Antigen-specific immunotherapy via delivery of tolerogenic dendritic cells for multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system resulting from loss of immune tolerance. Many disease-modifying therapies for MS have broad immunosuppressive effects on peripheral immune cells, but this can increase risks of infection and attenuate vaccine-elicited immunity. A more targeted approach is to re-establish immune tolerance in an autoantigen-specific manner. This review discusses methods to achieve this, focusing on tolerogenic dendritic cells. Clinical trials in other autoimmune diseases also provide learnings with regards to clinical translation of this approach, including identification of autoantigen(s), selection of appropriate patients and administration route and frequency.

Clinical trials for progressive multiple sclerosis: progress, new lessons learned, and remaining challenges.

Despite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis.

HLA-DRB1*15:01 and the MERTK Gene Interact to Selectively Influence the Profile of MERTK-Expressing Monocytes in Both Health and MS.

BACKGROUND AND OBJECTIVES: HLA-DRB1*15:01 (DR15) and MERTK are 2 risk genes for multiple sclerosis (MS). The variant rs7422195 is an expression quantitative trait locus for MERTK in CD14+ monocytes; cells with phagocytic and immunomodulatory potential. We aimed to understand how drivers of disease risk and pathogenesis vary with HLA and MERTK genotype and disease activity. METHODS: We investigated how proportions of monocytes vary with HLA and MERTK genotype and disease activity in MS. CD14+ monocytes were isolated from patients with MS at relapse (n = 40) and 3 months later (n = 23). Healthy controls (HCs) underwent 2 blood collections 3 months apart. Immunophenotypic profiling of monocytes was performed by flow cytometry. Methylation of 35 CpG sites within and near the MERTK gene was assessed in whole blood samples of individuals experiencing their first episode of clinical CNS demyelination (n = 204) and matched HCs (n = 345) using an Illumina EPIC array. RESULTS: DR15-positive patients had lower proportions of CD14+ MERTK+ monocytes than DR15-negative patients, independent of genotype at the MERTK SNP rs7422195. Proportions of CD14+ MERTK+ monocytes were further reduced during relapse in DR15-positive but not DR15-negative patients. Patients homozygous for the major G allele at rs7422195 exhibited higher proportions of CD14+ MERTK+ monocytes at both relapse and remission compared with controls. We observed that increased methylation of the MERTK gene was significantly associated with the presence of DR15. DISCUSSION: DR15 and MERTK genotype independently influence proportions of CD14+ MERTK+ monocytes in MS. We confirmed previous observations that the MERTK risk SNP rs7422195 is associated with altered MERTK expression in monocytes. We identified that expression of MERTK is stratified by disease in people homozygous for the major G allele of rs7422195. The finding that the proportion of CD14+ MERTK+ monocytes is reduced in DR15-positive individuals supports prior data identifying genetic links between these 2 loci in influencing MS risk. DR15 genotype-dependent alterations in methylation of the MERTK gene provides a molecular link between these loci and identifies a potential mechanism by which MERTK expression is influenced by DR15. This links DR15 haplotype to MS susceptibility beyond direct influence on antigen presentation and suggests the need for HLA-based stratification of approaches to MERTK as a therapeutic target.

The Tolerogenic Influence of Dexamethasone on Dendritic Cells Is Accompanied by the Induction of Efferocytosis, Promoted by MERTK.

Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs and upregulates MERTK expression. As MERTK can inhibit inflammation, we investigated whether dexamethasone's tolerogenic effects are mediated via MERTK, potentially providing a novel therapeutic approach. Monocyte-derived DCs were treated with dexamethasone, and with and without MERTK ligands or MERTK inhibitors. Flow cytometry was used to assess effects of MERTK modulation on co-stimulatory molecule expression, efferocytosis, cytokine secretion and T cell proliferation. The influence on expression of Rab17, which coordinates the diversion of efferocytosed material away from cell surface presentation, was assessed. Dexamethasone-treated DCs had upregulated MERTK expression, decreased expression of co-stimulatory molecules, maturation and proliferation of co-cultured T cells and increased uptake of myelin debris. MERTK ligands did not potentiate these properties, whilst specific MERTK inhibition only reversed dexamethasone's effect on myelin uptake. Cells undergoing efferocytosis had higher Rab17 expression. Dexamethasone-enhanced efferocytosis in DCs is MERTK-dependent and could exert its tolerogenic effects by increasing Rab17 expression to prevent the presentation of efferocytosed material on the cell surface to activate adaptive immune responses.

