Imperial College London

DrRichardNicholas

Faculty of MedicineDepartment of Brain Sciences

Professor of Practice (Neurology)
 
 
 
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r.nicholas

 
 
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12L12CLab BlockCharing Cross Campus

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Summary

 

Publications

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232 results found

Sridharan S, Raffel J, Nandoskar A, Record C, Brooks D, Owen D, Sharp D, Muraro P, Gunn R, Nicholas Ret al., 2018, Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [F-18]GE-180: a blocking study using XDB173 in multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 421-422, ISSN: 1352-4585

Conference paper

Baheerathan A, McNamara C, Kalam S, Rane N, Barwick TD, Grote H, Nicholas Ret al., 2018, The utility of FDG-PET imaging in distinguishing PML-IRIS from PML in a patient treated with natalizumab, NEUROLOGY, Vol: 91, Pages: 562-563, ISSN: 0028-3878

Journal article

Lozano S, Woolley P, Gabriel I, Palanicawandar R, Cencioni MT, Muraro P, Nicholas R, Omar M, Thomas S, Dlamini T, Elio R, Olavarria Eet al., 2018, Peripheral blood stem cell mobilisation with Cyclophosphamide and G-CSF in patients with Multiple Sclerosis: A safe and predictable procedure, 44th Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: 207-208, ISSN: 0268-3369

Conference paper

Supratak A, Datta G, Gafson AR, Nicholas R, Guo Y, Matthews PMet al., 2018, Remote monitoring in the home validates clinical gait measures for multiple sclerosis, Frontiers in Neurology, Vol: 9, Pages: 1-9, ISSN: 1664-2295

Background: The timed 25-foot walk (T25FW) is widely used as a clinic performance measure, but has yet to be directly validated against gait speed in the home environment.Objectives: To develop an accurate method for remote assessment of walking speed and to test how predictive the clinic T25FW is for real-life walking.Methods: An AX3-Axivity tri-axial accelerometer was positioned on 32 MS patients (Expanded Disability Status Scale [EDSS] 0–6) in the clinic, who subsequently wore it at home for up to 7 days. Gait speed was calculated from these data using both a model developed with healthy volunteers and individually personalized models generated from a machine learning algorithm.Results: The healthy volunteer model predicted gait speed poorly for more disabled people with MS. However, the accuracy of individually personalized models was high regardless of disability (R-value = 0.98, p-value = 1.85 × 10−22). With the latter, we confirmed that the clinic T25FW is strongly predictive of the maximum sustained gait speed in the home environment (R-value = 0.89, p-value = 4.34 × 10−8).Conclusion: Remote gait monitoring with individually personalized models is accurate for patients with MS. Using these models, we have directly validated the clinical meaningfulness (i.e., predictiveness) of the clinic T25FW for the first time.

Journal article

Gafson A, Kicheol K, Cencioni M, Van Hecke W, Nicholas R, Baranzini S, Matthews Pet al., 2018, Mononuclear cell transcriptome changes associated with dimethyl fumarate in multiple sclerosis., Neurology, Neuroimmunology and Neuroinflammation, Vol: 5, ISSN: 2332-7812

Objective To identify short-term changes in gene expression in peripheral blood mononuclear cells (PBMCs) associated with treatment response to dimethyl fumarate (DMF, Tecfidera) in patients with relapsing-remitting MS (RRMS).Methods Blood samples were collected from 24 patients with RRMS (median Expanded Disability Status Scale score, 2.0; range 1–7) at baseline, 6 weeks, and 15 months after the initiation of treatment with DMF (BG-12; Tecfidera). Seven healthy controls were also recruited, and blood samples were collected over the same time intervals. PBMCs were extracted from blood samples and sequenced using next-generation RNA sequencing. Treatment responders were defined using the composite outcome measure “no evidence of disease activity” (NEDA-4). Time-course and cross-sectional differential expression analyses were performed to identify transcriptomic markers of treatment response.Results Treatment responders (NEDA-4 positive, 8/24) over the 15-month period had 478 differentially expressed genes (DEGs) 6 weeks after the start of treatment. These were enriched for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inhibition of nuclear factor κB (NFκB) pathway transcripts. For patients who showed signs of disease activity, there were no DEGs at 6 weeks relative to their (untreated) baseline. Contrasting transcriptomes expressed at 6 weeks with those at 15 months of treatment, 0 and 1,264 DEGs were found in the responder and nonresponder groups, respectively. Transcripts in the nonresponder group (NEDA-4 negative, 18/24) were enriched for T-cell signaling genes.Conclusion Short-term PBMC transcriptome changes reflecting activation of the Nrf2 and inhibition of NFκB pathways distinguish patients who subsequently show a medium-term treatment response with DMF. Relative stabilization of gene expression patterns may accompany treatment-associated suppression of disease activity.

