Background

We have limited understanding of the risks and impact of COVID-19 in neuroinflammatory diseases (NID) of the central nervous system, particularly among patients receiving disease modifying therapies (DMTs).

Objectives

To report initial results of a planned multi-center year-long prospective study examining the risk and impact of COVID-19 among persons with NID.

Methods

In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of COVID-19 symptoms in persons with and without NID.

Results

Our cohort included 1,115 participants (630 NID, 98% MS; 485 reference) as of April 30, 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. Persons with NID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of persons with NID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (OR_adj=1.45, 1.17-1.84).

Conclusions

Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries that capture an excess of severe cases. Overall, persons with NID seem to have a risk of suspected COVID-19 similar to the reference population.

Background

The central vein sign (CVS) is a proposed MRI diagnostic biomarker for multiple sclerosis (MS). Use of gadolinium (Gd) in the CVS literature has been inconsistent, and it is unknown whether Gd improves detection of CVS when using FLAIR*.

Objectives

To determine if, and to what extent, gadolinium injection improves detection of CVS lesions when using FLAIR* imaging.

Methods

A cross-sectional multicenter study recruited adults clinically and/or radiologically suspected of having MS. High-isotropic-resolution, T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired pre- and post-injection of Gd-based contrast agent at 3T; pre-Gd 3D FLAIR images were also acquired. T2*-EPI and FLAIR images were processed on the QMENTA platform to generate FLAIR* images. FLAIR* pre-Gd and post-Gd scans from this substudy of 30 patients at 5 sites were analyzed. FLAIR images were used to create T2 lesion masks. Subsequently, FLAIR* images were evaluated in a random order. Lesions were categorized as CVS+, CVS-, or excluded based on the North American Imaging in MS (NAIMS) Criteria by two trained raters blinded to clinical data and Gd use. The proportion of CVS+ lesions was calculated for each scan, and differences in CVS detection based on Gd use were assessed by a Wilcoxon rank-sum test. Diagnostic performance was compared against McDonald 2017 Criteria.

Results

The mean participant age was 45 years (SD: 12); 23 (77%) were women. 14 (47%) met McDonald 2017 Criteria for MS, while 16 (53%) did not (“non-MS”). A total of 487 CVS+ lesions and 976 CVS- lesions were evaluated. The percentage of CVS+ lesions post-Gd in the MS group (median 67% [IQR 30%]) was higher than pre-Gd (41% [47%], p<0.001). There was no apparent difference in percentage of CVS+ lesion in the non-MS group (post-Gd: 10% [23%]; pre-Gd: 5% [29%]; p=0.1). In the MS group, 12/14 (86%) had ≥40% CVS+ lesions on post-Gd imaging, whereas only 8/14 (57%) exceeded that threshold on pre-Gd imaging. When evaluating CVS performance using the 40% CVS+ threshold, the sensitivity and specificity of the CVS post-Gd for MS were 86% and 81%, respectively, compared to 54% and 86% pre-Gd.

Conclusions

The detection of the CVS using FLAIR* at 3T is improved when Gd is used. Based on these results, a multicenter prospective CVS diagnostic study, sponsored by NINDS and NAIMS, will use Gd in the study protocol. Future clinical use of the CVS should balance the increased costs and potential risks of Gd use with the risks of misdiagnosis due to missing CVS on non-contrast imaging.

Background

Intrathecal production of immunoglobulin (Ig) and the presence of cerebrospinal fluid (CSF)–specific oligoclonal bands (OCBs) are hallmarks of multiple sclerosis (MS) that persist throughout the disease course and treatment.

Objectives

To describe baseline (BL) correlations of CSF IgM and IgG production with CSF biomarkers and to assess the pharmacodynamic effects of ocrelizumab (OCR) treatment on these parameters in patients with relapsing MS (RMS) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985).

Methods

Seventy-nine of 100 total patients with RMS had available BL CSF samples for assessment of IgG OCBs, IgG and IgM (measured at University Medical Center Göttingen), with demographic, MRI and clinical parameters representative of the total RMS population. CSF samples at either 12 (n=22), 24 (n=24) or 52 (n=17) weeks postdose and from a 12-week reference arm (no OCR; n=16) were assessed for longitudinal changes.

Results

Median (interquartile range [IQR]) CSF levels at BL were as follows: IgG index, 0.79 (0.63–1.28); IgM index, 0.19 (0.11–0.33); CD3⁺ T cell number, 2.52 (0.80–5.61) cells/µL; CXCL13, 9.89 (3.91–31.50) pg/mL; CCL19, 47.95 (31.09–70.86) pg/mL; neurofilament light chain (NfL) 1280.0 (828.1–2968.9) pg/mL. At BL, IgG index and IgM index correlated moderately with levels of B cells (r=0.65, r=0.4 respectively), T cells (r=0.54, r=0.3 respectively) and CXCL13 (r=0.58, r=0.43 respectively), but not CCL19 or NfL. IgG index tended to decrease with OCR treatment and was significantly reduced by 52 weeks (n=17/79; median [IQR] change from BL −9.5% [−20.4% to −0.1%]; p<0.02) compared with stable levels in the reference arm. While IgG OCBs were detected at BL in all patients, IgG OCBs tended to decrease with OCR treatment, with three of 17 patients having no detectable IgG OCBs at 52 weeks. Reductions in IgM index were not observed with OCR treatment.

