Intravenous immunoglobulin treatment for acute attacks in myelin oligodendrocyte glycoprotein antibody disease.

BACKGROUND: The potential therapeutic benefit of intravenous immunoglobulins (IVIGs) for acute attacks of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is unknown. OBJECTIVE: The objective was to describe the outcomes of IVIG treatment for acute MOGAD attacks. METHODS: A retrospective observational study involving seven tertiary neuroimmunology centers. Data collection included patients' demographics, Expanded Disability Status Scale (EDSS), and visual acuity (VA) before the attack, at the nadir of the attack before IVIG treatment, and at follow-up visits ⩾3 months after treatment. RESULTS: Thirty-nine patients were included, of which 21 (53.8%) were female. The median age was 23 years (range 5-74 years), and the median disease duration was 4 months (range 0-93 months). The most common type of attack treated with IVIG was isolated optic neuritis (ON) (unilateral n = 14, bilateral n = 5, associated with transverse myelitis (TM), n = 1), followed by acute disseminated encephalomyelitis (ADEM) (n = 8), multifocal (n = 7), TM (n = 3), brainstem (n = 1), and other encephalitis (n = 1). A significant improvement in both the EDSS and VA measures was observed at follow-up compared to the time of IVIG treatment initiation (p < 0.0001 for both outcome measures). CONCLUSION: IVIG may be an effective treatment option for acute MOGAD attacks. Further prospective studies are warranted to validate our results.

Alemtuzumab mediates the CD39+ T-regulatory cell response via CD23+ macrophages.

Alemtuzumab (ALM) effectively prevents relapses of multiple sclerosis (MS). It causes lymphocyte depletion with subsequent enhancement of the T-regulatory cell population. Direct administration of ALM to T cells causes cytolysis. However, the T cells may be indirectly affected by monocyte-derived cells, which are resistant to ALM cytotoxicity. We aimed to examine whether ALM modulates monocytes and whether the crosstalk between monocytes and lymphocytes previously exposed to ALM would result in anti-inflammatory effects. The CD14+ monocytes of 10 healthy controls and 10 MS (treatment naive) patients were isolated from peripheral blood mononuclear cells (PBMCs), exposed to ALM and reintroduced to PBMCs depleted of CD14+ cells. The macrophage profile was assessed and T-cell markers were measured. ALM promoted M2 anti-inflammatory phenotype as noted by an increased percentage in the populations of CD23+ , CD83+ and CD163+ cells. The CD23+ cells were the most upregulated (7-fold, P = 0.0002), and the observed effect was higher in patients with MS than in healthy subjects. ALM-exposed macrophages increased the proportion of T-regulatory cells, without affecting the proportion of T-effector cells. Neutralizing the CD23+ monocytes with antibodies reversed the effect specifically on the CD4+ CD39+ T-regulatory cell subpopulation but not on the CD4+ CD25hi CD127lo FOXP3+ subpopulation. ALM induces the conversion of monocytes into anti-inflammatory macrophages, which in turn promotes T-regulatory cell enhancement, in a CD23-dependent manner. These findings suggest that the mechanism of action of ALM is relevant to aspects of MS pathogenesis.

Safety of the BNT162b2 COVID-19 vaccine in multiple sclerosis (MS): Early experience from a tertiary MS center in Israel.

