High diagnostic accuracy of T2FLAIR at 3 T in the detection of optic nerve head edema in acute optic neuritis.

OBJECTIVES: Optic nerve head edema (ONHE) detected by fundoscopy is observed in one-third of patients presenting optic neuritis (ON). While ONHE is an important semiological feature, the correlation between ONHE and optic nerve head MRI abnormalities (ONHMA), sometimes called "optic nerve head swelling," remains unknown. Our study aimed to assess the diagnostic accuracy of T2 fluid-attenuated inversion recovery (FLAIR) MRI sequence in detecting ONHE in patients with acute ON. METHODS: In the present single-center study, data were extracted from two prospective cohort studies that consecutively included adults with a first episode of acute ON treated between 2015 and 2020. Two experienced readers blinded to study data independently analyzed imaging. A senior neuroradiologist resolved any discrepancies. The primary judgment criterion of ONHMA was assessed as optic nerve head high signal intensity on gadolinium-enhanced T2FLAIR MRI sequence. Its diagnostic accuracy was evaluated with both the gold standard of ONHE on fundus photography (FP) and peripapillary retinal nerve fiber layer thickening on optic coherence tomography (OCT). RESULTS: A total of 102 patients were included, providing 110 affected and 94 unaffected optic nerves. Agreement was high between the different modalities: 92% between MRI and FP (k = 0.77, 95% CI: 0.67-0.88) and 93% between MRI and OCT (k = 0.77, 95% CI: 0.67-0.87). MRI sensitivity was 0.84 (95% CI: 0.70-0.93) and specificity was 0.94 (95% CI: 0.89-0.97) when compared with the FP. CONCLUSION: Optic nerve head high T2FLAIR signal intensity corresponds indeed to the optic nerve head edema diagnosed by the ophthalmologists. MRI is a sensitive tool for detecting ONHE in patients presenting acute ON. CLINICAL RELEVANCE STATEMENT: In patients with optic neuritis the high T2FLAIR (fluid-attenuated inversion recovery) signal intensity of the optic nerve head corresponds indeed to optic nerve head edema, which is a useful feature in optic neuritis etiological evaluation and treatment. KEY POINTS: Optic nerve head edema is a prominent clinical feature of acute optic neuritis and is usually diagnosed during dilated or non-dilated eye fundus examination. Agreement was high between magnetic resonance imaging, fundus photography, and optical coherence tomography. Optic nerve head high T2 fluid attenuation inversion recovery signal intensity is a promising detection tool for optic nerve head edema in patients presenting acute optic neuritis.

Acute optic neuritis: What are the clues to the aetiological diagnosis in real life?

BACKGROUND: Previous cross-sectional studies have reported distinct clinical and radiological features among the different acute optic neuritis (ON) aetiologies. Nevertheless, these reports often included the same number of patients in each group, not taking into account the disparity in frequencies of ON aetiologies in a real-life setting and thus, it remains unclear what are the truly useful features for distinguishing the different ON causes. To determine whether clinical evaluation, ophthalmological assessment including the optical coherence tomography (OCT), CSF analysis, and MRI imaging may help to discriminate the different causes of acute ON in a real-life cohort. METHODS: In this prospective monocentric study, adult patients with recent acute ON (<1 month) underwent evaluation at baseline and 1 and 12 months, including, high- and low-contrast visual acuity, visual field assessment and OCT measurements, baseline CSF analysis and MRI. RESULTS: Among 108 patients, 71 (65.7%) had multiple sclerosis (MS), 19 (17.6%) had idiopathic ON, 13 (12.0%) and 5 (4.6%) had myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies, at last follow up respectively.At baseline, the distribution of bilateral ON, CSF-restricted oligoclonal bands, optic perineuritis, optic nerve length lesions and positive dissemination in space and dissemination in time criteria on MRI were significantly different between the four groups (p <0.001). No significant difference in visual acuity nor inner retinal layer thickness was found between the different ON aetiologies. CONCLUSIONS: In this large prospective study, bilateral visual involvement, CSF and MRI results are the most useful clues in distinguishing the different aetiologies of acute ON, whereas ophthalmological assessments including OCT measurements revealed no significant difference between the aetiologies.

