Erdheim Chester disease – 25 year history with early CNS involvement

We report a case of Erdheim-Chester disease (ECD) with a 25-year history following initial presentation with diabetes insipidus and brainstem involvement. The exceptionally long history is particularly notable, given that ECD is a life-threatening disorder and there is a recognised association between central nervous system involvement and poor outcome. The case is a timely reminder of the presenting features of the condition, given the emergence of potential new treatment options

KIF5A and the contribution of susceptibility genotypes as a predictive biomarker for multiple sclerosis

There is increasing interest in the development of multiple sclerosis (MS) biomarkers that reflect central nervous system tissue injury to determine prognosis. We aimed to assess the prognostic value of kinesin superfamily motor protein KIF5A in MS by measuring levels of KIF5A in cerebrospinal fluid (CSF) combined with analysis of single nucleotide polymorphisms (SNPs; rs12368653 and rs703842) located within a MS susceptibility gene locus at chromosome 12q13–14 region. Enzyme-linked immunosorbent assay was used to measure KIF5A in CSF obtained from two independent biobanks comprising non-inflammatory neurological disease controls (NINDC), clinically isolated syndrome (CIS) and MS cases. CSF KIF5A expression was significantly elevated in progressive MS cases compared with NINDCs, CIS and relapsing–remitting MS (RRMS). In addition, levels of KIF5A positively correlated with change in MS disease severity scores (EDSS, MSSS and ARMSSS), in RRMS patients who had documented disease progression at 2-year clinical follow-up. Copies of adenine risk alleles (AG/AA; rs12368653 and rs703842) corresponded with a higher proportion of individuals in relapse at the time of lumbar puncture (LP), higher use of disease-modifying therapies post LP and shorter MS duration. Our study suggests that CSF KIF5A has potential as a predictive biomarker in MS and further studies into the potential prognostic value of analysing MS susceptibility SNPs should be considered

Alemtuzumab for multiple sclerosis: Long term follow-up in a multi-centre cohort

Background: Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve. Objectives: To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab. Methods: Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review. Results: One hundred patients were identified with a mean follow-up of 6.1 years (range 1–13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity. Conclusion: Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime

Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis.

In June 1999, the Association of British Neurologists (ABN) first published guidelines for the use of the licensed multiple sclerosis (MS) disease-modifying treatments (at that time β-interferon and glatiramer acetate). The guidelines were revised in 2001 and have been periodically updated since then. In 2002, following the negative assessment of these treatments by the National Institute for Health and Care Excellence (NICE), the MS risk-sharing scheme started, in which patients eligible according to the 2001 ABN guidelines were provided with treatment funded through the UK National Health Service (NHS), and monitored annually for up to 10 years.1 Recruitment to the risk-sharing scheme cohort is complete. Pending a future final evaluation, the UK Department of Health's instruction to NHS funders remains in place: that patients who fulfil the ABN criteria should continue to receive treatment funded through the NHS. The British neurological community has fully accepted the risk-sharing scheme for prescribing β-interferon and glatiramer acetate. Approximately 70 ‘treating centres’ have recruited >5000 patients between 2002 and 2005, and these have been monitored annually for 10 years; many more patients have received these treatments since 2005. The ABN published revised guidelines in 2007, and then again in 2009, following the licensing of natalizumab and mitoxantrone. This 2015 revised guideline replaces former versions. It includes all newly approved or licensed treatments for MS and represents a consensus concerning their use. These guidelines will require future revision as other treatments receive approval (eg, daclizumab and ocrelizumab): we suggest they are reviewed after an interval of no longer than 12 months. The guideline is not intended to provide a complete description of the possible complications and monitoring of disease-modifying treatments in MS; we refer prescribing neurologists to the relevant summaries of product characteristics.PostprintPeer reviewe

Accidental carbon monoxide poisoning presenting without a history of exposure: A case report

