Publications by year
In Press
Rodgers WJ, Friede T, Vonberg FW, Constantinescu CS, Coles A, Chataway J, Duddy M, Emsley H, Ford H, Fisniku L, et al (In Press). The Impact of Smoking Cessation on Multiple Sclerosis Disease Progression.
2023
Young CA, Ealing J, McDermott CJ, Williams TL, Al-Chalabi A, Majeed T, Talbot K, Harrower T, Faull C, Malaspina A, et al (2023). Measuring disability in amyotrophic lateral sclerosis/motor neuron disease: the WHODAS 2.0-36, WHODAS 2.0-32, and WHODAS 2.0-12.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION,
24(1-2), 63-70.
Author URL.
Young CA, Ealing J, McDermott CJ, Williams TL, Al-Chalabi A, Majeed T, Talbot K, Harrower T, Faull C, Malaspina A, et al (2023). Prevalence of depression in amyotrophic lateral sclerosis/motor neuron disease: multi-attribute ascertainment and trajectories over 30 months.
Amyotroph Lateral Scler Frontotemporal Degener,
24(1-2), 82-90.
Abstract:
Prevalence of depression in amyotrophic lateral sclerosis/motor neuron disease: multi-attribute ascertainment and trajectories over 30 months.
Objective: Evidence is equivocal about the prevalence of depression in amyotrophic lateral sclerosis (ALS). This study uses a multi-attribute ascertainment of the prevalence of depression and examines this prevalence over time. Methods: Patients with ALS were recruited into the Trajectories of Outcome in Neurological Conditions (TONiC-ALS) study. Caseness was identified by the Modified-Hospital Anxiety and Depression Scale (M-HADS). In addition, participants provided data on co-morbidities and medication use. A combination of the three was used to derive the estimate for the prevalence of depression, treated or untreated. Longitudinal data were analyzed by trajectory analysis of interval level M-HADS-Depression data. Results: Among 1120 participants, the mean age was 65.0 years (SD 10.7), 60.4% male, and the median duration since diagnosis was 9 months (IQR 4-24). Caseness of probable depression at baseline, defined by M-HADS-Depression, was 6.45% (95%CI: 5.1-8.0). Taken together with antidepressant medication and co-morbidity data, the prevalence of depression was 23.1% (95%CI: 20.7-25.6). of those with depression, 17.8% were untreated. Trajectory analysis identified three groups, one of which contained the most cases; the level of depression for each group remained almost constant over time. Conclusion: Depression affects almost a quarter of those with ALS, largely confined to a single trajectory group. Prevalence estimates based on screening for current depressive symptoms substantially under-estimate the population experiencing depression. Future prevalence studies should differentiate data based on current symptoms from those including treated patients. Both have their place in assessing depression and the response by the health care system, including medication, depending upon the hypothesis under test.
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2022
Nicholas R, Harrower T, Su R, Licata S, Vonsy J (2022). 014 Long-term effectiveness of natalizumab for RRMS: UK and global interim results from TYSABRI observational program. Journal of Neurology Neurosurgery & Psychiatry, 93(6), a18.1-a1a18.
Nicholas R, Harrower T, Liao S, Vonsy J (2022). 119 Long-term effectiveness of natalizumab for RRMS: UK and global interim results from TYSABRI observational program. Journal of Neurology Neurosurgery & Psychiatry, 93(6), a138.2-a1a138.
Nicholas R, Harrower T, Sun Z, Vonsy J (2022). LONG-TERM EFFECTIVENESS OF NATALIZUMAB FOR RRMS: UK AND GLOBAL INTERIM RESULTS FROM TYSABRI OBSERVATIONAL PROGRAM.
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Gray R, Patel S, Ives N, Rick C, Woolley R, Muzerengi S, Gray A, Jenkinson C, McIntosh E, Wheatley K, et al (2022). Long-term Effectiveness of Adjuvant Treatment with Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared with Dopamine Agonists Among Patients with Parkinson Disease Uncontrolled by Levodopa Therapy: the PD MED Randomized Clinical Trial.
JAMA Neurol,
79(2), 131-140.
Abstract:
Long-term Effectiveness of Adjuvant Treatment with Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared with Dopamine Agonists Among Patients with Parkinson Disease Uncontrolled by Levodopa Therapy: the PD MED Randomized Clinical Trial.
IMPORTANCE: Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy. OBJECTIVE: to compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020. INTERVENTIONS: Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor. MAIN OUTCOMES AND MEASURES: Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach. RESULTS: Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P =. 07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar. CONCLUSIONS AND RELEVANCE: in this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.
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Young CA, Mills RJ, Langdon D, Rog DJ, Sharrack B, Kalra S, Majeed T, Footit D, Harrower T, Nicholas RS, et al (2022). Measuring coping in multiple sclerosis: the Coping Index-MS.