The role of the gut-microbiome-brain axis in metabolic remodeling amongst children with cerebral palsy and epilepsy.

Background: Epilepsy-associated dysbiosis in gut microbiota has been previously described, but the mechanistic roles of the gut microbiome in epileptogenesis among children with cerebral palsy (CP) have yet to be illustrated. Methods: Using shotgun metagenomic sequencing coupled with untargeted metabolomics analysis, this observational study compared the gut microbiome and metabolome of eight children with non-epileptic cerebral palsy (NECP) to those of 13 children with cerebral palsy with epilepsy (CPE). Among children with CPE, 8 had drug-sensitive epilepsy (DSE) and five had drug-resistant epilepsy (DRE). Characteristics at enrollment, medication history, and 7-day dietary intake were compared between groups. Results: At the species level, CPE subjects had significantly lower abundances of Bacteroides fragilis and Dialister invisus but higher abundances of Phascolarctobacterium faecium and Eubacterium limosum. By contrast, DRE subjects had a significantly higher colonization of Veillonella parvula. Regarding microbial functional pathways, CPE subjects had decreased abundances of pathways for serine degradation, quinolinic acid degradation, glutamate degradation I, glycerol degradation, sulfate reduction, and nitrate reduction but increased abundances of pathways related to ethanol production. As for metabolites, CPE subjects had higher concentrations of kynurenic acid, 2-oxindole, dopamine, 2-hydroxyphenyalanine, 3,4-dihydroxyphenylglycol, L-tartaric acid, and D-saccharic acid; DRE subjects had increased concentrations of indole and homovanilic acid. Conclusions: In this study, we found evidence of gut dysbiosis amongst children with cerebral palsy and epilepsy in terms of gut microbiota species, functional pathways, and metabolites. The combined metagenomic and metabolomic analyses have shed insights on the potential roles of B. fragilis and D. invisus in neuroprotection. The combined analyses have also provided evidence for the involvement of GMBA in the epilepsy-related dysbiosis of kynurenine, serotonin, and dopamine pathways and their complex interplay with neuroimmune and neuroendocrinological pathways.

Impact of telehealth on health care in a multiple sclerosis outpatient clinic during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has precipitated expansion of telemedicine in outpatient management of chronic diseases including multiple sclerosis (MS). Studies conducted pre-pandemic, when telehealth was an alternative to in-person consultations, represent a different setting to current practice. The aim of this study was to assess the impact of telehealth on MS outpatient care in a tertiary metropolitan hospital in Melbourne, Australia during the COVID-19 pandemic. METHOD: From March-December 2020, patients and clinicians in the MS outpatient clinic were surveyed regarding their attitudes towards telehealth. Scores on the Expanded Disability Status Scale (EDSS) from telehealth and face-to-face appointments during the study period were compared to scores from face-to-face consultations before and after this period. Medical records were reviewed to compare management decisions made during telehealth versus face-to-face consultations. Diagnoses and treatment of MS relapses were compared to 2019. RESULTS: Telehealth was used in 73% of outpatient appointments. Patient satisfaction was generally high. Patients and clinicians preferred face-to-face consultations but were willing to use telehealth longer term. Overall, there were no significant delays in identifying patients experiencing disability worsening via telehealth, but EDSS increase was recorded in more face-to-face than telehealth appointments particularly for those with lower baseline disability. Disease-modifying therapy commencement rates were similar, but symptomatic therapy initiation and investigation requests occurred more frequently in face-to-face visits. Comparable numbers of MS relapses were diagnosed and treated with corticosteroids in 2019 and 2020. CONCLUSIONS: Patient satisfaction with telehealth was high, but both clinicians and patients preferred in-person appointments. Telehealth implementation did not lead to high rates of undetected disability worsening or undiagnosed acute relapses, but telehealth-based EDSS assessment may underestimate lower scores. Treatment inertia may affect some management decisions during telehealth consultations. Telehealth will likely play a role in outpatient settings beyond the COVID-19 pandemic with further studies on its long-term impact on clinical outcomes required.

