Myelin Oligodendrocyte Glycoprotein Antibody Disease Optic Neuritis: A Structure-Function Paradox?

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a demyelinating disorder that most commonly presents with optic neuritis (ON) and affects children more often than adults. We report 8 pediatric patients with MOG-associated ON and characterize focal optical coherence tomography (OCT) abnormalities over time that help distinguish this condition from the trajectories of other demyelinating disorders. These OCT findings are examined in the context of longitudinal visual function testing. METHODS: This is a retrospective case series of 8 pediatric patients with MOG-associated ON who were referred for neuro-ophthalmic evaluation. Longitudinal data for demographics, clinical history, physical examination, and OCT obtained in the course of clinical evaluations were collected through retrospective medical record review. RESULTS: Patients demonstrated acute peripapillary retinal nerve fiber layer (RNFL) thickening in one or both eyes, consistent with optic disc swelling. This was followed by steady patterns of average RNFL thinning, with 9 of 16 eyes reaching significantly low RNFL thickness using OCT platform reference databases ( P < 0.01), accompanied by paradoxical recovery of high-contrast visual acuity (HCVA) in every patient. There was no correlation between HCVA and any OCT measures, although contrast sensitivity (CS) was associated with global thickness, PMB thickness, and nasal/temporal (N/T) ratio, and color vision was associated with PMB thickness. There was a lower global and papillomacular bundle (PMB) thickness ( P < 0.01) in clinically affected eyes compared with unaffected eyes. There was also a significantly higher N:T ratio in clinically affected eyes compared with unaffected eyes in the acute MOG-ON setting ( P = 0.03), but not in the long-term setting. CONCLUSIONS: MOG shows a pattern of prominent retinal atrophy, as demonstrated by global RNFL thinning, with remarkable preservation of HCVA but remaining deficits in CS and color vision. These tests may be better clinical markers of vision changes secondary to MOG-ON. Of the OCT parameters measured, PMB thickness demonstrated the most consistent correlation between structural and functional measures. Thus, it may be a more sensitive marker of clinically significant retinal atrophy in MOG-ON. The N:T ratio in acute clinically affected MOG-ON eyes in our study was higher than the N:T ratio of neuromyelitis optica (NMO)-ON eyes and similar to the N:T ratio in multiple sclerosis (MS)-ON eyes as presented in the prior literature. Therefore, MOG may share a more similar pathophysiology to MS compared with NMO.

[Optical coherence tomography angiography in the diagnosis of multiple sclerosis]. / Opticheskaya kogerentnaya tomografiya-angiografiya v diagnostike rasseyannogo skleroza.

PURPOSE: This study analyzes the main changes in retinal microcirculation in patients with multiple sclerosis (MS) and their relationship with the type of disease course. MATERIAL AND METHODS: 159 patients (318 eyes) were examined. The groups were formed according to the type of course and duration of MS: group 1 - 37 patients (74 eyes; 23.27%) with relapsing-remitting MS (RRMS) less than 1 year; group 2 - 47 patients (94 eyes; 29.56%) with RRMS from 1 year to 10 years; group 3 - 44 patients (86 eyes; 27.05%) with RRMS >10 years; group 4 - 32 patients (64 eyes; 20.12%) with secondary progressive MS (SPMS). Subgroups A and B were allocated within each group depending on the absence or presence of optic neuritis (ON). Patients underwent standard ophthalmological examination, including optical coherence tomography angiography (OCTA). RESULTS: A decrease in the vessel density (wiVD) and perfusion density (wiPD) in the macular and peripapillary regions was revealed, progressing with the duration of the disease and with its transition to the progressive type. The minimum values were observed in patients with SPMS (group 4), with the most pronounced in the subgroup with ON (wiVD = 16.06±3.65 mm/mm2, wiPD = 39.38±9.46%, ppwiPD = 44.06±3.09%, ppwiF = 0.41±0.05). CONCLUSION: OCTA provides the ability to detect subclinical vascular changes and can be considered a comprehensive, reliable method for early diagnosis and monitoring of MS progression.

Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models.

