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Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), whole-brain, gray matter and thalamic volumes in patients with and without focal inflammatory activity in 161 patients followed over 5 years. We used mixed models including focal inflammatory activity (the presence of at least one relapse or a new/enlarging T2-FLAIR or gadolinium- enhancing lesion), and its interaction with time adjusted by age, sex, use of disease-modifying therapies and steroids, and prior optic neuritis. The increased rate of neuro-axonal injury during the first five years after onset was more prominent among active patients, as reflected by the changes in GCIPL thickness (p = 0.02), whole brain (p = 0.002) and thalamic volumes (p < 0.001). Thereafter, rates of retinal and brain changes stabilized and were similar in active and stable patients. Focal inflammatory activity is associated with neurodegeneration early in MS which reinforces the use of an early intensive anti-inflammatory therapy to prevent neurodegeneration in MS.

Background: Optic neuritis (ON) and multiple sclerosis (MS) are complex diseases with multifactorial pathogenesis. The role of genetic factors in the development of these diseases is hypothesized, and specific biochemical components involved in the pathogenesis of ON and MS are yet to be determined. The aim of our study was to determine the associations between IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, and HTRA1 rs11200638 gene polymorphisms and development of ON with or without MS., Materials and Methods: The study subjects included 80 ON patients and 146 healthy controls (HCs). Genotyping of IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, and HTRA1 rs11200638 was performed using real-time polymerase chain reaction., Results: A/C genotype of IL1RL1 rs1041973 was more frequent in ON patients than in HC subjects ( p = 0.026). The IL1RL1 rs1041973 A/C genotype was associated with increased odds of ON development under the overdominant ( p = 0.041) model., Conclusions: Our study showed that IL1RAP rs4624606, IL-6 rs1800795, and HTRA1 rs11200638 are not associated with an increased risk of developing ON. However, the IL1RL1 rs1041973 A/C genotype might be associated with an increased risk of developing ON.

Objectives: Optic neuritis (ON) is the most common cause of optic neuropathy; typically presenting with a unilateral visual loss in young adults, with incidence of 1-5 in 100,000 per year. We evaluated the effect of Clemastine, a first-generation and CNS (central nervous system)-penetrant H1 receptor antagonist on visual evoked potential (VEP), retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL) complex in patients with optic neuritis., Patients and Methods: This is a prospective comparative interventional case series in 25 patients with acute optic neuritis. Patients were randomly assigned to group 1 (treated with Clemastine 1 mg orally twice a day for 90 days; 16 patients) or group 2 (received placebo for 90 days; 9 patients) and both groups received standard treatment of optic neuritis. We recorded VEP and peripapillary OCT (optical coherence tomography) of patients before and after three months of treatment., Results: In contrast to patients treated with Clemastine, RNFL thickness loss between base line phase and after three months follow up in control group were statistically significant in temporal, supra temporal, Infrotemporal and almost global sections of RNFL map. The reduction in GCL thickness between base line phase and after three months follow up in control group were significant, while it did not reach significance in treatment group except in inferior region., Conclusion: In contrast to treatment group, RNFL and GCL thickness of most quadrants are decreased significantly after three months in patients with ON in control group. In contrast to control group, p100 wave's amplitude recovered in a significant manner in treatment group., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Optic neuritis is a common manifestation of multiple sclerosis and frequently the presenting sign. The diagnosis of MS is heavily based on MRI findings but the latter is relatively insensitive in detecting optic nerve lesions. Identification of optic nerve lesion using ancillary tools such spectral-domain optical coherence tomography (SDOCT) by measuring the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL), and visual-evoked potentials latencies (VEP) may facilitate early diagnosis and treatment of multiple sclerosis., Objective: To determine the optimal of SDOCT measures in RFNL and GCIPL and the VEP latency value for the identification of a prior symptomatic optic nerve lesion., Methods: Thirty patients with diagnosed clinically with optic neuritis and fifty healthy control subjects were tested with SDOCT and VEP and the sensitivity, specificity, negative and positive predictive values of optimal values from healthy controls and optic neuritis patients were determined of for the identification unilateral optic nerve lesion., Results: The inter-eye GCIPL difference of 3.5 µm is highly sensitive (100%) and specific (98%) in identifying unilateral optic nerve lesion, while lowest 5th percentile normal GCIPL threshold values of 71 µm was highly sensitive (100%) but less specific (83.3%). The inter-eye RNFL difference of 5.5 µm had a sensitivity of 70% and specificity of 90% in identifying optic nerve lesion while the lower 5th percentile normal RNFL value of 92.3 µm was poorly sensitive (40%). Finally, the 95th percentile normal VEP latency of 104.50 milliseconds had sensitivity of 80% and specificity of 76% in identifying optic nerve lesion., Conclusions: The inter-eye GCIPL difference is a powerful index for identifying unilateral optic nerve lesion, while the inter-eye RNFL difference and 95th percentile normal VEP latency had very good sensitivity and specificity. These measures can be useful in the evaluation of the first demyelinating event of MS and therefor can facilitate early diagnosis and therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To study the association between serum neurofilament light chain (sNfL) and multiple optical coherence tomography (OCT) measures in patients with MS and healthy controls (HCs)., Methods: In this prospective study, 110 patients with MS were recruited, together with 52 age- and sex-matched HCs. Clinical evaluation and spectral domain OCT and sNfL were obtained at baseline and after 5.5 years of follow-up. Nested linear mixed models were used to assess differences between MS vs HC and associations between sNfL and OCT measures. Partial correlation coefficients are reported, and p values were adjusted for the false discovery rate., Results: At baseline, peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular ganglion cell and inner plexiform layer thickness (mGCIP) were significantly lower in MS than HC both in MS-associated optic neuritis (MSON) ( p = 0.007, p = 0.001) and nonaffected MSON (n-MSON) eyes ( p = 0.003, p = 0.018), along with total macular volume (TMV) in n-MSON eyes ( p = 0.011). At follow-up, MS showed significantly lower pRNFLT, mGCIP, and TMV both in MSON and n-MSON eyes ( p < 0.001) compared with HC. In MS n-MSON eyes, sNfL was significantly associated with baseline pRNFLT and mGCIP ( q = 0.019). No significant associations were found in MSON eyes., Conclusions: This study confirms the ability of sNfL to detect neurodegeneration in MS and advocates for the inclusion of sNfL and OCT measures in clinical trials., Classification of Evidence: This study provides Class III evidence that sNfL levels were associated with MS neurodegeneration measured by OCT., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Optic neuritis (ON) is an inflammatory demyelinating condition that causes acute - usually monocular - visual loss. It is highly associated with multiple sclerosis (MS). In general, ON is a clinical diagnosis based upon the history and examination findings., Objective: The aim was to assess the diagnostic accuracy of measuring optic nerve sheath diameter (ONSD) by ultrasound in acute optic neuritis., Methods: This is a prospective observational study with matched controls carried out on 25 patients and 25 controls. All patients presented with first attack of an acute demyelinating ON. Both patients and controls were submitted to clinical assessment, pattern and flash visual evoked potential and trans-orbital sonography (TOS) to measure the optic nerve sheath diameter (ONSD)., Results: The ONSD was significantly thicker in patients with unilateral (0.6 ± 0.05 cm) and bilateral (0.6 ± 0.1 cm) optic neuritis compared to controls (0.52 ± 0.06 cm). P-value was < 0.001 and 0.04 respectively, with a cutoff value 0.57 cm. A significant negative correlation was found between the thickness of the ONSD and the visual acuity (r= -0.613, P-value <0.05). No correlation was found between the age of the patients and ONSD or between ONSD and latency of P-VEP. TOS showed 68% sensitivity and 88% specificity in diagnosing cases of ON., Conclusion: ONSD measured by TOS is a noninvasive, inexpensive bed-side test, which represent a supporting tool to confirm the clinical diagnosis of ON. Yet its sensitivity and specificity are lower than P-VEP., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest including financial, consultant and other relationships that may lead to bias., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: Transorbital sonography (TOS) has emerged as promising imaging method for the diagnosis and follow-up of acute optic neuritis (ON). Available studies report an increase in the optic nerve diameter (OND) and the optic nerve sheath diameter (ONSD) in the case of a first episode of ON in the affected eye compared to either the contralateral unaffected eye or controls. However, the utility of TOS in the case of recurrent episodes of ON has never been assessed., Methods: In our prospective cohort study, the diagnostic utility of TOS in patients with demyelinating diseases of the central nervous system was assessed, and the association between TOS, optical coherence tomography (OCT) and visual evoked potentials was examined further., Results: Seventy-eight patients with a history of demyelinating disorders of the central nervous system (mean age 38.2 ± 14.2 years; 24% with acute ON) were included. No differences in the OND (3.2 ± 0.5 mm vs. 3.2 ± 0.4 mm) and ONSD (5.1 ± 0.8 mm vs. 5.1 ± 0.7 mm) measurements were found between patients with and without acute ON. Papillary swelling was more frequent in patients with acute ON (14.2% vs. 1.5%, P = 0.002). Patients with a history of previous ON were found to have lower OND (P < 0.001) and ONSD (P = 0.007) compared to patients without a history of previous ON. TOS measurements were inversely associated with disease duration and positively correlated with OCT findings. No association with visual evoked potential measurements was found., Conclusion: No evidence was found for TOS-sensitive differences in the OND and ONSD of patients with demyelinating diseases, according to the presence of acute ON. The association between TOS and OCT measurements deserves further investigation., (© 2019 European Academy of Neurology.)

