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Heidary G. Neuro-Ophthalmic Manifestations of Pediatric Neurodegenerative Disease. J Neuroophthalmol 2017;37 Suppl 1:S4-S13.Abstract
The topic of pediatric neurodegenerative disease is broad and ever expanding. Children who suffer from neurodegenerative disease often have concomitant visual dysfunction. Neuro-ophthalmologists may become involved in clinical care to identify corroborating eye findings when a specific condition is suspected, to monitor for disease progression, and in some cases, to assess treatment efficacy. Ophthalmic findings also may be the harbinger of a neurodegenerative process so a keen awareness of the possible manifestations of these conditions is important. The purpose of this review is to highlight common examples of the neuro-ophthalmic manifestations of pediatric neurodegenerative disease using a case-based approach in an effort to provide a framework for approaching these complex patients.
Henao-Restrepo J, López-Murillo C, Valderrama-Carmona P, Orozco-Santa N, Gomez J, Gutiérrez-Vargas J, Moraga R, Toledo J, Littau JL, Härtel S, Arboleda-Velásquez JF, Sepulveda-Falla D, Lopera F, Cardona-Gómez GP, Villegas A, Posada-Duque R. Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection. Brain Pathol 2022;:e13119.Abstract
In response to brain insults, astrocytes become reactive, promoting protection and tissue repair. However, astroglial reactivity is typical of brain pathologies, including Alzheimer's disease (AD). Considering the heterogeneity of the reactive response, the role of astrocytes in the course of different forms of AD has been underestimated. Colombia has the largest human group known to have familial AD (FAD). This group carries the autosomal dominant and fully penetrant mutation E280A in PSEN1, which causes early-onset AD. Recently, our group identified an E280A carrier who did not develop FAD. The individual was homozygous for the Christchurch mutation R136S in APOE3 (APOEch). Remarkably, APOE is the main genetic risk factor for developing sporadic AD (SAD) and most of cerebral ApoE is produced by astroglia. Here, we characterized astrocyte properties related to reactivity, glutamate homeostasis, and structural integrity of the gliovascular unit (GVU), as factors that could underlie the pathogenesis or protection of AD. Specifically, through histological and 3D microscopy analyses of postmortem samples, we briefly describe the histopathology and cytoarchitecture of the frontal cortex of SAD, FAD, and APOEch, and demonstrate that, while astrodegeneration and vascular deterioration are prominent in SAD, FAD is characterized by hyperreactive-like glia, and APOEch displays the mildest astrocytic and vascular alterations despite having the highest burden of Aβ. Notably, astroglial, gliovascular, and vascular disturbances, as well as brain cell death, correlate with the specific astrocytic phenotypes identified in each condition. This study provides new insights into the potential relevance of the gliovasculature in the development and protection of AD. To our knowledge, this is the first study assessing the components of the GVU in human samples of SAD, FAD, and APOEch.
Huang L, Sun X, Luo G, Liu S, Liu R, Mansouri B, Wong VWL, Wen W, Liu H, Wang A-H. Interocular Shift of Visual Attention Enhances Stereopsis and Visual Acuities of Anisometropic Amblyopes beyond the Critical Period of Visual Development: A Novel Approach. J Ophthalmol 2014;2014:615213.Abstract
Aims. Increasing evidence shows that imbalanced suppressive drive prior to binocular combination may be the key factor in amblyopia. We described a novel binocular approach, interocular shift of visual attention (ISVA), for treatment of amblyopia in adult patients. Methods. Visual stimuli were presented anaglyphically on a computer screen. A square target resembling Landolt C had 2 openings, one in red and one in cyan color. Through blue-red goggles, each eye could only see one of the two openings. The patient was required to report the location of the opening presented to the amblyopic eye. It started at an opening size of 800 sec of arc, went up and down in 160 sec of arc step, and stopped when reaching the 5th reversals. Ten patients with anisometropic amblyopia older than age 14 (average age: 26.7) were recruited and received ISVA treatment for 6 weeks, with 2 training sessions per day. Results. Both Titmus stereopsis (z = -2.809, P = 0.005) and Random-dot stereopsis (z = -2.317, P = 0.018) were significantly improved. Average improvement in best corrected visual acuity (BCVA) was 0.74 line (t = 5.842, P < 0.001). Conclusions. The ISVA treatment may be effective in treating amblyopia and restoring stereoscopic function.