Journal article

Scalfari A, Romualdi C, Nicholas RS, Mattoscio M, Magliozzi R, Morra A, Monaco S, Muraro PA, Calabrese Met al., 2018, The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis, NEUROLOGY, Vol: 90, Pages: E2107-E2118, ISSN: 0028-3878

Objective To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS).Methods In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS.Results Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model, older age at onset (HR 1.97, p < 0.001), a larger baseline CL (HR 2.21, p = 0.005) and WM lesion (HR 1.32, p = 0.03) volume, early changes of global Cth (HR 1.36, p = 0.03), and ≥3 ERs (HR 6.08, p < 0.001) independently predicted a higher probability of SP.Conclusions Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy.

Journal article

Vermersch P, Comi G, Siva A, Oreja-Guevara C, Wiendl H, Van Wijmeersch B, Eralinna J-P, Nicholas R, Buffels R, Bernasconi C, Kuhelj Ret al., 2018, Baseline characteristics of the CASTING Study population: a Phase IIIB Trial evaluating Ocrelizumab in patients with relapsing-remitting Multiple Sclerosis and suboptimal response to disease-modifying therapies, 4th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 190-190, ISSN: 1351-5101

Conference paper

Karamita M, Nicholas R, Kokoti L, Rizou S, Mitsikostas DD, Gorgoulis V, Probert L, Papadopoulos Det al., 2018, Cellular Senescence Correlates with Demyelination, Brain Atrophy and Motor Impairment in a Model of Multiple Sclerosis, 70th Annual Meeting of the American-Academy-of-Neurology (AAN), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878

Conference paper

Magliozzi R, Howell OW, Nicholas R, Cruciani C, Castellaro M, Romualdi C, Rossi S, Pitteri M, Benedetti MD, Gajofatto A, Pizzini FB, Montemezzi S, Rasia S, Capra R, Bertoldo A, Facchiano F, Monaco S, Reynolds R, Calabrese Met al., 2018, Inflammatory intrathecal profiles and cortical damage in multiple sclerosis, Annals of Neurology, Vol: 83, Pages: 739-755, ISSN: 0364-5134

OBJECTIVE: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved.

Journal article

Karamita M, Papadopoulos D, Mitsikostas DD, Gorgoulis V, Probert L, Nicholas Ret al., 2017, Axonal damage and motor impairment correlate with glial cell senescence in a model of multiple sclerosis, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 790-791, ISSN: 1352-4585

Conference paper

Dorsey-Campbell R, Motlagh BE, Quinn T, Delacruz D, Felongco T, Walters P, Scalfari A, Singh-Curry V, Malik O, Nicholas Ret al., 2017, Discontinuation of dimethyl fumarate in relapsing multiple sclerosis in a single centre, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 893-894, ISSN: 1352-4585

Conference paper

Magliozzi R, Roncaroli F, Muraro P, Howell O, Reynolds R, Friede T, Nicholas Ret al., 2017, The impact of high level of perivenular inflammation on active white matter lesions and disease progression in multiple sclerosis, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 172-172, ISSN: 1352-4585

Conference paper

Gallagher PJ, McGuigan C, Nicholas R, Hobart J, Ford H, Petheram K, Sharrack B, Robertson N, Mazibrada G, Scolding N, Wilson M, Pearson O, Silber E, Rog D, Turner B, Harikrishnan S, Duddy M, Gray O, Jones J, Overell Jet al., 2017, Alemtuzumab after Natalizumab SWitch in Evolving Rapidly Severe Multiple Sclerosis (ANSWERS MS), 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 357-358, ISSN: 1352-4585