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Predictors of attack location in relapsing-remitting multiple sclerosis (RRMS) are poorly known. It has been suggested that the site of the first relapse may influence the location of the subsequents. We aimed to ascertain this hypothesis in a sample of patients consecutively recruited in two Italian MS Centres, with at least two MS attacks. The following data were collected from medical records: demographic data, locations involved in the first two (or three) MS attacks (optic nerve, spinal cord, brain stem/cerebellum, cerebral hemispheres, according to symptoms presented), time elapsed between relapses and onset of disease-modifying treatment (DMT). We enrolled 199 patients (67% females; MS onset age 30.0 ± 8.69 years), in 148 of whom we could define the precise attack location. In 70/148 patients (47%) the second attack involved exactly the same location as the first. There was an increased risk of relapsing in the same location of the first attack when this involved the optic nerve (OR 4.5, 95% CI 2.2-9.2, p < 0.0001), the brainstem/cerebellum (OR 3.5, 95% CI 1.7-6.9, p < 0.0001), or the spinal cord (OR 3.0, 95% CI 1.5-5.9, p = 0.001). The location of third relapse (N = 90) was equally influenced by the site of first attack. In 24 patients with optic neuritis in both the two first attacks, the side coincided in 50% of cases. The location of first attack has a major role in influencing the site of subsequent ones in RRMS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons., Methods: Progressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up. Pairwise intereye comparison was performed between ON and fellow non-ON (NON) eyes of patients with MS using the linear mixed-effects model and survival analysis. The latency asymmetry of multifocal visual evoked potential (mfVEP) was used to determine the level of demyelination in the optic nerve., Results: Although both ON and NON eyes demonstrate significantly faster loss of RGC axons compared with normal subjects, ON eyes with severe chronic demyelination show accelerated thinning in the RNFL in the temporal sector of the optic disc (temporal RNFL [tRNFL]) compared with fellow eyes (evidenced by both the linear mixed-effects model and survival analysis). Furthermore, progressive tRNFL thinning is associated with the degree of optic nerve demyelination and reflects the topography of pathology in the optic nerve. More rapid axonal loss in ON eyes is also functionally evidenced by mfVEP amplitude reduction, which correlates with the level of optic nerve demyelination., Conclusions: Although the effect of demyelination on axonal survival has been demonstrated in experimental studies, our results provide first clinically meaningful evidence that chronic demyelination is associated with progressive axonal loss in human MS., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To differentiate between visual cortical network topology changes following optic neuritis (ON) stemming from different inflammatory disease types, we used mathematical graph theory-based tools to analyze functional imaging data., Methods: Sixty-two patients were recruited into this cross-sectional study, 23 of whom had neuromyelitis optica spectrum disorder (NMOSD) with ON, 18 with clinically isolated syndrome (CIS)-ON, and 21 with other CIS episodes. Twenty-six healthy controls (HCs) were also recruited. All participants underwent resting-state functional MRI. Visual networks were defined using 50 visual regions of interest. Analysis included graph theory metrics, including degree, density, modularity, and local and global efficiency., Results: Visual network density shows decreased connectivity in all patient groups compared with controls. A higher degree of connections is seen in both ON groups (CIS and NMOSD) compared with the the non-ON group. This pattern is most pronounced in dorsal-lateral regions. Information transfer efficiency and modularity were reduced in both CIS groups, but not in the NMOSD group, compared with the HC group., Conclusions: Visual network density appears affected by the neurologic deficit sustained (ON), and connectivity changes are more evident in dorsal-lateral regions. Efficiency and modularity appear to be associated with the specific disease type (CIS vs NMOSD). Thus, topological cortical changes in the visual system are associated with the type of neurologic deficit within the limits set on them by the underlying pathophysiology. We suggest that cortical patterns of activity should be considered in the outcome of the patients despite the localized nature of ON., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: This longitudinal study aimed to assess changes in retinal structure and visual function following a first-ever episode of acute optic neuritis (ON)., Methods: Clinical and optical coherence tomography (OCT) data obtained over a period of 12 months were retrospectively analyzed in 41 patients with a first-ever clinical episode of acute ON. OCT scans, high-contrast visual acuity (HCVA), and low-contrast visual acuity (LCVA) were acquired at baseline and at 1, 3, 6, and 12 months thereafter. Macular ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer (pRNFL), and macular inner nuclear layer (INL) thicknesses were assessed by OCT. Linear mixed-effects models were used to analyze OCT variables of ipsilateral ON and contralateral non-ON (NON) eyes over time., Results: The mean change of GCIP thickness in ON eyes was significant at all follow-up time points, with nearly 75% of the total reduction having occurred by month 1. In ON eyes, thinner GCIP thickness at month 1 correlated with lower LCVA at month 3. Mean pRNFL thickness in ON eyes differed significantly from NON eyes at all postbaseline time points. INL thickness was significantly increased in ON eyes (month 1) but also in contralateral NON eyes (month 12)., Conclusions: Retinal structural damage develops rapidly following acute ON and is associated with subsequent functional visual deficits. Our results also suggest bilateral retinal pathology following unilateral ON, possibly caused by subclinical involvement of the contralateral NON eyes. Moreover, our data may assist in clinical trial planning in studies targeting tissue damage in acute ON., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The visual pathway is commonly involved in multiple sclerosis (MS), even in its early stages, including clinical episodes of optic neuritis (ON). The long-term structural damage within the visual compartment in patients with ON, however, is yet to be elucidated., Objective: Our aim was to characterize visual system structure abnormalities using MRI along with optical coherence tomography (OCT) and pattern-reversal visual evoked potentials (VEPs) depending on a single history of ON., Methods: Twenty-eight patients with clinically definitive MS, either with a history of a single ON (HON) or without such history and normal VEP findings (NON), were included. OCT measures comprised OCT-derived peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell/inner plexiform layer (GCIPL) thickness. Cortical and global gray and white matter, thalamic, and T2 lesion volumes were assessed using structural MRI. Diffusion-weighted MRI-derived measures included fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivity within the optic radiation (OR)., Results: Mean (SD) duration after ON was 8.3 (3.7) years. Compared with the NON group, HON patients showed significant RNFL ( p = 0.01) and GCIPL thinning ( p = 0.002). OR FA ( p = 0.014), MD ( p = 0.005), RD ( p = 0.007), and AD ( p = 0.004) were altered compared with NON. Global gray and white as well as other regional gray matter structures did not differ between the 2 groups., Conclusion: A single history of ON induces long-term structural damage within the retina and OR suggestive of both retrograde and anterograde neuroaxonal degeneration., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: The aim of the study was to determine the risk of multiple sclerosis (MS) conversion after optic neuritis (ON) and to identify the predictive factors on conversion in Turkish patients., Methods: Patients whose first clinical attacks had been ON were included in the study. The primary end point was the diagnosis of clinical relapse-remitting MS., Result: Except for the bilateral involvement rate, the clinical and demographic characteristics of the cohort are similar to Western studies. Though one-third of the patients with ON had bilateral involvement, bilateral involvement reduces the risk of conversion. Also, active lesions at the initial cranial magnetic resonance imagination increase the conversion rate., Conclusion: This research confirms previous findings and contributes additional evidence that if the patients have unilateral involvement and active lesions, they should be closely monitored. Moreover, our research supports the hypothesis that risk factors may be affected by racial, environmental, and genetic factors., (© 2020 S. Karger AG, Basel.)

