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During the safety and feasibility 'Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS)', intravenous infusion of autologous marrow was well tolerated. The efficacy of the approach is being explored in a placebo-controlled randomised controlled trial (ACTiMuS, NCT01815632) but it is not known whether repeated infusions will be required to optimise benefit. The objective of the current study was to explore the safety and feasibility of repeat treatment with intravenous autologous bone marrow for patients with progressive multiple sclerosis (MS).'SIAMMS II' was a prospective, single centre phase I extension study in which participants in the SIAMMS study were offered repeat bone marrow harvest and infusion of autologous, unfractionated bone marrow as a day-case procedure. The primary outcome measure was number of adverse events and secondary outcome measures included change in clinical rating scales of disability, global evoked potential and cranial magnetic resonance imaging (MRI).In total, 4 of the 6 participants in the SIAMMS study had repeat bone marrow harvest and infusion of filtered autologous marrow as a day case procedure which was well tolerated. There were no serious adverse effects. Additional outcome measures including clinical scales, global evoked potentials and cranial MRI were stable.SIAMMS II demonstrates the safety and feasibility of repeated, non-myeloablative autologous bone marrow-derived cell therapy in progressive MS. more...

Background: Cell-based therapies for multiple sclerosis (MS), including those employing autologous bone marrow-derived mesenchymal stromal cells (MSC) are being examined in clinical trials. However, recent studies have identified abnormalities in the MS bone marrow microenvironment. Objective: We aimed to compare the secretome of MSC isolated from control subjects (C-MSC) and people with MS (MS-MSC) and explore the functional relevance of findings. Methods: We employed high throughput proteomic analysis, enzyme-linked immunosorbent assays and immunoblotting, as well as in vitro assays of enzyme activity and neuroprotection. Results: We demonstrated that, in progressive MS, the MSC secretome has lower levels of mitochondrial fumarate hydratase (mFH). Exogenous mFH restores the in vitro neuroprotective potential of MS-MSC. Furthermore, MS-MSC expresses reduced levels of fumarate hydratase (FH) with downstream reduction in expression of master regulators of oxidative stress. Conclusions: Our findings are further evidence of dysregulation of the bone marrow microenvironment in progressive MS with respect to anti-oxidative capacity and immunoregulatory potential. Given the clinical utility of the fumaric acid ester dimethyl fumarate in relapsing–remitting MS, our findings have potential implication for understanding MS pathophysiology and personalised therapeutic intervention. more...

IntroductionThe joint ABN and RCP 2011 report advocated for changes in planning of local services to improve access to specialist reviews.1At North Bristol Trust (NBT), we restructured our ‘in-hours’ on-call service to enable early neurology review; as Ali et al.2showed, this alters diagnosis and management in up to 79% of cases referred. These changes include an increase in HOT clinic appointments (rapid access service) and pro-active review of Acute Medical Unit (AMU) patients.MethodFrom 8th August 2019, two registrars have been placed on-call during ‘in-hours’. One is dedicated to referrals and the other runs the HOT clinics and picks up referrals in AMU. Data was collected from an on-call database and processed on Excel.Results>60% reduction in time to review from referralNBT average of time to review at HOT clinic was 3.44 daysNo. of appointments doubled in September compared to June 64% (n=37) of cases were discharged on the day of reviewConclusionsService improvement shown by significant reduction in delay from referral to review in HOT clinicsProactively picking up referrals increase discharges!Reducing length of stay and investigations reduce costs incurredReferenceRCP London and the ABN. Local adult neurology services for the next decade. London: RCP, 2011.Ali E et al. The ‘hidden work’ of a hospital neurologist: 1000 consults later.European Journal of neurology2010 Apr;17(4):e28–32.melissatan095@gmail.com more...

Background: Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. Objectives: To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Methods: Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. Results: In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Conclusion: Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. more...