Conference paper

Alidina A, Raffel J, Nicholas R, 2017, Using lumbar puncture to exclude progressive multifocal leukoencephalopathy in people with multiple sclerosis on natalizumab: real life experience in a single centre, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 918-918, ISSN: 1352-4585

Conference paper

Datta G, Colasanti A, Rabiner EA, Gunn RN, Malik O, Ciccarelli O, Nicholas R, Van Vlierberghe E, Van Hecke W, Searle G, Santos-Ribeiro A, Matthews PMet al., 2017, Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis, Brain, Vol: 140, Pages: 2927-2938, ISSN: 1460-2156

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient’s disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnet

Journal article

Cencioni MT, Magliozzi R, Nicholas R, Ali R, Malik O, Reynolds R, Borsellino G, Battistini L, Muraro PAet al., 2017, Programmed death 1 is highly expressed on CD8(+) CD57(+) T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus., Immunology, Vol: 152, Pages: 660-676, ISSN: 0019-2805

Growing evidence points to a deregulated response to Epstein-Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8(+) T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD-1) and human inhibitor receptor immunoglobulin-like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8(+) CD57(+) T cells are able to kill EBV-infected cells in healthy donors. In contrast, an anergic exhaustion-like phenotype of CD8(+) CD57(+) T cells with high expression of PD-1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8(+) CD57(+) T cells in meningeal inflammatory infiltrates from post-mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.

Journal article

Datta G, Colasanti A, Kalk N, Owen DR, Scott G, Rabiner EI, Gunn R, Lingford-Hughes A, Malik O, Ciccarelli O, Nicholas R, Nie L, Battaglini M, De Stefano N, Matthews Pet al., 2017, [(11)C]PBR28 or [(18)F]PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis, Journal of Nuclear Medicine, Vol: 58, Pages: 1477-1482, ISSN: 1535-5667

Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands ((11)C-PBR28 or (18)F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region). White matter lesions (WML) were classified as "active" (DVR highest in the lesion), "peripherally active" (peri-lesional DVR highest), "inactive" (DVR highest in surrounding normal appearing white matter, NAWM) or "undifferentiated" (similar DVR across lesion, peri-lesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4x10-11). A higher proportion of lesions were inactive in patients with SPMS (35 %) than RRMS (23 %), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in brains of MS patients relative to healthy controls with two TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.

Journal article

Kamourieh S, Gananandan K, Raffel J, Nicholas Ret al., 2017, Natalizumab granule cell neuronopathy: FDG-PET in diagnosis and immune reconstitution with G-CSF, Neurology, Neuroimmunology and Neuroinflammation, Vol: 4, ISSN: 2332-7812

Granule cell neuronopathy (GCN) is a rare presentation of JC virus (JCV) infection targeting the cerebellum.1 To date, 2 cases have been described in patients prescribed natalizumab for MS.2,3 Recent case reports have acknowledged the importance of controlled reconstitution of host immunity in treating JCV-related neurologic disorders.4 In particular, granulocyte-colony stimulating factor (G-CSF) has emerged as a potential treatment.5Here, we report a case of natalizumab-associated GCN where diagnosis was aided by the novel use of FDG-PET, and immune reconstitution driven by G-CSF lead to disease stabilization and subsequent improvement.

Journal article

Montgomery SM, Kusel J, Nicholas R, Adlard Net al., 2017, Costs and effectiveness of fingolimod versus alemtuzumab in the treatment of highly active relapsing-remitting multiple sclerosis in the UK: re-treatment, discount, and disutility, Journal of Medical Economics (JME), Vol: 20, Pages: 962-973, ISSN: 1941-837X