Hunter DG. Treatment of amblyopia: the "eye pad," or the iPad?. J AAPOS 2015;19(1):1-2.
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Ibrahim AS, Elmasry K, Wan M, Abdulmoneim S, Still A, Khan F, Khalil A, Saul A, Hoda MN, Al-Shabrawey M. A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse. Invest Ophthalmol Vis Sci 2018;59(13):5548-5557.Abstract
Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON. Methods: We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions. Results: The key results of validating this newly modified model, "controlled orbital impact (COI)," included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare. Conclusions: Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.
Ing E, Pagnoux C, Torun N. Advances in the diagnosis of giant cell arteritis. Curr Opin Ophthalmol 2019;30(6):407-411.Abstract
PURPOSE OF REVIEW: To summarize recent advances in the diagnosis of giant cell arteritis (GCA). RECENT FINDINGS: Less common manifestations of GCA include corneal edema, proptosis from lacrimal gland ischemia and sensorineuronal hearing loss. Histology studies have suggested that temporal artery biopsies (TAB) with fixed specimen lengths of 15 mm may be adequate to prevent false negative biopsies. In centers with appropriate radiologic expertise, a European rheumatology consensus guideline has proposed Doppler ultrasound as a first-line confirmatory test for GCA in lieu of temporal artery biopsy. Finding extracranial large vessel disease can help to diagnose GCA. Statistical prediction rules can help risk stratify patients with suspected GCA. Age and platelet level when maintained as continuous variables are the strongest predictors for GCA. SUMMARY: GCA can present with diverse ophthalmic and systemic presentations and expedient recognition of same can avoid diagnostic delay and possible vision loss, among other complications. TAB remains the conventional diagnostic standard test for GCA. The use of statistical prediction models and increased expertise in noninvasive imaging techniques such as ultrasound may decrease reliance on TAB, especially in patients determined to be at low risk for GCA.
Ing E, Pagnoux C, Tyndel F, Sundaram A, Hershenfeld S, Ranalli P, Chow S, Le T, Lutchman C, Rutherford S, Lam K, Bedi H, Torun N. Lower ocular pulse amplitude with dynamic contour tonometry is associated with biopsy-proven giant cell arteritis. Can J Ophthalmol 2018;53(3):215-221.Abstract
OBJECTIVES: To determine the role of the ocular pulse amplitude (OPA) from Pascal dynamic contour tonometry in predicting the temporal artery biopsy (TABx) result in patients with suspected giant cell arteritis (GCA). DESIGN: Prospective validation study. PARTICIPANTS: Adults aged 50 years or older who underwent TABx from March 2015 to April 2017. METHODS: Subjects on high-dose glucocorticoids more than 14 days or without serology before glucocorticoid initiation were excluded. The OPA from both eyes was obtained and averaged just before TABx of the predominantly symptomatic side. The variables chosen for the a priori prediction model were age, average OPA, and C-reactive protein (CRP). Erythrocyte sedimentation rate (ESR), platelets, jaw claudication, and eye findings were also recorded. In this study, subjects with a negative biopsy were considered not to have GCA, and contralateral biopsy was performed if the clinical suspicion for GCA remained high. An external validation set (XVAL) was obtained. RESULTS: Of 109 TABx, 19 were positive and 90 were negative. On univariate logistic regression, the average OPA had 0.60 odds for positive TABx (p = 0.03), with no statistically significant difference in age, sex, CRP, ESR, or jaw claudication. In suspected GCA, an OPA of 1 mm Hg had positive likelihood ratio 4.74 and negative likelihood ratio 0.87 for positive TABx. Multivariate regression of the prediction model using optimal mathematical transforms (inverse OPA, log CRP, age >65 years) had area under the receiver operating characteristic curve (AUROC) = 0.85 and AUROC = 0.81. CONCLUSIONS: OPA is lower in subjects with biopsy-proven GCA and is a statistically significant predictor of GCA.
