Different lymphocyte counts of multiple sclerosis patients treated with ofatumumab and ocrelizumab: A retrospective observational study.

Introduction: Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 (cluster of differentiation) monoclonal antibodies (mAbs) such as ocrelizumab (OCR) and ofatumumab (OFA) show a reduction mainly of B-lymphocytes, but also other lymphocyte subsets can be affected by these treatments. There is limited data on differences between lymphocyte subset counts of pwMS after treatment initiation with OCR or OFA. Objective: To compare lymphocyte subset counts after treatment initiation in pwMS treated with OCR and OFA. Methods: We analyzed 22 pwMS initiated on OFA and 56 sex-, age- and MS course matched pwMS initiated on OCR from 2 prospectively collected observational MS databases (Bern [n: OFA 14, OCR 44] and Vienna [n: OFA 8, OCR 12]) statistically comparing lymphocyte subset counts (Mann Whitney Test). Results: We found that pwMS treated with OCR showed a stronger reduction of CD20 B-lymphocytes (P = .001), and a trend towards lower counts of CD8+ T cells (P = .056) compared to pwMS treated with OFA, whereas reduction of total lymphocyte, CD4+ lymphocyte and NK cell count was equally distributed between both treatments. Conclusion: Different effects on lymphocyte subpopulations appear to be present in pwMS after treatment initiation with different anti-CD20 mAbs. Further studies are needed to determine potential effects on anti-CD20 treatment efficacy as well as treatment associated risks such as failed vaccinations and infections.

Klebsiella pneumoniae peptide hijacks a Streptococcus pneumoniae permease to subvert pneumococcal growth and colonization.

Treatment of pneumococcal infections is limited by antibiotic resistance and exacerbation of disease by bacterial lysis releasing pneumolysin toxin and other inflammatory factors. We identified a previously uncharacterized peptide in the Klebsiella pneumoniae secretome, which enters Streptococcus pneumoniae via its AmiA-AliA/AliB permease. Subsequent downregulation of genes for amino acid biosynthesis and peptide uptake was associated with reduction of pneumococcal growth in defined medium and human cerebrospinal fluid, irregular cell shape, decreased chain length and decreased genetic transformation. The bacteriostatic effect was specific to S. pneumoniae and Streptococcus pseudopneumoniae with no effect on Streptococcus mitis, Haemophilus influenzae, Staphylococcus aureus or K. pneumoniae. Peptide sequence and length were crucial to growth suppression. The peptide reduced pneumococcal adherence to primary human airway epithelial cell cultures and colonization of rat nasopharynx, without toxicity. We identified a peptide with potential as a therapeutic for pneumococcal diseases suppressing growth of multiple clinical isolates, including antibiotic resistant strains, while avoiding bacterial lysis and dysbiosis.

Sex differences in multiple sclerosis relapse presentation and outcome: a retrospective, monocentric study of 134 relapse events.

Background: Reporting of sex-specific analyses in multiple sclerosis (MS) is sparse. Disability accrual results from relapses (relapse-associated worsening) and independent thereof (progression independent of relapses). Objectives: A population of MS patients during relapse treated per standard of care was analyzed for sex differences and short-term relapse outcome (3-6 months) as measured by Expanded Disability Status Scale (EDSS) change. Design: Single-center retrospective study. Methods: We analyzed 134 MS relapses between March 2016 and August 2020. All events required relapse treatment (steroids and/or plasma exchange). Demographic, disease, and paraclinical characteristics [cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI)] were displayed separated by sex. Multivariable linear regression was run to identify factors associated with short-term EDSS change. Results: Mean age at relapse was 38.4 years (95% confidence interval: 36.3-40.4) with a proportion of 71.6% women in our cohort. Smoking was more than twice as prevalent in men (65.8%) than women (32.3%). In- and after-relapse EDSSs were higher in men [men: 3.3 (2.8-3.9), women: 2.7 (2.4-3.0); men: 3.0 (1.3-3.6); women: 1.8 (1.5-2.1)] despite similar relapse intervention. Paraclinical parameters revealed no sex differences. Our primary model identified female sex, younger age, and higher EDSS at relapse to be associated with EDSS improvement. A higher immunoglobulin G (IgG) quotient (CSF/serum) was associated with poorer short-term outcome [mean days between first relapse treatment and last EDSS assessment 130.2 (79.3-181.0)]. Conclusion: Sex and gender differences are important in outcome analyses of MS relapses. Effective treatment regimens need to respect putative markers for a worse outcome to modify long-term prognosis such as clinical and demographic variables, complemented by intrathecal IgG synthesis. Prospective trials should be designed to address these differences and confirm our results.

