Assessing Sustained B-Cell Depletion and Disease Activity in a French Multiple Sclerosis Cohort Treated by Long-Term IV Anti-CD20 Antibody Therapy.

Few studies have investigated sustained B-cell depletion after long-term intravenous (IV) anti-CD20 B-cell depleting therapy (BCDT) in multiple sclerosis (MS) with respect to strict and/or minimal disease activity. The main objective of this study was to investigate how sustained B-cell depletion after BCDT influences clinical and radiological stability as defined by "no evidence of disease activity" (NEDA-3) and "minimal evidence of disease activity" (MEDA) status in MS patients at 12 and 18 months. Furthermore, we assessed the frequency of serious adverse events (SAE), and the influence of prior lymphocytopenia-inducing treatment (LIT) on lymphocyte subset counts and gammaglobulins in MS patients receiving long-term BCDT. We performed a retrospective, prospectively collected, study in a cohort of 192 MS patients of all clinical phenotypes treated by BCDT between January 2014 and September 2021. Overall, 84.2% and 96.9% of patients attained NEDA-3 and MEDA status at 18 months, respectively. Sustained CD19+ depletion was observed in 85.8% of patients at 18 months. No significant difference was observed when comparing patients achieving either NEDA-3 or MEDA at 18 months and sustained B-cell depletion. Compared to baseline levels, IgM and IgG levels on BCDT significantly decreased at 6 months and 30 months, respectively. Patients receiving LIT prior to BCDT showed significant CD4+ lymphocytopenia and lower IgG levels compared to non-LIT patients. Grade 3 or above SAEs were rare. As nearly all patients achieved MEDA at 18 months, we suggest tailoring IV BCDT after 18 months given the occurrence of lymphocytopenia, hypogammaglobulinemia, and SAE after this time point.

Giant cell arteritis-related cerebrovascular ischemic events: a French retrospective study of 271 patients, systematic review of the literature and meta-analysis.

BACKGROUND: Cerebrovascular ischemic events (CIE) are among the most severe complications of giant cell arteritis (GCA). Heterogeneity between different studies in the definition of GCA-related CIE leads to uncertainty regarding their real prevalence. The aim of our study was to evaluate the prevalence and describe the characteristics of GCA-related CIE in a well-phenotyped cohort completed by a meta-analysis of the existing literature. METHODS: In this retrospective study performed in the Lille University Hospital, all consecutive patients with GCA according to American College of Rheumatology (ACR) diagnostic criteria were included from January 1, 2010, to December 31, 2020. A systematic review of the literature using MEDLINE and EMBASE was performed. Cohort studies of unselected GCA patients reporting CIE were included in the meta-analysis. We calculated the pooled summary estimate of GCA-related CIE prevalence. RESULTS: A total of 271 GCA patients (89 males, mean age 72 ± 9 years) were included in the study. Among them, 14 (5.2%) presented with GCA-related CIE including 8 in the vertebrobasilar territory, 5 in the carotid territory, and 1 patient having multifocal ischemic and hemorrhagic strokes related to intra-cranial vasculitis. Fourteen studies were included in the meta-analysis, representing a total population of 3553 patients. The pooled prevalence of GCA-related CIE was 4% (95% CI 3-6, I2 = 68%). Lower body mass index (BMI), vertebral artery thrombosis on Doppler US (17% vs 0.8%, p = 0.012), vertebral arteries involvement (50% vs 3.4%, p < 0.001) and intracranial arteries involvement (50% vs 1.8%, p < 0.001) on computed tomography angiography (CTA) and/or magnetic resonance angiography (MRA), and axillary arteries involvement on positron emission computed tomography (PET/CT) (55% vs 20%, p = 0.016) were more frequent in GCA patients with CIE in our population. CONCLUSIONS: The pooled prevalence of GCA-related CIE was 4%. Our cohort identified an association between GCA-related CIE, lower BMI, and vertebral, intracranial, and axillary arteries involvement on various imaging modalities.