Repulsive guidance molecule A (RGMa) is a potent inhibitor of axonal growth and a regulator of neuronal cell death. It is up-regulated following neuronal injury and accumulates in chronic neurodegenerative diseases. Neutralizing RGMa has the potential to promote neuroregeneration and neuroprotection. Previously we reported that a rat anti-N terminal RGMa (N-RGMa) antibody r5F9 and its humanized version h5F9 (ABT-207) promote neuroprotection and neuroregeneration in preclinical neurodegenerative disease models. However, due to its cross-reactivity to RGMc/hemojuvelin, ABT-207 causes iron accumulation in vivo, which could present a safety liability. Here we report the generation and characterization of a novel RGMa-selective anti-N-RGMa antibody elezanumab, which is currently under Phase 2 clinical evaluation in multiple disease indications. Elezanumab, a human monoclonal antibody generated by in vitro PROfusion mRNA display technology, competes with ABT-207 in binding to N-RGMa but lacks RGMc cross-reactivity with no impact on iron metabolism. It neutralizes repulsive activity of soluble RGMa in vitro and blocks membrane RGMa mediated BMP signaling. In the optic nerve crush and optic neuritis models, elezanumab promotes axonal regeneration and prevents retinal nerve fiber layer degeneration. In the spinal targeted experimental autoimmune encephalomyelitis (EAE) model, elezanumab promotes axonal regeneration and remyelination, decreases inflammatory lesion area and improves functional recovery. Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases.

Age-dependent favorable visual recovery despite significant retinal atrophy in pediatric MOGAD: how much retina do you really need to see well?

BACKGROUND: To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). METHODS: All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation <18 years were included in the pediatric (MOGADped) cohort and patients with ≥18 years in the adult (MOGADadult) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained. RESULTS: Twenty MOGADped (10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGADadult (34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8±1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 µm; GCIPL: 0.42±0.09 and 0.44±0.13 mm3, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4±9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA-logMAR 0.0) occurred in 73.3% of MOGADped and 31% MOGADadults ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. CONCLUSION: Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes.

Shortened Pattern Electroretinogram Latency and Impaired Autoregulatory Dynamics to Steady-State Stimuli in Patients With Multiple Sclerosis.

BACKGROUND: The steady-state pattern electroretinogram (PERG) is a sensitive measure of retinal ganglion cell (RGC) function that includes within-test progressive changes-adaptation-reflecting RGC autoregulatory dynamics. Comprehensive PERG assessment in patients with multiple sclerosis (MS) (with or without optic neuritis [ON]) may provide unique information about RGC dysfunction and its progression, as well as a comparison between functional loss and structural loss as measured by optical coherence tomography (OCT). The goal of this project was to measure steady-state PERG components and their associations with intraretinal layer thicknesses in MS. METHODS: One hundred forty eyes of 70 patients with relapsing-remitting MS and 126 eyes of 63 age- and sex-matched healthy control subjects (HC) were investigated using a new-generation PERG method and ultrahigh-resolution OCT. Of MS eyes, there were 30 eyes with ON (MSON), 22 non-ON fellow eyes (MSFE), and 88 non-ON MS eyes (MSNON). PERG amplitude, phase (latency), and adaptation of amplitude and phase were measured and correlated with OCT-determined thicknesses of intraretinal layers. RESULTS: The average PERG amplitude in MSON eyes was significantly lower than MSFE (P = 0.007), MSNON (P = 0.002), and HC (P < 0.001). The PERG amplitude in MSFE eyes was also significantly lower than HC (P = 0.039). The PERG latency in MSON eyes was significantly shorter than in MSFE (P = 0.001), MSNON (P = 0.002), and HC (P < 0.001). The PERG latency in MSFE (P = 0.007) and MSNON (P = 0.002) was significantly shorter than in HC. However, no significant differences were found between MSFE and MSNON (P > 0.05). PERG adaptation of amplitude in MSON was significantly lower than that in MSNON (P = 0.039) and HC (P = 0.037). Both the amplitude and latency in the MS eyes were significantly correlated with the thicknesses of the macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL). CONCLUSIONS: Shortened PERG latency and impaired autoregulatory dynamics occurred in MS, suggesting preferential dysfunction of small, slower RGC axons and decreased ability of RGC to autoregulate their gain in response to PERG stimulus. The established relations of PERG measurements with intraretinal thickness measurements suggested that PERG losses were primarily associated with GCIPL and mRNFL thinning.