Designing Multi-arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis.

There are few treatments shown to slow disability progression in progressive multiple sclerosis (PMS). One challenge has been efficiently testing the pipeline of candidate therapies from preclinical studies in clinical trials. Multi-arm multistage (MAMS) platform trials may accelerate evaluation of new therapies compared to traditional sequential clinical trials. We describe a MAMS design in PMS focusing on selection of interim and final outcome measures, sample size, and statistical considerations. The UK MS Society Expert Consortium for Progression in MS Clinical Trials reviewed recent phase II and III PMS trials to inform interim and final outcome selection and design measures. Simulations were performed to evaluate trial operating characteristics under different treatment effect, recruitment rate, and sample size assumptions. People with MS formed a patient and public involvement group and contributed to the trial design, ensuring it would meet the needs of the MS community. The proposed design evaluates 3 experimental arms compared to a common standard of care arm in 2 stages. Stage 1 (interim) outcome will be whole brain atrophy on MRI at 18 months, assessed for 123 participants per arm. Treatments with sufficient evidence for slowing brain atrophy will continue to the second stage. The stage 2 (final) outcome will be time to 6-month confirmed disability progression, based on a composite clinical score comprising the Expanded Disability Status Scale, Timed 25-Foot Walk test, and 9-Hole Peg Test. To detect a hazard ratio of 0.75 for this primary final outcome with 90% power, 600 participants per arm are required. Assuming one treatment progresses to stage 2, the trial will recruit ≈1,900 participants and last ≈6 years. This is approximately two-thirds the size and half the time of separate 2-arm phase II and III trials. The proposed MAMS trial design will substantially reduce duration and sample size compared to traditional clinical trials, accelerating discovery of effective treatments for PMS. The design was well-received by people with multiple sclerosis. The practical and statistical principles of MAMS trial design may be applicable to other neurodegenerative conditions to facilitate efficient testing of new therapies.

Predicting Infection Risk in Multiple Sclerosis Patients Treated with Ocrelizumab: A Retrospective Cohort Study.

BACKGROUND: Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting. OBJECTIVE: The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS. METHODS: A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models. RESULTS: A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25-0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88-0.99), higher serum IgA (OR 0.37, 95% CI 0.17-0.80) and higher serum IgG (OR 0.81, 95% CI 0.67-0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75-0.96) and higher serum IgA (OR 0.23, 95% CI 0.07-0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06-1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02-3.86) were associated with increased odds of antimicrobial use. CONCLUSIONS: Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy.

A clinico-neurophysiological study of urogenital dysfunction in MOG-antibody transverse myelitis.

OBJECTIVE: To assess the clinical, urodynamic, and neurophysiologic features of patients with persisting bladder, bowel, and sexual dysfunction after transverse myelitis in myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease. METHODS: Patients with a history of MOG-Ab disease-related transverse myelitis seen prospectively in a tertiary center uro-neurology service between 2017 and 2019 were included. They received cross-sectional clinical assessment; completed standardized questionnaires on bladder, bowel, and sexual symptoms; and underwent urodynamic and pelvic neurophysiologic investigations. RESULTS: Twelve patients (9 male) were included with a total of 17 episodes of transverse myelitis. Mean age at first attack was 26 (SD 9) years, and median follow-up duration was 50 (interquartile range 32-87) months. Acute urinary retention requiring bladder catheterization occurred in 14 episodes and was the first symptom in 10 episodes. Patients with lesions affecting the conus medullaris required catheterization for significantly longer durations than those without a conus lesion (median difference 15.5 days, p = 0.007). At follow-up, all patients had recovered full ambulatory function, but persisting bladder and bowel dysfunction moderately or severely affected quality of life in 55% and 36%, respectively, and 82% had sexual dysfunction. Pelvic neurophysiology demonstrated abnormal residual conus function in 6 patients. Urodynamic findings predominantly showed detrusor overactivity and/or detrusor-sphincter dyssynergia, indicative of a supraconal pattern of lower urinary tract dysfunction. CONCLUSIONS: Persisting urogenital and bowel dysfunction is common despite motor recovery. Although a proportion of patients had neurophysiologic evidence of residual conus abnormalities at follow-up, predominant urodyamic findings suggest that ongoing lower urinary tract dysfunction results from supraconal injury.