Relation between retina, cognition and brain volumes in MS: a consequence of asymptomatic optic nerve lesions.

INTRODUCTION: Asymptomatic optic nerve lesions are frequent in multiple sclerosis (MS) and their impact on cognition and/or brain volume has never been taken into account. PATIENTS AND METHODS: We used the data from the cross-sectional Visual Ways in MS (VWIMS) study including relapsing remitting MS. All patients underwent brain and optic nerve Magnetic Resonance Imaging (MRI) including Double Inversion Recuperation (DIR) sequence, retinal OCT, and cognitive evaluation with the Brief International Cognitive Assessment in MS (BICAMS). We measured the association between OCT findings (thickness/volume of retinal layers) and extra-visual parameters (cerebral volumes and BICAMS scores) in optic nerves with and/or without the presence of DIR asymptomatic optic nerve hypersignal. RESULTS: Between March and December 2017, we included 98 patients. Two patients were excluded. Over the 192 eyes, 73 had at least one clinical history of optic neuritis (ON-eyes) whereas 119 were asymptomatic (NON-eyes). Among the 119 NON-eyes, 58 had 3D-DIR optic nerve hypersignal (48.7%). We confirmed significant associations between some retinal OCT measures and some extra-visual parameters (cerebral volumes, cognitive scores) in NON-eyes. Unexpectedly, these associations were found when an asymptomatic optic nerve DIR-hypersignal was present on MRI, but not when it was absent. CONCLUSION: Our study showed a relation between OCT measures and extra-visual parameters in NON-eyes MS patients. As a confusion factor, asymptomatic optic nerve lesions may be the explanation of the relation between OCT measures and extra-visual parameters. Retinal OCT seems to be far more a "window over the optic nerve" than a "window over the brain".

Longitudinal Retinal Changes in MOGAD.

OBJECTIVE: Patients with myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro-axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON-independent retinal atrophy can be detected in MOGAD. METHODS: Eighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high-definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified. RESULTS: At baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD-ON) compared with MOGAD eyes without a history of ON (MOGAD-NON) and HCs (p < 0.001). MOGAD-NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow-up up to 3 years), MOGAD-ON with ON within the last 6-12 months before baseline exhibited greater pRNFL thinning than MOGAD-ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort. INTERPRETATION: Our study suggests the absence of attack-independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD. ANN NEUROL 2022;92:476-485.

Intrusive experiences in posttraumatic stress disorder: Treatment response induces changes in the directed functional connectivity of the anterior insula.

BACKGROUND: One of the core features of posttraumatic stress disorder (PTSD) is re-experiencing trauma. The anterior insula (AI) has been proposed to play a crucial role in these intrusive experiences. However, the dynamic function of the AI in re-experiencing trauma and its putative modulation by effective therapy need to be specified. METHODS: Thirty PTSD patients were enrolled and exposed to traumatic memory reactivation therapy. Resting-state functional magnetic resonance imaging (fMRI) scans were acquired before and after treatment. To explore AI-directed influences over the rest of the brain, we referred to a mixed model using pre-/posttreatment Granger causality analysis seeded on the AI as a within-subject factor and treatment response as a between-subject factor. To further identify correlates of re-experiencing trauma, we investigated how intrusive severity affected (i) causality maps and (ii) the spatial stability of other intrinsic brain networks. RESULTS: We observed changes in AI-directed functional connectivity patterns in PTSD patients. Many within- and between-network causal paths were found to be less influenced by the AI after effective therapy. Insular influences were found to be positively correlated with re-experiencing symptoms, while they were linked with a stronger default mode network (DMN) and more unstable central executive network (CEN) connectivity. CONCLUSION: We showed that directed changes in AI signaling to the DMN and CEN at rest may underlie the degree of re-experiencing symptoms in PTSD. A positive response to treatment further induced changes in network-to-network anticorrelated patterns. Such findings may guide targeted neuromodulation strategies in PTSD patients not suitably improved by conventional treatment.

