Bexarotene leads to durable improvements in visual evoked potential latency: A follow-up study of the Cambridge Centre for Myelin Repair One trial.

The Cambridge Centre for Myelin Repair One (CCMR-One) trial showed that 6 months of bexarotene reduces visual evoked potential (VEP) latency in people with relapsing-remitting multiple sclerosis (MS). In a single-centre follow-up study of these participants, we re-examined full-field VEP and clinical assessments. Twenty participants (12 bexarotene and 8 placebo) were seen on average 27 months after their trial involvement. In an analysis of all eyes with recordable signal (24 bexarotene and 14 placebo), the adjusted bexarotene-placebo treatment difference in P100 latency was -7.79 (95% confidence interval (CI) = -14.76, -0.82) ms, p = 0.044. We conclude that there were durable improvements in VEP latency, suggesting long-term benefits from exposure to a remyelinating drug.

Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury.

Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Autologous haematopoietic stem cell transplantation for immune-mediated neurological diseases: what, how, who and why?

In carefully selected patients, autologous haematopoietic stem cell transplantation (HSCT) is a safe, highly effective and cost-saving treatment modality for treatment-resistant, and potentially treatment-naïve, immune-mediated neurological disorders. Although the evidence base has been growing in the last decade, limited understanding has led to confusion, mistrust and increasing use of health tourism. In this article, we discuss what autologous HSCT is, which immune-mediated conditions can be treated with it, how to select patients, what are the expected outcomes and potential adverse effects, and how cost-effective this treatment is.

Diminished seroconversion following a single SARS-COV-2 vaccine in ocrelizumab-treated relapsing-remitting multiple sclerosis patients.

BACKGROUND: Despite impressive efficacy in immunocompetent individuals, the immunogenicity of a single dose of COVID-19 vaccine in B-cell-deplete patients remains unknown. OBJECTIVES: We aimed to quantify real-world vaccine immunogenicity in ocrelizumab recipients. METHODS: We measured post-vaccination SARS-COV-2 immunoglobulin G (IgG) in ocrelizumab recipients using a highly sensitive Luminex assay. RESULTS: 44.1% of patients had detectable SARS-COV-2-IgG 21+ days after one vaccine dose, regardless of vaccine type (AZD1222 vs BNT162b2, odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.157-2.32, p = 0.72). B-cell count strongly predicted seroconversion (ß1 = 12.38, 95% CI = 4.59-20.16, p = 0.0029), but undetectable B-cells did not preclude it. The second vaccine seroconverted 53% of the patients who had not already responded to dose 1. CONCLUSION: Humoral response after one COVID-19 vaccine dose is lower than expected in CD20-deplete patients.

Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data.

Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.

Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab.

BACKGROUND: In multiple sclerosis (MS), disease effects on magnetisation transfer ratio (MTR) increase towards the ventricles. This periventricular gradient is evident shortly after first symptoms and is independent of white matter lesions. OBJECTIVE: To explore if alemtuzumab, a peripherally acting disease-modifying treatment, modifies the gradient's evolution, and whether baseline gradients predict on-treatment relapses. METHODS: Thirty-four people with relapsing-remitting MS underwent annual magnetic resonance imaging (MRI) scanning (19 receiving alemtuzumab (four scans each), 15 untreated (three scans each)). The normal-appearing white matter was segmented into concentric bands. Gradients were measured over the three bands nearest the ventricles. Mixed-effects models adjusted for age, gender, relapse rate, lesion number and brain parenchymal fraction compared the groups' baseline gradients and evolution. RESULTS: Untreated, the mean MTR gradient increased (+0.030 pu/band/year) but decreased following alemtuzumab (-0.045 pu/band/year, p = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number (p = 0.568) nor brain parenchymal fraction (p = 0.187) between those who relapsed within 4 years (n = 4) and those who did not (n = 15). However, the baseline gradient was significantly different (p = 0.020). CONCLUSION: Untreated, abnormal periventricular gradients worsen with time, but appear reversible with peripheral immunotherapy. Baseline gradients - but not lesion loads or brain volumes - may predict on-treatment relapses. Larger confirmatory studies are required.

Neurological Implications of COVID-19 Infections.

The magnitude of the COVID-19 pandemic will result in substantial neurological disease, whether through direct infection (rare), para-infectious complications (less rare), or critical illness more generally (common). Here, we raise the importance of stringent diagnosis and data collection regarding neurological complications of COVID-19; we urge caution in the over-diagnosis of neurological disease where it does not exist, but equally strongly encourage the concerted surveillance for such conditions. Additional to the direct neurological complications of COVID-19 infection, neurological patients are at risk of harm from both structural limitations (such as number of intensive care beds), and a hesitancy to treat with certain necessary medications given risk of nosocomial COVID-19 infection. We therefore also outline the specific management of patients with neuroinflammatory diseases in the context of the pandemic. This article describes the implications of COVID-19 on neurological disease and advertises the Neurocritical Care Society's international data collection collaborative that seeks to align data elements.

Quantifying normal human brain metabolism using hyperpolarized [1-13C]pyruvate and magnetic resonance imaging.

Hyperpolarized 13C Magnetic Resonance Imaging (13C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the cerebral metabolism of intravenously injected hyperpolarized [1-13C]pyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13C images demonstrated 13C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (kPL) for exchange of the hyperpolarized 13C label between [1-13C]pyruvate and the endogenous lactate pool was 0.012 ±â€¯0.006 s-1 and the apparent rate constant (kPB) for the irreversible flux of [1-13C]pyruvate to [13C]bicarbonate was 0.002 ±â€¯0.002 s-1. Imaging also revealed that [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized [1-13C]pyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.

Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis.