Utilization of Visual Acuity Retroilluminated Charts for the Assessment of Afferent Visual System Dysfunction in a Pediatric Neuroimmunology Population.

BACKGROUND: Visual acuity has been a significant outcome measure in clinical trials for patients suffering from neuro-ophthalmological diseases and multiple sclerosis; however, there are limited data on the comparison of various testing strategies in pediatric patients with these disorders. Clinical trials using vision as an outcome could include a variety of tools to assess the acuity, including 2-m and 4-m standardized retroilluminated charts. METHODS: We investigated the difference in Early Treatment Diabetic Retinopathy Study (ETDRS) scores obtained using 2-m and 4-m charts, as well as the impact of optic neuritis, use of vision correction, age, and gender on visual acuity data from 71 patients with pediatric neuroimmunological conditions in a cross-sectional study. RESULTS: We determine that the ETDRS letter scores obtained using 4-m charts are on average 3.43 points less (P = 0.0034) when testing monocular ETDRS letter scores and on average 4.14 points less (P = 0.0008) when testing binocular ETDRS letter scores, relative to that obtained using the 2-m charts. However, we find that when performing monocular testing, optic neuritis in the eye being tested did not result in a statistically significant difference between 2-m and 4-m ETDRS letter scores. CONCLUSIONS: Although visual acuity charts are formatted by the distance, there are significant differences in the number of letters correctly identified between 2-m and 4-m charts. Although the differences may not impact the clinical acuity, research protocols should consider these differences before collapsing data across disparate studies.

The Course of Visual Recovery after Optic Neuritis: Experience of the Optic Neuritis Treatment Trial.

PURPOSE: To define the time course of visual recovery after optic neuritis and factors predictive of this course in the patients enrolled in the Optic Neuritis Treatment Trial. METHODS: The cohort for this study consisted of the 438 patients who completed the 6-month follow-up visit. Visual acuity was measured at baseline and at seven follow-up visits during the first 6 months. Factors predictive of recovery were evaluated with univariate and multivariate statistical tests. RESULTS: Visual recovery was rapid in all three treatment groups. In almost all patients, regardless of treatment group and initial severity of visual loss, improvement began within the first month. Among the 278 patients with baseline visual acuity of 20/ 50 or worse, all patients improved at least one line of visual acuity, and all except six improved at least three lines, during the 6-month follow-up period. Baseline visual acuity was the best predictor of the 6-month visual acuity outcome (P = 0.0001). Older age was statistically associated with a slightly worse outcome (P = 0.02), but this appeared to be of no clinical importance. CONCLUSIONS: In most patients with optic neuritis, visual recovery is rapid. The only factor of value in predicting the visual outcome is initial severity of visual loss. However, even when initial loss is severe, visual recovery is still good in most patients. Patients not following the usual course of visual recovery should be considered atypical. For such patients, further investigation in regard to etiology of the visual loss may be appropriate.

The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.

OBJECTIVES: The aim of this study was to assess the Dutch nationwide incidence of myelin oligodendrocyte glycoprotein (MOG)-IgG-associated acquired demyelinating syndromes (ADS) and to describe the clinical and serological characteristics of these patients. METHODS: All serum samples for routine diagnostics from February 2014 to December 2017 were sent to the single central reference laboratory for the full-length MOG-IgG cell-based assay (CBA) in the Netherlands. Clinical data from patients known in our National ADS centre were available. RESULTS: A total of 1414 samples of 1277 patients were received; of these, 92 patients (7%) were MOG-IgG-seropositive. The mean incidence was 0.16/100,000 people, with higher seropositivity in children (0.31/100,000) than in adults (0.13/100,000). In MOG-IgG-positive patients at the National ADS centre (61/92, 66%), the most common presenting phenotype is acute disseminated encephalomyelitis (ADEM, 56%) in children and optic neuritis (ON, 44%) in adults. Relapsing disease occurred in 9/34 (26%) children and 11/27 (41%) adults during median follow-up of 27.5 months. Patients were tested MOG-IgG-positive >200 months after the initial attack, suggesting an extended time to first relapse (TTFR). Longitudinal analysis of MOG-IgG (25/61, 41%) showed that 67% of the monophasic patients remain seropositive and 60% in relapsing patients. Majority of seronegative patients had no relapses (89%). CONCLUSION: This nationwide study shows that the overall incidence of MOG-IgG-seropositive disorders is 0.16 per 100,000 people. The distribution over the clinical phenotypes differs between adults and children. Seropositivity can be maintained over years even without clinical activity, while seronegative patients generally had no relapses.