Evaluating the perspective of patients with MS and related conditions on their DMT in relation to the COVID-19 pandemic in one MS centre in Australia.

OBJECTIVE: Patients with Multiple Sclerosis (MS) and on disease modifying therapies (DMTs) that can be immunosuppressive or immunomodulatory form a special group where risk of continuation of DMT needs to be taken into account with risk of contracting Covid-19. This concept can pose a degree of anxiety for patients as well as neurologists. We aimed to evaluate patient perspectives regarding the use of Natalizumab and anti-CD20 therapies (Rituximab and Ocrelizumab) in the context of the COVID-19 pandemic. METHODS: cross-sectional study conducted via voluntary survey filled in by patients with MS and related disorders receiving their infusional treatment in one MS centre in Australia, exploring their concerns regarding their therapy, their therapy and COVID-19, precautions undertaken in response to the pandemic, and factors impacting their decision-making. RESULTS: 170 patients completed the survey. Of patients on Natalizumab, the majority had either no or mild concern regarding their DMT and COVID-19, and of patients on B-cell depleting therapies, again, the majority had no or mild concern, though a slightly higher proportion had a moderate level of concern. Asked to delineate their concerns, an increased risk of contracting COVID-19 was more commonly conveyed than MS-specific factors or poor outcomes pertaining to COVID-19 if contracted, by patients in both groups. Conversely, being invited to specifically consider the possibility of contracting COVID-19 or experience a relapse of MS, almost half of the cohort rated both of equal of concern. More than half of the cohort were self-isolating more stringently than general government advice and government-related resources followed by information provided by patient's neurologist where the commonest means of information to guide decision making. CONCLUSIONS: Whilst a large proportion of patients had some concern regarding the impact of their DMT on COVID-19, whether on their risk of contracting COVID-19 or a theoretical risk for more severe disease, the overall level of concern in most cases was at most mild. Patients on B-cell depleting therapies were more inclined to express a higher level of concern. A similar concern was ascribed to a risk of a relapse or worsening MS symptoms compared to the risk of contracting COVID-19. Such attitudes may underscore a willingness of patients to continue their DMT where benefits outweigh risks during future phases of the COVID-19 pandemic.

The prevention and management of hospital admissions for urinary tract infection in patients with multiple sclerosis.

INTRODUCTION: Urinary tract infections (UTIs) are one of the commonest reasons for patients with multiple sclerosis (PwMS) presenting to hospital. Management of recurrent UTIs in PwMS can be challenging and characteristics of such patients are not well described. AIMS: To describe the neurological and urological features of PwMS presenting to hospital for UTIs and identify areas of management that could be improved to reduce UTI frequency. METHODS: Health episode statistics data were used to identify PwMS presenting to a tertiary hospital with UTI over a 5-year period. Medical records were reviewed for demographic, MS and urological history. The seven PwMS with the highest numbers of encounters were seen in a multidisciplinary clinic to enable detailed assessments. RESULTS: 52 PwMS (25 female, 27 male) with mean age of 60 had 112 emergency department presentations and 102 inpatient admissions for UTI. 24 presented multiple times and were more likely to be older and male with progressive MS. Almost two-thirds were using a urinary catheter. Less than half were under current urological and neurological follow-up. Escherichia coli and Pseudomonas spp were the commonest organisms cultured. Resistance to antibiotics was more frequent in patients with multiple presentations. CONCLUSIONS: PwMS presenting to hospital for UTIs are more often male, older, with progressive MS and high levels of disability. A small group of PwMS accounted for a large number of encounters. Preventative and management strategies can be applied in primary and secondary care settings, with an emphasis on bladder, catheter and general physical care.