Rituximab De-escalation in Patients With Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Exit strategies such as de-escalations have not been evaluated for rituximab in patients with neuromyelitis optica spectrum disorder (NMOSD). We hypothesized that they are associated with disease reactivations and aimed to estimate this risk. METHODS: We describe a case series of real-world de-escalations from the French NMOSD registry (NOMADMUS). All patients met the 2015 International Panel for NMO Diagnosis (IPND) diagnostic criteria for NMOSD. A computerized screening of the registry extracted patients with rituximab de-escalations and at least 12 months of subsequent follow-up. We searched for 7 de-escalation regimens: scheduled discontinuations or switches to an oral treatment after single infusion cycles, scheduled discontinuations or switches to an oral treatment after periodic infusions, de-escalations before pregnancies, de-escalations after tolerance issues, and increased infusion intervals. Rituximab discontinuations motivated by inefficacy or for unknown purposes were excluded. The primary outcome was the absolute risk of NMOSD reactivation (one or more relapses) at 12 months. AQP4+ and AQP4- serotypes were analyzed separately. RESULTS: We identified 137 rituximab de-escalations between 2006 and 2019 that corresponded to a predefined group: 13 discontinuations after a single infusion cycle, 6 switches to an oral treatment after a single infusion cycle, 9 discontinuations after periodic infusions, 5 switches to an oral treatment after periodic infusions, 4 de-escalations before pregnancies, 9 de-escalations after tolerance issues, and 91 increased infusion intervals. No group remained relapse-free over the whole de-escalation follow-up (mean: 3.2 years; range: 0.79-9.5), except pregnancies in AQP+ patients. In all groups combined and within 12 months, reactivations occurred after 11/119 de-escalations in patients with AQP4+ NMOSD (9.2%, 95% CI [4.7-15.9]), from 0.69 to 10.0 months, and in 5/18 de-escalations in patients with AQP4- NMOSD (27.8%, 95% CI [9.7-53.5]), from 1.1 to 9.9 months. DISCUSSION: There is a risk of NMOSD reactivation whatever the rituximab de-escalation regimen. TRIAL REGISTRATION INFORMATION: Registered on ClinicalTrials.gov: NCT02850705. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that de-escalation of rituximab increases the probability of disease reactivation.

Relevance of kappa free light chains index in patients with aquaporin-4 or myelin-oligodendrocyte-glycoprotein antibodies.

BACKGROUND: The kappa free light chains index (κ-index) is increasing in importance as a fast, easy, cost-effective, and quantitative biomarker in multiple sclerosis (MS), which can replace cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB) detection. In previous studies, controls often included mixed patients with several inflammatory central nervous system disorders. The aim of the present study was to assess the κ-index in patients with serum aquaporin-4 (AQP4)-IgG or myelin-oligodendrocyte-glycoprotein (MOG)-IgG. METHODS: We analyzed CSF/serum samples of patients with AQP4-IgG or MOG-Ig and evaluated distinct κ-index cut-offs. We described clinical and magnetic resonance imaging (MRI) features of patients with the highest κ-index values. RESULTS: In 11 patients with AQP4-IgG, median κ-index was 16.8 (range 0.2; 63) and 6/11 (54.5%) had κ-index >12. Among 42 patients with MOG-IgG, 2 had low positive MOG-IgG titers, were ultimately diagnosed with MS, and had a markedly increased κ-index (54.1 and 102.5 respectively). For the remaining 40 MOG-IgG-positive patients the median κ-index was 0.3 (range 0.1; 15.5). Some 6/40 (15%) and 1/40 (2.5%) patients had a κ-index >6 and >12, respectively. None fulfilled MRI dissemination in space and dissemination in time (DIS/DIT) criteria and the final diagnosis was MOG-IgG-associated disease (MOGAD) for these 40 patients. Four of the 40 (10%) MOG-IgG-positive patients had OCB. CONCLUSION: While a marked increase in κ-index could discriminate MS from MOGAD, a low κ-index threshold could lead to confusion between MS and MOGAD or AQP4 antibody-positive neuromyelitis optica spectrum disorder.