Optical coherence tomography: a window to the optic nerve in clinically isolated syndrome.

In this study, we aimed to evaluate the association of asymptomatic optic nerve demyelinating lesion in patients presenting a clinically isolated syndrome with the asymptomatic retinal neuro-axonal loss previously reported at clinically isolated syndrome. We prospectively recruited 66 patients presenting a clinically isolated syndrome and 66 healthy control subjects matched according to age and gender. All patients underwent brain magnetic resonance imaging including 3D-double inversion recovery (DIR) sequence, optical coherence tomography examination and visual function evaluation, at 2.5-4.5 months after CIS. Evaluation criteria were presence and length of optic nerve DIR hypersignal, retinal layers (including ganglion cell inner plexiform layer and inner nuclear layer) thickness/volume, and low contrast monocular vision acuity (number of letters correctly identified). All clinically isolated syndrome eyes with past history of optic neuritis (CIS-ON) presented an optic nerve DIR hypersignal. We observed asymptomatic optic nerve DIR hypersignal in 22.2% of clinically isolated syndrome eyes without optic neuritis (CIS-NON). In comparison with healthy control, GCIPL volume (in mm3) was significantly lower in CIS-ON eyes [ß (95% confidence interval, CI) = -0.121 (-0.168 to -0.074); P < 0.0001], and to a lesser extent in CIS-NON [ß (95% CI) = -0.023 (-0.039 to -0.008); P = 0.004]. In comparison to healthy controls, eyes with asymptomatic optic nerve DIR hypersignal presented significantly lower macular ganglion cell inner plexiform layer volume [ß (95% CI) = -0.043 (-0.068 to -0.019); P = 0.001], and eyes without did not [ß (95% CI) = -0.016 (-0.034 to 0.003); P = 0.083]. Among CIS-NON, macular ganglion cell inner plexiform layer volume decrease was associated with asymptomatic optic nerve DIR hypersignal independently of optic radiations T2 lesions and primary visual cortex volumes (P = 0.012). Symptomatic optic nerve DIR hypersignal were significantly longer (13.8 ± 6.7 mm) than asymptomatic optic nerve hypersignal (10.0 ± 5.5 mm; P = 0.047). Length of optic nerve DIR hypersignal was significantly associated with thinner inner retinal layers (P ≤ 0.001), thicker inner nuclear layer (P = 0.017) and lower low contrast monocular vision acuity (P < 0.05). Compared to healthy control, low contrast monocular vision acuity was significantly lower in CIS-ON eyes (P < 0.0001) and CIS-NON eyes with (P = 0.03) or without asymptomatic optic nerve DIR hypersignal (P = 0.0005). Asymptomatic demyelinating optic nerve DIR hypersignal at the earliest clinical stage of multiple sclerosis is frequent and associated with asymptomatic retinal neuro-axonal loss reported at clinically isolated syndrome stage. Length of optic nerve DIR hypersignal is a biomarker of retinal neuro-axonal loss and visual disability at clinically isolated syndrome stage. Visual disability of clinically isolated syndrome eyes without clinical and subclinical optic nerve involvement might be due to missed optic nerve lesions on MRI. At the earliest clinical stage of multiple sclerosis, our results support considering optical coherence tomography as a window to the optic nerve rather than to the brain.

Functional-structural assessment of the optic pathways in patients with optic neuritis.