Use of a symptom-based questionnaire to screen for the presence of significant voiding dysfunction in patients with multiple sclerosis and lower urinary tract symptoms: a pilot study.

INTRODUCTION: Lower urinary tract dysfunction is common in people with multiple sclerosis, leading to overactive bladder symptoms, voiding difficulties or a combination. First-line medications for overactive bladder symptoms are effective. Current guidelines recommend measuring post-void residual volume (PVR) before commencing these treatments, as they can potentially exacerbate voiding difficulties in those with significant underlying voiding dysfunction (pre-treatment PVR > 100 ml). However, facilities to do so are not readily available to all clinicians, potentially delaying effective therapy. AIMS: To conduct a pilot study investigating the association between lower urinary tract symptoms and PVR volume in people with multiple sclerosis using a validated questionnaire and to determine if questionnaire scores can be used to exclude a significantly elevated (> 100 ml) PVR volume. METHODS: Patients with multiple sclerosis referred to a tertiary hospital uro-neurology service completed the Urinary Symptom Profile questionnaire and underwent PVR measurement by bladder ultrasound. A ratio of the questionnaire low stream score/total score was calculated to standardise the relative degree of voiding symptoms compared to overall lower urinary tract symptoms. RESULTS: Of 40 patients (29 females, mean age 50 years), 30% had an elevated PVR volume. PVR volume was correlated with low stream score and ratio of low stream/total score. A cut-off of > 0.15 for low stream/total score ratio had 92% sensitivity and 71% specificity in predicting an elevated PVR volume. CONCLUSION: A symptom-based questionnaire maybe a useful screening tool to distinguish patients in whom PVR measurement is required from those who could safely start on treatment for overactive bladder symptoms.

Is It Possible to Conduct a Multi-Arm Multi-Stage Platform Trial in Parkinson's Disease: Lessons Learned from Other Neurodegenerative Disorders and Cancer.

Many potential disease modifying therapies have been identified as suitable for clinical evaluation in Parkinson's disease (PD). Currently, the evaluation of compounds in phase II and phase III clinical trials in PD are set up in isolation, a process that is lengthy, costly and lacks efficiency. This review will introduce the concept of a multi-arm, multi-stage (MAMS) trial platform which allows for the assessment of several potential therapies at once, transitioning seamlessly from a phase II safety and efficacy study to a phase III trial by means of an interim analysis. At the interim checkpoint, ineffective arms are dropped and replaced by new treatment arms, thereby allowing for the continuous evaluation of interventions. MAMS trial platforms already exist for prostate, renal and oropharyngeal cancer and are currently being developed for progressive multiple sclerosis (PMS) and motor neuron disease (MND) within the UK. As a MAMS trial will evaluate many potential treatments it is of critical importance that a widely endorsed core protocol is developed which will investigate outcomes and objectives meaningful to patients. This review will discuss the challenges of drug selection, trial design, stratification and outcome measures and will share strategies implemented in the planned MAMS trials for MND and PMS that may be of interest to the PD field.

A practical approach to assessing and managing sexual dysfunction in multiple sclerosis.

Sexual dysfunction is common in both men and women with multiple sclerosis but is often under-reported and undertreated. Neurologists report that a major barrier to discussing sexual dysfunction with patients is their lack of knowledge. Here we review the common presentations of sexual dysfunction, discuss its causes in people with multiple sclerosis, and provide a practical approach for neurologists to assess and manage these problems.

Epidemiology, symptomatology and treatment of patients with myasthenia gravis in an Australian hospital.

