Neuro-ophthalmology

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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.
Kurimoto T, Yin Y, Habboub G, Gilbert H-Y, Li Y, Nakao S, Hafezi-Moghadam A, Benowitz LI. Neutrophils express oncomodulin and promote optic nerve regeneration. J Neurosci 2013;33(37):14816-24.Abstract
Although neurons are normally unable to regenerate their axons after injury to the CNS, this situation can be partially reversed by activating the innate immune system. In a widely studied instance of this phenomenon, proinflammatory agents have been shown to cause retinal ganglion cells, the projection neurons of the eye, to regenerate lengthy axons through the injured optic nerve. However, the role of different molecules and cell populations in mediating this phenomenon remains unclear. We show here that neutrophils, the first responders of the innate immune system, play a central role in inflammation-induced regeneration. Numerous neutrophils enter the mouse eye within a few hours of inducing an inflammatory reaction and express high levels of the atypical growth factor oncomodulin (Ocm). Immunodepletion of neutrophils diminished Ocm levels in the eye without altering levels of CNTF, leukemia inhibitory factor, or IL-6, and suppressed the proregenerative effects of inflammation. A peptide antagonist of Ocm suppressed regeneration as effectively as neutrophil depletion. Macrophages enter the eye later in the inflammatory process but appear to be insufficient to stimulate extensive regeneration in the absence of neutrophils. These data provide the first evidence that neutrophils are a major source of Ocm and can promote axon regeneration in the CNS.
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Lains I, Diaz JD, Gittinger JW, Gaier ED. Anterior Ischemic Optic Neuropathy Secondary to Carotid Artery Dissection. J Neuroophthalmol 2021;41(4):e731-e733.
Lehky T, Joseph R, Toro C, Wu T, Van Ryzin C, Gropman A, Facio FM, Webb BD, Jabs EW, Barry BS, Engle EC, Collins FS, Manoli I, Manoli I. Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies. Muscle Nerve 2021;63(4):516-524.Abstract
INTRODUCTION: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW. METHODS: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography. RESULTS: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement. DISCUSSION: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.
Lessell S, E Grzybowski A. Idiopathic opticochiasmatic arachnoiditis. J Neuroophthalmol 2014;34(3):251-4.Abstract

: A critical review of the literature indicates that idiopathic opticochiasmatic arachnoiditis, once considered an important consideration in patients with otherwise unexplained optic atrophy, is not a valid disease entity.

Levy M, Chwalisz BK, Kozak BM, Yoon MK, Shih HA, Stagner AM. Case 36-2022: A 30-Year-Old Woman with Decreased Vision and Headache. N Engl J Med 2022;387(21):1980-1989.
Li Y, He X, Kawaguchi R, Zhang Y, Wang Q, Monavarfeshani A, Yang Z, Chen B, Shi Z, Meng H, Zhou S, Zhu J, Jacobi A, Swarup V, Popovich PG, Geschwind DH, He Z. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature 2020;587(7835):613-618.Abstract
Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal-but not adult-microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.
Li L-Y, Wang Y-Y, Gao J-W, Chen J, Kang M, Ying P, Liao XL, Wang Y, Zou J, Su T, Wei H, Shao Y. The Predictive Potential of Altered Voxel-Based Morphometry in Severely Obese Patients With Meibomian Gland Dysfunction. Front Neurosci 2022;16:939268.Abstract
Objective: To investigate voxel-based morphometry (VBM) by using magnetic resonance imaging (MRI) in meibomian gland dysfunction patients with severe obesity (PATs) and to explore the application of VBM in the early diagnosis, prevention of cognitive impairment and targeted treatment of this disease. Methods: Sixteen PATs and 12 healthy controls (HCs) were enrolled and underwent MRI. Whole-head images were analyzed using VBM and data were compared between groups using an independent samples t-test. Receiver operating characteristic (ROC) curves were utilized to assess the diagnostic value of this approach. Mini-mental state examination (MMSE) scores were used to assess cognitive impairment and were analyzed using an independent samples t-test. Results: Compared with HCs, the VBM values in PATs were reduced in the left cerebellum and right thalamus but increased in the right brainstem, right precuneus and right paracentral lobule. The results of ROC curve analysis indicated that VBM may be useful in meibomian gland disease diagnosis. Comparison of MMSE scores between groups showed mild cognitive impairment in PATs. Conclusion: PATs showed altered VBM values in some brain areas. These findings may provide information about the pathophysiology of meibomian gland dysfunction and may help to explain the underlying mechanisms of clinical manifestations in PATs, such as cognitive impairment. Abnormal VBM values in these brain areas may serve as predictive factors for development of meibomian gland disease in severely obese people and as indicators for individualized treatment.
