In some patients, migraine attacks are associated with symptoms of allodynia which can be localized (cephalic) or generalized (extracephalic). Using functional neuroimaging and cutaneous thermal stimulation, we aimed to investigate the differences in brain activation of patients with episodic migraine (n = 19) based on their allodynic status defined by changes between ictal and interictal pain tolerance threshold for each subject at the time of imaging. In this prospective imaging study, differences were found in brain activity between the ictal and interictal visits in the brainstem/pons, thalamus, insula, cerebellum and cingulate cortex. Significant differences were also observed in the pattern of activation along the trigeminal pathway to noxious heat stimuli in no allodynia vs. generalized allodynia in the thalamus and the trigeminal nucleus but there were no activation differences in the trigeminal ganglion. The functional magnetic resonance imaging (fMRI) findings provide direct evidence for the view that in migraine patients who are allodynic during the ictal phase of their attacks, the spinal trigeminal nucleus and posterior thalamus become hyper-responsive (sensitized)-to the extent that they mediate cephalic and extracephalic allodynia, respectively. In addition, descending analgesic systems seem as "switched off" in generalized allodynia.
BACKGROUND/AIM: To investigate the prevalence, causes and risk factors of visual impairment (VI) among the elderly in 'home for the aged' in Hyderabad, India. METHODS: Individuals aged ≥60 years were recruited from 41 'homes for the aged'. All participants had complete eye examinations including presenting visual acuity, refraction, slit-lamp examination, intraocular pressure measurement and fundus imaging by trained clinicians. VI was defined as presenting visual acuity worse than 6/18 in the better eye. Multivariate logistic regression was used to determine the risk factors associated with VI. RESULTS: 1512 elderly residents from 41 homes for the aged were enumerated, of whom 1182 (78.1%) were examined. The mean age of examined participants was 75.0 years (SD 8.8 years; range: 60-108 years); 35.4% of those examined were men. The prevalence of VI was 30.1% (95% CI 27.5 to 32.8). The leading cause of VI was cataract (46.3%, n=165), followed by uncorrected refractive error (27.0%, n=96), posterior capsular opacification (14.9%, n=53) and posterior segment disease (6.5%, n=23). Overall, 88.2% of the VI was either treatable or correctable. In multiple logistic regression, those aged 80 years and older (OR: 1.7, p<0.01), living in 'free' homes (OR: 1.5, p<0.01) and who were immobile/bedridden (OR: 3.02, p<0.01) had significantly higher odds of VI. Gender was not associated with VI. CONCLUSIONS: VI was common and largely avoidable in residents of 'homes for the aged' in Hyderabad, India. Screening for vision loss in 'homes for aged' and the provision of appropriate services should become routine practice to achieve the goal of healthy ageing in India.
Mouse Müller cells, considered as dormant retinal progenitors, often respond to retinal injury by undergoing reactive gliosis rather than displaying neural regenerative responses. Tumor necrosis factor alpha (TNFα) is a key cytokines induced after injury and implicated in mediating inflammatory and neural regenerative responses in zebrafish. To investigate the involvement of TNFα in mouse retinal injury, adult C57BL/6J mice were subjected to light damage for 14 consecutive days. TNFα was elevated in the retina of mice exposed to light damage, which induced Müller cell proliferation in vitro. Affymetrix microarray showed that, in Müller cells, TNFα induces up-regulation of inflammatory and proliferation-related genes, including NFKB2, leukemia inhibitory factor, interleukin-6, janus kinase (Jak) 1, Jak2, signal transducer and activator of transcription (Stat) 1, Stat2, mitogen-activated protein kinase (MAPK) 7, and MAP4K4 but down-regulation of neuroprogenitor genes, including Sox9, Ascl1, Wnt2 and Hes1. Blocking the Jak/Stat and MAPK pathways attenuated TNFα-induced Müller cell proliferation. These results suggest that TNFα may drive the proliferation and inflammatory response, rather than the neural regenerative potential, of mouse Müller cells.
