Chimeric antigen receptor T cells (CAR-T cells) have revolutionised cancer treatment by offering personalised therapy of unprecedented efficacy to patients with relapsed B-cell malignancies and myeloma. CAR-T cells are designed selectively to target CD19 or other B-cell antigens with high affinity, leading to a potent immune response and effective killing of malignant B cells. More recently, CAR-T treatment has been shown to be safe and effective in a very limited number of patients with severe, refractory autoimmune conditions such as systemic lupus erythematosus, systemic sclerosis and myositis. This paper describes the early use and feasibility of CAR-T therapies in the treatment of refractory autoimmune neurological diseases.

Immune checkpoint inhibition unleashes the power of the immune system against tumour cells. Immune checkpoint inhibitors (ICIs) block the inhibitory effects of cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed death protein 1 (PD-1), programmed death ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3) molecules on T-cells, and so enhance physiological cytotoxic effects. ICIs can significantly improve survival from cancers, including those previously associated with poor treatment response, such as metastatic melanoma. However, on-target off-tumour effects of ICIs result in immune-related adverse events. These toxicities are common and require new multidisciplinary expertise to manage. ICI neurotoxicity is relatively rare but ominous due to its severity, heterogenous manifestations and potential for long-term disability. Neurotoxic syndromes are novel and often present precipitously. Here, we describe ICI mechanisms of action, their impact on cancer outcomes and their frequency of immune-related adverse events. We focus particularly on neurotoxicity. We discuss the current appreciation of neurotoxic syndromes, management strategies and outcomes based on clinical expertise and consensus, multi-specialty guidance. The use of immunotherapy is expanding exponentially across multiple cancer types and so too will our approach to these cases.

Background: Neurological immune related adverse events (N-irAEs) following immune checkpoint inhibitor (ICI) therapy are associated with significant morbidity and mortality. The early involvement of neurological services is therefore recommended to assist diagnosis and guide management. However, the practical experience of specialist neurology involvement is poorly understood. Methods: A multi-centre, retrospective case note review was performed in a unified healthcare setting in the United Kingdom via predetermined proforma to investigate the involvement and impact of neurology services in this setting. Results: One hundred and nine patients with N-irAE were identified with a median time from ICI treatment to symptom onset of 52 days. Neurology service models, reasons for referral and referral rates varied by centre. Overall, eighty-seven (79.8%) patients (range 52.9–100% by centre) had neurology involvement. Neurology input was associated with younger age (median 67.2 vs. 72.8 years), anatomical location (Central > Peripheral) and severity of neurotoxicity (p < 0.001, q < 0.004). Patients with neurology involvement were more likely to undergo specialist investigations: MR imaging (p = 0.041, q = 0.043), lumbar puncture (p < 0.001, q < 0.004), and neurophysiology (p = 0.005, q = 0.007) resulting in a broader range of specific N-irAE diagnoses. Steroids were appropriately prescribed, with second line treatment (Intravenous immunoglobulins/Plasma exchange) associated with neurology involvement. At lower grades (CTCAE ≤ 2), resolution rates were similar in those with or without neurology involvement. At grades 3–4, one-third of patients with neurology involvement had resolution. In a centre with a model of early neurology involvement for all possible N-irAEs the aetiology of the neurological presentation was changed in 63.7%. Conclusions: This study highlights the potential to improve diagnosis and treatment algorithms and therefore patient outcomes through development of uniform N-irAE models of care to support this area of growing clinical need.

Multiproxy data collected from the largest inland wetland in Belize, Central America, demonstrate the presence of large-scale pre-Columbian fish-trapping facilities built by Late Archaic hunter-gatherer-fishers, which continued to be used by their Maya descendants during Formative times (approximately 2000 BCE to 200 CE). This is the earliest large-scale Archaic fish-trapping facility recorded in ancient Mesoamerica. We suggest that such landscape-scale intensification may have been a response to long-term climate disturbance recorded between 2200 and 1900 BCE. Agricultural intensification after 2000 BCE has been credited for supporting the rise of pre-Columbian civilizations in Formative Mesoamerica, but we suggest that some groups relied more heavily on the mass harvesting of aquatic resources. We argue that such early intensification of aquatic food production offered a high value subsistence strategy that was instrumental in the emergence of Formative period sedentarism and the development of complexity among pre-Columbian civilizations like the Maya.