BACKGROUND: The pattern-reversal visual evoked potential (pVEP) is widely used for the diagnosis of Optic Neuritis (ON), but this method has some limitations. The aim of this study was to examine the added value of multifocal visual evoked potentials (mfVEP) and spectral-domain optical coherence tomography (SD-OCT) in the diagnosis of ON in patients that exhibit a normal pVEP. METHOD: Thirty-three patients with a history of having ON and 30 sex- and age-matched healthy controls (HC) were investigated. We included patients who were suspected of having a first-time ON and in whom pVEP showed normal results. Both eyes of the patients and HC were systematically investigated with SD-OCT, visual acuity, pVEP and mfVEP. The ON-affected eyes of the patients were compared with only one randomly selected eye per person in the HC group. The fellow "non-affected" eye of patients was held as a separate group. Statistical analyses were performed (including t test, Spearman's rank-order correlation test) using SPSS Statistics, Version 24.0. RESULTS: A significant difference was found in OCT mean retinal nerve fibre layer thickness (RNFLt) between patients and HC (p = 0.013) (i.e. 84.24 (± 17.00) µm versus 93.48(± 6.44) µm). An association was detected in patients between mean inter-eye asymmetry of the RNFLt and global (averaged) mfVEP amplitude (r = 0.565, p = 0.002). When analysing mfVEP signals from sectors in the upper hemifield, a significant difference was found in mean mfVEP amplitude between patients and HC (p = 0.005). CONCLUSIONS: Abnormality is potentially measurable (via reduced RNFLt and focal analyses with mfVEP amplitude) in patients suspected of having a first episode of ON where pVEP reports no abnormality. The mfVEP and SD-OCT may together be of value as supplementary tools in diagnosing ON in this patient group.

Chromatic visual evoked potentials indicate early dysfunction of color processing in young patients with demyelinating disease.

PURPOSE: Chromatic visual evoked potentials (cVEP) primarily reflect the parvocellular visual pathway function, which has been shown to be predominantly affected in demyelinating disease (DD). The purpose of this study was to evaluate cVEP responses and to compare them with other structural and functional findings in young patients with DD. METHODS: Thirty patients (8-28 years of age) with DD with or without a history of optic neuritis (ON) were investigated. Twenty-five eyes had at least one episode of ON (ON-group) and 35 eyes had no clinically evident episode of ON (nON-group). OCT imaging was performed using a high-resolution spectral-domain OCT (SD-OCT), measuring retinal nerve fiber layer (RNFL) thickness. Pattern reversal electroretinography (PERG) and visual evoked potentials (VEP) were recorded according to the ISCEV standard, and chromatic visual evoked potentials (cVEP) were recorded to isoluminant red-green (R-G) and blue-yellow (B-Y) 7° circle stimuli, composed of horizontal sinusoidal gratings with spatial frequency 2 cycles/°, 90% chromatic contrast and onset-offset (300:700 ms) mode of stimulation. Structural and functional measures were analyzed and compared between the groups. RESULTS: Both general (G) and temporal (T) RNFL thicknesses were reduced below normal limits in most of the eyes. However, in the ON-group (G: 77.5 ± 20.6, T: 51.4 ± 23.4 µm), the thinning was more significant (p < 0.001) than in the nON-group (G: 95.4 ± 12.1, T: 70.1 ± 11.5 µm). PERG N95 was within normal limits in the nON-group, while it was significantly more affected in the ON-group (7.4 ± 1.0 vs. 5.1 ± 2.0 µV; p < 0.0001). Similarly, also VEP P100 latency and amplitude showed a greater percentage of abnormality in the ON-group, the latency being longer (117.2 ± 16.9 vs. 99.4 ± 4.6 ms; p < 0.0001) and the amplitude lower (9.1 ± 5.1 vs. 16.4 ± 7.5 µV; p < 0.0001). The cVEP N-wave amplitude to R-G and B-Y stimuli was reduced below normal limits in both ON- and nON-groups; however, cVEP to B-Y stimulation were slightly more affected in the ON-group (4.0 ± 3.8 vs. 5.9 ± 3.3 µm; p = 0.02). A positive correlation between cVEP amplitude and RNFL thickness and between cVEP amplitude and PERG N95 amplitude, as well as a strong negative correlation between cVEP amplitude and P100 latency was observed. CONCLUSIONS: These findings demonstrate that cVEP indicate early abnormality of parvocellular pathway function in eyes with or without a history of optic neuritis and can be used together with other structural and functional parameters to evaluate visual pathway integrity of young patients with DD.

Optic neuritis induced by 5-fluorouracil chemotherapy: Case report and review of the literature.