BACKGROUND AND PURPOSE: Although the COVID-19 vaccines are currently recommended for people with multiple sclerosis (MS), the fact that they were not specifically tested in people with MS raises uncertainty regarding their safety in this population. The purpose of this study was to report real-life safety data of the BNT162b2 COVID-19 vaccine in a cohort of MS patients. METHODS: An anonymous survey was distributed to 425 MS patients. Participants were asked general demographic and disease-related questions and specific questions regarding the safety profile of the COVID-19 vaccine. RESULTS: Of the 425 MS patients, 262 completed the questionnaire. The median (range) participant age was 42 (22-79) years, 199 participants were women (75.9%), and 66 participants (25.2%) had associated comorbidities. A total of 198 participants (75.6%) were treated with disease-modifying therapies. In all, 239 participants (91.2% of the responders) had received the BNT162b2 COVID-19 vaccine. Of these, 182 (76.1%) were aged <55 years, and 57 (23.9%) were aged >55 years. Adverse events were reported by 136 participants (56.9%; 52.5% of those aged <55 years and 40.3% of those aged >55 years; p = 0.1517) and 36 participants (15.1%) reported new or worsening neurological symptoms following the vaccination, the most frequent being sensory disturbances (21 participants, 58.3%). Most symptoms occurred within the first 24 h after vaccination and resolved within 3 days. A total of 28 participants (77.8%) did not require any medication to treat their symptoms. CONCLUSIONS: This survey indicates an overall favorable safety profile of the BNT162b2 vaccine in people with MS. These data should be confirmed in further prospective, large-scale studies.

Incidence of AChR Ab-positive myasthenia gravis in Israel: A population-based study.

BACKGROUND: The incidence of myasthenia gravis (MG) has traditionally been low, ranging between 2-6/106 . Several recent epidemiological studies have reported a higher incidence. We, therefore, aimed to assess and characterize the incidence of MG in Israel. METHODS: We retrospectively reviewed the records of all four laboratories that performed the acetylcholine receptor antibody (AChR Ab) test in Israel between 1994 and 2013 and documented the number of newly diagnosed seropositive MG patients each year. To assure that data indeed reflect only newly diagnosed patients, patient's names and ID numbers were screened at the Hadassah medical center database since 1978, the year when the test was first performed in Israel. In order to calculate the annual incidence of the disease, the population at risk was derived from the annual publication of the Israeli Central Bureau of Statistics. RESULTS: The annual incidence of MG for this time period was 13.1/106 inhabitants. The mean incidence of MG between 1994 and 2003 was 7.695/106 /y, while the mean incidence between 2004 and 2013 was 18.49/106 (P < .0001). Mean age of diagnosis between 1994 and 2003 was 56.65 ± 0.9351, while between 2004 and 2013, it was 59.89 ± 0.5336 (P = .0012). Male to female (M:F) incidence ratio in the years 1994-2003 and 2004-2013 was 2:3.2 and 3:1.8, respectively, reflecting increased incidence among males (P < .0001). CONCLUSIONS: The incidence of MG in Israel has increased significantly during the last decade, especially among males of older age. These findings may reflect an etiological role of an environmental factor, increased awareness, and increased longevity in general.

Neuromyelitis Optica Spectrum Disorder: Disease Course and Long-Term Visual Outcome.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that classically manifests as attacks of optic neuritis (ON) and transverse myelitis (TM). The prevalence, course, and severity of NMOSD vary considerably. Few studies report the neuro-ophthalmologic disease course and visual outcome. OBJECTIVE: We sought to describe the course and long-term visual outcome in a cohort of NMOSD patients treated in a single tertiary referral center. METHODS: The database was searched for all patients with NMOSD who were treated in our center from 2005 to 2014. Data collected included detailed visual outcome, grade of final visual disability, neuroimaging, and results of optical coherence tomography. Details on relapses, acute episodes, and maintenance therapies were recorded. RESULTS: Of the 12 patients with NMOSD who were followed for a mean duration of 9.06 years, 10 (83%) were women. Mean age at presentation was 33.90 ± 16.94 years. Patients with acute attacks were treated with high-dose intravenous methylprednisolone and offered immunosuppressive maintenance. ON occurred in 18 eyes of 12 patients, with a cumulative total of 37 ON episodes. At the end of the follow-up period, no patient had become legally blind and only 1 patient had lost her driver's license. Pain associated with acute ON was common (83%), whereas optic disc edema was a rare finding in our patient cohort (6%). CONCLUSIONS: In this retrospective series of 12 patients with NMOSD, followed for a mean of 9.06 years, acute-phase treatment was given within 8 days of relapse, followed by maintenance therapy. Functional visual outcome, as measured by the World Health Organization/International Classification of Diseases, Tenth Revision visual disability scale was better than reported in previous studies and driver's license was preserved in 11 of 12 patients. Pain accompanied 83% of ON attacks and may not aid differentiating multiple sclerosis from NMOSD-related ON.