Mult Scler,
28(14), 2274-2284.
Abstract:
Measuring coping in multiple sclerosis: the Coping Index-MS.
BACKGROUND: Coping in multiple sclerosis (MS) refers to cognitive and behavioural efforts to manage stresses imposed by the illness. Existing generic and disease-specific coping scales do not meet modern guidelines for scale development and cannot produce interval-level metrics to allow for change scores. OBJECTIVE: the main aim of this study was to develop a brief patient-reported outcome measure for coping in MS, capable of interval-level measurement. METHODS: Qualitative work in 43 people with MS leads to a draft scale which was administered to 5747 participants, with longitudinal collection in 2290. A calibration sample of 1000 subjects split into development and validation sets was used to generate three scales consistent with Rasch model expectations. RESULTS: the total Coping Index-MS (CI-MS-T), CI-MS-Internal (CI-MS-I) and CI-MS-External (CI-MS-E) cover total, internal and externally focused coping. All three scales are capable of interval-level measurement. Trajectory analysis of 9000 questionnaires showed two trajectories in CI-MS-T: Group 1 showed a low level of coping with slight decline over 40 months, while Group 2 had a better and stable level of coping due to improving CI-MS-I which compensated for the deteriorating CI-MS-E over time. CI-MS-T
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2021
Young CA, McDermott CJ, Williams TL, Ealing J, Majeed T, Al-Chalabi A, Dick DJ, Talbot K, Harrower T, Pinto A, et al (2021). Measuring coping in people with amyotrophic lateral sclerosis using the Coping Index-ALS: a patient derived, Rasch compliant scale.
J Neurol Sci,
421Abstract:
Measuring coping in people with amyotrophic lateral sclerosis using the Coping Index-ALS: a patient derived, Rasch compliant scale.
OBJECTIVE: the progressively disabling and terminal nature of ALS/MND imposes major coping demands on patients. We wished to improve the psychometric properties of our previously published MND-Coping Scale, so that parametric analyses were valid, and to make it simpler for patients to complete and clinicians to score. METHODS: After a new qualitative analysis of 26 patients with ALS/MND, the draft Coping Index-ALS (CI-ALS) was administered to 465 additional patients, alongside COPE-60, General Perceived Self Efficacy scale, and WHOQOL-BREF. Validity of the CI-ALS was assessed using the Rasch model. External validity was checked against comparator measures. RESULTS: Thirteen centres contributed 465 patients, mean age 64.9 years (SD 10.8), mean disease duration 28.4 months (SD 37.5). The CI-ALS-Self and CI-ALS-Others both satisfied Rasch model expectations and showed invariance across age, gender, marital status and type of onset. Expected correlations were observed with comparator scales. A nomogram is available to convert the raw scores to interval level measures suitable for parametric analysis. CONCLUSIONS: Coping abilities in ALS/MND can now be measured using a simple 21 item self-report measure, offering two subscales with a focus of 'coping by self ' and 'coping with others'. This allows clinicians to identify individuals with poor coping and facilitates research on interventions that may improve coping skills.
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Young CA, Mills R, Rog D, Sharrack B, Majeed T, Constantinescu CS, Kalra S, Harrower T, Santander H, Courtald G, et al (2021). Quality of life in multiple sclerosis is dominated by fatigue, disability and self-efficacy.
J Neurol Sci,
426Abstract:
Quality of life in multiple sclerosis is dominated by fatigue, disability and self-efficacy.
BACKGROUND AND OBJECTIVE: Quality of life in multiple sclerosis (MS) reflects complex relationships between symptoms (fatigue, spasticity pain, and bladder or vision dysfunction), disability, health perceptions, and self-efficacy. METHODS: in this cross-sectional study, a self-report questionnaire pack of patient reported outcome measures was collected from 5695 people with MS (pwMS) alongside clinical data from their neurologists. Each patient reported outcome measure was converted to interval-scaled estimates following fit to the Rasch model. The patient reported outcome measures, as well as perceived health, age, disease subtype and gender, were then subject to path analysis to analyse their relationships with quality of life (QoL), guided by the Wilson and Clearly conceptual framework. RESULTS: the final model explains 81.2% of the variance of QoL. Fatigue is clearly dominant, suggesting a means to intervene and improve QoL. The next most influential factors were disability and self-efficacy, which have similar effect levels. The model can be replicated for pwMS on disease modifying therapy and is largely invariant for gender and disease subtype. Age had an insignificant effect. CONCLUSIONS: in order to promote better QoL, MS care should include management of fatigue, interventions to ameliorate disability, and support to enhance self-efficacy. The range of skills needed for these treatments will require input from medical, nursing, therapy and psychology staff, so these findings provide evidence substantiating the need for pwMS to be provided with care by comprehensive multidisciplinary teams.