An analysis of 134 acute relapses of multiple sclerosis reveal sex differences influencing recovery from relapse Sex-specific analyses are important in medicine, but more knowledge is still needed. Multiple sclerosis (MS) as an inflammatory disease of the brain and spinal cord mainly affects younger people who are at risk for development of disability. Disability may result from acute relapses of the disease that insufficiently recover. Our analysis aimed to assess sex differences with a special focus on the acute relapse and 3 to 6 months later on average. We collected existing data from our center and identified 134 relapse events with sufficient data for further analysis. All relapses were treated with medical (high-dose steroids) and/or interventional treatment (plasma exchange). We analyzed the influence of sex, age, smoking, relapse severity, relapse treatment and other treatment (immunotherapy) for MS. In a second analysis, cerebrospinal fluid (CSF) and imaging (MRI) parameters were included. Our cohort consisted of 72% women. The mean age was 38 years. Smoking was twice as common in men (66%) than in women (32%). Men also experienced more severe disability in and after the relapse. Several other factors were similar between men and women. Female sex and younger age were associated with lower disability after a relapse. Paradoxically, also higher disability in the relapse was associated with lower disability later on. This might be a statistical phenomenon and partly explained by overall low disability levels in our analysis. It might therefore not be true for more advanced disease stages with higher disability. The presence of a certain CSF marker (intrathecal IgG synthesis) was associated with higher disability after the relapse. Our analysis thus identified markers associated with different relapse recovery, male vs. female sex being one of them.

Growing importance of brain morphometry analysis in the clinical routine: The hidden impact of MR sequence parameters.

Volumetric assessment based on structural MRI is increasingly recognized as an auxiliary tool to visual reading, also in examinations acquired in the clinical routine. However, MRI acquisition parameters can significantly influence these measures, which must be considered when interpreting the results on an individual patient level. This Technical Note shall demonstrate the problem. Using data from a dedicated experiment, we show the influence of two crucial sequence parameters on the GM/WM contrast and their impact on the measured volumes. A simulated contrast derived from acquisition parameters TI/TR may serve as surrogate and is highly correlated (r=0.96) with the measured contrast.

Predicting glucocorticoid resistance in multiple sclerosis relapse via a whole blood transcriptomic analysis.

AIMS: Treatment of multiple sclerosis (MS) relapses consists of short-term administration of high-dose glucocorticoids (GCs). However, over 40% of patients show an insufficient response to GC treatment. We aimed to develop a predictive model for such GC resistance. METHODS: We performed a receiver operating characteristic (ROC) curve analysis following the transcriptomic assay of whole blood samples from stable, relapsing GC-sensitive and relapsing GC-resistant patients with MS in two different European centers. RESULTS: We identified 12 genes being regulated during a relapse and differentially expressed between GC-sensitive and GC-resistant patients with MS. Using these genes, we defined a statistical model to predict GC resistance with an area under the curve (AUC) of the ROC analysis of 0.913. Furthermore, we observed that relapsing GC-resistant patients with MS have decreased GR, DUSP1, and TSC22D3 mRNA levels compared with relapsing GC-sensitive patients with MS. Finally, we showed that the transcriptome of relapsing GC-resistant patients with MS resembles those of stable patients with MS. CONCLUSION: Predicting GC resistance would allow patients to benefit from prompt initiation of an alternative relapse treatment leading to increased treatment efficacy. Thus, we think our model could contribute to reducing disability development in people with MS.

Socioeconomic and Regional Disparities in Industry-Sponsored Clinical Trials in Multiple Sclerosis.

This cross-sectional study examines the geographical and socioeconomic factors associated with trial distribution and outcome of treatment for multiple sclerosis (MS).

In Vivo and In Vitro Evidence for an Interplay between the Glucocorticoid Receptor and the Vitamin D Receptor Signaling.