Natalizumab extended-interval dosing in a real-life setting.

BACKGROUND: Natalizumab is a high-efficacy therapy for recurrent multiple sclerosis (RMS) with a four-week administration interval. Controlled trials have shown that extending this interval to six weeks led to better safety without increasing the risk of relapse. We aimed to analyze the safety of extending the natalizumab interdose interval from 4 to 6 weeks in a real-life setting. METHODS: This monocentric retrospective self-controlled study included adult patients with RMS treated with natalizumab with a four-week interval between infusions for a minimum of six months, before switching to a six-week interval. The main outcomes were the incidence of MS relapse, new MRI lesions, and MRI activity signs during the two periods, with patients being their own controls. RESULTS: Fifty-seven patients were included in the analysis. The mean (95%CI) annualized relapse rate (AAR) before natalizumab introduction was 1.03 (0.52; 1.55). During the four-week interval dosing period, no patient presented with an MS relapse, and seven (13.5%) patients had new MRI lesions. During the six-week interval dosing period, no relapse was observed and two (3.6%) patients had new MRI lesions. CONCLUSION: We did not observe more relapses or signs of MRI activity when extending the interval between natalizumab infusions from four to six weeks.

Retinal Nerve Fiber Layer Thickness/Minimum Rim Width Ratio Differentiates Glaucoma From Other Optic Neuropathies.

PRCIS: Global peripapillary retinal nerve fiber layer thickness (pRNFL)/Bruch membrane opening-minimum rim width (BMO-MRW) ratio is an objective and effective parameter to separate glaucomatous optic neuropathies (GONs) from nonGONs (NGONs). PURPOSE: This study was undertaken to evaluate the diagnostic capability of the pRNFL/ BMO-MRW ratio to differentiate GONs from NGONs. PATIENTS AND METHODS: This retrospective study included patients with an optic neuropathy (ON), visual loss for>6 months and a confirmed single etiology. pRNFL thickness and BMO-MRW were measured with spectral-domain optical coherence tomography (Spectralis, Heidelberg Engineering, Heidelberg, Germany). The diagnostic accuracies of pRNFL, BMO-MRW and the global pRNFL/BMO-MRW ratio were evaluated with the areas under receiver operating characteristics curves. RESULTS: One eye each from 171 patients was investigated: 50 primary open angle glaucomas, 15 normal pressure glaucomas, 50 optic neuritises, 15 nonarteritic anterior ischemic ONs, 24 compressive ONs, 10 dominant optic atrophies, and 7 nutritional ONs. The global pRNFL/BMO-MRW ratio had the highest area under receiver operating characteristics curve [0.97 vs. 0.92; P =0.01]. It was able to distinguish between GONs and NGONs with a cutoff value of 0.34. Increased mean deviation of the visual field-defect severity was associated with a higher ratio for GONs and a lower ratio for NGONs. CONCLUSION: Compared with NGONs and for the same degree of pRNFL thinning, lower BMO- MRW was found to be a specific marker of glaucoma, reflecting the neuroglial architecture changes within the optic nerve head typical of glaucoma and supporting fundamental pathophysiological differences.

Visual Outcomes Following Plasma Exchange for Optic Neuritis: An International Multicenter Retrospective Analysis of 395 Optic Neuritis Attacks.