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2020
Middleton RM, Pearson OR, Ingram G, Craig EM, Rodgers WJ, Downing-Wood H, Hill J, Tuite-Dalton K, Roberts C, Watson L, et al (2020). A Rapid Electronic Cognitive Assessment Measure for Multiple Sclerosis: Validation of Cognitive Reaction, an Electronic Version of the Symbol Digit Modalities Test.
Journal of Medical Internet Research,
22(9), e18234-e18234.
Abstract:
A Rapid Electronic Cognitive Assessment Measure for Multiple Sclerosis: Validation of Cognitive Reaction, an Electronic Version of the Symbol Digit Modalities Test
. Background
. Incorporating cognitive testing into routine clinical practice is a challenge in multiple sclerosis (MS), given the wide spectrum of both cognitive and physical impairments people can have and the time that testing requires. Shortened paper and verbal assessments predominate but still are not used routinely. Computer-based tests are becoming more widespread; however, changes in how a paper test is implemented can impact what exactly is being assessed in an individual. The Symbol Digit Modalities Test (SDMT) is one validated test that forms part of the cognitive batteries used in MS and has some computer-based versions. We developed a tablet-based SDMT variant that has the potential to be ultimately deployed to patients’ own devices.
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. Objective
. This paper aims to develop, validate, and deploy a computer-based SDMT variant, the Cognition Reaction (CoRe) test, that can reliably replicate the characteristics of the paper-based SDMT.
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. Methods
. We carried out analysis using Pearson and intraclass correlations, as well as a Bland-Altman comparison, to examine consistency between the SDMT and CoRe tests and for test-retest reliability. The SDMT and CoRe tests were evaluated for sensitivity to disability levels and age. A novel metric in CoRe was found: question answering velocity could be calculated. This was evaluated in relation to disability levels and age for people with MS and compared with a group of healthy control volunteers.
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. Results
. SDMT and CoRe test scores were highly correlated and consistent with 1-month retest values. Lower scores were seen in patients with higher age and some effect was seen with increasing disability. There was no learning effect evident. Question answering velocity demonstrated a small increase in speed over the 90-second duration of the test in people with MS and healthy controls.
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. Conclusions
. This study validates a computer-based alternative to the SDMT that can be used in clinics and beyond. It enables accurate recording of elements of cognition relevant in MS but offers additional metrics that may offer further value to clinicians and people with MS.
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Lin S, Green HD, Hendy P, Heerasing NM, Chanchlani N, Hamilton B, Walker GJ, Heap GA, Hobart J, Martin RJ, et al (2020). Clinical Features and Genetic Risk of Demyelination Following Anti-TNF Treatment.
J Crohns Colitis,
14(12), 1653-1661.
Abstract:
Clinical Features and Genetic Risk of Demyelination Following Anti-TNF Treatment.
BACKGROUND: Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and to test whether affected patients were genetically predisposed to multiple sclerosis [MS]. METHODS: We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF exposure. We compared genetic risk scores [GRS], calculated using carriage of 43 susceptibility loci for MS, in 48 cases with 1219 patients exposed to anti-TNF who did not develop demyelination. RESULTS: Overall, 39 [74%] cases were female. The median age [range] of patients at time of demyelination was 41.5 years [20.7-63.2]. The median duration of anti-TNF treatment was 21.3 months [0.5-99.4] and 19 [36%] patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord, or both. Complete recovery was reported in 12 [23%] patients after a median time of 6.8 months [0.1-28.7]. After 33.0 months of follow-up, partial recovery was observed in 29 [55%] patients, relapsing and remitting episodes in nine [17%], progressive symptoms in three [6%]: two [4%] patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 × 10-4, standard deviation [SD] 0.0039) and controls [mean -1.1 × 10-3, SD 0.0042] [p = 0.23]. CONCLUSIONS: Patients who experienced demyelination events following anti-TNF exposure were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not experience demyelination events. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.
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Edge R, Mills R, Tennant A, Diggle PJ, Young CA, Al-Chalabi A, Williams TL, Dick DJ, Talbot K, Burke G, et al (2020). Do pain, anxiety and depression influence quality of life for people with amyotrophic lateral sclerosis/motor neuron disease? a national study reconciling previous conflicting literature.
JOURNAL OF NEUROLOGY,
267(3), 607-615.
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Edge R, Mills R, Tennant A, Diggle PJ, Young CA, Al-Chalabi A, Williams TL, Dick DJ, Talbot K, Burke G, et al (2020). Do pain, anxiety and depression influence quality of life for people with amyotrophic lateral sclerosis/motor neuron disease? a national study reconciling previous conflicting literature (vol 267, pg 607, 2020).
