments and perseverative tendencies that are commonly observed in autistic spectrum disorder (ASD). The effects of RORα on brain lipid metabolism associated with cerebellar atrophy remain unexplored. The aim of this study is to examine the effects of RORα deficiency on brain phospholipid fatty acid concentrations and compositions. Staggerer mice (Rora) and wildtype littermates (Rora) were fed n-3 polyunsaturated fatty acids (PUFA) containing diets ad libitum. At 2 months and 7 or more months old, brain total phospholipid fatty acids were quantified by gas chromatography-flame ionization detection. In the cerebellum, all fatty acid concentrations were reduced in 2 months old mice. Since total fatty acid concentrations were significantly different at 2-month-old, we examined changes in fatty acid composition. The composition of ARA was not significantly different between genotypes; though DHA composition remained significantly lowered. Despite cerebellar atrophy at >7-months-old, cerebellar fatty acid concentrations had recovered comparably to wildtype control. Therefore, RORα may be necessary for fatty acid accretions during neurodevelopment. Specifically, the effects of RORα on PUFA metabolisms are region-specific and age-dependent.
Douglas VP, Douglas KA, Rizzo JF, Chwalisz BK. Case report: Orbital myositis triggering oxygen-responsive cluster headache. Cephalalgia 2020;40(3):313-316.Abstract
BACKGROUND: Orbital myositis is an idiopathic, non-infectious condition, typically seen in young females and usually affecting one extraocular muscle. Orbital myositis mimicking cluster headache is a rare clinical entity, and this is the first description of a case of a secondary trigeminal autonomic cephalalgia from orbital myositis responsive to high-flow oxygen. CASE: A young woman presented with new-onset, oxygen-responsive headache, periorbital pain and autonomic features. She had associated vertical diplopia on downgaze and subtle ocular misalignment. An initial diagnosis of cluster headache was made. Initial brain MRI was unrevealing, but dedicated MRI of the orbits showed enhancement of orbital muscles. The diplopia and the imaging findings were consistent with orbital myositis. CONCLUSION: Orbital myositis mimicking cluster headache is rare, and not previously reported as an oxygen-responsive headache.
Rizzo JF. Unraveling the Enigma of Nonarteritic Anterior Ischemic Optic Neuropathy. J Neuroophthalmol 2019;39(4):529-544.Abstract
Non-arteritic anterior ischemic optic neuropathy (NAON) is the second most common optic neuropathy in adults. Despite extensive study, the etiology of NAION is not definitively known. The best evidence suggests that NAION is caused by an infarction in the region of the optic nerve head (ONH), which is perfused by paraoptic short posterior ciliary arteries (sPCAs) and their branches. To examine the gaps in knowledge that defies our understanding of NAION, a historical review was performed both of anatomical investigations of the ONH and its relevant blood vessels and the evolution of clinical understanding of NAION. Notably, almost all of the in vitro vascular research was performed prior our current understanding of NAION, which has largely precluded a hypothesis-based laboratory approach to study the etiological conundrum of NAION. More recent investigative techniques, like fluorescein angiography, have provided valuable insight into vascular physiology, but such light-based techniques have not been able to image blood vessels located within or behind the dense connective tissue of the sclera and laminar cribrosa, sites that are likely culpable in NAION. The lingering gaps in knowledge clarify investigative paths that might be taken to uncover the pathogenesis of NAION and possibly glaucoma, the most common optic neuropathy for which evidence of a vascular pathology also exists.
Bakaeva T, Mallery R, Prasad S. Emerging Treatments for Leber's Hereditary Optic Neuropathy and Other Genetic Causes of Visual Loss. Semin Neurol 2019;39(6):732-738.Abstract
Leber's hereditary optic neuropathy (LHON) and other genetic causes of visual loss are important clinical entities that can cause profound visual loss. To date, therapeutic options have been quite limited, but insights into the genetic basis of these diseases and advances in the ability to deliver effective and safe gene therapy have opened the door for new therapeutics that may revolutionize the approach to treating these conditions. This article reviews emerging gene therapies of LHON and other inherited ophthalmological diseases, addressing the technical, clinical, and ethical challenges that researchers and clinicians will encounter as new treatments become available for these conditions.