Mucin secretion from conjunctival goblet cells forms the tear film mucin layer and requires regulation to function properly. Maresin 1 (MaR1) is a specialized proresolving mediator produced during the resolution of inflammation. We determined if MaR1 stimulates mucin secretion and signaling pathways used. Cultured rat conjunctival goblet cells were used to measure the increase in intracellular Ca ([Ca ] ) concentration and mucin secretion. MaR1-increased [Ca ] and secretion were blocked by inhibitors of phospholipase C, protein kinase C, Ca /calmodulin-dependent protein kinase II, and extracellular-regulated kinase 1/2. MaR1 added before addition of histamine counterregulated histamine-stimulated increase in [Ca ] and secretion. We conclude that MaR1 likely has two actions in conjunctival goblet cells: first, maintaining optimal tear film mucin levels by increasing [Ca ] and stimulating mucin secretion in health and, second, attenuating the increase in [Ca ] and overproduction of mucin secretion by counterregulating the effect of histamine as occurs in ocular allergy.
Fuchs endothelial corneal dystrophy (FECD) is the most common primary corneal endothelial dystrophy and the leading indication for corneal transplantation worldwide. FECD is characterized by the progressive decline of corneal endothelial cells (CECs) and the formation of extracellular matrix (ECM) excrescences in Descemet's membrane (DM), called guttae, that lead to corneal edema and loss of vision. FECD typically manifests in the fifth decades of life and has a greater incidence in women. FECD is a complex and heterogeneous genetic disease where interaction between genetic and environmental factors results in cellular apoptosis and aberrant ECM deposition. In this review, we will discuss a complex interplay of genetic, epigenetic, and exogenous factors in inciting oxidative stress, auto(mito)phagy, unfolded protein response, and mitochondrial dysfunction during CEC degeneration. Specifically, we explore the factors that influence cellular fate to undergo apoptosis, senescence, and endothelial-to-mesenchymal transition. These findings will highlight the importance of abnormal CEC-DM interactions in triggering the vicious cycle of FECD pathogenesis. We will also review clinical characteristics, diagnostic tools, and current medical and surgical management options for FECD patients. These new paradigms in FECD pathogenesis present an opportunity to develop novel therapeutics for the treatment of FECD.
BACKGROUND/PURPOSE: To report a case of acute recurrent central serous chorioretinopathy that developed after a regimen of corticosteroid enemas and suppositories. METHODS: Observational case report. Fluorescein angiography and spectral domain optical coherence tomography. RESULTS: A 47-year-old male patient with ulcerative colitis managed through hydrocortisone enemas presented to clinic with a 1-day history of blurry vision of his left eye. Posterior segment examination revealed subretinal fluid in the superotemporal macula of the left eye extending centrally. After diagnosis of acute central serous chorioretinopathy, the patient was advised to taper steroid enemas and his visual symptoms and subretinal fluid resolved within the month. Seven years later, several months after using steroid suppositories for the first time since the original central serous chorioretinopathy episode, asymptomatic subretinal fluid accumulation with foveal sparing was found on routine ophthalmic examination. Three months later, most of this fluid had resolved with minimal residual subretinal fluid on clinical examination. CONCLUSION: Acute central serous chorioretinopathy may develop after corticosteroid enema or suppository use, a route of administration that has not been previously reported in association with the disease.
BACKGROUND/AIMS: As swept-source optical coherence tomography (SS-OCT) simultaneously obtains 128 meridional scans, it is important to identify which scans are playing the main role in classifying gonioscopic angle closure to simplify the analysis. We aimed to evaluate the diagnostic performance of every meridional scan in its ability to detect gonioscopic angle closure. METHODS: Observational study with 2027 phakic subjects consecutively recruited from a community polyclinic. Gonioscopy and SS-OCT were performed. Gonioscopic angle closure was defined as non-visibility of the posterior trabecular meshwork in ≥180° of the angle, while SS-OCT was defined as iridotrabecular contact anterior to the scleral spur. The area under the receiver operating characteristic curve (AUC) was calculated to assess the diagnostic performance of each single scan, the sequential anticlockwise cumulative effect of those single scans and different combinations of them. RESULTS: The AUCs of each scan ranged from 0.73 to 0.82. The single scan at 80°-260° had the highest AUC (0.82, 95% CI 0.79 to 0.84) and performed significantly better than most of the temporonasal scans (from 0° to 52° and from 153° to 179°). The superoinferior scans achieved higher AUCs compared with the temporonasal ones. When assessing the cumulative effect of adding individual scans consecutively, the peak AUC (0.80) was obtained when considering the superoinferior scans closer to 80°-85°, but no further positive cumulative effect was seen when adding the rest of the temporonasal scans of the circumference. CONCLUSIONS: In conclusion, the single SS-OCT scan at 80°-260° had the highest diagnostic performance. Our study suggests that the 360° evaluation may not translate to better clinical utility for detection of gonioscopic angle closure.