Neurological complications related to anti-rabies vaccine are uncommon. The involvement of the optic nerve is extremely rare. It has been occasionally reported after Semple's vaccine administration due to the presence of highly antigenic sheep brain tissue in the vaccine. To our knowledge, this is the first case report of optic neuritis after chick embryo-derived anti-rabies vaccine.

Increasing reliance on electronic medical records at large medical centers provides unique opportunities to perform population level analyses exploring disease progression and etiology. The massive accumulation of diagnostic, procedure, and laboratory codes in one place has enabled the exploration of co-occurring conditions, their risk factors, and potential prognostic factors. While most of the readily identifiable associations in medical records are (now) well known to the scientific community, there is no doubt many more relationships are still to be uncovered in EMR data. In this paper, we introduce a novel finding index to help with that task. This new index uses data mined from real-time PubMed abstracts to indicate the extent to which empirically discovered associations are already known (i.e., present in the scientific literature). Our methods leverage second-generation p-values, which better identify associations that are truly clinically meaningful. We illustrate our new method with three examples: Autism Spectrum Disorder, Alzheimer's Disease, and Optic Neuritis. Our results demonstrate wide utility for identifying new associations in EMR data that have the highest priority among the complex web of correlations and causalities. Data scientists and clinicians can work together more effectively to discover novel associations that are both empirically reliable and clinically understudied., Competing Interests: The authors have declared that no competing interests exist.

Background: Thinning of the retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCIPL) occur in the chronic phase after optic neuritis (ON) in children and reflect neuroaxonal injury. The objective of this study was to describe changes in RNFL and GCIPL thickness in the acute phase following pediatric ON., Methods: Data were collected prospectively from consecutive children presenting with ON as part of an incident acquired demyelinating event. Children with a final diagnosis of multiple sclerosis (n = 9, 10 ON-affected eyes) or monophasic demyelination (n = 16, 25 ON-affected eyes) who underwent spectral-domain optical coherence tomography (OCT) testing within 30 days of symptom onset were included. Standardized visual assessment was performed at presentation and 6-18 months follow-up. OCT measures were compared to those of healthy controls (n = 25, 50 eyes)., Results: Median (interquartile range [IQR]) global RNFL thickness was increased in ON-affected eyes (155 μm [114-199 μm]) compared to control eyes (104 μm [98.5-107.5 μm]; p < 0.0001). Compared to controls, fellow eyes demonstrated a reduced temporal quadrant RNFL thickness (59 μm [53-72 μm] versus 71.5 μm [65-81 μm]; p = 0.013) and lower GCIPL thickness (80.5 μm [74-88 μm] versus 87 μm [85-89 μm]; p = 0.003). The ON-affected eyes of children with monophasic demyelination demonstrated a greater global RNFL thickness (183.5 μm [146.5-206 μm]) compared to the ON-affected eyes of children with multiple sclerosis (108.5 μm [95-124 μm]; p = 0.01). OCT measures at presentation did not predict low-contrast visual acuity nor color vision at 6-18 months follow-up., Conclusion: Children with multiple sclerosis show less RNFL swelling in their ON-affected eyes at onset compared to children with monophasic demyelination. Lower GCIPL and temporal RNFL thickness in the clinically unaffected eyes of those children with unilateral ON suggests the presence of pre-existing neuroaxonal injury in children presenting with a first episode of ON. This finding may be driven by the subset of children with multiple sclerosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: Pediatric-onset multiple sclerosis (POMS) is associated with focal inflammatory lesions and the loss of cortical and deep gray matter. Optic neuritis (ON) and white matter (WM) lesions in the visual pathway can directly contribute to visual cortical mantle thinning. We determine the relative contributions of MS insult on anterior and posterior visual pathway integrity., Methods: High- and low-contrast visual acuity, optical coherence tomography (OCT), and 3T MRI scans were obtained from 20 POMS patients (10 with remote ON) and 22 age- and sex-matched healthy controls. Cortical mantle thickness was measured using FreeSurfer. Fractional anisotropy (FA) and mean diffusivity were calculated for postchiasmal optic radiations (with and without WM lesions). Groups were compared using Student's t-test (adjusted for multiple comparisons), and simple linear regression was used to investigate interrelationships between measures., Results: Mean cortical thickness of the whole brain was reduced in patients (2.49 mm) versus controls (2.58 mm, P = .0432) and in the visual cortex (2.07 mm vs. 2.17 mm, P = .0059), although the foveal confluence was spared. Mean FA of the optic radiations was reduced in POMS (.40) versus controls (.43, P = .0042) and correlated with visual cortical mantle thickness in POMS (P = .017). Visual acuity, OCT measures, and lesion volumes in the optic radiations were not associated with cortical mantle thickness., Conclusions: POMS negatively impacts the integrity of the anterior visual pathway, but it is the loss of WM integrity that drives anterograde loss of the cortical mantle. Preserved visual acuity and foveal sparing imply some degree of functional and structural resilience., (© 2019 by the American Society of Neuroimaging.)