Association between clinical characteristics, acute steroid treatment and oligoclonal bands result in multiple sclerosis: A retrospective study.

BACKGROUND: Detection of oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) is important for diagnosis of multiple sclerosis (MS). Previous studies reported that treatment with intravenous methylprednisolone (IVMP) before lumber puncture (LP) could suppress OCBs production. The aim of this study was to assess whether IVMP initiation prior to CSF collection affects OCBs results in patients with an acute demyelinating event. Additionally, we examined which clinical characteristics are associated with the presence of OCBs in the CSF. METHODS: We retrospectively evaluated patients admitted to the neurology department at rabin medical center (RMC) between 2010 and 2022 who underwent LP with OCBs analysis as part of their demyelinating attack workup. Patients were divided into OCB-positive and OCB-negative groups and demographical and clinical characteristics (including timing and duration of acute steroid treatment and history of prior demyelinating attacks) were analyzed for association with OCBs results. RESULTS: A total of 342 patients were included with a median age of 35 years (IQR, 27-46). Two hundred thirty-eight (69.6 %) were OCB-positive. Initiation of IVMP before LP was not associated with negative OCBs (11.8 % Vs. 13.5 %, P = 0.721), nor was it correlated with OCBs positivity (OR=0.86, P = 0.66). CSF cell count was higher in OCB-positive patients (5 Vs. 3, P = 0.001), and a history of prior demyelinating attacks was associated with- (33.6 % Vs. 20.2 %, P = 0.014) and predictive of OCBs positivity (OR=2, P = 0.013). CONCLUSIONS: Timing of steroids was not associated with OCB positivity. However, pleocytosis and a prior attack were associated with OCB positivity in this cohort. Our results suggest that steroid treatment is unlikely to affect OCBs results. Ideally, larger prospective studies would be needed to confirm our observations.

The effect of COVID-19 vaccination on multiple sclerosis activity as reflected by MRI.

INTRODUCTION: Examining the safety of theBNT162b2 mRNA vaccine in multiple sclerosis (MS) patients remains inconclusive, particularly regarding the potential for disease exacerbations. This study aims to assess the effects of BNT162b2 COVID-19 vaccination on disease activity in MS patients through sequential MRI imaging. METHODS: A retrospective study of 84 MS patients from five Israeli hospitals was conducted. MS lesion load was determined from three brain MRI scans, one postvaccination and two prevaccination scans. A post hoc analysis compared subgroups featuring vaccinated and unvaccinated patients respectively, with early onset MS. RESULTS: The cohort included 70 women with early onset (mean age 16.4 ± 0.8 years) and adult onset (mean age 34.9 ± 1.1 years) MS. Among the early onset group, vaccinated patients showed an increased risk of new lesions (p = .00026), while there was no increased risk among adult-onset patients. Additionally, a comparison between early onset vaccinated and nonvaccinated groups revealed a higher risk of increased lesions in the vaccinated group (p = .024). DISCUSSION: Overall, the study suggests that the BNT162b2 vaccine is generally safe in MS patients, with no association found between vaccination and new lesions in most patients. However, close MRI follow-up is recommended for early-onset MS cases to monitor lesion development.

Effectiveness of oral prednisone tapering following intravenous methylprednisolone for acute optic neuritis in multiple sclerosis.