Since the new coronavirus known as 2019-nCoV (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has widely spread in Wuhan, China, with severe pneumonia, scientists and physicians have made remarkable efforts to use various options such as monoclonal antibodies, peptides, vaccines, small-molecule drugs and interferon therapies to control, prevent or treatment infections of 2019-nCoV. However, no vaccine or drug has yet been confirmed to completely treat 2019-nCoV. In this review, we focus on the use of potential available small-molecule drug candidates for treating infections caused by 2019-nCoV.
Importance: Orbital fractures are common in ocular trauma, and there is a need to develop predictive tools to estimate risk of concurrent ocular injury. Objective: To identify clinical and radiographic features that are associated with increased risk of substantial ocular injury in the setting of orbital fracture. Design, Setting, and Participants: Retrospective consecutive case series of patients who sustained orbital fractures between 2012 and 2018. Examinations were done at 1 of 2 level 1 trauma centers in the emergency or inpatient setting. A total of 430 consecutive patients (500 eyes) between 2012 and 2017 met inclusion criteria for the training sample. After building a predictive model, 88 additional consecutive patients (97 eyes) between 2017 and 2018 who met inclusion criteria were collected as a test sample. Main Outcomes and Measures: The primary outcome measure was substantial ocular injury distinct from orbital fracture. Results: The mean age of our patient population was 53.5 years (range, 16-100 years). The overall rate of substantial ocular injury was 20.4%, and the rate of injury requiring immediate ophthalmic attention was 14.4%. Five variables were found to be associated with increased risk of substantial ocular injury: blunt trauma with a foreign object (odds ratio [OR], 19.4; 95% CI, 6.3-64.1; P < .001), inability to count fingers (OR, 10.1; 95% CI, 2.8-41.1; P = .002), roof fracture (OR, 9.1; 95% CI, 2.8-30.0; P = .002), diplopia on primary gaze (OR, 6.7; 95% CI, 1.7-25.1; P = .003), and conjunctival hemorrhage or chemosis (OR, 4.2; 95% CI, 2.2-8.5; P < .001). The results were translated into a bedside tool that was tested in an independent group of eyes (n = 97) and found to be associated with substantial ocular injury with a 95% sensitivity (95% CI, 77.2-99.9), 40% specificity (95% CI, 28.9-52.0), 31.8% positive predictive value (95% CI, 27.5-36.5), and 96.8% negative predictive value (95% CI, 81.3-99.5). Conclusions and Relevance: A minority of patients with an orbital fracture had a substantial ocular injury. Certain radiographic and clinical findings were associated with substantial ocular injury. Testing of the algorithm in prospective longitudinal settings appears warranted.
The hippocampus is thought to guide navigation by forming a cognitive map of space. Different environments differ in geometry and the availability of cues that can be used for navigation. Although several spatial coding mechanisms are known to coexist in the hippocampus, how they are influenced by various environmental features is not well understood. To address this issue, we examined the spatial coding characteristics of hippocampal neurons in mice and rats navigating in different environments. We found that CA1 place cells located in the superficial sublayer were more active in cue-poor environments and preferentially used a firing rate code driven by intra-hippocampal inputs. In contrast, place cells located in the deep sublayer were more active in cue-rich environments and used a phase code driven by entorhinal inputs. Switching between these two spatial coding modes was supported by the interaction between excitatory gamma inputs and local inhibition.