Myasthenia gravis (MG) is a disorder affecting neuromuscular transmission with heterogeneous manifestations and treatments. This study describes clinical features and management of MG patients at a metropolitan hospital in Australia. Overall findings were consistent with previously published data. However, frequency of intravenous immuno-globulin use was higher, reasons for which are explored. Management is best conducted through specialist clinics with necessary expertise and standardised treatment protocols.

Screening for urinary tract colonisation prior to corticosteroid administration in acute multiple sclerosis relapses: Validation of an updated algorithm.

INTRODUCTION: To evaluate an updated algorithm in the detection of urinary tract infection (UTI) prior to high-dose corticosteroid treatment in acute relapses in multiple sclerosis (MS). This updated algorithm aimed to decrease the unnecessary use of antibiotics, whilst maintaining accuracy and safety. METHODS: Prospective cohort study of 471 consecutive patients with MS relapses in a hospital-based outpatient acute relapse clinic. 172 patients met exclusion criteria, leaving 299 patients for analysis. Patients underwent urine dipstick and were treated for UTI if 2 or more of: nitrites, leukocyte esterase and cloudy urine were positive. Patients with confirmed acute MS relapse were treated with high dose intravenous or oral methylprednisolone. RESULTS: Significant bacteriuria (>105 colony forming units/mL) was present in 33 (11%, 95% CI 8-15) patients. The algorithm sensitivity and specificity was 24% and 94% respectively; the negative predictive value was 91%. The overall accuracy of the algorithm was 87%. No adverse sequelae were identified in 25 patients who received high dose methylprednisolone in the presence of an untreated UTI. CONCLUSION: With an improved specificity, this updated algorithm addresses previous issues concerning the unnecessary prescription of antibiotics, whilst improving accuracy and maintaining safety.

Diagnostic delay in a case of T-cell neurolymphomatosis.

A 69-year-old woman presented with severe subacute painful meningoradiculoneuritis. Neurophysiology showed a patchy, proximal axonal process with widespread denervation. Cerebrospinal fluid (CSF) was lymphocytic (normal T-cell predominant) with negative cytology. MRI revealed multiple sites of enhancement, but fluorodeoxyglucose positron emission tomography was negative. Bone marrow aspirate and trephine (BMAT) showed no evidence of a lymphoproliferative condition. Right brachial plexus biopsy demonstrated mixed T-cell/B-cell endoneurial inflammation not fulfilling criteria for vasculitis. She was stabilised with high-dose steroids and cyclophosphamide, followed by mycophenolate for inflammatory myeloradiculoneuritis. However, symptoms recurred when prednisolone was weaned. Although T-cell receptor gene analysis from the initial CSF demonstrated clonal rearrangements, it was only when the same clones were identified on two repeat BMATs and CSF that T-cell neurolymphomatosis, an exceedingly rare condition, was diagnosed. This case highlights the diagnostic challenge in peripheral neurolymphomatosis related to patchy disease, variable sensitivity and specificity of investigative tools, and the influence of therapies on traditional cytological definitions of lymphoma. The clinical picture, exhaustive exclusion of alternative causes and the persistence of an abnormal T-cell clone ultimately lead to a diagnostic consensus between specialist neurology and haematology clinicians.

Cerebrospinal fluid cannot be used to distinguish inflammatory myelitis from congestive myelopathy due to spinal dural arteriovenous fistula: case series.

Patients with congestive myelopathy due to spinal dural arteriovenous fistula (SDAVF) typically present with progressive sensory and motor disturbance in association with sphincter dysfunction. Spinal MRI usually shows longitudinally extensive T2 signal change. Here, we report four patients with progressive myelopathy due to SDAVF who also presented with findings on cerebrospinal fluid (CSF) examination suggestive of an inflammatory aetiology. Such CSF findings in SDAVF are important to recognise, to avoid the erroneous diagnosis of an inflammatory myelitis and inappropriate treatment with immunosuppression. SDAVF can be difficult to detect and may require repeated investigation, with formal angiography as the gold standard.