Acute optic neuritis treatment lacks standardized protocols. The value of oral prednisone taper (OPT) following intravenous methylprednisolone (IVMP) on visual outcome parameters in optic neuritis (ON) has never been explored. In the present retrospective study, we investigated whether OPT after IVMP affects the structural and functional visual outcomes of inaugural clinically isolated syndrome (CIS)- or multiple sclerosis (MS)-ON. Adult patients with acute, inaugural, unilateral CIS- or MS-ON, treated with IVMP in Germany and Israel were stratified into patients treated with IVMP alone-versus IVMP and OPT. Inclusion criteria were age ≥18, CIS or MS diagnosis according to McDonald criteria 2017, available visual acuity (VA) at nadir before treatment initiation and at follow-up ≥5 months, as well as a spectral domain optic coherence tomography (OCT) data scan at follow-up. Exclusion criteria included recurrent ON, concomitant ophthalmological comorbidities, optical coherence tomography (OCT) of insufficient quality and ON-related escalation therapy after IVMP. The structural outcome was defined as the average retinal nerve fiber layer (RNFL) difference between the ON-affected and the unaffected eye, while the functional outcome was defined as the final high-contrast best-corrected VA (HC-BCVA) at follow-up compared to nadir. The comparative analysis was performed using linear regression analysis, adjusted for sex, age, and days-to-treatment. Fifty-one patients met the inclusion criteria (25% male). The mean age was 33.9 (±10.23) years. Twenty-six patients (51%) received OPT following IVMP. There was no difference in nadir HC-BCVA between the groups (0.39 No OPT; 0.49 With OPT, P = 0.36). Adjusted linear regression analysis did not indicate an influence of OPT on RNFL thickness or on HC-BCVA (beta coefficient for RNFL difference in percentages: 0.51, 95%-CI: [-4.58, 5.59], beta coefficient for logMAR: 0.11, 95%; CI [-0.12, 0.35] at follow-up. In conclusion, the addition of OPT to IVMP did not affect RNFL thickness or the final VA in a retrospective cohort of 51 patients with inaugural acute CIS- or MS-ON. The results of this exploratory study are currently being re-examined in a large-scale, demographically diverse, prospective study.

The Acute Optic Neuritis Network (ACON): Study protocol of a non-interventional prospective multicenter study on diagnosis and treatment of acute optic neuritis.

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON. Trial registration: ClinicalTrials.gov, identifier: NCT05605951.

Repeated lumbar puncture in search of oligoclonal bands - What is the yield?

BACKGROUND: Cerebrospinal fluid (CSF) oligoclonal bands (OCBs) are immunoglobulins that represent intrathecal synthesis during central nervous system infection or inflammation. As repeated lumbar puncture (LP) is usually not performed unless clinically indicated, there is very limited data on the natural history and course of OCBs status in the CSF, its relation to disease activity, duration of persistence, and the rate of either CSF conversion of OCBs or disappearance. METHODS: We retrospectively collected data from adult patients with various neurological syndromes who had repeated CSF samplings. OCBs were analyzed by agarose gel electrophoresis or by isoelectric focusing. RESULTS: During the years 2010-2020, we identified 48 patients with at least two CSF OCBs results in Rabin Medical Center. These included 11 patients with Multiple Sclerosis, ADEM and NMOSD (one patient each), 7 patients with unspecified demyelinating disease, 4 with optic neuropathy, 15 patients with unknown diagnosis. Overall, 6/48 (12.5%) patients had change in OCBs status between first and second LP's. Four (8.33%) patients changed OCBs from positive to negative, and two patients (4.2%) from negative to positive. There was no significant difference in demographic, disease category, CSF constituents or time interval to second LP between patients who changed their OCBs status to those who did not. CONCLUSION: Repeated LP for OCBs analysis in our cohort did not yield a practical benefit. The conversion rate of OCBs status was low (12.5%) and in most cases did not lead to a change in the final diagnosis or patient's clinical management.

Early safety and tolerability profile of the BNT162b2 COVID-19 vaccine in myasthenia gravis.