Conclusions

Baseline CSF levels of B cells, T cells and CXCL13 correlated with IgG index and to a lesser degree IgM index in patients with RMS from the OBOE study. Significant reductions were observed in IgG index with OCR treatment, along with a trend toward reduced OCBs, with three patients showing no detectable OCBs. These data suggest that OCR impacts CSF Ig production, a hallmark of MS not previously thought to be affected by B-cell depletion therapy. These 1-year observations need to be confirmed with longer-term data and correlated with clinical response.

Background

The central vein sign (CVS) is a proposed diagnostic biomarker for MS that can be identified using FLAIR*. The robustness of 3T FLAIR*, with and without the injection of gadolinium contrast agent (Gd), for imaging the CVS in a multicenter setting has not yet been demonstrated.

Objectives

To assess the conspicuity of the CVS on 3T FLAIR* imaging acquired across different sites with and without the injection of Gd.

Methods

A cross-sectional multicenter study recruited adults with a clinical and/or radiological suspicion of having MS from 10 sites within the North American Imaging in MS (NAIMS) Cooperative. High-isotropic-resolution T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired at 3T, pre- and post-injection of Gd, along with 3D FLAIR on different scanner brands and models. T2*-EPI and FLAIR images were processed on an online imaging platform (QMENTA) to generate FLAIR* images. To objectively assess the conspicuity of the CVS inside MS lesions, lesions and veins were segmented automatically and used to compute lesion-to-vein contrast-to-noise ratio (CNR) measures. ANOVA was used to compare CNR values across sites with post-hoc Tukey Honest Significant Difference testing. Multiple testing between sites was considered by controlling the false discovery rate. One-sided paired t-testing was used to compare the overall lesion-to-vein CNR values between pre- and post-Gd FLAIR*.

Results

Seventy-eight patients from nine sites were included in the analysis; one site was excluded due to low enrollment. The overall mean(coefficient of variation, CV) lesion-to-vein CNR values across the nine sites were 0.35(14%) and 0.37(12%) for pre- and post-Gd FLAIR*, respectively. Excluding an additional site that used an unharmonized FLAIR acquisition, the resulting mean(CV) CNR values were 0.36(12%) for pre-Gd and 0.37(11%) for post-Gd FLAIR*. Across most sites, there was a significant improvement in lesion-to-vein CNR measures for post-Gd compared to pre-Gd FLAIR* [mean difference = 0.011, p < 0.001, 95% CI: (0.008,0.015)].

Conclusions

Lesion-to-vein CNR measures across sites are in line with values first published for 3T FLAIR* and demonstrate the robustness of 3T FLAIR* for imaging the CVS in a multicenter setting. Moreover, there was an increase in vein conspicuity with improvement in CNR on post-Gd FLAIR*. Based on these results, a prospective multicenter NAIMS CVS diagnostic study, sponsored by NINDS, will use 3T FLAIR* imaging with Gd in the study protocol.

Background

The mechanisms by which B-cell depletion ameliorates multiple sclerosis (MS) have not been fully delineated. Gut bacteria and their metabolites are important regulators of the systemic immune response, and early work demonstrated dysbiosis in MS. Dysregulation of immunomodulatory bacteria may contribute to the pathologic immune response in MS. We hypothesized that ocrelizumab, a B-cell depleting monoclonal antibody used to treat MS, would normalize the phenotype of gut bacteria, promoting an anti-inflammatory immune milieu.

Objectives

To characterize the taxonomic and functional shifts in the gut microbiota of MS patients induced by B-cell depletion.

Methods

We enrolled untreated, new onset MS patients and obtained longitudinal samples of paired blood and stool. We also recruited healthy controls. To date, 11 healthy controls, 16 baseline MS, 8 1-month, 9 6-month and 3 12-month post-ocrelizumab samples have been sequenced. Recruitment and follow up are ongoing; updated numbers will be presented. Gut microbiota were characterized using high-throughput long amplicon sequencing of the 16S-ITS-23S rRNA operon, allowing increased bacterial taxonomic resolution. We also performed IgA-Seq, a technique differentiating immune-reactive (IgA-coated) bacteria from those not eliciting an immune response (IgA-uncoated). IgA coating index (ICI) was calculated by dividing the IgA-coated bacteria by the uncoated fraction. Intestinal inflammation was measured using lipocalin-2 ELISA.