The potential of autologous cell-based therapies including those using multipotent mesenchymal stromal cells (MSCs) is being investigated for multiple sclerosis (MS) and other neurological conditions. However, the phenotype of MSC in neurological diseases has not been fully characterized. We have previously shown that MSC isolated from patients with progressive MS (MS-MSC) have reduced expansion potential, premature senescence, and reduced neuroprotective potential in vitro. In view of the role of antioxidants in ageing and neuroprotection, we examined the antioxidant capacity of MS-MSC demonstrating that MS-MSC secretion of antioxidants superoxide dismutase 1 (SOD1) and glutathione S-transferase P (GSTP) is reduced and correlates negatively with the duration of progressive phase of MS. We confirmed reduced expression of SOD1 and GSTP by MS-MSC along with reduced activity of SOD and GST and, to examine the antioxidant capacity of MS-MSC under conditions of nitrosative stress, we established an in vitro cell survival assay using nitric oxide-induced cell death. MS-MSC displayed differential susceptibility to nitrosative stress with accelerated senescence and greater decline in expression of SOD1 and GSTP in keeping with reduced expression of master regulators of antioxidant responses nuclear factor erythroid 2-related factor 2 and peroxisome proliferator-activated receptor gamma coactivator 1-α. Our results are compatible with dysregulation of antioxidant responses in MS-MSC and have significant implications for development of autologous MSC-based therapies for MS, optimization of which may require that these functional deficits are reversed. Furthermore, improved understanding of the underlying mechanisms may yield novel insights into MS pathophysiology and biomarker identification. more...

Background Clinical trials using ex vivo expansion of autologous mesenchymal stromal cells (MSCs) are in progress for several neurological diseases including multiple sclerosis (MS). Given that environment alters MSC function, we examined whether in vitro expansion, increasing donor age and progressive MS affect the neuroprotective properties of the MSC secretome. Methods Comparative analyses of neuronal survival in the presence of MSC-conditioned medium (MSCcm) isolated from control subjects (C-MSCcm) and those with MS (MS-MSCcm) were performed following (1) trophic factor withdrawal and (2) nitric oxide–induced neurotoxicity. Results Reduced neuronal survival following trophic factor withdrawal was seen in association with increasing expansion of MSCs in vitro and MSC donor age. Controlling for these factors, there was an independent, negative effect of progressive MS. In nitric oxide neurotoxicity, MSCcm-mediated neuroprotection was reduced when C-MSCcm was isolated from higher-passage MSCs and was negatively associated with increasing MSC passage number and donor age. Furthermore, the neuroprotective effect of MSCcm was lost when MSCs were isolated from patients with MS. Discussion Our findings have significant implications for MSC-based therapy in neurodegenerative conditions, particularly for autologous MSC therapy in MS. Impaired neuroprotection mediated by the MSC secretome in progressive MS may reflect reduced reparative potential of autologous MSC-based therapy in MS and it is likely that the causes must be addressed before the full potential of MSC-based therapy is realized. Additionally, we anticipate that understanding the mechanisms responsible will contribute new insights into MS pathogenesis and may also be of wider relevance to other neurodegenerative conditions. more...

When reconfiguring the muscle biopsy service at our hospital, it became apparent that the referral form used was inadequate. The clinical information acquired was minimal. The form did not comply with National Coding practice.1The absence of good clinical information could negatively affect the neuropathological diagnosis and income generated by the muscle biopsy service. Therefore, in collaboration with Neuropathology and Clinical Coding, we developed a new form to capture relevant clinical and coding information. To determine the impact of the new referral form, we undertook a quality improvement project.Forty muscle biopsies (2012–2016) were selected at random from the Neuropathology archives. The notes were reviewed and used to complete the new referral form. Using this information, the coding and tariffs were reassessed and compared to those produced using the original referral form. Prospective data from muscle biopsy cases (01–06/2018) were also analysed.Results demonstrated a significant improvement in quality of documentation supplied to Clinical Coding and increased diagnostic usefulness for Neuropathology. Although the new form has significantly helped the Clinical Coding team, with a simpler and more efficient coding outline that has reached National Coding Standards1, it had little impact on the income generated.References‘National Clinical Coding Standards ICD-10 5th Edition 2017 -https://hscic.kahootz.com/gf2.ti/f/762498/27838213.1/PDF/-/NCCSICD102017.pdf more...