PURPOSE: To report the results of a glaucoma screening campaign targeting first-degree relatives of glaucoma patients in South India. METHODS: 1598 glaucoma patients were contacted via letter or letter and phone call and asked to bring their siblings and children to a glaucoma screening. Participants underwent standardised eye examinations and completed questionnaires that assessed barriers to participation and awareness of glaucoma risk. Two-proportion z-tests were used to compare categorical data. Costs associated with the screening were recorded. RESULTS: 206 probands (12.9%) attended the screening along with 50 siblings and children. Probands were nearly twice as likely to attend if they had been contacted via both letter and phone call rather than letter only. Over half of probands reported that their relatives could not participate because they did not live in the region, and one-fifth reported that their relatives had other commitments. Fifty-eight per cent of the siblings and children who attended did not know that they were at increased risk for glaucoma due to their family history, and 32.0% did not know that the relative who had invited them to the screening had glaucoma. Thirteen siblings and children (26.0% of those who attended) were found to have findings concerning for glaucoma. The average cost per first-degree relative who was screened was INR2422 (£26). CONCLUSION: Participation in this glaucoma screening campaign was poor. The major barrier to participation was distance from the screening site and associated indirect costs. Better strategies for bringing first-degree relatives in for examinations are needed.
Purpose: One rehabilitation strategy taught to individuals with hemianopic field loss (HFL) is to make a large blind side scan to quickly identify hazards. However, it is not clear what the minimum threshold is for how large the scan should be. Using driving simulation, we evaluated thresholds (criteria) for gaze and head scan magnitudes that best predict detection safety. Methods: Seventeen participants with complete HFL and 15 with normal vision (NV) drove through 4 routes in a virtual city while their eyes and head were tracked. Participants pressed the horn as soon as they detected a motorcycle (10 per drive) that appeared 54 degrees eccentricity on cross-streets and approached toward the driver. Results: Those with HFL detected fewer motorcycles than those with NV and had worse detection on the blind side than the seeing side. On the blind side, both safe detections and early detections (detections before the hazard entered the intersection) could be predicted with both gaze (safe 18.5 degrees and early 33.8 degrees) and head (safe 19.3 degrees and early 27 degrees) scans. However, on the seeing side, only early detections could be classified with gaze (25.3 degrees) and head (9.0 degrees). Conclusions: Both head and gaze scan magnitude were significant predictors of detection on the blind side, but less predictive on the seeing side, which was likely driven by the ability to use peripheral vision. Interestingly, head scans were as predictive as gaze scans. Translational Relevance: The minimum scan magnitude could be a useful criterion for scanning training or for developing assistive technologies to improve scanning.
AIMS/HYPOTHESIS: Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR. METHODS: We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27-80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration. RESULTS: We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024). CONCLUSIONS/INTERPRETATION: These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR. Graphical abstract.
Purpose: To investigate the nature of anatomical and functional recovery kinetics after epiretinal membrane (ERM) removal. Methods: The records of 42 patients (45 eyes) with idiopathic ERM treated with pars plana vitrectomy and surgical peeling of the ERM performed by a single surgeon at Massachusetts Eye and Ear between 2012 and 2017 were retrospectively reviewed. Outcome measures included spectral domain optical coherence tomography-measured central macular thickness (CMT) pre-operatively and at post-operative day 1, week 1, months 1, 3, 6, 12 and 24 as well as best-corrected visual acuity (BCVA). Correlations between baseline or early values and final anatomical and functional outcomes were investigated. Results: Improvement in CMT was statistically significant after 1 week, 1, 3, 6, 12 and 24 months ( < 0.01). BCVA improvement was statistically significant after 1, 6, 12 and 24 months follow-up (<0.01). The improvement of BCVA and CMT with time was found to be logarithmic (R =0.96, R =0.84) suggesting that early (<30 days) post-operative functional and anatomical changes may be predictive of long-term outcomes. Preoperative BCVA and CMT revealed a weak positive correlation with the respective BCVA and CMT at 24 months (R=0.13 and R=0.16). When plotted as a percentage of the fellow normal eye CMT, first week proportional improvement in CMT from pre-operative baseline was found to be correlated with final CMT proportional decrease (R=0.72) suggesting that first week postoperative CMT could be predictive of final CMT. Conclusion: There is a logarithmic improvement in CMT and BCVA after ERM peel with BCVA improvement following the CMT improvement. Early (less than 30 days) post-operative anatomical changes can be predictive of long-term anatomical outcomes.