Introduction: For over 50 years, 5-Fluorouracil has played a critical role in the treatment of numerous malignancies, including colorectal cancer. Ocular side effects are uncommon and include blurred vision, conjunctivitis, excessive lacrimation and keratitis. Case report: We report a 57-year-old male with metastatic colorectal cancer who had received extensive chemotherapy with 5-Fluorouracil-based regimens for over 12 months. Following his seventh cycle of cetuximab/FOLFIRI, he developed acute onset global headache, nausea and loss of vision in the right eye. After detailed investigations, including ophthalmologic and neurologic consultations, a diagnosis of optic neuritis was made. Management and outcome: Chemotherapy was ceased immediately, and intravenous methylprednisolone (1 g) daily for five days was commenced. His headache resolved and vision started to improve within 24 h. Three weeks after completion of corticosteroids, constriction of the right visual field had fully resolved. Discussion: Atypical optic neuritis is an inflammatory optic neuropathy that can be caused by ischaemia, mechanical compression, nutritional deficiency, toxins and drugs. Drug-induced optic neuritis, while rare, is associated with cytotoxic medications including methotrexate, cisplatin, carboplatin, vincristine and paclitaxel. There have only been five previous case reports implicating 5-Fluorouracil in the development of optic neuropathy. The likelihood of the adverse drug reaction due to 5-Fluorouracil was assessed using the Naranjo algorithm. A score of +7 indicates probable causality. Clinicians should be alert to this potential ocular toxicity in order to initiate prompt cessation of treatment and early ophthalmology referral to prevent visual loss and damage to ocular structures.

Dimethyl fumarate mitigates optic neuritis.

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; MOG35-55). 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.

Epidemiologic and Clinical Characteristics of Optic Neuritis in Japan.

PURPOSE: To elucidate the clinical and epidemiologic characteristics of optic neuritis in Japan. DESIGN: Multicenter cross-sectional, observational cohort study. PARTICIPANTS: A total of 531 cases of unilateral or bilateral noninfectious optic neuritis identified in 33 institutions nationwide in Japan. METHODS: Serum samples from patients with optic neuritis were tested for anti-aquaporin-4 antibodies (AQP4-Abs) and anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) using a cell-based assay and were correlated with the clinical findings. MAIN OUTCOME MEASURES: Antibody positivity, clinical and radiologic characteristics, and visual outcome. RESULTS: Among 531 cases of optic neuritis, 12% were AQP4-Ab positive, 10% were MOG-Ab positive, 77% were negative for both antibodies (double-negative), and 1 case was positive for both antibodies. Pretreatment visual acuity (VA) worsened to more than a median 1.0 logarithm of the minimum angle of resolution (logMAR) in all groups. After steroid pulse therapy (combined with plasmapheresis in 32% of patients in AQP4-Ab-positive group), median VA improved to 0.4 logMAR in the AQP4-Ab-positive group, 0 logMAR in the MOG-Ab-positive group, and 0.1 logMAR in the double-negative group. The AQP4-Ab-positive group showed a high proportion of females, exhibited diverse visual field abnormalities, and demonstrated concurrent spinal cord lesions on magnetic resonance imaging (MRI) in 22% of the patients. In the MOG-Ab-positive group, although posttreatment visual outcome was good, the rates of optic disc swelling and pain with eye movement were significantly higher than those in the AQP4-Ab-positive and double-negative groups. However, most cases showed isolated optic neuritis lesions on MRI. In the double-negative group, 4% of the patients had multiple sclerosis. Multivariate logistic regression analysis of all participants identified age and presence of antibodies (MOG-Ab and AQP4-Ab) as significant factors affecting visual outcome. CONCLUSIONS: The present large-scale cohort study revealed the clinicoepidemiologic features of noninfectious optic neuritis in Japan. Anti-aquaporin-4 antibody-positive optic neuritis has poor visual outcome. In contrast, MOG-Ab positive cases manifested severe clinical findings of optic neuritis before treatment, but few showed concurrent lesions in sites other than the optic nerve and generally showed good treatment response with favorable visual outcome. These findings indicate that autoantibody measurement is useful for prompt diagnosis and proper management of optic neuritis that tends to become refractory.

Differing Structural and Functional Patterns of Optic Nerve Damage in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder.