Although the COVID-19 vaccines are currently recommended for people with myasthenia gravis (MG), there is no data regarding the safety of the vaccines in this population. In order to investigate the real-life safety data of the BNT162b2 COVID-19 vaccine in people with MG, an anonymous survey was distributed to 142 MG patients. Fifty-six MG patients completed the questionnaire. The median age was 53 years (range 23-83 years); 35 (62.5%) were males, and 25 (44.6%) had associated comorbidities. Thirty-seven participants (66.1%) were treated with immunotherapies. Fifty-five participants (98.2% of the responders) received the BNT162b2 COVID-19 vaccine. Of these, 32 (58.2%) were < 55 years old, and 23 (41.8%) were > 55 years old. Adverse events were more common in patients younger than 55 years old (46.9% Vs. 17.4%; p = 0.0428). Eight participants (14.5%) reported worsening neurological symptoms following the vaccination. Three of those who reported worsening of neurological symptoms (37.5%) required additional treatment. Most events occurred within the first few days after vaccination and resolved within a few weeks. This survey indicates an overall favorable safety and tolerability profile of the BNT162b2 vaccine in people with MG. Additional prospective, large-scale studies are warranted to confirm these findings.

Humoral and Cellular Immune Responses to SARS-CoV-2 mRNA Vaccination in Patients with Multiple Sclerosis: An Israeli Multi-Center Experience Following 3 Vaccine Doses.

Background: Immunomodulatory/immunosuppressive activity of multiple sclerosis (MS) disease modifying therapies (DMTs) might affect immune responses to SARS-CoV-2 exposure or vaccination in patients with MS (PwMS). We evaluated the effect of DMTs on humoral and cell-mediated immune responses to 2 and 3 vaccinations and the longevity of SARS-Cov-2 IgG levels in PwMS. Methods: 522 PwMS and 68 healthy controls vaccinated with BNT162b2-Pfizer mRNA vaccine against SARS-CoV-2, or recovering from COVID-19, were recruited in a nation-wide multi-center study. Blood was collected at 3 time-points: 2-16 weeks and ~6 months post 2nd vaccination and 1-16 weeks following 3rd vaccination. Serological responses were measured by quantifying IgG levels against the spike-receptor-binding-domain of SARS-CoV-2, and cellular responses (in a subgroup analysis) by quantifying IFNγ secretion in blood incubated with COVID-19 spike-antigen. Results: 75% PwMS were seropositive post 2nd or 3rd vaccination. IgG levels decreased by 82% within 6 months from vaccination (p<0.0001), but were boosted 10.3 fold by the 3rd vaccination (p<0.0001), and 1.8 fold compared to ≤3m post 2nd vaccination (p=0.025). Patients treated with most DMTs were seropositive post 2nd and 3rd vaccinations, however only 38% and 44% of ocrelizumab-treated patients and 54% and 46% of fingolimod-treated patients, respectively, were seropositive. Similarly, in COVID-19-recovered patients only 54% of ocrelizumab-treated, 75% of fingolimod-treated and 67% of cladribine-treated patients were seropositive. A time interval of ≥5 months between ocrelizumab infusion and vaccination was associated with higher IgG levels (p=0.039 post-2nd vaccination; p=0.036 post-3rd vaccination), and with higher proportions of seropositive patients. Most fingolimod- and ocrelizumab-treated patients responded similarly to 2nd and 3rd vaccination. IFNγ-T-cell responses were detected in 89% and 63% of PwMS post 2nd and 3rd vaccination, however in only 25% and 0% of fingolimod-treated patients, while in 100% and 86% of ocrelizumab-treated patients, respectively. Conclusion: PwMS treated with most DMTs developed humoral and T-cell responses following 2 and 3 mRNA SARS-CoV-2 vaccinations. Fingolimod- or ocrelizumab-treated patients had diminished humoral responses, and fingolimod compromised the cellular responses, with no improvement after a 3rd booster. Vaccination following >5 months since ocrelizumab infusion was associated with better sero-positivity. These findings may contribute to the development of treatment-stratified vaccination guidelines for PwMS.