PURPOSE: To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON). METHODS: We conducted an international multicenter retrospective study evaluating the outcomes of ON following PLEX. Outcomes were compared to raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset. RESULTS: A total of 395 ON attack treated with PLEX from 317 patients were evaluated. The median age was 37 years (range 9-75), and 71% were female. Causes of ON included multiple sclerosis (108), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (92), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (75), seronegative-NMOSD (34), idiopathic (83), and other (3). Median time from onset of vision loss to PLEX was 2.6 weeks (interquartile range [IQR], 1.4-4.0). Median visual acuity (VA) at the time of PLEX was count fingers (IQR, 20/200-hand motion), and median final VA was 20/25 (IQR, 20/20-20/60) with no differences among etiologies except MOGAD-ON, which had better outcomes. In 81 (20.5%) ON attacks, the final VA was 20/200 or worse. Patients with poor outcomes were older (P = .002), had worse VA at the time of PLEX (P < .001), and longer delay to PLEX (P < .001). In comparison with the ONTT subset with severe corticosteroid-unresponsive ON, a final VA of worse than 20/40 occurred in 6 of 50 (12%) PLEX-treated ON vs 7 of 19 (37%) from the ONTT treated with intravenous methylprednisolone without PLEX (P = .04). CONCLUSION: Most ON attacks improved with PLEX, and outcomes were better than attacks with similar severity in the ONTT. The presence of severe vision loss at nadir, older age, and longer delay to PLEX predicted a worse outcome whereas MOGAD-ON had a more favorable prognosis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Time to steroids impacts visual outcome of optic neuritis in MOGAD.

BACKGROUND: To characterise the response to treatment of inaugural optic neuritis (ON) in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: We searched the French MOGAD database for adults with inaugural ON with a detailed report of acute treatment modalities and measures of high-contrast best-corrected visual acuity (BCVA) at nadir and after 3 months. Predictors of visual outcomes were assessed by multivariable analysis. RESULTS: Among 245 patients with at least one episode of ON, 82 fulfilled all criteria, and data on the peripapillary retinal nerve fibre layer (pRNFL) were available for 44. All patients received methylprednisolone (MP), combined with plasma exchange in 18. After 3 months, 75 of 82 (91%) patients retained full BCVA recovery, and median (range) pRNFL of the affected eye was 72 µm (40-102). Failure to regain 0.0 logarithmic minimum angle of resolution vision (Snellen 20/20) at 3 months was associated with time to first MP treatment ≥10 days (OR 16, 95% CI 1.14 to 213, p=0.01). pRNFL thickness after 3 months was related to better BCVA at nadir and time to first MP treatment <10 days (r2=19%, p=0.004 and r2=11%, p=0.03, respectively). CONCLUSIONS: Time to MP affects functional but also structural visual outcomes of ON in MOGAD.

Are PHOMS a clinical sign of optic neuritis?

PURPOSE: Assess the prevalence and evolution of PHOMS in optic neuritis. METHODS: We analysed the medical files of 126 patients included in the OCTON cohort. Patients' medical files, digital retinal images and OCT examinations were reviewed, searching for optic nerve head oedema and PHOMS at the initial presentation and during the follow-up. RESULTS: We included 102 patients in the final analysis. Twenty-nine (29) eyes had optic nerve head oedema at the initial presentation. PHOMS were found to be present in 8 eyes affected with optic neuritis. All cases of PHOMS were associated with optic nerve head oedema. All the PHOMS decreased in size and disappeared with the improvement of the oedema. DISCUSSION: Our results show that PHOMS is not a common sign of optic neuritis. We didn't observe any case of PHOMS in the absence of optic nerve head oedema in eyes with optic neuritis. PHOMS seem to be a rare sign of optic neuritis associated to optic nerve head oedema, and they tend to disappear with the improvement of the optic nerve head oedema. We suggest that the presence of PHOMS in optic neuritis eyes with no optic nerve oedema should be a considered warning sign.

Pregnancy and multiple sclerosis: 2022 recommendations from the French multiple sclerosis society.

OBJECTIVE: The objective of this study was to develop evidence-based recommendations on pregnancy management for persons with multiple sclerosis (MS). BACKGROUND: MS typically affects young women in their childbearing years. Increasing evidence is available to inform questions raised by MS patients and health professionals about pregnancy issues. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and university databases (January 1975 through June 2021). The RAND/UCLA appropriateness method was developed to synthesise the scientific literature and expert opinions on healthcare topics; it was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 104 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, locoregional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses and disease-modifying treatments. CONCLUSION: The 2022 recommendations of the French MS society should be helpful to harmonise counselling and treatment practice for pregnancy in persons with MS, allowing for better and individualised choices.