Objective: Patients with relapsing-remitting multiple sclerosis (RRMS) treated with disease modifying therapies (DMTs) who continue to experience disease activity may be considered for escalation therapies such as fingolimod, or may be considered for alemtuzumab. Previous economic modeling used Markov models; applying one alternative technique, discrete event simulation (DES) modeling, allows re-treatment and long-term adverse events (AEs) to be included in the analysis.Methods: A DES was adapted to model relapse-triggered re-treatment with alemtuzumab and the effect of including ongoing quality-adjusted life year (QALY) decrements for AEs that extend beyond previous 1-year Markov cycles. As the price to the NHS of fingolimod in the UK is unknown, due to a confidential patient access scheme (PAS), a variety of possible discounts were tested. The interaction of re-treatment assumptions for alemtuzumab with the possible discounts for fingolimod was tested to determine which DMT resulted in lower lifetime costs. The lifetime QALY results were derived from modeled treatment effect and short- and long-term AEs.Results: Most permutations of fingolimod PAS discount and alemtuzumab re-treatment rate resulted in fingolimod being less costly than alemtuzumab. As the percentage of patients who are re-treated with alemtuzumab due to experiencing a relapse approaches 100% of those who relapse whilst on treatment, the discount required for fingolimod to be less costly drops below 5%. Consideration of treatment effect alone found alemtuzumab generated 0.2 more QALYs/patient; the inclusion of AEs up to a duration of 1 year reduced this advantage to only 0.14 QALYs/patient. Modeling AEs with a lifetime QALY decrement found that both DMTs generated very similar QALYs with the difference only 0.04 QALYs/patient.Conclusions: When the model captured alemtuzumab re-treatment and long-term AE decrements, it was found that fingolimod is cost-effective compared to alemtuzumab, assuming appl

Journal article

Raffel J, Wallace A, Gveric D, Reynolds R, Friede T, Nicholas Ret al., 2017, Patient-reported outcomes and survival in multiple sclerosis: a 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29, PLOS Medicine, Vol: 14, ISSN: 1549-1277

BackgroundThere is increasing emphasis on using patient-reported outcomes (PROs) to complement traditional clinical outcomes in medical research, including in multiple sclerosis (MS). Research, particularly in oncology and heart failure, has shown that PROs can be prognostic of hard clinical endpoints such as survival time (time from study entry until death). However, unlike in oncology or cardiology, it is unknown whether PROs are associated with survival time in neurological diseases. The Multiple Sclerosis Impact Scale–29 (MSIS-29) is a PRO sensitive to short-term change in MS, with questions covering both physical and psychological quality of life. This study aimed to investigate whether MSIS-29 scores can be prognostic for survival time in MS, using a large observational cohort of people with MS.Methods and findingsFrom 15 July 2004 onwards, MSIS-29 questionnaires were completed by people with MS registered with the MS Society Tissue Bank (n = 2,126, repeated 1 year later with n = 872 of the original respondents). By 2014, 264 participants (12.4%) had died. Higher baseline MSIS-29 physical (MSIS-29-PHYS) score was associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: hazard ratio [HR] 5.7, 95% CI 3.1–10.5, p < 0.001). Higher baseline MSIS-29 psychological score was also associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: HR 2.8, 95% CI 1.8–4.4, p < 0.001). In those with high baseline MSIS-29 scores, mortality risk was even greater if the MSIS-29 score worsened over 1 year (HR 2.3, 95% CI 1.2–4.4, p = 0.02). MSIS-29-PHYS scores were associated with survival time independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis (per 1-SD increase in MSIS-29-PHYS score: HR 1.8, 95% CI 1.1–2.9, p = 0.03). A limitation of the study is that this cohort had high baseline age and disabi

Journal article

Rhone E, Silber E, Mccormick J, Nicholas R, Malik O, Muraro P, Pagliuca A, Kazmi Met al., 2017, Investigating frequency of EBV reactivation following autologous HSCT in patients with multiple sclerosis, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S495-S495, ISSN: 0268-3369

Conference paper

Rhone E, Silber E, Mccormick J, Nicholas R, Malik O, Muraro P, Pagliuca A, Kazmi Met al., 2017, Autologous haematopoietic stem cell transplant in multiple sclerosis: Updated results from the Pan-London MS group, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S482-S483, ISSN: 0268-3369

Conference paper

Monsalvo S, Gabriel I, Sevillano B, Palanicawandar R, Innes A, Milojkovic D, Macdonald D, Chaidos A, Jakob C, Pavlu J, Nicholas R, Malik O, Kazmi M, Silber E, Kanfer E, Muraro P, Apperley JF, Olavarria Eet al., 2017, Exacerbation of multiple sclerosis symptoms in patients undergoing autologous stem cell transplantation, 43rd Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), Publisher: NATURE PUBLISHING GROUP, Pages: S419-S420, ISSN: 0268-3369