Optic Nerve Lesion Length at the Acute Phase of Optic Neuritis Is Predictive of Retinal Neuronal Loss.

BACKGROUND AND OBJECTIVES: Acute optic neuritis (ON) is a classical presenting symptom of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and anti-MOG-associated disorders. The resulting visual impairment is variable and can be severe. Clinicians are in need of predictive biomarkers to optimize the management of acute ON. In this longitudinal study (IRMANO, NCT03651662), we evaluated the ability of optic nerve lesion length measured on MRI at the acute phase of ON to predict retinal neuro-axonal loss and visual impairment at a chronic stage. METHODS: We conducted a longitudinal study (IRMANO, NCT03651662) of patients who presented a clinical episode of ON (≤8 weeks). All patients underwent a retinal optical coherence tomography (OCT) and a brain/optic nerve MRI, including 3D double-inversion recovery (DIR) sequence at the acute phase of ON and 12 months later. Primary outcomes were optic nerve DIR hypersignal lesion length, macular ganglion cell-inner plexiform layer (GCIPL) volume measured on OCT, and low-contrast monocular visual acuity (LCMVA). RESULTS: The study group included 51 patients (33 women, mean age of 32.4 years ± 7.9). We recruited patients with a clinically isolated syndrome (n = 20), a relapsing-remitting MS (n = 23), an isolated ON (n = 6), and a first clinical episode of NMOSD (n = 2). Optic nerve DIR hypersignal was observed in all but 1 symptomatic optic nerves. At inclusion, the mean optic nerve lesion length (in mm) was 12.35 ± 5.98. The mean GCIPL volume (in mm3) significantly decreased between inclusion (1.90 ± 0.18) and M12 (1.67 ± 0.21; p < 0.0001). Optic nerve lesion length at inclusion was significantly associated with GCIPL thinning (estimate ± SD; -0.012 ± 0.004; p = 0.0016) and LCMVA at M12 (0.016 ± 0.003; p < 0.001). Optic nerve lesion length significantly increased at M12 (15.76 ± 8.70; p = 0.0007). The increase in optic nerve lesion length was significantly associated with the GCIPL thinning between inclusion and M12 (-0.012 ± 0.003; p = 0.0011). DISCUSSION: At the acute phase of ON, optic nerve lesion length is an imaging biomarker predictive of retinal neuro-axonal loss and chronic visual impairment, which can help to stratify future therapeutic strategies in acute ON. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that optic nerve lesion length measured on MRI during the acute phase of a first episode of ON is associated with long-term retinal neuro-axonal loss and visual impairment.

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

OBJECTIVE: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.

Patterns of use, effectiveness and safety of gadolinium contrast agents: a European prospective cross-sectional multicentre observational study.

BACKGROUND: The EU gadolinium-based contrast agents (GBCA) market has changed in recent years due to the European Medicines Agency decision to suspend the marketing authorisation of linear GBCA and the marketing authorisation of new generic macrocyclic GBCA. The study aims to understand the patterns of (GBCA) use, and to study the effectiveness and safety of GBCA in routine practice across Europe. METHODS: Prospective, cross-sectional, multicentre, observational study in patients undergoing contrast-enhanced magnetic resonance. Reported usage patterns included indication, referral and examination details. Assessment of effectiveness included changes in radiological diagnosis, diagnostic confidence and image quality. Safety data were collected by spontaneous patient adverse event (AE) reporting. RESULTS: 2118 patients were included from 8 centres across 5 European countries between December 2018 and November 2019. Clariscan, Dotarem (gadoteric acid), Gadovist (gadobutrol) and ProHance (gadoteridol) were utilised in 1513 (71.4%), 356 (16.8%), 237 (11.2%) and 12 (0.6%) patients, respectively. Most were performed in CNS-related indications (46.2%). Mean GBCA doses were 0.10 mmol/kg body weight, except for Gadovist (mean 0.12 mmol/kg). GBCA use increased confidence in diagnosis in 96.2% of examinations and resulted in a change in radiological diagnosis in 73.9% of patients. Image quality was considered excellent or good in 96.1% of patients and across all GBCA. Four patients reported AEs (0.19%), with only 1 (0.05%) considered serious. CONCLUSIONS: This European study confirmed that GBCAs are used appropriately in Europe for a wide range of indications. The study demonstrated a significant increase in diagnostic confidence after GBCA use and confirmed the good safety profile of GBCAs, with comparable results for all agents used.