BACKGROUND: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. OBJECTIVE: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. METHODS: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. RESULTS: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. CONCLUSION: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.

Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study.

BACKGROUND: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years. OBJECTIVE: To evaluate infections over 6 years in alemtuzumab-treated patients. METHODS: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 µg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment. RESULTS: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%-1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk. CONCLUSION: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

Hypothyroid ataxia complicating monoclonal antibody therapy.

We present a case of cerebellar dysfunction due to severe hypothyroidism induced by pembrolizumab, a member of the 'immune checkpoint inhibitor' class of cancer immunotherapies. Thyroxine replacement completely resolved his symptoms and signs. We also discuss the neurological immune-related complications of checkpoint inhibitors.

Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation.

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28(-)CD57(+)), highly proliferative (Ki67(+)), oligoclonal, memory-like CD4 and CD8 T cells (CCR7(-)CD45RA(-) or CCR7(-)CD45RA(+)) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.

Clinical relevance of serum antibodies to extracellular N-methyl-D-aspartate receptor epitopes.

OBJECTIVE: There are now a large number of requests for N-methyl-D-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as 'Low Positive'. METHODS: The clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as 'Definite', 'Possible' or 'Unlikely'. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated. RESULTS: Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases. INTERPRETATION: Using live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.

Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis.

OBJECTIVE: We have previously shown that autoimmunity following alemtuzumab treatment of multiple sclerosis can be predicted by high baseline serum interleukin IL-21 (IL-21), as measured using a now 'redundant' enzyme linked immunosorbent assay (ELISA). Here we ask whether currently available ELISAs have similar prognostic value. DESIGN: Serum IL-21 from 141 individuals with relapsing remitting multiple sclerosis was measured using the now 'redundant' IL-21 ELISA and five further currently available kits. All patients had been treated with alemtuzumab; 61/141 had developed secondary autoimmunity. RESULTS: The 'redundant kit', and one current kit, confirmed higher baseline serum IL-21 in patients with autoimmunity (542 pg/mL vs. 222 pg/mL and 53.1 pg/mL vs. 9.3 pg/mL respectively) and showed positive correlation. However, only the 'redundant' kit had predictive utility. CONCLUSIONS: Currently available IL-21 ELISA kits should not be used to counsel individuals with multiple sclerosis considering treatment with alemtuzumab.

Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis.

Autologous haematopoietic stem cell transplantation has been tried as one experimental strategy for the treatment of patients with aggressive multiple sclerosis refractory to other immunotherapies. The procedure is aimed at ablating and repopulating the immune repertoire by sequentially mobilizing and harvesting haematopoietic stem cells, administering an immunosuppressive conditioning regimen, and re-infusing the autologous haematopoietic cell product. 'Non-myeloablative' conditioning regimens to achieve lymphocytic ablation without marrow suppression have been proposed to improve safety and tolerability. One trial with non-myeloablative autologous haematopoietic stem cell transplantation reported clinical improvement and inflammatory stabilization in treated patients with highly active multiple sclerosis. The aim of the present study was to understand the changes in the reconstituted immune repertoire bearing potential relevance to its mode of action. Peripheral blood was obtained from 12 patients with multiple sclerosis participating in the aforementioned trial and longitudinally followed for 2 years. We examined the phenotype and function of peripheral blood lymphocytes by cell surface or intracellular staining and multi-colour fluorescence activated cell sorting alone or in combination with proliferation assays. During immune reconstitution post-transplantation we observed significant though transient increases in the proportion of CD4+ FoxP3+ T cells and CD56(high) natural killer cell subsets, which are cell subsets associated with immunoregulatory function. CD8+ CD57+ cytotoxic T cells were persistently increased after therapy and were able to suppress CD4+ T cell proliferation with variable potency. In contrast, a CD161(high) proinflammatory CD8+ T cell subset was depleted at all time-points post-transplantation. Phenotypic characterization revealed that the CD161(high)CD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating in the gut mucosa but expressing the central nervous system-homing receptor CCR6. Detection of mucosal-associated invariant T cells in post-mortem multiple sclerosis brain white matter active lesions confirmed their involvement in the disease pathology. Intracellular cytokine staining demonstrated interferon γ and interleukin 17 production and lack of interleukin 10 production, a pro-inflammatory profile. Mucosal-associated invariant T cell frequency did not change in patients treated with interferon ß; and was more depleted after autologous haematopoietic stem cell transplantation than in patients who had received high-dose cyclophosphamide (n = 7) or alemtuzumab (n = 21) treatment alone, suggesting an additive or synergistic effect of the conditioning regime components. We propose that a favourably modified balance of regulatory and pro-inflammatory lymphocytes underlies the suppression of central nervous system inflammation in patients with multiple sclerosis following non-myeloablative autologous haematopoietic stem cell transplantation with a conditioning regimen consisting of cyclophosphamide and alemtuzumab.

Visual outcome measures in clinical trials of remyelinating drugs.

One of the most promising approaches to delay, prevent or reverse disability progression in multiple sclerosis (MS) is to enhance endogenous remyelination and limit axonal degeneration. In clinical trials of remyelinating drugs, there is a need for reliable, sensitive and clinically relevant outcome measures. The visual pathway, which is frequently affected by MS, provides a unique model system to evaluate remyelination of acute and chronic MS lesions in vivo and non-invasively. In this review, we discuss the different measures that have been used and scrutinise visual outcome measure selection in current and future remyelination trials.

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.

Addressing ethnic disparities in neurological research in the United Kingdom: An example from the prospective multicentre COVID-19 Clinical Neuroscience Study.

BACKGROUND: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection. METHODS: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment. RESULTS: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups. CONCLUSIONS: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here.