Botulinum toxin is an important treatment for many conditions in ophthalmology, including strabismus, nystagmus, blepharospasm, hemifacial spasm, spastic and congenital entropion, corneal exposure, and persistent epithelial defects. The mechanism of action of botulinum toxin for both strabismus and nystagmus is the neuromuscular blockade and transient paralysis of extraocular muscles, but when botulinum toxin is used for some forms of strabismus, a single injection can convey indefinite benefits. There are two unique mechanisms of action that account for the long-term effect on ocular alignment: (1) the disruption of a balanced system of agonist-antagonist extraocular muscles and (2) the reestablishment of central control of alignment by the binocular visual system. For other ocular conditions, botulinum toxin acts through transient paralysis of periocular muscles. Botulinum toxin is a powerful tool in ophthalmology, achieving its therapeutic effects by direct neuromuscular blockade of extraocular and periocular muscles and by unique mechanisms related to the underlying structure and function of the visual system.
Acute isolated optic neuritis can be the initial presentation of demyelinating inflammatory central nervous system disease related to multiple sclerosis (MS), neuromyelitis optica (NMO) or myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to the well-characterized brain and spinal cord imaging features, important and characteristic differences in the radiologic appearance of the optic nerves in these disorders are being described, and magnetic resonance imaging (MRI) of the optic nerves is becoming an essential tool in the differential diagnosis of optic neuritis. Whereas typical demyelinating optic neuritis is a relatively mild and self-limited disease, atypical optic neuritis in NMO and MOG-AD is potentially much more vision-threatening and merits a different treatment approach. Thus, differentiation based on MRI features may be particularly important during the first attack of optic neuritis, when antibody status is not yet known. This review discusses the optic nerve imaging in the major demyelinating disorders with an emphasis on clinically relevant differences that can help clinicians assess and manage these important neuro-ophthalmic disorders. It also reviews the utility of optic nerve MRI as a prognostic indicator in acute optic neuritis.
The assessment of tear fluid components is a common and valuable approach to understanding ocular surface disease and testing the efficacy of novel therapeutic strategies. However, the interpretation and utility of the findings can be limited by changes in the composition of the tear film, particularly in studies requiring repetitive patient sampling. Here, tear samples were collected twice within a one-hour interval to evaluate the short-term reproducibility of an immunoassay aimed to measure the amount of MUC5AC mucin. We found no statistical difference in total protein or MUC5AC content between the two consecutive collections of tear fluid, although the inter-individual variability in each group was high, with coefficients of variation exceeding 30% and 50%, respectively. Scatterplots showed a significant correlation in both protein and MUC5AC following collection within a one-hour interval. These data indicate that, regardless of the high inter-individual variability, repeated collection of tear fluid within an hour interval produces reproducible intra-individual data in terms of MUC5AC mucin content, and suggest that the normal mucin composition of the tear fluid can be re-established within an hour of the initial collection.
Nrf2, a transcription factor that regulates the response to oxidative stress, has been shown to rescue cone photoreceptors and slow vision loss in mouse models of retinal degeneration (rd). The retinal pigment epithelium (RPE) is damaged in these models, but whether it also could be rescued by Nrf2 has not been previously examined. We used an adeno-associated virus (AAV) with an RPE-specific (Best1) promoter to overexpress Nrf2 in the RPE of rd mice. Control rd mice showed disruption of the regular array of the RPE, as well as loss of RPE cells. Cones were lost in circumscribed regions within the cone photoreceptor layer. Overexpression of Nrf2 specifically in the RPE was sufficient to rescue the RPE, as well as the disruptions in the cone photoreceptor layer. Electron microscopy showed compromised apical microvilli in control rd mice but showed preserved microvilli in Best1-Nrf2-treated mice. The rd mice treated with Best1-Nrf2 had slightly better visual acuity. Transcriptome profiling showed that Nrf2 upregulates multiple oxidative defense pathways, reversing declines seen in the glutathione pathway in control rd mice. In summary, Nrf2 overexpression in the RPE preserves RPE morphology and survival in rd mice, and it is a potential therapeutic for diseases involving RPE degeneration, including age-related macular degeneration (AMD).