Long-term effect of natalizumab in patients with RRMS: TYSTEN cohort.

BACKGROUND: Data are needed on long-term effect of natalizumab (NTZ) in relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To evaluate the time of onset of secondary progressive phase in patients with an RRMS treated with NTZ and to investigate predictive factors. METHODS: TYSTEN is an observational study. Patients starting NTZ between 2007 and 2012 were included and followed up until October 2018. Relapses, Expanded Disability Status Scale (EDSS) scores, and results of brain magnetic resonance imaging (MRI) were collected each year. Data were used to estimate the cumulative probability of several poor outcomes such as secondary progressive multiple sclerosis (SPMS) conversion, EDSS worsening, EDSS 4.0, and EDSS 6.0. RESULTS: 770 patients were included. The mean follow-up duration was 97 months and the mean time exposure to NTZ was 66 months. At 10 years, the cumulative probability of SPMS was 27.7%. Predictive factors for poor outcomes were a ⩾1-point increase in EDSS score from baseline, new T2 lesion or T1 gadolinium-enhancing lesion, the occurrence of relapse at 1 or 2 years and No Evidence of Disease Activity (NEDA-3; no relapse, no new T2 or T1 gadolinium-enhancing lesions, no progression) was a protective factor. CONCLUSION: In our cohort of patients treated with NTZ, poor outcomes were infrequent and are driven by disease activity.

Optical coherence tomography for detection of asymptomatic optic nerve lesions in clinically isolated syndrome.

OBJECTIVE: To evaluate the ability of intereye retinal thickness difference (IETD) measured by optical coherence tomography (OCT) to detect asymptomatic optic nerve involvement in clinically isolated syndrome (CIS). METHODS: We conducted a cross-sectional study of patients who recently presented a CIS (≤4.5 months). All patients underwent OCT and brain/optic nerve MRI. Optic nerve involvement was defined clinically (episode of optic neuritis [ON] or not) and radiologically (optic nerve hypersignal on 3D double inversion recovery [3D-DIR]). We evaluated the sensitivity and specificity of previously published IETD thresholds and report the observed optimal thresholds for identifying symptomatic optic nerve involvement but also for identifying asymptomatic optic nerve involvement (optic nerve hypersignal without ON history). Primary outcomes were ganglion cell-inner plexiform layer (GC-IPL) and peripapillary retinal nerve fiber layer IETD. RESULTS: The study group consisted of 130 patients. In the CIS with ON group, 3D-DIR showed a hypersignal in all 41 symptomatic optic nerves and in 11 asymptomatic optic nerves. In the CIS without ON group, 3D-DIR showed a unilateral optic nerve hypersignal in 22 patients and a bilateral optic nerve hypersignal in 7 patients. For the detection of symptomatic and asymptomatic optic nerve lesion, GC-IPL IETD had better performance. We found an optimal GC-IPL IETD threshold ≥2.83 µm (sensitivity 88.2, specificity 83.3%) for the detection of symptomatic lesions and an optimal GC-IPL IETD ≥1.42 µm (sensitivity 89.3%, specificity 72.6%) for the detection of asymptomatic lesions. CONCLUSIONS: Detection of asymptomatic optic nerve lesions in CIS requires lower IETD thresholds than previously reported. GC-IPL IETD represents an alternative biomarker to MRI for the detection of asymptomatic optic nerve lesions. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that OCT accurately identifies asymptomatic optic nerve involvement in patients with CIS.