Pregnancy and post-partum in patients with myelin-oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND AND OBJECTIVE: Myelin-oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) frequently initiates during childbearing years. This study investigated the impact of pregnancy and post-partum on MOGAD activity. METHODS: Retrospective analysis of clinical and demographic data from a multicenter French cohort of adult patients with MOGAD. All adult female patients who had a pregnancy after disease onset or in the year before disease onset were included. The annualized relapse rate was evaluated in patients who had a pregnancy after disease onset, to evaluate the impact of pregnancy and post-partum on MOGAD course. RESULTS: Twenty-five informative pregnancies after disease onset were identified. No relapse was recorded during these pregnancies and only three relapses occurred during the first 3 months post-partum. The annualized relapse rate decreased from 0.67 (95% confidence interval: 0.40-1.10) during the pre-pregnancy period to 0 (95% confidence interval: 0-0.21) during pregnancy and to 0.22 (95% confidence interval: 0.09-0.53) during the first year post-partum. Among 144 female patients in their childbearing age recorded in the database, 18 (12.5%) reported their first symptoms during pregnancy or in the 12 months post-partum. DISCUSSION: Our study suggests a marked reduction of MOGAD relapse rate during pregnancy and the post-partum period. Prospective studies on the role of pregnancy and delivery in MOGAD course are needed.

Pregnancy and neuromyelitis optica spectrum disorders: 2022 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: In 2020, the French Multiple Sclerosis (MS) Society (SFSEP) decided to develop a national evidence-based consensus on pregnancy in MS. As neuromyelitis optica spectrum disorders (NMOSD) shares a series of commonalities with MS, but also some significant differences, specific recommendations had to be developed. OBJECTIVES: To establish recommendations on pregnancy in women with NMOSD. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and universities databases (January 1975 through June 2021). The RAND/UCLA appropriateness method, which was developed to synthesise the scientific literature and expert opinions on health care topics, was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A sub-group of nine NMOSD experts was dedicated to analysing available data on NMOSD. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 66 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, loco-regional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses, and disease-modifying treatments. CONCLUSION: Physicians and patients should be aware of the new and specific evidence-based recommendations of the French MS Society for pregnancy in women with NMOSD. They should help harmonise counselling and treatment practise, allowing for better individualised choices.

Diagnosis and classification of optic neuritis.

There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.

Generalization of ocular myasthenia gravis 10 years after onset.

BACKGROUND: Generalization of ocular myasthenia gravis (OMG) represents a pejorative evolution, and no validated generalization-prevention strategy exists. The study aimed to determine the percentage of patients with OMG generalization and identify factors predictive of it to establish a prediction score. METHODS: This retrospective, observational study included 151 patients diagnosed with OMG after an initial work-up in our institution. The outcome measure was time to MG generalization. The explanatory variables were age at onset (> 55 years), sex, first-year anti-acetylcholine-receptor antibody-positivity, repetitive nerve stimulation showing electromyogram decrement and corticosteroid use. Kaplan-Meier estimations of the probability of risk of generalization, and descriptive and multivariate Cox model analyses were computed. A nomogram combining explanatory variables was used to establish a score to predict the probability of OMG generalization. RESULTS: Among 183 patients' charts identified, 151 had confirmed OMG. Their median follow-up was 5.7 years. Estimations (95% CI) of OMG-generalization risk at 1, 3 and 10 years post-symptom onset, respectively, were: 13.0% (7.3-18.2), 25.1% (17.5-32.0) and 37.8% (27.2-45.2). The p-value-based multivariate analysis associated generalization with female sex, electromyogram decrement and first-year anti-acetylcholine-receptor antibody positivity, and Akaike information criterion-based analysis retained those three parameters and corticosteroid use. A nomogram was built and validated with an optimism-corrected C-statistic of 0.68, and calibration plots showed good fit. CONCLUSIONS: Our population's percentage of OMG generalization is in line with recent publications. Using the identified prognostic factors, the nomogram provided a score to predict the probable risk of generalization in our cohort.