Objectives: The aim of the study is to compare coronal spectrally fat-suppressed 2D turbo spin-echo (TSE) with 2D short-tau inversion-recovery (STIR) sequences for the detection of optic nerve hyperintensities in patients with acute optic nerve neuritis (ON)., Methods: A retrospective review of patients with suspected unilateral ON and pathological visual evoked potentials, who received coronal TSE and STIR sequences with similar fast and clinically feasible acquisition times in addition to our standard imaging protocol. All images were evaluated and compared concerning the presence of optic nerve lesions, lesion lengths, and signal intensities in different anatomical parts of the optic nerves and CNR measures. A summary confidence score (CS) was calculated based on each reader's subjective confidence regarding the scoring items., Results: Interobserver agreements regarding the detection of optic nerve lesions were excellent for both sequences (TSE, κ = 0.89 and STIR, κ = 0.80). Greater extensions (17.4 ± 6.3 mm vs. 14.1 ± 5.8 mm), as well as higher numbers of optic nerve lesions in symptomatic nerves, were detected on TSE (49/52) compared with STIR (45/52) sequences (both p < 0.001). Overall CS were significantly (p < 0.001) higher for TSE (2.8) compared with STIR (2.1) sequences regarding the presence or absence of optic nerve lesions. CNR ratios of lesions' mean signal intensities vs. ipsilateral surrounding orbital fat and vs. signal intensity measurements from contralateral optic nerves were significantly higher on TSE compared with STIR (p < 0.001 for both comparisons)., Conclusion: Spectrally fat-suppressed coronal 2D TSE sequences appear to be more sensitive for the detection of hyperintense optic lesions compared with 2D STIR sequences., Key Points: • Spectrally fat-suppressed TSE sequences showed higher detection rates of hyperintense optic nerve lesions, as well as a higher reader confidence scores compared with STIR. • Optic nerve signal abnormalities on TSE sequences were brighter and showed a greater expansion along the optic nerve course. • CNR measures were significantly higher on TSE compared with STIR, when comparing the ratios of mean signal intensities of optic nerve lesions to ipsilateral orbital fat and to contralateral healthy optic nerves of both sequences.

Neuroinflammatory diseases are characterized by blood-brain barrier disruption (BBB) and leukocyte infiltration. We investigated the involvement of monocyte recruitment in visual pathway damage provoked by primary optic neuritis (ON) induced by a microinjection of bacterial lipopolysaccharide (LPS) into the optic nerve from male Wistar rats. Increased Evans blue extravasation and cellularity were observed at 6 h post-LPS injection. In WT-GFPþ/WT chimeric rat optic nerves, the presence of GFP(+) neutrophils and GFP(+) monocytes, and in wild-type rat optic nerves, an increase in CD11b + CD45 low and CD11b + CD45 high cell number, were observed at 24 h post-LPS. Gamma-irradiation did not affect the increase in BBB permeability, but significantly lessened the decrease in pupil light reflex (PLR), and retinal ganglion cell (RGC) number induced by LPS. At 6 h post-LPS, an increase in chemokine (C-C motif) ligand 2 (CCL2) immunoreactivity co-localized with neutrophils (but not microglia/macrophages or astrocytes) was observed, while at 24 h post-injection, an increase in Iba-1-immunoreactivity and its co-localization with CCL2 became evident. The co-injection of LPS with bindarit (a CCL2 synthesis inhibitor) lessened the effect of LPS on PLR, and RGC loss. The treatment with etoposide or gadolinium chloride that significantly decreased peripheral monocyte (but not neutrophil or lymphocyte) percentage decreased the effect of LPS on PLR, and RGC number. Moreover, a negative correlation between PRL and monocyte (but not lymphocyte or neutrophil) percentage was observed at 7 days post-LPS. Taken together, these results support that monocytes are key players in the initial events that take place during primary ON.

Purpose: The goal was to visualize topographic thickness maps of the intraretinal layers and evaluate their discrimination abilities and relationships with clinical manifestations in patients with multiple sclerosis (MS) and a history of optic neuritis (ON)., Methods: Thirty patients with relapsing-remitting MS (34 eyes with a history of ON [MSON] and 26 non-ON fellow eyes [MSFE]) were recruited together with 63 age- and sex-matched controls (HC). Ultrahigh resolution optical coherence tomography was used to image the macula and the volumetric data set was segmented to yield six intraretinal layers. Topographic thickness maps were aligned and averaged for the visualization. The thickness maps were partitioned using the Early Treatment Diabetic Retinopathy Study (ETDRS) and related to Sloan low-contrast letter acuity (LCLA), Expanded Disability Status Scale (EDSS), and disease duration., Results: Focal thickness reduction occurred in the macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL), with the most profound reduction occurring in MSON eyes (P < 0.05). A horseshoe-like thickness reduction pattern (U Zone) in the GCIPL appeared in MSON. The thickness of the U Zone had better discrimination power than the ETDRS partitions (area under the curve = 0.97) and differentiated 96% of MSON from HC. The thickness of the U Zone was positively correlated to 2.5% LCLA (r = 0.38, P < 0.05) and 1.25% LCLA (r = 0.57, P < 0.05)., Conclusions: The horseshoe-like thickness reduction of the GCIPL appeared to be an ON-specific focal thickness alteration with the highest discrimination power of prior ON.

Background: We investigated the frequency of blood-retina barrier impairment in optic neuritis (ON) using gadolinium leakage in ocular structures (GLOS), a novel imaging marker on contrast enhanced fluid attenuated inversion recovery images (FLAIR)., Methods: In 12 patients with acute ON who underwent repeated MRI the presence of GLOS was noted on contrast-enhanced FLAIR., Results: Bilateral GLOS was observed in 4 (33.3%): in 3 symmetrical, and in 1 asymmetrical. In the latter GLOS was ipsilateral to the ON., Conclusions: GLOS may be observed frequently in ON. Asymmetrical GLOS may be caused by a more local effect of ON., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The spectrum of Myelin Oligodendrocytes Glycoprotein (MOG) antibody disease constitutes a recently described challenging entity, referring to a relatively new spectrum of autoimmune disorders with antibodies against MOG predominantly involving the optic nerve and spinal cord. The purpose of this article is to describe MRI features of MOG-AD involvement in the optic nerves, spinal cord and the brain of adults., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Purpose: Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a demyelinating autoimmune disease characterized by acute episodes of motor, sensory, and cognitive symptoms. Optic neuritis is an episodic sequela experienced by some patients with RRMS that typically presents as acute, monocular vision loss. Episodes of optic neuritis damage and kill retinal ganglion cells (RGCs), and can culminate in permanent vision loss. The purpose of these studies was to evaluate the capacity of DMF to mitigate optic neuritis. The work presented combines studies of a mouse model of MS and a retrospective chart analysis of files of patients with RRMS treated at the MS Center of Excellence within the Oklahoma Medical Research Foundation., Methods: Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model that recapitulates cardinal features of somatic and visual MS pathologies. EAE was induced in female C57BL/6J mice by inoculation with myelin oligodendrocyte glycoprotein peptide (residues 35-55; MOG 35-55 ). DMF or vehicle was administered twice a day by oral gavage. Visual acuity was measured longitudinally with optokinetic tracking. Post-mortem analyses included quantification of RGCs in retinal flatmounts and quantitative PCR (qPCR) of Nrf2 target genes and regulators of myelin. Retrospective chart analyses were performed using data obtained from deidentified files of patients with RRMS., Results: In the EAE mouse studies, DMF decreased optic neuritis severity, preserved vision and RGCs, and concomitantly reduced motor deficits when administered by two different treatment regimens (prevention or interventional). DMF was more efficacious when administered as an interventional therapy, and the beneficial effects occurred independently of the induction of Nrf2 target genes. A complementary retrospective chart analysis demonstrated that DMF increased the time to a recurrence of optic neuritis, and protected against subsequent bouts of optic neuritis., Conclusions: This work underscores the potential of DMF to mitigate the severity and recurrence of optic neuritis episodes in patients with RRMS.

Dysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and occurs in both MS patients and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Divalent Metal Transporter1, a major iron importer in cells, is stimulated by signaling of Dexras1, a small G protein member of the Ras family. Dexras1 is activated by S-nitrosylation by nitric oxide (NO) produced by either inducible nitric oxide synthase in activated microglia/macrophages or neuronal nitric oxide synthase in neurons. Here we show Dexras1 exacerbates oxidative stress-induced neurodegeneration in experimental optic neuritis, an inflammatory demyelinating optic nerve condition that occurs in MS and EAE. Dexras1 deletion, as well as treatment with the iron chelator deferiprone, preserves vision and attenuates retinal ganglion cell (RGC) and axonal loss during EAE optic neuritis. These results suggest that iron entry triggered by NO-activated Dexras1 signaling is a potential mechanism of neuronal death in experimental optic neuritis. The current data suggest modulation of Dexras1 signaling and iron chelation are potential novel treatment strategies for optic neuritis and MS, and possibly other optic neuropathies as well.

Pathologies of the optic nerve could result as primary insults in the visual tract or as secondary deficits due to inflammation, demyelination, or compressing effects of the surrounding tissue. The extent of damage may vary from mild to severe, differently affecting patient vision, with the most severe forms leading to complete uni- or bilateral visual loss. The aim of researchers and clinicians in the field is to alleviate the symptoms of these, yet uncurable pathologies, taking advantage of known and novel potential therapeutic approaches, alone or in combinations, and applying them in a limited time window after the insult. In this review, we discuss the epidemiological and clinical profile as well as the pathophysiological mechanisms of two main categories of optic nerve pathologies, namely traumatic optic neuropathy and optic neuritis, focusing on the demyelinating form of the latter. Moreover, we report on the main rodent models mimicking these pathologies or some of their clinical aspects. The current treatment options will also be reviewed and novel approaches will be discussed., (© 2019 Wiley Periodicals, Inc.)

The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE).Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images.Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation.Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis.

Purpose of Review: Multiple sclerosis (MS) and related autoimmune disorders of the central nervous system such as neuromyelitis optica spectrum disorders (NMOSD) are characterized by chronic disability resulting from autoimmune neuroinflammation, with demyelination, astrocyte damage, impaired axonal transmission and neuroaxonal loss. Novel therapeutics stopping or reversing the progression of disability are still urgently warranted. This review addresses research on optic neuritis in preclinical experimental models and their translation to clinical trials., Recent Findings: Optic neuritis can be used as paradigm for an MS relapse which can serve to evaluate the efficacy of novel therapeutics in clinical trials with a reasonable duration and cohort size. The advantage is the linear structure of the visual pathway allowing the assessment of visual function and retinal structure as highly sensitive outcome parameters. Experimental autoimmune encephalomyelitis is an inducible, inflammatory and demyelinating central nervous system disease extensively used as animal model of MS. Optic neuritis is part of the clinicopathological manifestations in a number of experimental autoimmune encephalomyelitis models. These have gained increasing interest for studies evaluating neuroprotective and/or remyelinating substances as longitudinal, visual and retinal readouts have become available., Summary: Translation of preclinical experiments, evaluating neuroprotective or remyelinating therapeutics to clinical studies is challenging. In-vivo readouts like optical coherence tomography, offers the possibility to transfer experimental study designs to clinical optic neuritis trials.

Objectives : Optic neuritis (ON) is defined as inflammation of the optic nerve, which is mostly idiopathic. However, it can be associated with various causes (demyelinating lesions, autoimmune disorders, infectious and inflammatory conditions). Inflammatory demyelinating disorder of the optic nerve can be associated with multiple sclerosis. It is thought that CETP, SIRT1, FGFR2, STAT3, VEGFA and IL6 genes play a key role in this autoimmune inflammatory disease. The aim of our study was to determine if the frequency of the CETP, SIRT1, FGFR2, STAT3, VEGFA and IL6 gene polymorphisms have an influence on the development of acute ON. Methods : The study enrolled patients with ON and a random sample of healthy population. The genotyping test of the CETPrs5882,rs708272, SIRT1 rs12778366, FGFR2rs2981582, STAT3 rs744166, VEGFA rs833068, IL6 rs1800795 polymorphisms was carried out using the RT-PCR method. Results : Our study determined that the G/A genotype of CETP rs708272 was associated with two-fold-decreased odds of ON development under the codominant (OR = 0.495;95%CI:0.256-0.959) and overdominant (OR = 0.501;95%CI:0.280-0.895) models. Also, each allele C at VEGFA rs833068 was associated with 1.7-fold increased odds of ON development under the additive model (OR = 1.733;95%CI:1.148-2.615). Furthermore, IL6 rs1800795 G/G genotype was associated with increased odds of ON development under the codominant (OR = 2.869;95%CI:1.280-6.434) and recessive (OR = 2.315;95%CI:1.251-4.285) models. Conclusions : We revealed that the genotypes of CETP rs708272 G/A, IL6 rs1800795 G/G, and each allele C at VEGFA rs833068 were associated with ON. CETP rs708272 G/G genotype was associated with decreased by 62% odds of ON with MS development under the recessive (OR = 0.379;95%CI:0.155-0.929; p = .034) model.

Background: Because of limitations of conventional tools for diagnosing optic neuritis (ON), transorbital ultrasonography (TOUS) was introduced as a promising tool to evaluate the optic nerve. However, studies demonstrating its utility are scarce., Objective: To assess the practical diagnostic value of TOUS in patients with ON along with other diagnostic tools such as visual evoked potential (VEP), MRI, and optical coherence tomography (OCT)., Methods: Seventeen patients with first-attack unilateral acute ON were enrolled. Clinical characteristics, visual acuity, TOUS, MRI, VEP, and OCT results were evaluated. Bilateral optic nerves were scanned using TOUS to obtain axial images showing the optic nerve and the disc in the longitudinal plane., Results: TOUS revealed thickening of the optic nerve sheath and optic nerve diameter with sheath on the affected side compared with the unaffected side (p = 0.002 and p = 0.003, respectively). Time since onset of initial symptoms was inversely correlated with optic nerve diameter (ρ = -0.517, p = 0.040) and retinal nerve fiber layer thickness (ρ = -0.831, p < 0.001)., Conclusion: TOUS could be a cost-effective tool for morphologically evaluating acute ON showing a significant thickening of the optic nerve and sheath, although only a limited retrobulbar area could be explored., (Copyright © 2019. Published by Elsevier B.V.)

Multipotent mesenchymal stem cells (MSCs) have been employed in numerous pre-clinical and clinical settings for various diseases. MSCs have been used in treating degenerative disorders pertaining to the eye, for example, age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and optic neuritis. Despite the known therapeutic role and mechanisms of MSCs, low cell precision towards the targeted area and cell survivability at tissue needing repair often resulted in a disparity in therapeutic outcomes. In this review, we will discuss the current and feasible strategy options to enhance treatment outcomes with MSC therapy. We will review the application of various types of biomaterials and advances in nanotechnology, which have been employed on MSCs to augment cellular function and differentiation for improving treatment of visual functions. In addition, several modes of gene delivery into MSCs and the types of associated therapeutic genes that are important for modulation of ocular tissue function and repair will be highlighted., Competing Interests: The authors declare no conflict of interest.