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

The disabling consequences of Mycetoma

Mycetoma is a neglected tropical disease endemic in tropical and subtropical countries, particularly Sudan. The disease is characterised by the triad of painless subcutaneous mass, multiple sinuses and discharge that contain grains. It is a chronic, debilitating disease most commonly affecting the feet or hands and leads to substantial morbidity, loss of function and even amputation. It predominantly affects poor, rural populations and patients typically present late with advanced disease and complications. In this descriptive cross-sectional study, we characterise the disabling consequences of mycetoma. The study included 300 patients; 228 (76%) male and 72 (24%) female with confirmed mycetoma seen at the Mycetoma Research Centre, University of Khartoum, Sudan in the period May 2016 and January 2017. The study design was based upon the International Classification of Functioning, Disability and Health, examining the impact of mycetoma on eight life domains. Our major finding is that mycetoma is a significantly disabling disease. Over 60% of the study population (181 patients) had moderate impairment or difficulty in at least one domain variable. The important disability was mobility impairment and walking difficulty that was reported in 119 patients (39.7%). There was significant pain associated with mycetoma lesions in 103 patients (34%), challenging the traditional view of mycetoma as a painless disease. The economic burden was also found to be substantial, with 126 patients (46.7%) reporting barriers to their ability to sustain themselves. This is the first study evaluating the disabling consequences of mycetoma and shows clear areas for intervention and further research. Options for mitigating social and economic impacts include routine integration of analgesia and physiotherapy into treatment protocols, and adapting educational provision and working practices based on disability assessment. Our data show that mycetoma is a public health issue with direct implications on quality of life

Glial Progenitor-Like Phenotype in Low-Grade Glioma and Enhanced CD133-Expression and Neuronal Lineage Differentiation Potential in High-Grade Glioma

Background: While neurosphere-as well as xenograft tumor-initiating cells have been identified in gliomas, the resemblance between glioma cells and neural stem/progenitor cells as well as the prognostic value of stem/progenitor cell marker expression in glioma are poorly clarified. Methodology/Principal Findings: Viable glioma cells were characterized for surface marker expression along the glial genesis hierarchy. Six low-grade and 17 high-grade glioma specimens were flow-cytometrically analyzed for markers characteristics of stem cells (CD133); glial progenitors (PDGFR alpha, A2B5, O4, and CD44); and late oligodendrocyte progenitors (O1). In parallel, the expression of glial fibrillary acidic protein (GFAP), synaptophysin and neuron-specific enolase (NSE) was immunohistochemically analyzed in fixed tissue specimens. Irrespective of the grade and morphological diagnosis of gliomas, glioma cells concomitantly expressed PDGFRa, A2B5, O4, CD44 and GFAP. In contrast, O1 was weakly expressed in all low-grade and the majority of high-grade glioma specimens analyzed. Co-expression of neuronal markers was observed in all high-grade, but not low-grade, glioma specimens analyzed. The rare CD133 expressing cells in low-grade glioma specimens typically co-expressed vessel endothelial marker CD31. In contrast, distinct CD133 expression profiles in up to 90% of CD45-negative glioma cells were observed in 12 of the 17 high-grade glioma specimens and the majority of these CD133 expressing cells were CD31 negative. The CD133 expression correlates inversely with length of patient survival. Surprisingly, cytogenetic analysis showed that gliomas contained normal and abnormal cell karyotypes with hitherto indistinguishable phenotype. Conclusions/Significance: This study constitutes an important step towards clarification of lineage commitment and differentiation blockage of glioma cells. Our data suggest that glioma cells may resemble expansion of glial lineage progenitor cells with compromised differentiation capacity downstream of A2B5 and O4 expression. The concurrent expression of neuronal markers demonstrates that high-grade glioma cells are endowed with multi-lineage differentiation potential in vivo. Importantly, enhanced CD133 expression marks a poor prognosis in gliomas

OPTIMISE: MS study protocol: a pragmatic, prospective observational study to address the need for, and challenges with, real world pharmacovigilance in multiple sclerosis

IntroductionThe power of ‘real world’ data to improve our understanding of the clinical aspects of multiple sclerosis (MS) is starting to be realised. Disease modifying therapy (DMT) use across the UK is driven by national prescribing guidelines. As such, the UK provides an ideal country in which to gather MS outcomes data. A rigorously conducted observational study with a focus on pharmacovigilance has the potential to provide important data to inform clinicians and patients while testing the reliability of estimates from pivotal trials when applied to patients in the UK.Methods and analysisThe primary aim of this study is to characterise the incidence and compare the risk of serious adverse events in people with MS treated with DMTs. The OPTIMISE:MS database enables electronic data capture and secure data transfer. Selected clinical data, clinical histories and patient-reported outcomes are collected in a harmonised fashion across sites at the time of routine clinical visits. The first patient was recruited to the study on 24 May 2019. As of January 2021, 1615 individuals have baseline data recorded; follow-up data are being captured and will be reported in due course.Ethics and disseminationThis study has ethical permission (London City and East; Ref 19/LO/0064). Potential concerns around data storage and sharing are mitigated by the separation of identifiable data from all other clinical data, and limiting access to any identifiable data. The results of this study will be disseminated via publication. Participants provide consent for anonymised data to be shared for further research use, further enhancing the value of the study.</jats:sec