PURPOSE: To assess differential patterns of axonal loss and demyelination in the optic nerve in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). DESIGN: Cross-sectional study. PARTICIPANTS: One hundred ninety-two participants, including 136 MS patients (272 eyes), 19 NMOSD patients (38 eyes), and 37 healthy control participants (74 eyes). METHODS: All participants underwent spectral-domain OCT scans and multifocal visual evoked potential (mfVEP) recordings. High-resolution magnetic resonance imaging (MRI) with the diffusion protocol also was performed in all patients. MAIN OUTCOME MEASURES: Ganglion cell-inner plexiform layer (GCIPL) thickness and mfVEP amplitude and latency at 5 eccentricities; global and temporal retinal nerve fiber layer thickness. RESULTS: In optic neuritis (ON) eyes, the NMOSD patients had more severe GCIPL loss (P < 0.001) and mfVEP amplitude reduction (P < 0.001) compared with MS patients, whereas in contrast, mfVEP latency delay was more evident in MS patients (P < 0.001). The NMOSD patients showed more morphologic and functional loss at the foveal to parafoveal region, whereas the MS patients showed evenly distributed damage at the macula. Correlation analysis demonstrated a strong structure-function (OCT-mfVEP) association in the NMOSD patients, which was only moderate in the MS patients. In non-ON (NON) eyes, the MS patients showed significantly thinner GCIPL than controls (P < 0.001), whereas no GCIPL loss was observed in NON eyes in NMOSD. In addition, a significant correlation was found between all OCT and mfVEP measures in MS patients, but not in NMOSD patients. MRI demonstrated significant lesional load in the optic radiation in MS compared to NMOSD eyes (P = 0.002), which was related to the above OCT and mfVEP changes in NON eyes. CONCLUSIONS: Our study demonstrated different patterns of ON damage in NMOSD and MS. In MS, the ON damage was less severe, with demyelination as the main pathologic component, whereas in NMOSD, axonal loss was more severe compared with myelin loss. The disproportional mfVEP amplitude and latency changes suggested predominant axonal damage within the anterior visual pathway as the main clinical feature of NMOSD, in contrast to MS, where demyelination spreads along the entire visual pathway.

MOG antibody-associated encephalomyelitis/encephalitis.

Myelin oligodendrocyte glycoprotein (MOG) antibody disease is a rare autoimmune disorder with antibodies against the MOG predominantly involving the optic nerve and spinal cord leading to vision loss and paralysis. When MOG antibody disease involves the brain, the phenotype is similar to acute disseminated encephalomyelitis (ADEM). In this review, we discuss MOG-positive cases presenting with encephalitis, encephalopathy, or ADEM-like presentation based on recently published series.

Relationship between thiol-disulphide homeostasis and visual evoked potentials in patients with multiple sclerosis.

PURPOSE: To examine the thiol-disulphide homeostasis during an optic neuritis episode in patients with multiple sclerosis and the relationship between this homeostasis and P100 wave latency. MATERIALS AND METHOD: Visual evoked potential reviews of multiple sclerosis patients who presented with an optic neuritis episode were conducted and P100 latencies were measured. Peripheral blood samples were collected from all patients. Native thiol and total thiol concentrations were measured with the automated method that was recently developed. Their amount of disulphide bonds, disulphide/native thiol, disulphide/total thiol and native thiol/total thiol ratios were calculated. The relationship between P100 latency and thiol-disulphide homeostasis was investigated. RESULTS: A significant positive correlation was determined between the disulphide/native thiol ratio and both mean P100 latency and maximum P100 latency (p = 0.021, r = 0.136; p = 0.030, r = 0.177, respectively). DISCUSSION: As the balance of the plasma dominated by antioxidants moves towards the oxidant side, in other words as a higher rate of thiol is oxidised from the thiol pool, P100 latency is extended. N-acetylcysteine and alpha lipoic acid as well as thiol supplements can improve the thiol-disulphide balance, reinforce antioxidant defence and it can help in slowing down the demyelinating damage.

Incidence and timing of recurrence of optic neuritis.