Prospective longitudinal study on prognostic factors of visual recovery and structural change after a first episode of optic neuritis.

BACKGROUND AND PURPOSE: This study was undertaken to determine the role of optical coherence tomography (OCT) in predicting the final visual and structural outcome, and to evaluate the correlation between functional eye outcome and retinal changes, in patients with a first episode of optic neuritis (ON). METHODS: In this prospective study, consecutive adult patients with acute ON underwent ophthalmological evaluation at baseline and at 1 and 12 months, including OCT measurements of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell and inner plexiform layer, and inner nuclear layer thicknesses; high- and low-contrast visual acuity; visual field assessment; and baseline brain magnetic resonance imaging. Univariate and multivariate linear regressions were used to assess predictive factors of outcome. Correlations between 12-month visual function and retinal structure were estimated by Spearman coefficients. Two groups of patients were analyzed, with or without multiple sclerosis (MS). RESULTS: Among 116 patients, 79 (68.1%) had MS, and 37 (31.9%) had ON not related to MS (including 19 idiopathic [i.e., isolated] ON, and 13 and five with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies, respectively). We found no independent predictive factor of visual and retinal outcome. Analysis of the relationship between the visual field test (mean deviation) and pRNFL thickness demonstrated a threshold of 75.4 µm and 66.4 µm, below which the mean deviation was worse, for patients with MS (p = 0.007) and without MS (p < 0.001), respectively. CONCLUSIONS: We found that inner retinal layer measurements during the first month are not predictive of final outcome. The critical threshold of axonal integrity, below which visual function is damaged, is different between patients with and without MS.

Pure Relapsing Short Myelitis: Part of the Multiple Sclerosis Spectrum or New Entity?

BACKGROUND AND OBJECTIVES: Pure relapsing short myelitis with clinical and paraclinical features suggesting multiple sclerosis (MS) has been described recently. Here, we evaluated the existence of this potential new form of MS by retrospectively searching for similar cases in the databases of the French tertiary MS centers. METHODS: Patients were included based on the present criteria: at least 2 short (<3 vertebral segments) myelitis episodes; minimum follow-up of 3 years; no MS-like brain lesion during all the follow-up; tested negative for both anti-myelin oligodendrocyte glycoprotein and anti-aquaporin 4 antibodies in serum; presence of oligoclonal bands in CSF; and comprehensive workup to exclude alternative diagnoses. RESULTS: Eighteen patients fulfilled all criteria. The sex ratio (females/males) was 5/1; the median (range) age at first relapse was 35.5 (25-54) years, the disease duration was 80.5 (50-308) months, and the annualized relapse rate was 0.36 (0.1-0.5). The median (range) number of relapses per patient was 2 (2-5), and the median (range) Expanded Disability Status Scale score at last follow-up was 1 (0-7.5). In CSF, the median (range) protein level was 0.34 g/L (0.18-0.77), and the median (range) number of mononuclear cells was 3 (0-28). Spinal cord MRI demonstrated a median (range) number of 2 (1-5) lesions per examination and 3 [1-7] on the last examination. Fifty-five percent of lesions involved the cervical levels. Secondary progressive evolution occurred in 3 of 18 (17%) patients. DISCUSSION: Pure spinal MS could be a rare entity in the MS disease spectrum. However, the existence of a distinct entity in the inflammatory CNS disorders cannot be excluded.