Our previous work demonstrated that vitamin D (VitD) reduces experimental autoimmune encephalomyelitis (EAE) disease severity in wild-type (WT) but not in T cell-specific glucocorticoid (GC) receptor (GR)-deficient (GRlck) mice. This study aimed to investigate the interplay between the GR- and VitD receptor (VDR) signaling. In vivo, we confirmed the involvement of the GR in the VitD-induced effects in EAE using WT and GRlck mice. Furthermore, we observed that VitD-enhanced T cell apoptosis and T regulatory cell differentiation are diminished in vitro in CD3+ T cells of GRlck but not WT mice. Mechanistically, VitD does not appear to signal directly via the GR, as it does not bind to the GR, does not induce its nuclear translocation, and does not modulate the expression of two GR-induced genes. However, we observed that VitD enhances VDR protein expression in CD3+ T cells from WT but not GRlck mice in vitro, that the GR and the VDR spatially co-localize after VitD treatment, and that VitD does not modulate the expression of two VDR-induced genes in the absence of the GR. Our data suggest that a functional GR, specifically in T cells, is required for the VDR to signal appropriately to mediate the therapeutic effects of VitD.

Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort.

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce. Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort. Design: Cross-sectional analysis within a multicenter observational study. Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms. Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient (c) = 1.48, p = 0.016], more severe fatigue (c = 0.26, p < 0.0001), lower 25-OH-VD (c = -0.03, p = 0.034) and smoking (c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not. Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies.

Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial.

Importance: Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective: To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions: Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes: Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results: Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant. Conclusion and Relevance: Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration: ClinicalTrials.gov Identifier: NCT03122652.

The impact of immunotherapies on COVID-19 case fatality rates during the US vaccination campaign: a multidisciplinary open data analysis using FDA Adverse Event Reporting System and Our World in Data.

Introduction: Patients under immunotherapies were excluded from the pivotal trials of vaccinations against the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), and no population-level data on disease outcomes such as case fatality rates in relation to vaccination coverage exist. Our study aims to fill this gap by investigating whether CFRs in patients with immunotherapies decrease with increasing vaccination coverage in the total population. Methods: We combined aggregated open source data on COVID-19 vaccination coverage from "Our World in Data" with publicly available anonymized COVID-19 case reports from the FDA Adverse Event Reporting System to compute COVID-19 CFRs for patients under immunotherapy at different vaccination coverage levels in the total population. CFRs at different vaccination coverage levels were then compared to CFRs before vaccination campaign start. Results: While we found an overall decrease in CFRs on population level with increasing vaccination coverage, we found no decrease in people using anti-CD20 or glucocorticoids. Discussion: Risk-mitigation strategies on an individual- and population-level are thus still needed to lower the probability of fatal SARS-CoV2 infection for these vulnerable populations.

Modeling MOG Antibody-Associated Disorder and Neuromyelitis Optica Spectrum Disorder in Animal Models: Visual System Manifestations.

BACKGROUND AND OBJECTIVES: Mechanisms of visual impairment in aquaporin 4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disorder (MOGAD) are incompletely understood. The respective impact of optic nerve demyelination and primary and secondary retinal neurodegeneration are yet to be investigated in animal models. METHODS: Active MOG35-55 experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6Jrj mice, and monoclonal MOG-IgG (8-18C5, murine), recombinant AQP4-IgG (rAb-53, human), or isotype-matched control IgG (Iso-IgG, human) was administered 10 days postimmunization. Mobility impairment was scored daily. Visual acuity by optomotor reflex and ganglion cell complex thickness (GCC, 3 innermost retinal layers) by optical coherence tomography (OCT) were longitudinally assessed. Histopathology of optic nerve and retina was investigated during presymptomatic, acute, and chronic disease phases for immune cells, demyelination, complement deposition, natural killer (NK) cell, AQP4, and astrocyte involvement, retinal ganglion cells (RGCs), and Müller cell activation. Groups were compared by nonparametric tests with a p value <0.05 indicating statistical significance. RESULTS: Visual acuity decreased from baseline to chronic phase in MOG-IgG (mean ± standard error of the mean: 0.54 ± 0.01 to 0.46 ± 0.02 cycles/degree, p < 0.05) and AQP4-IgG EAE (0.54 ± 0.01 to 0.43 ± 0.02, cycles/degree, p < 0.05). Immune cell infiltration of optic nerves started in presymptomatic AQP4-IgG, but not in MOG-IgG EAE (5.85 ± 2.26 vs 0.13 ± 0.10 macrophages/region of interest [ROI] and 1.88 ± 0.63 vs 0.15 ± 0.06 T cells/ROI, both p < 0.05). Few NK cells, no complement deposition, and stable glial fibrillary acid protein and AQP4 fluorescence intensity characterized all EAE optic nerves. Lower GCC thickness (Spearman correlation coefficient r = -0.44, p < 0.05) and RGC counts (r = -0.47, p < 0.05) correlated with higher mobility impairment. RGCs decreased from presymptomatic to chronic disease phase in MOG-IgG (1,705 ± 51 vs 1,412 ± 45, p < 0.05) and AQP4-IgG EAE (1,758 ± 14 vs 1,526 ± 48, p < 0.01). Müller cell activation was not observed in either model. DISCUSSION: In a multimodal longitudinal characterization of visual outcome in animal models of MOGAD and NMOSD, differential retinal injury and optic nerve involvement were not conclusively clarified. Yet optic nerve inflammation was earlier in AQP4-IgG-associated pathophysiology. Retinal atrophy determined by GCC thickness (OCT) and RGC counts correlating with mobility impairment in the chronic phase of MOG-IgG and AQP4-IgG EAE may serve as a generalizable marker of neurodegeneration.