Asymptomatic optic nerve lesions: An underestimated cause of silent retinal atrophy in MS.

OBJECTIVE: To evaluate the frequency of asymptomatic optic nerve lesions and their role in the asymptomatic retinal neuroaxonal loss observed in multiple sclerosis (MS). METHODS: We included patients with remitting-relapsing MS in the VWIMS study (Analysis of Neurodegenerative Process Within Visual Ways In Multiple Sclerosis) (ClinicalTrials.gov Identifier: 03656055). Included patients underwent optical coherence tomography (OCT), optic nerve and brain MRI, and low-contrast visual acuity measurement. In eyes of patients with MS without optic neuritis (MS-NON), an optic nerve lesion on MRI (3D double inversion recovery [DIR] sequence) was considered as an asymptomatic lesion. We considered the following OCT/MRI measures: peripapillary retinal nerve fiber layer thickness, macular ganglion cell + inner plexiform layer (mGCIPL) volumes, optic nerve lesion length, T2 lesion burden, and fractional anisotropy within optic radiations. RESULTS: An optic nerve lesion was detected in half of MS-NON eyes. Compared to optic nerves without any lesion and independently of the optic radiation lesions, the asymptomatic lesions were associated with thinner inner retinal layers (p < 0.0001) and a lower contrast visual acuity (p ≤ 0.003). Within eyes with asymptomatic optic nerve lesions, optic nerve lesion length was the only MRI measure significantly associated with retinal neuroaxonal loss (p < 0.03). Intereye mGCIPL thickness difference (IETD) was lower in patients with bilateral optic nerve DIR hypersignal compared to patients with unilateral hypersignal (p = 0.0317). For the diagnosis of history of optic neuritis, sensitivity of 3D DIR and of mGCIPL IETD were 84.9% and 63.5%, respectively. CONCLUSIONS: Asymptomatic optic nerve lesions are an underestimated and preponderant cause of retinal neuroaxonal loss in MS. 3D DIR sequence may be more sensitive than IETD measured by OCT for the detection of optic nerve lesions.

A Fully Automatic Method for Optic Radiation Tractography Applicable to Multiple Sclerosis Patients.

The optic radiations (OR) are white matter tracts forming the posterior part of the visual ways. As an important inter-individual variability exists, atlases may be inefficient to locate the OR in a given subject. We designed a fully automatic method to delimitate the OR on a magnetic resonance imaging using tractography. On 15 healthy subjects, we evaluated the validity of our method by comparing the outputs to the Jülich post-mortem histological atlas, and its reproducibility. We also evaluated its feasibility on 98 multiple sclerosis (MS) patients. We correlated different visual outcomes with the inflammatory lesions volume within the OR reconstructed with different methods (our method, atlas, TractSeg). Our method reconstructed the OR bundle in all healthy subjects (< 2 h for most of them), and was reproducible. It demonstrated good classification indexes: sensitivity up to 0.996, specificity up to 0.993, Dice coefficient up to 0.842, and an area under the receiver operating characteristic (ROC) curve of 0.981. Our method reconstructed the OR in 91 of the 98 MS patients (92.9%, < 6 h for most of patients). Compared to an atlas-based approach and the TractSeg method, the inflammatory lesions volume in the OR measured with our method better correlated with the visual cortex volume, visual acuity and mean peripapillar retinal nerve fiber layer thickness. Our method seems to be efficient to reconstruct the OR in healthy subjects, and seems applicable to MS patients. It may be more relevant than an atlas based approach.

Evaluation of efficacy and tolerability of first-line therapies in NMOSD.