Li Y, Andereggen L, Yuki K, Omura K, Yin Y, Gilbert H-Y, Erdogan B, Asdourian MS, Shrock C, de Lima S, Apfel U-P, Zhuo Y, Hershfinkel M, Lippard SJ, Rosenberg PA, Benowitz L. Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration. Proc Natl Acad Sci U S A 2017;114(2):E209-E218.Abstract

Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn(2+)) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn(2+) increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn(2+) accumulation in amacrine cell processes involves the Zn(2+) transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn(2+) chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn(2+) chelation extends for several days after nerve injury. These results show that retinal Zn(2+) dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn(2+) chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.

Liebman DL, Tam EK, Lithgow MY, Kane JE, Fischbein NJ, Lefebvre DR, Chwalisz BK, Gaier ED. Optic Perineuritis Associated With Cryptococcal Meningitis Presenting With a "Hot Orbit" in a Patient With Chronic Lymphocytic Leukemia. J Neuroophthalmol 2022;42(2):272-277.Abstract
ABSTRACT: A 75-year-old man presented with 3 days of progressive left retro-orbital pain, eyelid swelling, tearing, and pain with extraocular movement. His medical history was significant for type II diabetes mellitus and chronic lymphocytic leukemia, stable on no therapy since diagnosis 8 years prior. The initial examination was significant for diffuse restriction of left ocular motility, marked lid edema, and mild dyschromatopsia. Computed tomography demonstrated asymmetric left periorbital soft tissue swelling and intraconal fat stranding with an irregular left optic nerve sheath complex and clear paranasal sinuses. He was hospitalized for orbital cellulitis and treated empirically with broad-spectrum intravenous antibiotics, but his visual acuity declined over the ensuing 2 days. Subsequent MRI demonstrated left-greater-than-right circumferential optic nerve sheath enhancement, and leptomeningeal enhancement. An orbital biopsy demonstrated monoclonal B-cell lymphocyte aggregation, whereas a lumbar puncture was positive for Cryptococcus antigen with subsequent demonstration of abundant Cryptococcus by Papanicolaou stain. The final diagnosis was optic perineuritis secondary to cryptococcal meningitis presenting with orbital inflammation. Although his clinical course was complicated by immune reconstitution inflammatory syndrome, symptoms and signs of optic neuropathy ultimately resolved after 1 month of intensive antifungal therapy.
Lin LY, Pan W, Ying G-S, Binenbaum G. Ocular Findings in Children with Headache. Ophthalmic Epidemiol 2022;:1-8.Abstract
PURPOSE: To determine the prevalence of ophthalmological findings suggesting an ocular cause for headache or occult neurological disease, among children with headache. METHODS: Retrospective cross-sectional study on children with headache at a tertiary outpatient ophthalmology clinic. All children underwent sensorimotor, anterior segment, and dilated fundoscopic examinations, with or without cycloplegic refraction. Prevalence of one or more new findings of ocular or occult neurological cause of headache, including glaucoma, uveitis, optic nerve elevation, or possible asthenopia from strabismus or refractive issues. Headache characteristics and associated symptoms were evaluated as risk factors for ocular findings. RESULTS: Among 1,878 children with headache (mean age 10 yrs, range 2-18), 492 (26.1%, 95% CI 24.3-28.2%) children had one or more new ocular findings that could cause headache or indicate intracranial disease: refractive issues (342, 18.2%), strabismus (83, 4.4%), optic nerve elevation (51, 2.7%; 26 with papilledema, 25 with pseudopapilledema), uveitis (6, 0.3%), and glaucoma (2, 0.1%). Shorter headache duration was associated with ocular findings (p = .047), but headache frequency, photophobia, nausea/vomiting, and visual changes were not. In univariable analysis, visual changes (p ≤ .001), nausea/vomiting (p ≤ .002), and morning headache (p = .02) were associated with optic nerve elevation. CONCLUSION: An ophthalmologic examination including cycloplegic refraction is indicated in children with headache, as one-quarter have a treatable ocular condition, which may be related to the headache, or sign of intracranial pathology. While nausea, visual changes, or morning headache should raise concern, coincident visual, ocular, or systemic symptoms are not reliable predictors of discovering ocular pathology in a child with headache.