BACKGROUND AND PURPOSE:Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a relatively recently described disease, most commonly presenting with optic neuritis and longitudinally extensive transverse myelitis. Cerebral cortical encephalitis is a rare manifestation of MOGAD. METHODS:We identified patients presenting with cerebral cortical encephalitis with positive MOG antibodies in serum across a large specialized service. Demographic and clinical information were collected. We describe clinical and laboratory characteristics, treatment response, and subsequent relapse risk in adults presenting with this phenotype. RESULTS:We identified eight patients meeting clinical criteria for cerebral cortical encephalitis with MOG antibodies. All had seizures; four had focal onset seizures with or without secondary generalization. Two patients exhibited encephalopathy, and six demonstrated focal neurological deficits at presentation. All had fluid-attenuated inversion recovery hyperintensities. Five of eight displayed cerebral swelling, and two of eight displayed leptomeningeal enhancement. Where cerebrospinal fluid (CSF) results were available, five of seven had CSF pleocytosis, protein was raised in two of seven, and one patient had oligoclonal bands unique to CSF. Median time to seizure control was 1.25 months, and all clinical features and magnetic resonance imaging abnormalities resolved. Four of eight patients (50%) had a clinical relapse, with a median time to relapse of 6.4 months. CONCLUSIONS:Cerebral cortical encephalitis appears to share similar CSF findings, steroid responsiveness, and risk of relapse with other clinical manifestations of MOGAD. This informs treatment decisions and patient counselling.

Arnhem Land, which has one of the longest records of human activity on the Australian continent, also holds one of the most important assemblages of rock art in the world. Indigenous artistic practice in this region has continued since before the Last Glacial Maximum through to the modern day, a period of at least 28 thousand years, during which time the region has undergone significant environmental and palaeogeographical changes. Rock art research in the area, however, has not considered high resolution palaeolandscape data, but rather has used coarser scale regional environmental models. This paper addresses this issue, applying detailed palaeogeographic modelling of current and former landscapes in the Red Lily Lagoon region in eastern Arnhem Land, to the spatial analysis of rock art site placement in this important cultural landscape. The resultant elevation, land cover and visibility modelling reveal significant changes in site placement strategies for rock art in the region, which appear to relate to four key phases of the landscape change that have occurred from the late Pleistocene to the late Holocene.

Background: People with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs) have attenuated IgG response following COVID-19 vaccination; however, the clinical consequences remain unclear. Objective: To report COVID-19 rates in pwMS according to vaccine serology. Methods: PwMS with available (1) serology 2–12 weeks following COVID-19 vaccine 2 and/or vaccine 3 and (2) clinical data on COVID-19 infection/hospitalisation were included. Logistic regression was performed to examine whether seroconversion following vaccination predicted risk of subsequent COVID-19 infection after adjusting for potential confounders. Rates of severe COVID-19 (requiring hospitalisation) were also calculated. Results: A total of 647 pwMS were included (mean age 48 years, 500 (77%) female, median Expanded Disability Status Scale (EDSS) 3.5% and 524 (81%) exposed to DMT at the time of vaccine 1). Overall, 472 out of 588 (73%) were seropositive after vaccines 1 and 2 and 222 out of 305 (73%) after vaccine 3. Seronegative status after vaccine 2 was associated with significantly higher odds of subsequent COVID-19 infection (odds ratio (OR): 2.35, 95% confidence interval (CI): 1.34–4.12, p = 0.0029), whereas seronegative status after vaccine 3 was not (OR: 1.05, 95% CI: 0.57–1.91). Five people (0.8%) experienced severe COVID-19, all of whom were seronegative after most recent vaccination. Conclusion: Attenuated humoral response to initial COVID-19 vaccination predicts increased risk of COVID-19 in pwMS, but overall low rates of severe COVID-19 were seen.

OBJECTIVE:Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome-wide association studies recently found the first genome-wide significant single-nucleotide variant (SNV; rs10191329A ) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management. METHODS:We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well-characterized prospective cohort of 1,455 MS patients. We used logistic regression, survival analysis, and propensity score matching to predict relevant long-term clinical outcomes. RESULTS:We were unable to detect any association between rs10191329A and a range of clinically relevant outcomes (eg, time to Expanded Disability Status Scale milestones, age-related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case-control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329A . However, we were able to replicate the association of two suggestive SNVs (rs7289446G and rs868824C ) with the development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset. INTERPRETATION:Identification of rs10191329A and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome-wide association studies associated with disease progression in neurodegenerative disorders. ANN NEUROL 2024;95:459-470.