OBJECTIVE: To compare the efficacy and the risk of severe infectious events of immunosuppressive agents used early as first-line therapy in patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: We retrospectively included patients with NMOSD and a seropositive status for aquaporin 4 or myelin oligodendrocyte glycoprotein antibodies beginning first-line immunosuppressants within 3 years after the disease onset. The main outcome was occurrence of relapse after the initiation of immunosuppressants; the secondary outcome was the annual relapse rate (AAR). RESULTS: A total of 136 patients were included: 62 (45.6%) were treated with rituximab (RTX), 42 (30.9%) with mycophenolate mofetil (MMF), and 23 (16.9%) with azathioprine (AZA). Compared with RTX-treated patients, the risk of relapse was higher among MMF-treated patients (hazard ratio [HR], 2.74 [1.17-6.40]; p = 0.020) after adjusting for age at disease onset, sex, antibody status, disease duration, ARR before treatment, corticosteroid intake, and relapse location. We did not observe any difference between RTX-treated and AZA-treated patients (HR, 2.13 [0.72-6.28]; p = 0.17). No interaction was found between the antibody status and immunosuppressive treatments. ARR was lower with RTX than with MMF (p = 0.039), but no difference was observed with AZA. We observed 9 serious infectious events with MMF, 6 with RTX, and none with AZA. CONCLUSIONS: The use of first-line RTX in NMOSD appears more effective than MMF in suppressing clinical activity, independent of the antibody status. CLASSIFICATION OF EVIDENCE: That study provides Class III evidence that for patients with NMOSD, first-line RTX is superior to MMF to reduce the risk of relapse.

Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study.

BACKGROUND: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. OBJECTIVE: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS.Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. RESULTS: There was a significant increase in INL volume in eyes with new MSON during the study (N = 61/1562, ß = 0.01 mm3, p < .001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (ß = 0.005, p = .025). INL volume was independent of disease progression (ß = 0.002 mm3, p = .474). CONCLUSION: Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials.

Optical coherence tomography in myelin-oligodendrocyte-glycoprotein antibody-seropositive patients: a longitudinal study.

BACKGROUND: Serum antibodies against myelin-oligodendrocyte-glycoprotein (MOG-IgG) are detectable in a proportion of patients with acute or relapsing neuroinflammation. It is unclear, if neuro-axonal damage occurs only in an attack-dependent manner or also progressively. Therefore, this study aimed to investigate longitudinally intra-retinal layer changes in eyes without new optic neuritis (ON) in MOG-IgG-seropositive patients. METHODS: We included 38 eyes of 24 patients without ON during follow-up (F/U) [median years (IQR)] 1.9 (1.0-2.2) and 56 eyes of 28 age- and sex-matched healthy controls (HC). The patient group's eyes included 18 eyes without (EyeON-) and 20 eyes with history of ON (EyeON+). Using spectral domain optical coherence tomography (OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIP), inner nuclear layer (INL), and macular volume (MV). High-contrast visual acuity (VA) was assessed at baseline. RESULTS: At baseline in EyeON-, pRNFL (94.3 ± 15.9 µm, p = 0.36), INL (0.26 ± 0.03 mm3, p = 0.11), and MV (2.34 ± 0.11 mm3, p = 0.29) were not reduced compared to HC; GCIP showed thinning (0.57 ± 0.07 mm3; p = 0.008), and VA was reduced (logMAR 0.05 ± 0.15 vs. - 0.09 ± 0.14, p = 0.008) in comparison to HC. Longitudinally, we observed pRNFL thinning in models including all patient eyes (annual reduction - 2.20 ± 4.29 µm vs. - 0.35 ± 1.17 µm, p = 0.009) in comparison to HC. Twelve EyeON- with other than ipsilateral ON attacks ≤ 6 months before baseline showed thicker pRNFL at baseline and more severe pRNFL thinning in comparison to 6 EyeON- without other clinical relapses. CONCLUSIONS: We observed pRNFL thinning in patients with MOG-IgG during F/U, which was not accompanied by progressive GCIP reduction. This effect could be caused by a small number of EyeON- with other than ipsilateral ON attacks within 6 months before baseline. One possible interpretation could be a reduction of the swelling, which could mean that MOG-IgG patients show immune-related swelling in the CNS also outside of an attack's target area.

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.