Optic neuritis is a common manifestation of multiple sclerosis, an inflammatory demyelinating disease of the CNS. Although it is the presenting symptom in many cases, the initial events are currently unknown. However, in the earliest stages of autoimmune optic neuritis in rats, pathological changes are already apparent such as microglial activation and disturbances in myelin ultrastructure of the optic nerves. αB-crystallin is a heat-shock protein induced in cells undergoing cellular stress and has been reported to be up-regulated in both multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Therefore, we wished to investigate the timing and localization of its expression in autoimmune optic neuritis. Although loss of oligodendrocytes was not observed until the later disease stages accompanying immune cell infiltration and demyelination, an increase in oligodendrocyte αB-crystallin was observed during the preclinical stages. This was most pronounced within the optic nerve head and was associated with areas of IgG deposition. Since treatment of isolated oligodendrocytes with sera from myelin oligodendrocyte glycoprotein (MOG)-immunized animals induced an increase in αB-crystallin expression, as did passive transfer of sera from MOG-immunized animals to unimmunized recipients, we propose that the partially permeable blood-brain barrier of the optic nerve head may present an opportunity for blood-borne components such as anti-MOG antibodies to come into contact with oligodendrocytes as one of the earliest events in disease development., (© 2018 The Authors. Glia published by Wiley Periodicals, Inc.)

Objective: To explore sensitivity of optical coherence tomography (OCT) in detecting prior unilateral optic neuritis., Methods: This is a retrospective, observational clinical study of all patients who presented from January 1, 2014, to January 6, 2017, with unilateral optic neuritis and OCT available at least 3 months after the attack. We compared OCT retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thicknesses between affected and unaffected contralateral eyes. We excluded patients with concomitant glaucoma or other optic neuropathies. Based on analysis of normal controls, thinning was considered significant if RNFL was at least 9 µm or GCIPL was at least 6 µm less in the affected eye compared to the unaffected eye., Results: Fifty-one patients (18 male and 33 female) were included in the study. RNFL and GCIPL thicknesses were significantly lower in eyes with optic neuritis compared to unaffected eyes ( p < 0.001). RNFL was thinner by ≥9 µm in 73% of optic neuritis eyes compared to the unaffected eye. GCIPL was thinner by ≥6 µm in 96% of optic neuritis eyes, which was more sensitive than using RNFL ( p < 0.001). When using a threshold ≤1st percentile of age-matched controls, sensitivities were 37% for RNFL and 76% for GCIPL, each of which was lower than those calculated using the intereye difference as the threshold ( p < 0.01)., Conclusions: OCT, especially with GCIPL analysis, is a highly sensitive modality in detecting prior optic neuritis, which is made more robust by using intereye differences to approximate change., Classification of Evidence: This study provides Class III evidence that OCT accurately identifies patients with prior unilateral optic neuritis., (© 2019 American Academy of Neurology.)

Background: Patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) may show alterations of retinal layer architecture as measured by optical coherence tomography. Little is known about changes in the retinal vascular network during MS., Objective: To characterize retinal vessel structures in patients with MS and CIS and to test for associations with MS disease activity., Method: In all, 42 patients with MS or CIS and 50 healthy controls underwent retinal optical coherence tomography angiography (OCT-A) with analysis of the superficial and deep vascular plexuses and the choriocapillaries. We tested OCT-A parameters for associations with retinal layer volumes, history of optic neuritis (ON), and the retrospective disease activity., Results: Inner retinal layer volumes correlated positively with the density of both the superficial and deep vascular plexuses. Eyes of MS/CIS patients with a history of ON revealed reduced vessel densities of the superficial and deep vascular plexuses as compared to healthy controls. Higher choriocapillary vessel densities were associated with ongoing inflammatory disease activity during 24 months prior to OCT-A examination in MS and CIS patients., Conclusion: Optic neuritis is associated with rarefaction of the superficial and deep retinal vessels. Alterations of the choriocapillaries might be linked to disease activity in MS.

Background: Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC)., Objective: To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON)., Methods: A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures. Participants aged 18-55 years, ≤28 days of onset of first episode unilateral ON, were randomised to amiloride (10 mg daily for 5 months) or placebo ( clinicaltrials.gov , NCT 01802489)., Results: Intention-to-treat (ITT) cohort consisted of 43 patients; 23 placebo and 20 amiloride. No significant drug-related adverse events occurred. No significant differences were found in GDx ( p = 0.840). Visual evoked potentials (VEP) were significantly prolonged in the amiloride group compared to placebo ( p = 0.004). All other secondary outcome measures showed no significant difference. Baseline analysis of OCT data demonstrated a significant pre-randomisation thinning of ganglion cell layer., Conclusion: Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.

Optic neuritis (ON) is an inflammatory, demyelinating, neurodegenerative, and presently untreatable condition of the optic nerve which might induce blindness. We analyzed the effect of environmental enrichment (EE) on visual pathway damage provoked by experimental ON induced by a microinjection of bacterial lipopolysaccharide (LPS) into the optic nerve. For this purpose, LPS was microinjected into the optic nerve from male Wistar rats. After injection, one group of animals was submitted to EE, and another group remained in standard environment (SE) for 21 days. EE prevented the decrease in pupil light reflex (PLR), visual evoked potentials, retinal anterograde transport, phosphorylated neurofilament immunoreactivity, myelination (luxol fast blue staining), and axon (toluidine blue staining) and retinal ganglion cell (Brn3a-immunoreactivity) number. EE also prevented microglial/macrophage reactivity (Iba-1- and ED1-immunoreactivity), and astrocytosis (glial fibrillary acidic protein-immunostaining) induced by experimental ON. LPS-injected optic nerves displayed oxidative damage and increased inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-1β and TNFα mRNA levels which were prevented by EE. EE increased optic nerve brain-derived neurotrophic factor levels. When EE started at 4 (but not 7) days post-injection of LPS, a preservation of the PLR was observed at 21 days post-LPS, which was blocked by the daily administration of ANA-12 from day 4 to day 7 post-LPS. Moreover, EE from day 4 to day 7 post-LPS significantly preserved the PLR at 21 days post-injection. Taken together, our data suggest that EE preserved visual functions and reduced neuroinflammation of the optic nerve. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment"., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Idiopathic bilateral optic neuritis in adult has been reported very rarely. The objective of this report is to present a case of idiopathic bilateral optic neuritis in adult and treatment responses. A nineteen year old female presented with bilateral optic neuritis. It was characterized by decreased visual acuity, painful ocular motility and sluggish pupillary reaction with Relative Afferent Pupillary Defect (RAPD) in left eye, hyperemic and generalized optic disc swelling and central scotoma in Humphrey visual field of both eyes. MRI showed diffuse thickening and irregularly outlined optic nerves of both eyes. Idiopathic bilateral optic neuritis in adults is a rare presentation. Prompt treatment with optic neuritis treatment trial (ONTT) improved the visual outcome.

Purpose : This study was undertaken to analyze the characteristics of optic neuritis in Korean patients seropositive for Toxocara . Methods : We retrospectively reviewed data from patients diagnosed with optic neuritis and followed up for at least one month between 2012 and 2016. Patients were grouped according to Toxocara serological testing outcomes (positive or negative) and clinical characteristics were compared. Results : The seropositive and seronegative groups comprised 13 and 12 patients, respectively. The seropositive patients were older (56.8 years versus 34.5 years), reported ocular pain less frequently (30.8% versus 91.7%), and showed more frequent asymmetric optic disc swelling (72.7% versus 22.2%). During follow-up, visual acuity of all seronegative patients improved to 20/40 or better, compared with 38.5% of the seropositive group. Conclusion : Atypical features such as painless, older age, or asymmetric disc swelling in optic neuritis may be related to seropositivity for Toxocara , suggesting the possibility of undiagnosed Toxocara optic neuropathy.