Modelling MOG antibody-associated disorder and neuromyelitis optica spectrum disorder in animal models: Spinal cord manifestations.

Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) or aquaporin 4 (AQP4-IgG) are associated with CNS inflammatory disorders. We directly compared MOG35-55-induced experimental autoimmune encephalomyelitis exacerbated by MOG- and AQP4-IgG (versus isotype IgG, Iso-IgG). Disease severity was highest after MOG-IgG application. MOG- and AQP4-IgG administration increased disease incidence compared to Iso-IgG. Inflammatory lesions appeared earlier and with distinct localizations after AQP4-IgG administration. AQP4 intensity was more reduced after AQP4- than MOG-IgG administration at acute disease phase. The described models are suitable for comparative analyses of pathological features associated with MOG- and AQP4-IgG and the investigation of therapeutic interventions.

Multidisciplinary recommendations for essential baseline functional and laboratory tests to facilitate early diagnosis and management of immune-related adverse events among cancer patients.

Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2-3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment.

Anti-kelchlike protein 11 antibody-associated encephalitis: Two case reports and review of the literature.

BACKGROUND AND PURPOSE: Kelchlike protein 11 antibodies (KLHL11-IgGs) were first described in 2019 as a marker of paraneoplastic neurological syndromes (PNSs). They have mostly been associated with testicular germ cell tumors (tGCTs). METHODS: Two patients with KLHL11-IgG encephalitis are reported, and the literature is comprehensively reviewed. RESULTS: Patient 1 had been in remission from a tGCT 10 years prior. He developed episodic vertigo and diplopia progressing over a few days. Treatment with corticosteroids (CSs) was started a few days after symptom onset. Patient 2 had transient diplopia, which resolved spontaneously. Visual problems persisted for 7 months, when he additionally developed a progressive cerebellar syndrome. One year after onset, CS treatment was started. Initial magnetic resonance imaging was unremarkable in both patients, but analysis of cerebrospinal fluid (CSF) revealed chronic inflammation. KLHL11-IgG was positive in both patients (Patient 1 only in CSF, Patient 2 in serum). Neoplastic screening has so far not revealed any signs of active underlying malignancy. We found 15 publications of 112 patients in total with KLHL11-IgG encephalitis. Most patients (n = 82) had a cerebellar syndrome with or without signs of rhombencephalitis. The most common symptoms were ataxia (n = 82) and vertigo (n = 47), followed by oculomotor disturbances (n = 35) and hearing disorders (n = 31). Eighty of 84 patients had a GCT as an underlying tumor. CONCLUSIONS: Our cases demonstrate classical symptoms of KLHL11-IgG encephalitis. Early diagnosis and therapy are imperative. As with other PNSs, clinical awareness is needed and further studies are required especially in regard to therapeutic management.

MRI signs helpful in the differentiation of patients with anterior ischaemic optic neuropathy and optic neuritis.