Ing EB, Wang DN, Kirubarajan A, Benard-Seguin E, Ma J, Farmer JP, Belliveau MJ, Sholohov G, Torun N. Systematic Review of the Yield of Temporal Artery Biopsy for Suspected Giant Cell Arteritis. Neuroophthalmology 2019;43(1):18-25.Abstract
PURPOSE: To determine the positive yield (utility rate) of temporal artery biopsy (TAB) in patients with suspected giant cell arteritis (GCA). STUDY DESIGN: Systematic review (CRD42017078508) and meta-regression. MATERIALS AND METHODS: All articles concerning TAB for suspected GCA with English language abstracts from 1998 to 2017 were retrieved. Articles were excluded if they exclusively reported positive TAB, or only cases of known GCA. Where available, the pre-specified predictors of age, sex, vision symptoms, jaw claudication, duration of steroid treatment prior to TAB, specimen length, bilateral TAB, and use of ultrasound/MRI (imaging) were recorded for meta-regression. RESULTS: One hundred and thirteen articles met eligibility criteria. The was 92%, and with such high heterogeneity, meta-analysis is unsuitable. The median yield of TAB was 0.25 (95% confidence interval 0.21 to 0.27), with interquartile range 0.17 to 0.34. On univariate meta-regression age (coefficient 0.012,  = 0.025) was the only statistically significant patient factor associated with TAB yield. CONCLUSIONS: Systematic review revealed high heterogeneity in the yield of TAB. The median utility rate of 25% and its interquartile range provides a benchmark for decisions regarding the under/overutilization of TAB and aids in the evaluation of non-invasive alternatives for the investigation of GCA.
Ing EB, Miller NR, Ten Hove M, Torun N. Diplopia and Giant Cell Arteritis. J Neuroophthalmol 2019;39(4):546-547.
Ing E, Sambhi G, Torun N, Pagnoux C. Comments on the giant cell arteritis probability score. Clin Exp Rheumatol 2019;
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Jacobs HIL, Schoemaker D, Torrico-Teave H, Zuluaga Y, Velilla-Jimenez L, Ospina-Villegas C, Lopera F, Arboleda-Velasquez JF, Quiroz YT. Specific Abnormalities in White Matter Pathways as Interface to Small Vessels Disease and Cognition in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Individuals. Brain Connect 2022;12(1):52-60.Abstract
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by leukoencephalopathy leading to cognitive impairment. Subtle cognitive deficits can be observed early in the course of the disease, before the occurrence of the first stroke. Therefore, markers that can predict disease progression at this early stage, when interventions are likely to alter disease course, are needed. We aimed to examine the biological cascade of microstructural and macrostructural white matter (WM) abnormalities underlying cognitive deficits in CADASIL. Methods: We examined 20 nondemented CADASIL mutation carriers and 23 noncarriers who underwent neuropsychological evaluation and magnetic resonance imaging. Using probabilistic tractography of key WM tracts, we examined group differences in diffusivity measures and WM hyperintensity volume. Successive mediation models examined whether tract-specific WM abnormalities mediated subtle cognitive differences between CADASIL mutation carriers and noncarriers. Results: The largest effect size differentiating the two groups was observed for left superior longitudinal fasciculus-temporal (SLFt) diffusivity (Cohen's f = 0.49). No group differences were observed with a global diffusion measure. These specific microstructural differences in the SLFt were associated with higher WM hyperintensities burden, and subtle executive deficits in CADASIL mutation carriers. Discussion: Worse diffusivity in the left SLFt is related to greater severity of small vessel disease and worse executive functioning in the asymptomatic stage of the disease. Worse diffusivity of the left SLFt may potentially hold promise as an indicator of disease progression. Impact statement Diffusion tensor imaging outperforms conventional imaging of subcortical small vessel disease as a potential marker of future disease progression. Here we identified the left superior longitudinal temporal fasciculus as a critical white matter fiber bundle, of which worse diffusivity can link presence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy mutations to greater severity of small vessel disease and worse executive functioning in asymptomatic stages of the disease. This tract may hold promise and deserves further examination as an early indicator of disease progression.