Lin LY, Reshef ER, Lansberg MP, Barshak MB, Chwalisz BK, Holbrook EH, Wolkow N. Posterior Ischemic Optic Neuropathy in the Setting of Cocaine-Induced Orbital and Sinonasal Inflammation. Ophthalmic Plast Reconstr Surg 2022;38(5):e141-e144.Abstract
Intranasal cocaine abuse can lead to significant sinus and orbital complications, including optic neuropathy. A 46-year-old man with a history of recurrent cocaine-induced sino-orbital inflammation and infection with bony destruction presented with acute, painless, vision loss. Examination revealed no light perception vision. MRI of the orbits demonstrated new restricted diffusion of the right optic nerve on diffusion-weighted imaging and apparent diffusion coefficient sequences, consistent with posterior ischemic optic neuropathy. This is the first among cases of cocaine-induced optic neuropathy in the literature to illustrate ischemic changes on MRI in the optic nerve, highlighting the utility of diffusion-weighted imaging/apparent diffusion coefficient sequences when optic neuropathy is suspected and further suggesting an underlying ischemic etiology in similar cases.
Liou VD, Yoon MK, Maher M, Chwalisz BK. Orbital Inflammation in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: A Case Report and Review of the Literature. J Neuroophthalmol 2022;Abstract
BACKGROUND: To present 2 patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease with unilateral orbital inflammation, optic nerve head edema, and abnormalities of the optic nerve and nerve sheath on imaging. We review the most current literature on this important and uncommon clinical phenotype. METHODS: A case report of 2 patients and a comprehensive review of the relevant literature on orbital inflammation in MOG antibody-associated disease (MOG-AD). RESULTS: Two patients presented with decreased vision and unilateral orbital inflammation. Both had optic nerve head edema and abnormalities of the optic nerve and nerve sheath on imaging. The patients were treated with immunosuppressants and had improvement of vision changes as well as their orbital inflammatory signs. MOG antibody was positive in high titers in both patients. Only 3 other cases of orbital inflammation associated with MOG antibody have been described. In all cases, orbital signs responded rapidly to intravenous methylprednisolone, but the improvement in visual acuity was variable and less robust. CONCLUSION: Orbital inflammation is a unique and underrecognized phenotype of MOG-AD with only a few reports in the literature. In patients who present with vision loss and orbital inflammation, MOG-AD should be considered in the differential.
Littau JL, Velilla L, Hase Y, Villalba-Moreno ND, Hagel C, Drexler D, Osorio Restrepo S, Villegas A, Lopera F, Vargas S, Glatzel M, Krasemann S, Quiroz YT, Arboleda-Velasquez JF, Kalaria R, Sepulveda-Falla D. Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease. Brain Pathol 2022;32(6):e13097.Abstract
We studied small vessel disease (SVD) pathology in Familial Alzheimer's disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer's disease (SAD) as a positive control for Alzheimer's pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post-mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen-positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ-independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia.
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M Mallery R, Poolman P, J Thurtell M, Full JM, Ledolter J, Kimbrough D, Frohman EM, Frohman TC, Kardon RH. Visual Fixation Instability in Multiple Sclerosis Measured Using SLO-OCT. Invest Ophthalmol Vis Sci 2018;59(1):196-201.Abstract
Purpose: Precise measurements of visual fixation and its instability were recorded during optical coherence tomography (OCT) as a marker of neural network dysfunction in multiple sclerosis (MS), which could be used to monitor disease progression or response to treatment. Methods: A total of 16 MS patients and 26 normal subjects underwent 30 seconds of scanning laser ophthalmoscope (SLO)-based eye tracking during OCT scanning of retinal layer thickness. Study groups consisted of normal eyes, MS eyes without prior optic neuritis (MS wo ON), and MS eyes with prior optic neuritis (MS + ON). Kernel density estimation quantified fixation instability from the distribution of fixation points on the retina. In MS wo ON eyes, fixation instability was compared to other measures of visual and neurologic function. Results: Fixation instability was increased in MS wo ON eyes (0.062 deg2) compared to normal eyes (0.030 deg2, P = 0.015). A further increase was seen for MS + ON eyes (0.11 deg2) compared to MS wo ON (P = 0.04) and normal (P = 0.006) eyes. Fixation instability correlated weakly with ganglion cell layer (GCL) volume and showed no correlation with low-contrast letter acuity, EDSS score, or SDMT score. Conclusions: Fixation instability reflects the integrity of a widespread neural network germane to visual processing and ocular motor control, and is disturbed in MS. Further study of visual fixation, including the contribution of microsaccades to fixation instability, may provide insight into the localization of fixation abnormalities in MS and introduce innovative and easily measured outcomes for monitoring progression and treatment response.
M Mallery R, Friedman DI, Digre KB, Liu GT. Utility of Magnetic Resonance Imaging Features for Improving the Diagnosis of Idiopathic Intracranial Hypertension Without Papilledema: Response. J Neuroophthalmol 2019;39(3):439.