This article provides an up-to-date evidence-based framework for the management of first presentation of an adult seizure in the emergency department. It reviews current guidelines and outlines a patient pathway from decisions to admit to discharge in the emergency department. more...

We report the case of a previously well 80-year-old man who presented with subacute bilateral painful optic neuropathy with initial response to corticosteroids but ultimately progressed to a fatal skull base syndrome. Initial presentation of steroid-responsive painful bilateral posterior optic neuropathy, preliminary normal enhanced MRI, normal cerebrospinal fluid and inflammatory markers indicated atypical optic neuritis. However, this progressed to a bilateral orbital apex syndrome with ophthalmoplegia and evidence of abnormal skull base enhancement on subsequent MRI. Biopsy of radiologically abnormal dura was non-diagnostic and negative for fungal stains. He deteriorated and died 8 months after initial presentation. At postmortem, fungal skull base infection was diagnosed. This case demonstrates that chronic skull base fungal infection can: (1) present in elderly immunocompetent patients, (2) show initial improvement with corticosteroids and (3) evade diagnosis on biopsy. We encourage a high index of suspicion for fungal skull base infection in similar cases. more...

Multiple sclerosis (MS) is a common cause of progressive neurological disability, particularly affecting young adults, and no currently available therapies have any clinically meaningful impact in reversing, halting, or even slowing progression. Stem cell therapies have for several decades held out the prospect of addressing this major therapeutic challenge. Classical cell replacement approaches envisaged transplanting stem cells to replace lost oligodendrocytes and to remyelinate denuded axons in focal MS lesions. However, the prominent role of diffuse axonal damage in generating progressive disability limits the applicability of this strategy. A second disparate approach to stem cell therapy in MS is to use autologous hematopoietic stem cells, aiming to regenerate the subject’s dysfunctional immune system and halt inflammatory damage. Finally, what we have termed restorative cell therapy aims to exploit the multiple reparative and/or disease-modifying capacities of autologous mesenchymal or other cell populations, principally from the bone marrow, but potentially from alternative tissues (such as fat), to limit and reverse tissue damage in multiple sclerosis. more...

We report the case of a 62-year-old Caucasian woman who was admitted with urinary retention and lower limb paraesthesia following a week's prodromal illness of headache and malaise. Liver function tests showed a picture of acute hepatocellular dysfunction. She developed reduced lower limb power, brisk reflexes, extensor plantars, a sensory level at T8 and reduced anal sphincter tone, establishing a clinical diagnosis of transverse myelitis. A spinal MRI showed no evidence of cauda equina or spinal cord compression. Cerebrospinal fluid (CSF) analysis showed raised protein and raised white cell count. Hepatitis E IgM and IgG were positive and hepatitis E virus was found in her CSF. She was treated with methylprednisolone and is slowly recovering with physiotherapy. more...

Objective To assess the uptake and impact of a peer mentoring scheme for core medical trainees on both mentors and mentees. Method All second year core medical trainees in the Southwest London Training programme in September 2012 were invited to mentor a first year core medical trainee. In parallel, all first year core medical trainees were invited to be mentored. Both potential mentors and mentees were asked to submit personal statements, to attend a three-session mentoring training programme and to be matched into mentoring pairs. The impact of the mentoring scheme on trainees’ behaviour and outlook was assessed through questionnaires distributed at the start and at the end of the year. Results 31 of 72 (43%) core medical trainees submitted personal statements and 40 of 72 (56%) attended training sessions. 42 trainees (58%) participated in the scheme (21 mentor/mentee pairs were established). Of the trainees who participated, 23 of 42 (55%) completed the end of year questionnaire. Participating trainees viewed the scheme positively. Reported benefits included changes in their behaviour and acquiring transferable skills that might help them in later career roles, such as an educational supervisor. The end of year questionnaire was sent to all trainees and 10 responded who had not participated. They were asked why they had not participated and their reasons included lack of time, lack of inclination and a desire for more senior mentors. Their suggestions for improvement included more structured sessions to allow the mentor/mentee pairs to meet. Conclusions This simple peer mentoring scheme was popular despite busy workloads and benefited all concerned. It is a simple effective way of supporting doctors. More work is needed to improve training for mentors and to improve access to mentoring. more...