Jamuar SS, Schmitz-Abe K, D'Gama AM, Drottar M, Chan W-M, Peeva M, Servattalab S, Lam A-TN, Delgado MR, Clegg NJ, Zayed ZA, Dogar MA, Alorainy IA, Jamea AA, Abu-Amero K, Griebel M, Ward W, Lein ES, Markianos K, Barkovich JA, Robson CD, Grant EP, Bosley TM, Engle EC, Walsh CA, Yu TW. Biallelic mutations in human DCC cause developmental split-brain syndrome. Nat Genet 2017;49(4):606-612.Abstract

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.

Jeng-Miller KW, Cestari DM, Gaier ED. Congenital anomalies of the optic disc: insights from optical coherence tomography imaging. Curr Opin Ophthalmol 2017;28(6):579-586.Abstract
PURPOSE OF REVIEW: Congenital anomalies of the optic nerve are rare but significant causes of visual dysfunction in children and adults. Accurate diagnosis is dependent on a thorough funduscopic examination, but can be enhanced by imaging information garnered from optical coherence tomography (OCT). We review common congenital optic nerve anomalies, including optic disc pit, optic nerve coloboma, morning glory disc anomaly, and hypoplasia of the optic nerve, review their systemic associations, and discuss insights from OCT imaging. RECENT FINDINGS: Optic disc pits are a result of a defect in the lamina cribrosa and abnormal vitreomacular adhesions have been shown to cause maculopathy. In patients with optic nerve colobomas, OCT can be instrumental in diagnosing choroidal neovascularization, a rare but visually devastating complication. The pathogenesis of morning glory disc anomaly has been more clearly elucidated by OCT as occurring from a secondary postnatal mesenchymal abnormality rather than only the initial neuroectodermal dysgenesis of the terminal optic stalk in isolation. OCT studies of optic nerve hypoplasia have demonstrated significant thinning of the inner and outer retinal layers of the perifoveal region and thicker layers in the fovea itself, resulting in a foveal hypoplasia-like pathology, that is, significantly correlated to poorer visual outcomes. SUMMARY: OCT provides detailed in-vivo analysis of these anatomic anomalies and their resulting pathologies, shedding new insights on the pathogenesis, diagnosis, and potential visual outcomes of these conditions in children. Further study employing OCT to elucidate structure-function relationships of congenital optic nerve anomalies will help expand the role of OCT in clinical practice related to diagnosis, prognosis, and management of these entities.
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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.
Kanu LN, Ciolino JB. Nerve Growth Factor as an Ocular Therapy: Applications, Challenges, and Future Directions. Semin Ophthalmol 2021;36(4):224-231.Abstract
Nerve growth factor (NGF), the prototypical neurotrophin first discovered in the 1950s, has recently garnered increased interest as a therapeutic agent promoting neuronal health and regeneration. After gaining orphan drug status within the last decade, NGF-related research and drug development has accelerated. The purpose of this article is to review the preclinical and clinical evidence of NGF in various applications, including central and peripheral nervous system, skin, and ophthalmic disorders. We focus on the ophthalmic applications including not only the FDA-approved indication of neurotrophic keratitis but also retinal disease and glaucoma. NGF represents a promising therapy whose therapeutic profile is evolving. The challenges related to this therapy are reviewed, along with possible solutions and future directions.
Karki P, Kim C, Smith K, Son D-S, Aschner M, Lee E. Transcriptional Regulation of the Astrocytic Excitatory Amino Acid Transporter 1 (EAAT1) via NF-κB and Yin Yang 1 (YY1). J Biol Chem 2015;290(39):23725-37.Abstract

Astrocytic glutamate transporter excitatory amino acid transporter (EAAT) 1, also known as glutamate aspartate transporter (GLAST) in rodents, is one of two glial glutamate transporters that are responsible for removing excess glutamate from synaptic clefts to prevent excitotoxic neuronal death. Despite its important role in neurophysiological functions, the molecular mechanisms of EAAT1 regulation at the transcriptional level remain to be established. Here, we report that NF-κB is a main positive transcription factor for EAAT1, supported by the following: 1) EAAT1 contains two consensus sites for NF-κB, 2) mutation of NF-κB binding sites decreased EAAT1 promoter activity, and 3) activation of NF-κB increased, whereas inhibition of NF-κB decreased EAAT1 promoter activity and mRNA/protein levels. EGF increased EAAT1 mRNA/protein levels and glutamate uptake via NF-κB. The transcription factor yin yang 1 (YY1) plays a role as a critical negative regulator of EAAT1, supported by the following: 1) the EAAT1 promoter contains multiple consensus sites for YY1, 2) overexpression of YY1 decreased EAAT1 promoter activity and mRNA/protein levels, and 3) knockdown of YY1 increased EAAT1 promoter activity and mRNA/protein levels. Manganese decreased EAAT1 expression via YY1. Epigenetic modifiers histone deacetylases (HDACs) served as co-repressors of YY1 to further decrease EAAT1 promoter activity, whereas inhibition of HDACs reversed manganese-induced decrease of EAAT1 expression. Taken together, our findings suggest that NF-κB is a critical positive regulator of EAAT1, mediating the stimulatory effects of EGF, whereas YY1 is a negative regulator of EAAT1 with HDACs as co-repressors, mediating the inhibitory effects of manganese on EAAT1 regulation.