M Mallery R, Rehmani OF, Woo JH, Chen YJ, Reddi S, Salzman KL, Pinho MC, Ledbetter L, Tamhankar MA, Shindler KS, Digre KB, Friedman DI, Liu GT. Utility of Magnetic Resonance Imaging Features for Improving the Diagnosis of Idiopathic Intracranial Hypertension Without Papilledema. J Neuroophthalmol 2019;39(3):299-307.Abstract
OBJECTIVE: Revised diagnostic criteria for idiopathic intracranial hypertension (IIH) were proposed in part to reduce misdiagnosis of intracranial hypertension without papilledema (WOP) by using 3 or 4 MRI features of intracranial hypertension when a sixth nerve palsy is absent. This study was undertaken to evaluate the sensitivity and specificity of the MRI criteria and to validate their utility for diagnosing IIH in patients with chronic headaches and elevated opening pressure (CH + EOP), but WOP. METHODS: Brain MRIs from 80 patients with IIH with papilledema (WP), 33 patients with CH + EOP, and 70 control patients with infrequent episodic migraine were assessed in a masked fashion for MRI features of intracranial hypertension. RESULTS: Reduced pituitary gland height was moderately sensitive for IIH WP (80%) but had low specificity (64%). Increased optic nerve sheath diameter was less sensitive (51%) and only moderately specific (83%). Flattening of the posterior globe was highly specific (97%) but had low sensitivity (57%). Transverse venous sinus stenosis was moderately sensitive for IIH WP (78%) but of undetermined specificity. A combination of any 3 of 4 MRI features was nearly 100% specific, while maintaining a sensitivity of 64%. Of patients with CH + EOP, 30% had 3 or more MRI features, suggesting IIH WOP in those patients. CONCLUSION: A combination of any 3 of 4 MRI features is highly specific for intracranial hypertension and suggests IIH WOP when present in patients with chronic headache and no papilledema.
Maallo AMS, Moulton EA, Sieberg CB, Giddon DB, Borsook D, Holmes SA. A lateralized model of the pain-depression dyad. Neurosci Biobehav Rev 2021;127:876-883.Abstract
Chronic pain and depression are two frequently co-occurring and debilitating conditions. Even though the former is treated as a physical affliction, and the latter as a mental illness, both disorders closely share neural substrates. Here, we review the association of pain with depression, especially when symptoms are lateralized on either side of the body. We also explore the overlapping regions in the forebrain implicated in these conditions. Finally, we synthesize these findings into a model, which addresses gaps in our understanding of comorbid pain and depression. Our lateralized pain-depression dyad model suggests that individuals diagnosed with depression should be closely monitored for pain symptoms in the left hemibody. Conversely, for patients in pain, with the exception of acute pain with a known source, referrals in today's pain centers for psychological evaluation should be part of standard practice, within the framework of an interdisciplinary approach to pain treatment.
MacIntosh PW, Fay AM. Update on the ophthalmic management of facial paralysis. Surv Ophthalmol 2019;64(1):79-89.Abstract
Bell's palsy is the most common neurologic condition affecting the cranial nerves. Lagophthalmos, exposure keratopathy, and corneal ulceration are potential complications. In this review, we evaluate various causes of facial paralysis as well as the level 1 evidence supporting the use of a short course of oral steroids for idiopathic Bell's palsy to improve functional outcomes. Various surgical and nonsurgical techniques are also discussed for the management of residual facial dysfunction.
Madhavan R, Bansal AK, Madsen JR, Golby AJ, Tierney TS, Eskandar EN, Anderson WS, Kreiman G. Neural Interactions Underlying Visuomotor Associations in the Human Brain. Cereb Cortex 2019;29(11):4551-4567.Abstract
Rapid and flexible learning during behavioral choices is critical to our daily endeavors and constitutes a hallmark of dynamic reasoning. An important paradigm to examine flexible behavior involves learning new arbitrary associations mapping visual inputs to motor outputs. We conjectured that visuomotor rules are instantiated by translating visual signals into actions through dynamic interactions between visual, frontal and motor cortex. We evaluated the neural representation of such visuomotor rules by performing intracranial field potential recordings in epilepsy subjects during a rule-learning delayed match-to-behavior task. Learning new visuomotor mappings led to the emergence of specific responses associating visual signals with motor outputs in 3 anatomical clusters in frontal, anteroventral temporal and posterior parietal cortex. After learning, mapping selective signals during the delay period showed interactions with visual and motor signals. These observations provide initial steps towards elucidating the dynamic circuits underlying flexible behavior and how communication between subregions of frontal, temporal, and parietal cortex leads to rapid learning of task-relevant choices.

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