BACKGROUND/AIMS: The aim of this study was to identify specific MRI characteristics of anterior ischaemic optic neuropathy (AION) and optic neuritis (ON) that would aid in the differentiation between these two diagnoses. METHODS: We retrospectively analysed a consecutive case series including all patients with an MRI study of brain and orbit and the clinical diagnosis of either ON or AION. We examined the scans for restricted diffusion of the optic nerve, optic sheath diameter, enhancement and location of enhancement of the optic nerve and distribution of the white matter lesions. RESULTS: Fifty patients met the inclusion criteria. We found an accuracy of 0.98 for the discrimination between AION and ON based solely on parameters extracted from MRI data. Dominance analysis to determine the most influential parameters showed that the enhancement pattern of the optic nerve and distribution of the white matter lesions had the biggest impact on the classification and led to a discrimination accuracy of 0.9 when used alone. CONCLUSION: In patients with an inconclusive clinical diagnosis, optic nerve enhancement pattern and distribution of white matter lesions can aid in the diagnosis and differentiation between AION and ON. Diffusion-weighted imaging did not add significant information to the diagnosis or help to differentiate between the two conditions.

Anti-neurochondrin antibody as a biomarker in primary autoimmune cerebellar ataxia-a case report and review of the literature.

BACKGROUND AND PURPOSE: Neuronal autoantibodies can support the diagnosis of primary autoimmune cerebellar ataxia (PACA). Knowledge of PACA is still sparce. This article aims to highlight the relevance of anti-neurochondrin antibodies and possible therapeutical consequences in people with PACA. METHODS: This is a case presentation and literature review of PACA associated with anti-neurochondrin antibodies. RESULTS: A 33-year-old man noticed reduced control of the right leg in May 2020. During his first clinic appointment at our institution in September 2021, he complained about gait imbalance, fine motor disorders, tremor, intermittent diplopia and slurred speech. He presented a pancerebellar syndrome with stance, gait and limb ataxia, scanning speech and oculomotor dysfunction. Within 3 months the symptoms progressed. An initial cerebral magnetic resonance imaging, June 2020, was normal, but follow-up imaging in October 2021 and July 2022 revealed marked cerebellar atrophy (29% volume loss). Cerebrospinal fluid analysis showed lymphocytic pleocytosis of 11 x 103 /L (normal range 0-4) and oligoclonal bands type II. Anti-neurochondrin antibodies (immunoglobulin G) were detected in serum (1:10,000) and cerebrospinal fluid (1:320, by cell-based indirect immunofluorescence assay and immunoblot, analysed by the EUROIMMUN laboratory). After ruling out alternative causes and neoplasia, diagnosis of PACA was given and immunotherapy (steroids and cyclophosphamide) was started in January 2022. In March 2022 a stabilization of disease was observed. CONCLUSION: Cerebellar ataxia associated with anti-neurochondrin antibodies has only been described in 19 cases; however, the number of unrecognized PACAs may be higher. As anti-neurochondrin antibodies target an intracellular antigen and exhibit a mainly cytotoxic T-cell-mediated pathogenesis, important therapeutic implications may result. Because of the severe and rapid clinical progression, aggressive immunotherapy was warranted. This case highlights the need for rapid diagnosis and therapy in PACA, as stabilization and even improvement of symptoms are attainable.

Submillimeter T1 atlas for subject-specific abnormality detection at 7T.

PURPOSE: Studies at 3T have shown that T1 relaxometry enables characterization of brain tissues at the single-subject level by comparing individual physical properties to a normative atlas. In this work, an atlas of normative T1 values at 7T is introduced with 0.6 mm isotropic resolution and its clinical potential is explored in comparison to 3T. METHODS: T1 maps were acquired in two separate healthy cohorts scanned at 3T and 7T. Using transfer learning, a template-based brain segmentation algorithm was adapted to ultra-high field imaging data. After segmenting brain tissues, volumes were normalized into a common space, and an atlas of normative T1 values was established by modeling the T1 inter-subject variability. A method for single-subject comparisons restricted to white matter and subcortical structures was developed by computing Z-scores. The comparison was applied to eight patients scanned at both field strengths for proof of concept. RESULTS: The proposed method for morphometry delivered segmentation masks without statistically significant differences from those derived with the original pipeline at 3T and achieved accurate segmentation at 7T. The established normative atlas allowed characterizing tissue alterations in single-subject comparisons at 7T, and showed greater anatomical details compared with 3T results. CONCLUSION: A high-resolution quantitative atlas with an adapted pipeline was introduced and validated. Several case studies on different clinical conditions showed the feasibility, potential and limitations of high-resolution single-subject comparisons based on quantitative MRI atlases. This method in conjunction with 7T higher resolution broadens the range of potential applications of quantitative MRI in clinical practice.