Results

Alpha and beta-diversity in the fecal microbiome of untreated MS patients appeared similar to that of healthy controls. B-cell depletion was not associated with changes in overall alpha or beta diversity. Analysis of composition of microbiomes (ANCOM) comparing all MS to healthy samples indicated enrichment of Monoglobus species. There was concurrent elevation of the ICI for Monoglobus. B-cell depletion was associated with trends for individual-level reductions in ICI for organisms that were highly coated at baseline. Fecal lipocalin-2 was significantly increased in MS patients and decreased after B-cell depletion.

Conclusions

Untreated MS patients exhibit increased intestinal inflammation. Moreover, a subset of immunomodulatory gut bacteria recognized as pathogenic by the immune system of untreated MS patients (e.g. with high levels of IgA coating) is less targeted by the immune system after B-cell depletion. This could impact differentiation of circulating immune cells and contribute to the efficacy of B-cell depletion in MS.

Background

Glutamic Acid Decarboxylase (GAD65) antibodies may be asymptomatic or associated with a variety of neurological manifestations. It is frequently associated with Type 1 diabetes.

Objectives

The main objective is to determine the clinical characteristics and treatments used for patients with GAD-65 antibodies.

Methods

This was an observational, retrospective, single-center study enrolling all patients found to be positive for GAD65 antibodies between January 2010 and December 2019. To select for cases thought to have neurologic manifestations of GAD65 autoantibodies, we further selected for subjects who were evaluated and assessed by the neurology service.

Results

1015 patients tested positive for GAD65 autoantibodies, but only 123 (12.1%) patients were evaluated by the neurology service. Among the subset evaluated by Neurology, the mean age was 47.1 (±20.8) and 67 (54.5%) were female. Diabetes mellitus (DM) was seen in 60 (48.8%) of the cases. The most common neurological manifestation was as follows: seizure 32 (26%), stiff-person syndrome 30 (24.4%), encephalitis 17 (13.8%), ataxia 16 (13%) and nystagmus 6 (4.9%). Thirty nine (31.7%) patients were diagnosed with peripheral neuropathy, which was likely secondary to DM in most cases. Seizure and stiffness were observed more frequently in females, although this was not a statistically significant difference.

Abnormal MRI brain was seen in 60 (48.8%) of the cases. Patient were treated with: intravenous steroid 45 (36.6%), oral steroid 59 (48%), intravenous immunoglobulin 58 (47.2%), plasmapheresis 14 (11.4%), rituximab 25 (20.3%), azathioprine 15 (12.2%), mycophenolate mofetil 12 (9.8%) and cyclophosphamide 6 (4.9%).

Conclusions

At least one tenth of GAD-65 antibody positive cases needed a neurological evaluation. The most common clinical presentations in our cohort were seizures and stiff-person syndrome.

Background

Seropositive autoimmune encephalitis is a heterogeneous and rapidly expanding diagnostic category with variable presentations and treatment responsivity.

Objectives

To determine the distribution, clinical characteristics, responses to treatment and clinical outcomes for real-world cases of confirmed seropositive autoimmune encephalitis.

Methods

Patients within a single, tertiary medical center identified to have positive blood or CSF autoantibodies on panels sent to Mayo Laboratories between January 2010 and December 2019 were identified and retrospective chart reviews were performed. Patient with low antibody titers and clinical features not suggestive of an autoimmune syndrome were excluded.

Results

1858 patients were tested for autoimmune encephalitis antibody panel. Two hundred nineteen (11.79%) had positive autoantibodies but only 42 cases fulfilled the inclusion criteria. The mean age of the patients was 53.4 (± 21.4) with 71.4% female predominance. The majority of the patients presented with altered mental status (n=15, 35.7%) or new onset seizure (n=13, 30.9%).The most common autoantibodies detected were anti NMDA (n=12, 28.6%) followed by anti LGI (n=11, 26.2%) and anti-neuronal nuclear antibody (ANNA, or anti-Hu, n=9, 21.4%). The most common treatments used were steroids (n=37, 88.1%) and IVIg (n=31, 73.8%). Rituximab was the most common second line treatment (n=20, 47.6%). The worst clinical outcomes were seen with ANNA-associated syndromes; these patients had a mean modified Rankin score of 5.8(± 0.3). Six of these patients had a small cell lung cancer. Patients with NMDA and LGI autoantibodies had a better response to treatment with mean mRS of 1.8 (± 1.03) and 1.5 (± 1.36) respectively.

Conclusions

Anti-NMDA and LGI were the most commonly detected autoantibodies in our cohort and also had the best clinical outcomes. Patient with ANNA had the worst clinical outcomes and small cell lung cancer was the most common associated malignancy.