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease of the central nervous system (CNS) with axonal degeneration as major determinant of neurological disability. Assessment of unmyelinated retinal nerve fibers using optical coherence tomography (OCT) may be useful for diagnosing the onset and rate of progression of neurodegeneration., Objective: To assess the incidence and severity of damage of the peripapillary retinal nerve fiber layer (RNFL) in two different MS subtypes: non-progressive [Prog(-)MS] and progressive [Prog(+)MS]., Methods: 48 patients (96 eyes) with MS were included: 13 males, 35 females; aged 22-62 years (mean 38.8; SD ± 10.02) in two subgroups: 26 Prog(-)MS and 22 Prog(+)MS. 3 subtypes of Prog(+)MS were identified by neurologist, according to Lublin criteria: 3 patients had PPMS (14%), 7 had SPMS(32%), 12 had PRMS(54%). RRMS subtype was considered a non-progressive phenotype, designated as Prog(-)MS. All 22 patients with progressive MS phenotypes were included in one group, designated as Prog(+)MS. Progressive disease can be defined over 1 year. The expanded EDSS score was determined by the treating MS specialist and confirmed by the study investigators through the records review. Definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step≥4 and pyramidal score≥2. 11 Prog(-)MS (16 eyes) and 10 Prog(+)MS (13 eyes) patients had a history of optic neuritis (ON). EDSS score was 1.5-6.5 (mean 3.83 ± 1.62) in the Prog(+)MS group and 1.0-3.5 (mean 1.40 ± 0.57) in the Prog(-)MS., Control Group: 31 healthy volunteers (3 males, 28 females), aged 20-62 years (mean 37.4 ± 10.88). Peripapillary RNFL thickness was measured around the optic nerve head (ONH) using spectral-domain OCT (Topcon OCT 1000 MarkII, FastMap v. 3.40, Topcon, Japan). Scans were obtained according to OSCAR-IB consensus criteria. The generalized estimating equation model (GEE) was used in the statistical analysis to assess differences in RNFL thickness between Prog(-)MS and Prog(+)MS patients, taking into consideration history of ON, EDSS score, immunomodulatory therapy, MS progression, MS duration, age and gender. The protocol was approved by the Ethical Committee of the Medical Centre of Postgraduate Education, Warsaw, Poland and informed consent was obtained from all subjects., Results: There was a significant difference between Prog(-)MS and Prog(+)MS groups for mean, nasal and superior quadrant of RNFL thickness. For individuals with a history of ON, significant differences were found between the two MS phenotypes regardless of RNFL thickness measurements., Conclusions: A significant correlation was established between RNFL thickness and progression of neurodegeneration in MS patients with no regard to history of ON. RNFL thickness may be considered a MS biomarker and potential diagnostic tool for assessment of disease progression., (Copyright © 2018. Published by Elsevier B.V.)

Background: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS)., Objective: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort., Methods: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy., Results: Mean RNFL and GCIPL values of patients ( n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (-0.31 µm/year) and GCIPL (-0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (-0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy., Conclusion: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations.

Optic neuritis is characterized by optic nerve inflammation, demyelination and axonal loss. Intravenous immunoglobulin (IVIg) has been reported to be effective for steroid-resistant patients. However, there is no report investigating the histopathological efficacy of IVIg in optic neuritis models. In this study, we examined the effects of IVIg on optic neuritis of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune optic neuritis (EAON). Inflammation, demyelination and axonal loss were assessed in the optic nerve sections. IVIg showed dose-dependent prevention of clinical symptoms in EAON. IVIg provided an anti-inflammatory effect in both EAE and EAON, associated with improved demyelination. Axonal loss in EAE was also significantly attenuated. These results suggest that IVIg has neuroprotective properties in experimental optic neuritis, and is a promising new treatment for optic neuritis.