RationaleRelapses remain a key outcome measure in multiple sclerosis (MS), are targeted by disease- modifying therapies (DMT), and guide treatment. As DMT prescribing continues to increase, it remains unclear what effect this has had on relapse frequency and phenotype over time.AimTo examine relapse patterns using 20 years of longitudinal data and correlate with DMT use.MethodProspectively collected relapse data from the South Wales MS registry was analysed from 2000- 2020. Relapse rate and phenotype according to DMT use were analysed across time epochs.ResultsOf 6,165 relapses in 1,460 patients; 76% were in females and 15% occurred on DMT. Annualised relapse rates (ARR) showed a decreasing trend from 2000 (ARR=0.23) to 2020 (ARR=0.08). Using cross- sectional analysis of data from years 2005 versus 2020, rates of DMT exposure increased from 6% to 31%, and ARR was significantly associated with DMT use (p<0.01). Polysymptomatic relapses and relapses associated with full recovery, were both more likely to occur in people on DMT.ConclusionIncreasing use of DMTs was associated with decreasing ARR in this population-based MS cohort over 20 years. We also demonstrate that relapses occurring on DMTs appear to be associated with more favourable recovery.

Infection in people with multiple sclerosis (MS) is of major concern, particularly for those receiving disease-modifying therapies. This article explores the risk of infection in people with MS and provides guidance—developed by Delphi consensus by specialists involved in their management—on how to screen for, prevent and manage infection in this population.

BackgroundSuccess of disease modifying therapy (DMT) for relapsing MS (RMS) is dependent on both effectiveness and adherence. We have explored reasons for stopping DMT in a large multicentre RMS cohort to inform disease management.MethodsData was collected from sequential RMS patients receiving a DMT in 8 UK MS centres. DMT discontinuation events were recorded according to a standardised classification comprising: adverse event, increased risk of adverse event, lack of efficacy, onset of progressive disease, patient choice, pregnancy/pre-conceptual care, other, unknown.ResultsData from 6,816 prescriptions in 4,102 patients (female 72%, mean 1.7 prescriptions, range 1-6 per patient) were analysed. The most common reason for stopping was lack of efficacy (37%) followed by adverse event (31%), increased risk of adverse event (10%) and then pregnancy/preconceptual care (9%). Reasons for stopping varied by treatment duration, age, sex and DMT. DMT discontinuation due to adverse events fell from 51% in year 1, to 15% in years 5-10; discontinuation due to lack of efficacy rose from 22% to 45%. Increasing disability was rarely a reason to stop DMT.ConclusionsThese data provide valuable insights into the real-world utility of MS DMTs and could provide a rationale to refine existing treatment pathways.

BACKGROUND:People with MS treated with anti-CD20 therapies and fingolimod often have attenuated responses to initial COVID-19 vaccination. However, uncertainties remain about the benefit of a 3rd (booster) COVID-19 vaccine in this group. METHODS:PwMS without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/- venous blood sample 2-12 weeks following COVID-19 vaccine 3. Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. RESULTS:Of 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There was no association between laboratory evidence of prior COVID-19 and seroconversion following vaccine 3. CONCLUSIONS:Approximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine.

BackgroundReal-world, long-term adherence and effectiveness data is vital to complement our under- standing of therapies, which is often based on short-term clinical trials. Here we explored disease modifying therapy (DMT) durability in a UK-wide cohort of people with Multiple Sclerosis (pwMS).MethodsIn this cohort study, which included 4,415 pwMS from 10 UK MS centres, 6,960 DMT prescrip- tions were included in the analysis (mean 1.7, range 1-6 per patient). Prescriptions without accurate start dates were excluded (n=90). Kaplan-Meier survival analysis was used to model DMT persistence (days from prescription start to stop), which was used to calculate 2, 5 and 10-year durability (% of prescrip- tions continuing).ResultsTwo-year durability was highest for immune reconstitution therapies cladribine (98%), ocrelizumab (96%), and alemtuzumab (95%). Oral therapies fingolimod (74%) and dimethyl fumarate (73%), and intravenous natalizumab (78%) shared similar durability. Injectable therapies glatiramer acetate (51%) and interferon (55%), had lowest durability. Potential confounding factors include variable date of DMT licensing, change in DMT algorithms over time and increasing DMT options.ConclusionThis multi-centre study has revealed highly variable durability between DMTs over time, which may impact real-world effectiveness. These results may inform DMT clinical decision-making and improve outcomes for pwMS.

Correction to: Chapter 6 in: E. Ch’ng et al. (eds.), Visual Heritage: Digital Approaches in Heritage Science, Springer Series on Cultural Computing, https://doi.org/10.1007/978-3-030-77028-0_6