Conference paper

Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi Ret al., 2017, Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis, Nature Reviews Neurology, Vol: 13, Pages: 391-405, ISSN: 1759-4758

Autologous haematopoietic stem cell transplantation (AHSCT) is a multistep procedure that enables destruction of the immune system and its reconstitution from haematopoietic stem cells. Originally developed for the treatment of haematological malignancies, the procedure has been adapted for the treatment of severe immune-mediated disorders. Results from ~20 years of research make a compelling case for selective use of AHSCT in patients with highly active multiple sclerosis (MS), and for controlled trials. Immunological studies support the notion that AHSCT causes qualitative immune resetting, and have provided insight into the mechanisms that might underlie the powerful treatment effects that last well beyond recovery of immune cell numbers. Indeed, studies have demonstrated that AHSCT can entirely suppress MS disease activity for 4–5 years in 70–80% of patients, a rate that is higher than those achieved with any other therapies for MS. Treatment-related mortality, which was 3.6% in studies before 2005, has decreased to 0.3% in studies since 2005. Current evidence indicates that the patients who are most likely to benefit from and tolerate AHSCT are young, ambulatory and have inflammatory MS activity. Clinical trials are required to rigorously test the efficacy, safety and cost-effectiveness of AHSCT against highly active MS drugs.

Journal article

Chan D, Binks S, Nicholas JM, Frost C, Cardoso MJ, Ourselin S, Wilkie D, Nicholas R, Chataway Jet al., 2017, Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial, Lancet Neurology, Vol: 16, Pages: 591-600, ISSN: 1474-4422

BackgroundIn the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures.MethodsWe did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348.FindingsBaseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6–7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8–8·7; p<0·

Journal article

Houston S, Nandoskar A, Nicholas R, Chataway J, Greenwood J, Dubis AMet al., 2017, Microvascular Abnormalities and Inner Retinal Thickness in Multiple Sclerosis, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404

Conference paper

Montgomery SM, Maruszczak MJ, Slater D, Kusel J, Nicholas R, Adlard Net al., 2017, A discrete event simulation to model the cost-utility of fingolimod and natalizumab in rapidly evolving severe relapsing-remitting multiple sclerosis in the UK, JOURNAL OF MEDICAL ECONOMICS, Vol: 20, Pages: 474-482, ISSN: 1369-6998

Journal article

Nandoskar A, Raffel J, Scalfari AS, Friede T, Nicholas RSet al., 2017, Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis, DRUGS, Vol: 77, Pages: 885-910, ISSN: 0012-6667

Journal article

Raffel J, Sridharan S, Nicholas R, 2017, [C-11]PBR-28 positron emission tomography in multiple sclerosis: Neuroinflammation or otherwise?, Annals of Neurology, Vol: 81, Pages: 323-324, ISSN: 0364-5134

Journal article

Raffel J, Gafson AR, Dahdaleh S, Malik O, Jones B, nicholas Ret al., 2017, Inflammatory Activity on Natalizumab Predicts Short-term but not Long-term Disability in Multiple Sclerosis, PLOS One, Vol: 12, ISSN: 1932-6203

BACKGROUND: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis. OBJECTIVE: To study this association in those receiving natalizumab. METHODS: Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability. These were correlated with Expanded Disability Status Scale (EDSS) progression at years 1, 2, 3, and 3-7 after treatment initiation, versus pre-treatment baseline. RESULTS: 46/161 patients had a relapse in the first year and 44/161 had EDSS progression by year 2. Relapses and Modified Rio Score in the first year of treatment predicted EDSS progression at year 1 and 2 after treatment initiation. However, this effect disappeared with longer follow-up. Paradoxically, there was a trend towards inflammatory activity on treatment (first year Modified Rio Score, relapses, and MRI activity) predicting a lower risk of EDSS progression by years 3-7, although this did not reach statistical significance. Those with and without EDSS progression did not differ in baseline age, EDSS, or pre-treatment relapse rate. Relapses in year 0-1 predicted further relapses in years 1-3. CONCLUSIONS: Breakthrough inflammatory activity after natalizumab treatment is predictive of short-term outcome measures of relapses or EDSS progression, but does not predict longer term EDSS progression, in this cohort with high baseline disability.

Journal article

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