PURPOSE: To describe the incidence and timing of recurrence in patients with optic neuritis (ON). METHODS: Medical documents of adult patients with ON were retrospectively reviewed. The incidence and timing of recurrence of an ON episode were analyzed. RESULTS: One hundred eleven patients with ON were included in this study. Their mean follow-up duration was 4.1 ± 3.1 years. Seven relapses occurred after intravenous methylprednisolone treatment. The estimated cumulative incidence of recurrence in either eye was 26% at 1 year, 33% at 3 years, 37% at 5 years, and 50% at 10 years after the first episode of ON. If there was no recurrence until 6 months after the first episode of ON, the next 5-year recurrence-free survival probability was 67%. If there was no recurrence until 1 year, the next 5-year survival probability was 72%. If there was no recurrence until 2 years, the next 5-year survival probability was 81%. Relapse within 1 month and the presence of neuromyelitis optica-immunoglobulin G were factors that increased the recurrence rate over time. CONCLUSIONS: We evaluated the incidence and timing of the recurrence in patients with ON after the first episode. Lower probability of recurrence was observed in patients with longer recurrence-free follow-up period. However, monitoring for recurrence is needed even in patients with a single episode of ON due to the increasing tendency of the estimated cumulative incidence of recurrence over many years.

Aquaporin-4 Serostatus and Visual Outcomes in Clinically Isolated Acute Optic Neuritis.

BACKGROUND: Aquaporin-4 antibodies (AQP4-Ab) are associated with neuromyelitis optica spectrum disorder (NMOSD) and typically this disorder has a poor visual prognosis as a result of optic neuritis (ON). Our aim was to report the clinical features at onset and final visual outcomes at 6 months of patients with ON who were positive for AQP4-Ab vs. those who were negative for AQP4-Ab. METHODS: Retrospective cohort study. AQP4-Ab were tested by indirect immunofluorescence in 57 patients with a first episode of ON. All patients initially were referred for consideration of multiple sclerosis ON (MSON), NMOSD, or any other inflammatory central nervous system disorder during follow-up (41.31 ± 24.32 months). Our patients were diagnosed as having NMOSD, MSON, chronic relapsing inflammatory ON, and single isolated ON. Risk factors associated with visual outcomes of ON patients were assessed through an ordinal regression model. RESULTS: Positive AQP4-Ab were associated with male sex (P = 0.02), earlier age of onset (P = 0.01), and myelitis relapses (P = 0.04). Seronegative group had fewer recurrences of ON than the seropositive group (35% vs 58%, P = 0.14). Patients that were positive for AQP4-Ab did not have worse visual acuity at baseline and after 6 months. However, poor visual acuity during first attack was associated with a worse visual acuity at 6 months (odds ratio = 2.28, 95% CI [1.58-3.28], P = 0.03). CONCLUSIONS: At 6 months, positive AQP4-Ab vs negative AQP4-Ab patients no evidence of poorer visual acuity. Lower visual acuity at baseline was associated with poor visual recovery at 6 months.

Unfavorable Structural and Functional Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis.

BACKGROUND: Recurrent optic neuritis (rON) associated with myelin oligodendrocyte glycoprotein (MOG)-specific antibodies has been initially reported to show a better clinical outcome than aquaporin-4 (AQP4)-seropositive ON in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterize clinical and neuroimaging findings in severe cases of MOG antibody-positive and AQP4 antibody-negative bilateral rON. METHODS: Three male adults with rON (ages 18, 44, and 63 years) were evaluated with optical coherence tomography (OCT), MRI, cerebrospinal fluid (CSF), and serological studies. RESULTS: All patients experienced >7 relapses of ON with severe reduction of visual acuity and partial response to steroid treatment. Optic nerves were affected bilaterally, although unilateral relapses were more frequent than simultaneous bilateral recurrences. Patients were MOG-seropositive but repeatedly tested negative for AQP4 antibodies. OCT showed severe thinning of the peripapillary retinal nerve fiber layer. On MRI, contrast-enhancing lesions extended over more than half the length of the optic nerve. CSF analyses during ON episodes were normal. Severe visual deficits accumulated over time in 2 of 3 patients, despite immunosuppressive therapy. CONCLUSIONS: MOG-seropositive and AQP4-seronegative rON may be associated with an aggressive disease course and poor functional and structural outcomes. In contrast to previous reports, the severity and pattern of retinal and optic nerve damage closely resembled phenotypes commonly observed in AQP4-seropositive rON without fulfilling current diagnostic criteria for NMOSD.