Anand P, Chwalisz BK. Inflammatory Disorders of the Skull Base: a Review. Curr Neurol Neurosci Rep 2019;19(12):96.Abstract
PURPOSE OF REVIEW: In recent years, literature on neuroinflammatory disorders has dramatically expanded, as have options for treatment. However, few reviews have focused on skull-based manifestations of inflammatory disorders. RECENT FINDINGS: Here, we review the clinical manifestations, etiologies, diagnostic workup, and treatment of both systemic and localized inflammatory diseases of the skull base with a focus on recent updates to the literature. This review aims to guide the workup and management of this complex set of diseases.
Yin Y, de Lima S, Gilbert H-Y, Hanovice NJ, Peterson SL, Sand R, Sergeeva EG, Wong KA, Xie L, Benowitz LI. Optic nerve regeneration: A long view. Restor Neurol Neurosci 2019;Abstract
The optic nerve conveys information about the outside world from the retina to multiple subcortical relay centers. Until recently, the optic nerve was widely believed to be incapable of re-growing if injured, with dire consequences for victims of traumatic, ischemic, or neurodegenerative diseases of this pathway. Over the past 10-20 years, research from our lab and others has made considerable progress in defining factors that normally suppress axon regeneration and the ability of retinal ganglion cells, the projection neurons of the retina, to survive after nerve injury. Here we describe research from our lab on the role of inflammation-derived growth factors, suppression of inter-cellular signals among diverse retinal cell types, and combinatorial therapies, along with related studies from other labs, that enable animals with optic nerve injury to regenerate damaged retinal axons back to the brain. These studies raise the possibility that vision might one day be restored to people with optic nerve damage.
Kumar V. Endoplasmic Reticulum-Mitochondrial Cross-Talk in Neurodegenerative and Eye Diseases. Neurology (ECronicon) 2019;11(9):864-873.Abstract
Neurodegenerative diseases demonstrate the progressive decline of brain functions resulting in a significant deterioration in the quality of patient's life. With increasing life expectancy, there has been a significant increase in the incidence of these diseases. Neurodegenerative diseases like Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis are devastating and afflicts a large world population. Eye, given the similar neural and vascular similarity to the brain, demonstrates many pathological hallmarks of some of these neurological diseases. Moreover, these diseases create an economic and social burden to society. Despite tremendous efforts made in the drug discovery, there is no cure for these fatal diseases. Thus, there is an unmet need to understand cellular and molecular pathophysiology of these diseases. All these diseases demonstrate damage to a large number of seemingly disparate cellular processes and functions such as Ca homeostasis, lipid metabolism, axonal transport, unfolded protein response, autophagy and inflammatory responses. Mitochondria are closely associated with Endoplasmic reticulum (ER) and ER-mitochondrial cross-talk regulates many of these cellular processes and functions damaged in neurodegenerative and eye diseases. Several studies have implicated the disruption of ER-mitochondria contacts in these diseases. This review is aimed at understanding and summarizing the role of ER-mitochondria interacting proteins in major neurodegenerative and eye diseases studied so far.
Caron-Cantin M, Cestari DM, Fortin E. Clinical and radiologic approach to 'typical' versus antibody-related optic neuritis. Curr Opin Ophthalmol 2019;30(6):412-417.Abstract
PURPOSE OF REVIEW: Optic neuritis is an autoimmune optic neuropathy that has been associated with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and more recently antimyelin oligodendrocyte glycoprotein (anti-MOG)-positive disorder. At initial presentation, it is often difficult to differentiate these entities given their significant overlap in clinical presentation and MRI findings. This review summarizes the distinguishing clinical and radiological features of MS, NMOSD, and anti-MOG disorders to help clinicians accurately diagnose and manage patients affected by these conditions. RECENT FINDINGS: Antiaquaporin-4 (AQP4) and more recently anti-MOG antibodies are both associated with central nervous system demyelinating diseases that often initially present with optic neuritis. Serologic testing now allows for a new classification of these overlapping conditions that can help to differentiate 'typical' optic neuritis that is often associated with MS from 'atypical' optic neuritis associated with NMOSD and anti-MOG-positive disorder. SUMMARY: Optic neuritis associated with MS, NMOSD, and anti-MOG-positive disease can have a similar clinical presentation. However, some clinical and radiologic findings can help clinicians to differentiate these entities so that they can be properly managed to optimize visual prognosis.

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