Background Percutaneous endoscopic gastrostomy (PEG) tube insertion is a well-established method of long term enteral feeding. Although artificial feeding in the context of neurodegenerative disease presents particular challenges, relatively little is known regarding the safety and utility of PEG tube insertion in these patients with the notable exceptions of dementia, stroke and motor neurone disease. Aims and Method We sought to determine the safety and utility of PEG feeding in the context of neurodegenerative disease in a single neurosciences centre and to complete a literature review with the aim of identifying whether particular factors need to be taken into consideration to improve safety and outcome. Patients with a diagnosis of stroke or dementia were not included. Results Short term mortality and morbidity associated with PEG tube insertion were significant. Age greater than 75 years was associated with poor outcome and there was a trend towards adverse outcome in those with low serum albumin. Conclusion This study highlights the relatively high risk of PEG tube placement in patients with neurodegenerative disease. We present a number of points for consideration with the aim of improving the outcome in this particularly vulnerable group of patients. more...

Multipotent mesenchymal stromal cells (MSCs) have neuro- and glial protective properties and can influence the differentiation and maturation of oligodendrocytes. Clinical trials employing autologous MSC transplantation for the treatment of multiple sclerosis (MS) and other neurodegenerative diseases are ongoing. Extending previous studies, we have performed detailed analysis of the phenotype of MSCs derived from patients with MS using marrow samples donated as part of the ‘ACTiMuS’ trial which is examining the efficacy of unfractionated autologous bone marrow in progressive MS (NCT01815632). In keeping with previous findings, MS MSCs have comparable mesenchymal differentiation potential to MSCs isolated from control subjects. However, donor age negatively correlates with clonogenic potential and premature senescence. Using in vitro models of neuroglial toxicity, we have demonstrated that the neuroglial protective effects of soluble factors produced by MSCs decline with expansion in vitro. Significantly, media conditioned by MSCs isolated from patients with long duration of progressive disease have reduced neuroglial protective capacity. Using tandem mass spectroscopy, we have identified over 40 factors whose secretion by MSCs is altered in progressive MS. Further work will explore their relevance to MS pathogenesis and repair with the aim of identifying new drug candidates and optimisation of cell-based therapy for MS. more...

A lady in her 70s with a background of multiple sclerosis (MS) and late-onset asthma was admitted with a 2-week history of cough and shortness of breath, progressive right-sided weakness and functional decline. Investigation revealed eosinophilia, elevated myeloperoxidase antineutrophil cytoplasmic antibody, CT sinuses showed long-standing inflammatory changes consistent with sinonasal polyposis and MRI head showed lesions consistent with vasculitis. She then developed left-sided weakness and increased wheeze. Review of her case notes demonstrated that, the eosinophilia was long-standing, her asthma was severe and steroid-dependent, and her neurologic syndrome was atypical for MS. Intravenous methylprednisolone then cyclophosphamide were administered. She demonstrated remarkable improvement, becoming more alert, with improvement in left-sided weakness. A diagnosis of Churg–Strauss syndrome was established. She was discharged to a nursing home with outpatient rheumatology follow-up. The diagnosis of MS was revisited. more...

We report a case of Herpes Simplex Virus Encephalitis (HSVE) with a fatal outcome of a patient in his 70s presenting to a local teaching hospital with fever and confusion. We highlight pertinent issues regarding diagnosis, investigation and management, and consider ways of improving clinical outcomes. Finally, we discuss the differential diagnoses of acute encephalitis and review the management of HSVE. more...