Obesity is associated with myelin oligodendrocyte glycoprotein antibody-associated disease in acute optic neuritis.

Optic neuritis (ON) is a frequent presentation at onset of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The pathophysiology underlying these diseases, especially MOGAD, is still being elucidated. While obesity has been reported to potentially be a risk factor for MS, this has not been explored in NMOSD or MOGAD. We aimed to investigate a possible association between obesity (body mass index [BMI] > 30 kg/m2) in patients with MOGAD, aquaporin 4-IgG positive NMOSD (AQP4-IgG+ NMOSD) or MS. In this multicenter non-interventional retrospective study, data was collected from patients with a first ever demyelinating attack of ON subsequently diagnosed with MOGAD (n = 44), AQP4-IgG+ NMOSD (n = 49) or MS (n = 90) between 2005 and 2020. The following data was collected: age, sex, ethnicity, BMI (documented before corticosteroid treatment), and the ON etiology after diagnostic work-up. A mixed model analysis was performed to assess the potential of obesity or BMI to predict MOGAD-ON, and to distinguish MOGAD-ON from AQP4-IgG+ NMOSD-ON and MS-ON. Main outcome measures included BMI in patients with acute ON and subsequent diagnosis of MOGAD, AQP4-IgG+ NMOSD or MS. A higher BMI was significantly associated with a diagnosis of MOGAD-ON (p < 0.001); in MOGAD patients the mean BMI was 31.6 kg/m2 (standard deviation (SD) 7.2), while the mean BMI was 24.7 kg/m2 (SD 5.3) in AQP4-IgG+ NMOSD patients, and 26.9 kg/m2 (SD 6.2) in MS patients. Mixed-effects multinomial logistic regression, adjusted for age and sex, with obesity as a binary variable, revealed that obesity was associated with a higher odds ratio (OR) of a subsequent MOGAD diagnosis (OR 5.466, 95% CI [2.039, 14.650], p = 0.001) in contradistinction with AQP4-IgG+ NMOSD. This study suggests an association between obesity and MOGAD. Our findings require further exploration, but could have significant pathophysiologic implications if confirmed in larger prospective studies.

Details and outcomes of a large cohort of MOG-IgG associated optic neuritis.

BACKGROUND: The goal of this study was to examine the temporal relationship of eye pain to visual loss and investigate whether timing of steroid treatment affects the rate and extent of visual recovery in optic neuritis (ON) from MOG-IgG associated disease (MOGAD) in a large cohort of MOGAD patients with ON. METHODS: This is a multicenter, retrospective cohort study of consecutive MOGAD patients with ON attacks seen from 2017 to 2021 fulfilling the following criteria: (1) clinical history of ON; (2) MOG-IgG seropositivity. ON attacks were evaluated for presence/duration of eye pain, nadir of vision loss, time to intravenous methylprednisolone (IVMP) treatment, time to recovery, and final visual outcomes. RESULTS: There were 107 patients with 140 attacks treated with IVMP and details on timing of treatment and outcomes. Eye pain was present in 125/140 (89%) attacks with pain onset a median of 3 days (range, 0 to 20) prior to vision loss. Among 46 ON attacks treated with IVMP within 2 days of onset of vision loss, median time to recovery was 4 days (range, 0 to 103) compared to 15 days (range, 0 to 365) in 94 ON attacks treated after 2 days (p = 0.004). Those treated within 2 days had less severe VA loss at time of treatment (median LogMAR VA 0.48, range, 0.1 to 3) compared to those treated after 2 days (median LogMAR VA 1.7, range, 0 to 3; p < 0.001), and were more likely to have a VA outcome of 20/40 or better (98% vs 83%, p = 0.01). After adjustment for the initial VA at time of treatment, the differences in final VA were no longer significantly different (p = 0.14). In addition, some patients were documented to recover without steroid treatment. CONCLUSION: This study suggests that pain precedes vision loss in the majority of ON attacks and early steroids may lead to better outcomes in MOG-IgG ON, but some patients can recover without steroid treatment. Prospective randomized clinical trials are required to confirm these findings.