Kekunnaya R, Kraft S, Rao VB, Velez FG, Sachdeva V, Hunter DG. Surgical management of strabismus in Duane retraction syndrome. J AAPOS 2015;19(1):63-9.Abstract

SUMMARY: While Duane retraction syndrome (DRS) is relatively common, surgical management of the associated strabismus can be challenging because of the lack of abduction/adduction, the variable severity of muscle contracture, and the variety of clinical presentations. In this workshop a panel of experienced surgeons provide their perspective and practical tips on the management of strabismus in patients with DRS.

Kennedy B, Bex P, Hunter DG, Nasr S. Two fine-scale channels for encoding motion and stereopsis within the human magnocellular stream. Prog Neurobiol 2022;220:102374.Abstract
In humans and non-human primates (NHPs), motion and stereopsis are processed within fine-scale cortical sites, including V2 thick stripes and their extensions into areas V3 and V3A that are believed to be under the influence of magnocellular stream. However, in both species, the relative functional organization (overlapping vs. none overlapping) of these sites remains unclear. Using high-resolution functional MRI (fMRI), we found evidence for two minimally-overlapping channels within human extrastriate areas that contribute to processing motion and stereopsis. Across multiple experiments that included different stimuli (random dots, gratings, and natural scenes), the functional selectivity of these channels for motion vs. stereopsis remained consistent. Furthermore, an analysis of resting-state functional connectivity revealed stronger functional connectivity within the two channels rather than between them. This finding provides a new perspective toward the mesoscale organization of the magnocellular stream within the human extrastriate visual cortex, beyond our previous understanding based on animal models.
Kloek CE, Jeng-Miller KW, Jacobs DS, Dunn IF. Prosthetic Replacement of the Ocular Surface Ecosystem Treatment of Ocular Surface Disease After Skull Base Tumor Resection. World Neurosurg 2018;110:e124-e128.Abstract
BACKGROUND: Prosthetic replacement of the ocular surface ecosystem (PROSE) treatment is an effective, nonsurgical therapeutic option for patients with ocular surface disease related to cranial nerve deficits secondary to skull base tumor resection. METHODS: This case series describes the impact of PROSE treatment in patients with symptomatic exposure keratopathy or neurotrophic keratitis after skull base tumor surgery. RESULTS: All patients improved symptomatically and functionally with PROSE treatment, and have had sustained improvement for as long as 3 years. CONCLUSIONS: In postneurosurgical cases in which neurologic function may recover, PROSE treatment offers a safe, nonsurgical treatment option to support the ocular surface during the period of observation awaiting neurologic recovery.
Kruger JM, Lessell S, Cestari DM. Neuro-imaging: a review for the general ophthalmologist. Semin Ophthalmol 2012;27(5-6):192-6.Abstract
The diagnosis of many neuro-ophthalmic conditions is facilitated with neuro-imaging. The two main modalities are Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Clinicians who refer patients for either of these techniques must not only know which of them to choose, but also where the imaging should be performed (e.g. brain, orbit), whether or not contrast is indicated, and if angiography should be supplemented. These complexities often result in imaging studies that are either unneeded or unhelpful. The goal of this manuscript is to provide a practical set of guidelines for the general ophthalmologist of how to choose the correct parameters for neuro-imaging studies.

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