Dark-Agouti rats were immunized with spinal cord homogenate to develop Experimental Autoimmune Encephalomyelitis, a model of multiple sclerosis. We assessed motor signs and recorded VEPs for five or eight weeks with epidural or epidermal electrodes, respectively, with final histopathology of optic nerves (ONs). Injected rats exhibited motor deficits a week after immunization. VEP delays arose from the 2nd to the 5th week, when a recovery occurred in epidermal-recorded rats. ON damage appeared in epidural-, but not in epidermal-recorded rats, probably due to a remyelination process. VEP could be exploited as neurophysiological marker to test novel treatments against neurodegeneration involving ONs., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD., Methods: Out of 157 patients with NMOSD screened, 94 eyes of 51 patients without optic neuritis (ON) during follow-up (F/U) and 56 eyes of 28 age-matched and sex-matched healthy controls (HC) were included (median F/U 2.3 years). The NMOSD cohort included 60 eyes without (Eye ON - ) and 34 eyes with a history of ON prior to enrolment (Eye ON+ ). Peripapillary retinal nerve fibre layer thickness (pRNFL), fovea thickness (FT), volumes of the combined ganglion cell and inner plexiform layer (GCIP) and the inner nuclear layer (INL) and total macular volume (TMV) were acquired by optical coherence tomography (OCT)., Results: At baseline, GCIP, FT and TMV were reduced in Eye ON+ (GCIP p<2e -16 ; FT p=3.7e -4 ; TMV p=3.7e -12 ) and in Eye ON -  (GCIP p=0.002; FT p=0.040; TMV p=6.1e -6 ) compared with HC. Longitudinally, we observed GCIP thinning in Eye ON- (p=0.044) but not in Eye ON+ . Seven patients had attacks during F/U; they presented pRNFL thickening compared with patients without attacks (p=0.003)., Conclusion: This study clearly shows GCIP loss independent of ON attacks in aquaporin4-antibody-seropositive NMOSD. Potential explanations for progressive GCIP thinning include primary retinopathy, drug-induced neurodegeneration and retrograde neuroaxonal degeneration from lesions or optic neuropathy. pRNFL thickening in the patients presenting with attacks during F/U might be indicative of pRNFL susceptibility to inflammation., Competing Interests: Competing interests: FCO has nothing to disclose. JH reports personal fees and non-financial support from Merck, grants, personal fees and non-financial support from Novartis, personal fees from Roche, non-financial support from Bayer Healthcare, personal fees from Santhera, personal fees and non-financial support from Biogen, personal fees and non-financial support from Sanofi Genzyme, all outside the submitted work. ARF is sponsored by Abide Therapeutic outside of the submitted work and reports no potential conflicts of interest. NL has nothing to disclose. HZ reports grants from Novartis, during the conduct of the study. SM has nothing to disclose; he is named as inventor on a patent application describing OCT image analysis. NB has nothing to disclose. JBS received speaking fees and travel grants from Bayer Healthcare, Sanofi-Aventis/Genzyme, Biogen and Teva Pharmaceuticals, unrelated to the present scientific work. PA reports grants, personal fees and non-financial support from Allergan, personal fees and non-financial support from Bayer Healthcare, grants, personal fees and non-financial support from Biogen, grants, personal fees and non-financial support from Ipsen, grants, personal fees and non-financial support from Merz Pharmaceuticals, personal fees and non-financial support from Merck, grants, personal fees and non-financial support from Novartis, non-financial support from Sanofi-Aventis/Genzyme, personal fees and non-financial support from Teva Pharmaceuticals, grants, personal fees and non-financial support from Roche, outside the submitted work. KR reports research support from Novartis and Merck Serono as well as speaking fees or travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche, Novartis and the Guthy-Jackson Charitable Foundation, all unrelated to this work. TK received travel expenses and personal compensations from Bayer Healthcare, Teva Pharmaceuticals, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma, unrelated to this work. OW has nothing to disclose. SJ has nothing to disclose. MIL reports personal fees from Biogen Idec and grants from Novartis, outside the submitted work. JP reports grants Journal of Neurology, Neurosurgery and Psychiatry and personal fees from Merck Serono, grants and personal fees from Biogen Idec, personal fees from Teva Pharmaceuticals, grants from Chugai, grants and personal fees from MedImmun, grants and personal fees from Alexion, grants and personal fees from Novartis, personal fees from Roche, grants from Genzyme, grants and personal fees from ABIDE, personal fees from TG Therapeutics, outside the submitted work. In addition, JP has a patent Isis: Diagnosing Multiple Sclerosis. FP reports research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune and is member of the steering committee of the OCTIMS study (Novartis), all unrelated to this work. AUB is cofounder and holds shares of commercial entities Motognosis and Nocturne. He is named as inventor on several patent applications describing serum biomarkers for MS, perceptive visual computing for tracking of motor dysfunction and OCT image analysis., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To measure early structural damage caused by autoimmune inflammatory optic neuritis (ON) by optical coherence tomography (OCT) in a population-based cohort., Methods: In a prospective population-based study over 24 months in Southern Denmark, patients diagnosed with acute ON and without prior diagnosis of a chronic neuroinflammatory disorder were included and examined with OCT, visual evoked potentials (VEP), visual fields, high contrast visual acuity (HCVA), and low contrast letter acuity (LCLA). Structural and functional outcomes were determined at 6-month follow-up based on interocular differences., Results: The 50 included patients had on average 16.9 μm peripapillary retinal nerve fiber layer loss, 10.6 μm ganglion cell and inner plexiform layer (GCIP) loss, and an average HCVA decrease of 0.22 dec. Based on a linear regression model, average GCIP loss amounted to -0.2 μm per day and started 8 days after onset. OCT outcomes but not VEP correlated well with all visual function measurements at follow-up. Structural and functional damage in 20 patients (40%) diagnosed de novo with multiple sclerosis (MS) and in 2 patients (4%) with positive myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) test did not differ from patients with idiopathic ON., Conclusions: Optic neuritis causes substantial retinal damage and vision loss independent of the underlying disease. Our study supports that GCIP damage starts closely to clinical onset. Good structure-function correlations between OCT and vision support the importance of OCT in monitoring acute ON., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Optic neuritis is one of the first manifestations of multiple sclerosis. Its pathogenesis is incompletely understood, but considered to be initiated by an auto-immune response directed against myelin sheaths of the optic nerve. Here, we demonstrate in two frequently used and well-validated mouse models of optic neuritis that ribbon synapses in the myelin-free retina are targeted by an auto-reactive immune system even before alterations in the optic nerve have developed. The auto-immune response is directed against two adhesion proteins (CASPR1/CNTN1) that are present both in the paranodal region of myelinated nerves as well as at retinal ribbon synapses. This occurs in parallel with altered synaptic vesicle cycling in retinal ribbon synapses and altered visual behavior before the onset of optic nerve demyelination. These findings indicate that early synaptic dysfunctions in the retina contribute to the pathology of optic neuritis in multiple sclerosis., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Knowledge has been expanding on myelin oligodendrocyte glycoprotein (MOG) antibody-associated central nervous system disorders. We delineate the clinical and paraclinical findings and outcome of our pediatric patients with MOG antibody seropositive disease., Methods: We retrospectively analyzed the clinical presentation, cerebrospinal fluid findings, magnetic resonance imaging (MRI) studies, course and outcome of children seropositive for anti-MOG IgG., Results: Total 20 children with neurological symptoms and serum anti-MOG IgG were identified from six centers in Turkey. Median age at onset was 9 years (mean 8.8 ± 5.0 years, range: 1.5-16.5 years). Final diagnoses were acute disseminated encephalomyelitis (ADEM) (n = 5), ADEM + optic neuritis (n = 4), neuromyelitis optica spectrum disorder (NMOSD) (n = 3), myelitis (n = 2), relapsing optic neuritis (n = 2), multiphasic DEM (n = 3), and unclassified relapsing demyelinating disease (n = 1). Seven/20 (35%) children experienced a single episode while 13/20 (65%) had a least one relapse during follow-up. On MRI, subcortical white matter, brainstem, and corpus callosum were preferentially involved regions. Full recovery was observed in 15/20 (75%) children., Conclusion: MOG autoimmunity in children has a wide clinical spectrum, tendency to relapse, and a favourable outcome compared with other relapsing demyelinating diseases., (Copyright © 2018. Published by Elsevier B.V.)

Background: Optical coherence tomography (OCT) angiography is a new method to assess the density of the vascular networks. Vascular abnormalities are considered involved in multiple sclerosis (MS) pathology., Objective: To assess the presence of vascular abnormalities in MS and to evaluate their correlation to disease features., Methods: A total of 50 MS patients with and without history of optic neuritis (ON) and 46 healthy subjects were included. All underwent spectral domain (SD)-OCT and OCT angiography. Clinical history, Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Score (MSSS) and disease duration were collected., Results: Angio-OCT showed a vessel density reduction in eyes of MS patients when compared to controls. A statistically significant reduction in all SD-OCT and OCT angiography parameters was noticed both in eyes with and without ON when compared with control eyes. We found an inverse correlation between SD-OCT parameters and MSSS ( p = 0.003) and between vessel density parameters and EDSS ( p = 0.007)., Conclusion: We report a vessel density reduction in retina of MS patients. We highlight the clinical correlation between vessel density and EDSS, suggesting that angio-OCT could be a good marker of disease and of disability in MS.

Phenytoin is a non-sedative barbiturate derivate and has been recently rediscovered as a neuroprotective and retinoprotective compound in patients affected by optic neuritis secondary to multiple sclerosis. However, currently there are still no neuroprotective compounds registered and available in the clinic. We reviewed the literature supporting the retinoprotective properties of phenytoin and analyzed the various approaches and definitions from the first research periods onwards. The retinoprotective role of phenytoin was already known in the 1970s, but only recently has this effect been rediscovered, confirming that it could indeed provide structural protection of the retinal cells., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

In the experimental autoimmune encephalomyelitis (EAE) mouse model of optic neuritis, we recently demonstrated that diet supplementation with a balanced mixture of fatty acids (FAs), including omega 3 and omega 6, efficiently limited inflammatory events in the retina and prevented retinal ganglion cell (RGC) death, although mechanisms underlying the efficacy of FAs were to be elucidated. Whether FAs effectiveness was accompanied by efficient rescue of demyelinating events in the optic nerve was also unresolved. Finally, the possibility that RGC rescue might result in ameliorated visual performance remained to be investigated. Here, the EAE model of optic neuritis was used to investigate mechanisms underlying the anti-inflammatory effects of FAs, including their potential efficacy on macrophage polarization. In addition, we determined how FAs-induced rescue of RGC degeneration was related to optic nerve histopathology by performing ultrastructural morphometric analysis with transmission electron microscopy. Finally, RGC rescue was correlated with visual performance by recording photopic electroretinogram, an efficient methodology to unravel the role of RGCs in the generation of electroretinographic waves. We conclude that the ameliorative effects of FAs were dependent on a predominant anti-inflammatory action including a role on promoting the shift of macrophages from the inflammatory M1 phenotype towards the anti-inflammatory M2 phenotype. This would finally result in restored optic nerve histopathology and ameliorated visual performance. These findings can now offer new perspectives for implementing our knowledge on the effectiveness of diet supplementation in counteracting optic neuritis and suggest the importance of FAs as possible adjuvants in therapies against inflammatory diseases of the eye.