OCT retinal nerve fiber layer thickness differentiates acute optic neuritis from MOG antibody-associated disease and Multiple Sclerosis: RNFL thickening in acute optic neuritis from MOGAD vs MS.

BACKGROUND: Optic neuritis (ON) is the most common manifestation of myelin oligodendrocyte glycoprotein antibody associated disorder (MOGAD) and multiple sclerosis (MS). Acute ON in MOGAD is thought to be associated with more severe optic disk edema than in other demyelinating diseases, but this has not been quantitatively confirmed. The goal of this study was to determine whether optical coherence tomography (OCT) can distinguish acute ON in MOGAD from MS, and establish the sensitivity of OCT as a confirmatory biomarker of ON in these entities. METHODS: This was a multicenter cross-sectional study of MOGAD and MS patients with peripapillary retinal nerve fiber layer (pRNFL) thickness measured with OCT within two weeks of acute ON symptom. Cirrus HD-OCT (Carl Zeiss Meditec, Inc. Dublin, CA, USA) was used to measure the pRNFL during acute ON. Eyes with prior ON or disk pallor were excluded. A receiver operating characteristic (ROC) curve analysis was performed to assess the ability of pRNFL thickness to distinguish MOGAD from MS. RESULTS: Sixty-four MOGAD and 50 MS patients met study inclusion criteria. Median age was 46.5 years (interquartile range [IQR]: 34.3-57.0) for the MOGAD group and 30.4 years (IQR: 25.7-38.4) for the MS group (p<0.001). Thirty-nine (61%) of MOGAD patients were female compared to 42 (84%) for MS (p = 0.007). The median pRNFL thickness was 164 µm (IQR: 116-212) in 96 acute MOGAD ON eyes compared to 103 µm (IQR: 93-113) in 51 acute MS ON eyes (p<0.001). The ROC area under the curve for pRNFL thickness was 0.81 (95% confidence interval 0.74-0.88) to discriminate MOGAD from MS. The pRNFL cutoff that maximized Youden's index was 118 µm, which provided a sensitivity of 74% and specificity of 82% for MOGAD. Among 31 MOGAD and 48 MS eyes with an unaffected contralateral eye or a prior baseline, the symptomatic eye had a median estimated pRNFL thickening of 45 µm (IQR: 17-105) and 7.5 µm (IQR: 1-18), respectively (p<0.001). All MOGAD affected eyes had a ≥ 5 µm pRNFL thickening, whereas 26 (54%) MS affected eyes had a ≥ 5 µm thickening. CONCLUSION: OCT-derived pRNFL thickness in acute ON can help differentiate MOGAD from MS. This can aid with early diagnosis and guide disease-specific therapy in the acute setting before antibody testing returns, and help differentiate borderline cases. In addition, pRNFL thickening is a sensitive biomarker for confirming acute ON in MOGAD, which is clinically helpful and could be used for adjudication of attacks in future MOGAD clinical trials.

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.

Exacerbation of myasthenia gravis following corticosteroid treatment: what is the evidence? A systematic review.

Corticosteroids (CS) are among the most widely- used immunosuppressive agents for immune-mediated conditions, including myasthenia gravis (MG). While their effectiveness in MG is documented and supported in the clinical practice over several decades, one of the main drawbacks of treatment results from the notion that MG patients may experience symptom worsening following CS treatment initiation. This may lead to the administration of lower than necessary doses of CS for the disorder, or even avoiding them altogether. As a consequence, some patients may not receive the optimal treatment to control their disease. In the present review, we analyzed 27 relevant publications and determined the prevalence of clinical exacerbation following CS treatment, its' severity and relation to the type and dose of CS. The rate of MG exacerbation is highest with the administration of cortisone, intermediate with prednisone, and lowest with methylprednisolone. High dose daily or alternate-day prednisone is associated with exacerbation more frequently than low-dose treatment, but most exacerbations are of mild to moderate severity. Other factors related to increased risk of an initial exacerbation include older age, generalized MG, bulbar symptoms, disease severity, presence of thymoma, and thymectomy. However, the current information is based mostly on heterogeneous studies of low quality, and prospective clinical trials designed to compare between the various agents and doses and assess the rate and severity of the exacerbation by a unified scale are warranted.