Association of Maintenance Intravenous Immunoglobulin With Prevention of Relapse in Adult Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Importance: Recent studies suggest that maintenance intravenous immunoglobulin (IVIG) may be an effective treatment to prevent relapses in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD); however, most of these studies had pediatric cohorts, and few studies have evaluated IVIG in adult patients. Objective: To determine the association of maintenance IVIG with the prevention of disease relapse in a large adult cohort of patients with MOGAD. Design, Setting, and Participants: This was a retrospective cohort study conducted from January 1, 2010, to October 31, 2021. Patients were recruited from 14 hospitals in 9 countries and were included in the analysis if they (1) had a history of 1 or more central nervous system demyelinating attacks consistent with MOGAD, (2) had MOG-IgG seropositivity tested by cell-based assay, and (3) were age 18 years or older when starting IVIG treatment. These patients were retrospectively evaluated for a history of maintenance IVIG treatment. Exposures: Maintenance IVIG. Main Outcomes and Measures: Relapse rates while receiving maintenance IVIG compared with before initiation of therapy. Results: Of the 876 adult patients initially identified with MOGAD, 59 (median [range] age, 36 [18-69] years; 33 women [56%]) were treated with maintenance IVIG. IVIG was initiated as first-line immunotherapy in 15 patients (25%) and as second-line therapy in 37 patients (63%) owing to failure of prior immunotherapy and in 7 patients (12%) owing to intolerance to prior immunotherapy. The median (range) annualized relapse rate before IVIG treatment was 1.4 (0-6.1), compared with a median (range) annualized relapse rate while receiving IVIG of 0 (0-3) (t108 = 7.14; P < .001). Twenty patients (34%) had at least 1 relapse while receiving IVIG with a median (range) time to first relapse of 1 (0.03-4.8) years, and 17 patients (29%) were treated with concomitant maintenance immunotherapy. Only 5 of 29 patients (17%) who received 1 g/kg of IVIG every 4 weeks or more experienced disease relapse compared with 15 of 30 patients (50%) treated with lower or less frequent dosing (hazard ratio, 3.31; 95% CI, 1.19-9.09; P = .02). At final follow-up, 52 patients (88%) were still receiving maintenance IVIG with a median (range) duration of 1.7 (0.5-9.9) years of therapy. Seven of 59 patients (12%) discontinued IVIG therapy: 4 (57%) for inefficacy, 2 (29%) for adverse effects, and 1 (14%) for a trial not receiving therapy after a period of disease inactivity. Conclusions and Relevance: Results of this retrospective, multicenter, cohort study of adult patients with MOGAD suggest that maintenance IVIG was associated with a reduction in disease relapse. Less frequent and lower dosing of IVIG may be associated with treatment failure. Future prospective randomized clinical trials are warranted to confirm these findings.

Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders.

BACKGROUND AND OBJECTIVES: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). METHODS: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. RESULTS: Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. DISCUSSION: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

A meta-analysis comparing first-line immunosuppressants in neuromyelitis optica.

OBJECTIVE: As phase III trials have shown interest in innovative but expensive drugs in the treatment of neuromyelitis optica spectrum disorder (NMOSD), data are needed to clarify strategies in the treatment of neuromyelitis optica (NMO). This meta-analysis compares the efficacy of first-line strategies using rituximab (RTX), mycophenolate mofetil (MMF), or azathioprine (AZA), which are still widely used. METHODS: Studies identified by the systematic review of Huang et al. (2019) were selected if they considered at least two first-line immunosuppressants among RTX, MMF, and AZA. We updated this review. The Medline, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials databases were queried between November 2018 and April 2020. To be included, the hazard ratio (HR) [95% CI] for the time to first relapse after first-line immunosuppression had to be available, calculable, or provided by the authors. RESULTS: We gathered data from 919 NMO patients (232 RTX-, 294 MMF-, and 393 AZA-treated patients). The risk of first relapse after first-line immunosuppression was 1.55 [1.04, 2.31] (p = 0.03) for MMF compared with RTX, 1.42 [0.87, 2.30] (p = 0.16) for AZA compared with RTX, and 0.94 [0.58, 1.54] (p = 0.08) for MMF compared with AZA. INTERPRETATION: The findings suggest that RTX is more efficient than MMF as a first-line therapy. Even if the results of our meta-analysis cannot conclude that RTX has a better efficacy in delaying the first relapse than AZA, the observed effect difference between both treatments combined with the results of previous studies using as outcome the annualized relapse rate may be in favor of RTX.