Chronic low-dose intravenous immunoglobulins as steroid-sparing therapy in myasthenia gravis.

INTRODUCTION: Intravenous immunoglobulin (IVIg) has been proven beneficial in myasthenic crisis, but their role as maintenance therapy is unclear. The aim of this study was to determine if maintenance therapy with low-dose IVIg improves clinical outcome and may be used as a steroid-sparing agent in myasthenia gravis (MG). METHODS: We retrospectively reviewed charts of all MG patients treated with IVIg from January 2006 to December 2019. Long-term treatment response to IVIg was assessed by improvement in the Myasthenia Gravis Foundation of America (MGFA) clinical classification scale as primary end point, as well as the ability to reduce the time-weighted average required dose of prednisone as secondary end-point, in a follow-up period of 36 months. RESULTS: 109 patients were treated with IVIg. The mean follow-up time was 34.03 ± 5.5 months. Sixty-seven patients (61.4%) responded to therapy with at least one-point improvement of the MGFA scale. There was no statistical difference in demographic and clinical characteristics between IVIg responders and non-responders. The mean prednisone dose decreased significantly from 33.1 ± 14.5 mg at baseline to 7.2 ± 7.8 mg after 36 months of IVIg treatment (P < 0.0001), with the greatest effect after 6 months (33.1 ± 14.5 mg Vs. 17.9 ± 11.7 mg; P < 0.0001). In the follow-up period of 36 months, most patients (92.5%) remained clinically and pharmacologically stable under chronic IVIg treatment. CONCLUSION: This retrospective study demonstrates that chronic low-dose IVIg treatment in patients with MG improves clinical outcomes and has a prolonged and significant steroid-sparing effect over a period of 3 years.

Mild Phenotype of Wolfram Syndrome Associated With a Common Pathogenic Variant Is Predicted by a Structural Model of Wolframin.

OBJECTIVE: To describe the WFS1 c.1672C>T; p.R558C missense variant, found in 1.34% of Ashkenazi Jews, that has a relatively mild phenotype and to use computational normal mode analysis (NMA) to explain the genotype-phenotype relationship. METHODS: The clinical, laboratory, and genetic features of 8 homozygotes were collected. A model of the wolframin protein was constructed, and NMA was used to simulate the effect of the variant on protein thermodynamics. RESULTS: Mean age at Wolfram syndrome (WS) diagnosis among homozygotes was 30 years; diabetes (7/8) was diagnosed at mean age 19 years (15-21 years), and bilateral optic atrophy (with MRI evidence of optic/chiasm atrophy) (6/8) at mean age 29 years (15-48 years). The oldest patient (62 years) also had gait difficulties, memory problems, parietal and cerebellar atrophy, and white matter hyperintense lesions. All retained functional vision with independent ambulation and self-care; none had diabetes insipidus or hearing loss. The p.R558C variant caused less impairment of protein entropy than WFS1 variants associated with a more severe phenotype. CONCLUSIONS: The p.R558C variant causes a milder, late-onset phenotype of WS. We report a structural model of wolframin protein based on empirical functional studies and use NMA modeling to show a genotype-phenotype correlation across all homozygotes. Clinicians should be alert to this condition in patients with juvenile diabetes and patients of any age with a combination of diabetes and optic atrophy. Computational NMA has potential benefit for prediction of the genotype-phenotype relationship.