JOURNAL OF NEUROLOGY,
267(3), 616-617.
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Butzkueven H, Kappos L, Wiendl H, Trojano M, Spelman T, Chang I, Kasliwal R, Jaitly S, Campbell N, Ho P-R, et al (2020). Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP).
Journal of Neurology, Neurosurgery & Psychiatry,
91(6), 660-668.
Abstract:
Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP)
ObjectiveThe Tysabri Observational Programme (TOP), which began >10 years ago, is an open-label, multinational, prospective observational study evaluating the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients.MethodsThese data provide a 10-year interim analysis of safety and effectiveness in TOP. Annualised relapse rates (ARRs) and disability progression/improvement were analysed using the Poisson model and the Kaplan-Meier method, respectively. Analyses included patients on natalizumab and those who discontinued natalizumab but remained in TOP.ResultsAs of November 2017, TOP included 6148 patients. Overall, 829 patients (13.5%) experienced ≥1 serious adverse event (SAE), with infection the most common (4.1%). Fifty-three patients (0.9%) had confirmed progressive multifocal leukoencephalopathy. SAE data were consistent with natalizumab’s known safety profile; no new safety signals were identified. A total of 3210 patients (52.2%) discontinued natalizumab; 2117 (34.4%) withdrew from TOP. Median time on natalizumab was 3.3 (range 0–11.6) years; median follow-up time was 5.2 (range 0–10.8) years. The on-natalizumab ARR was 0.15, a 92.5% reduction from the year before initiation. Ten-year cumulative probabilities of disability worsening and improvement were 27.8% and 33.1%, respectively. On-natalizumab ARRs were similar between patients who discontinued or remained on natalizumab, suggesting limited attrition bias.ConclusionsSince the TOP 5-year interim analysis (December 2012), cohort size (6148 vs 4821), median exposure (3.3 vs 1.8 years) and median follow-up time (62 vs 26 months) have increased. This 10-year interim analysis further supports the robust real-world effectiveness and well-established safety profile of natalizumab.Trial registration numberNCT00493298.
Abstract.
Young CA, Mills R, Al-Chalabi A, Burke G, Chandran S, Dick DJ, Ealing J, Hanemann CO, Harrower T, Mcdermott CJ, et al (2020). Measuring quality of life in ALS/MND: validation of the WHOQOL-BREF.
Amyotroph Lateral Scler Frontotemporal Degener, 1-9.
Abstract:
Measuring quality of life in ALS/MND: validation of the WHOQOL-BREF.
Objectives: the World Health Organization Quality of Life-BREF Scale (WHOQOL-BREF) is a generic QOL measure with four domains covering Physical, Psychological, Social and Environment. Providing the opportunity to contrast QoL with other conditions, or with population norms, the current study had three aims: 1) can the established domains of the WHOQOL-BREF be validated within a large ALS/MND population; 2) can a total score be validated and 3) can they provide interval level measurement? Methods: Data were obtained from the Trajectories of Outcomes in Neurological Conditions study. Internal construct validity was determined by fit of the data to the Rasch measurement model. Results: 636 participants with ALS/MND were included. All domains, except the Social domain, showed satisfactory fit to the Rasch model. All were unidimensional, and showed no Differential Item Functioning by age, gender, or onset type. Finally, a total score was validated from a bi-factor perspective. Conclusions: the WHOQOL-BREF is valid for use in populations with ALS/MND and can be analyzed to yield interval level measurement: it offers a range of domains that reflect QOL, which can be used for parametric analysis and for comparison with other conditions or general populations, two advantages for its inclusion as a trial outcome measure and for observational studies.
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2019
Hawton A, Green C, Goodwin E, Harrower T (2019). Health state utility values (QALY weights) for Huntington's disease: an analysis of data from the European Huntington's Disease Network (EHDN).
Eur J Health Econ,
20(9), 1335-1347.
Abstract:
Health state utility values (QALY weights) for Huntington's disease: an analysis of data from the European Huntington's Disease Network (EHDN).
BACKGROUND: Huntington's Disease (HD) is a hereditary neurodegenerative disorder which affects individuals' ability to walk, talk, think, and reason. Onset is usually in the forties, there are no therapies currently available that alter disease course, and life expectancy is 10-20 years from diagnosis. The gene causing HD is fully penetrant, with a 50% probability of passing the disease to offspring. Although the impacts of HD are substantial, there has been little report of the quality of life of people with the condition in a manner that can be used in economic evaluations of treatments for HD. Health state utility values (HSUVs), used to calculate quality-adjusted life-years (QALYs), are the metric commonly used to inform such healthcare policy decision-making. OBJECTIVES: the aim was to report HSUVs for HD, with specific objectives to use European data to: (i) describe HSUVs by demographic and clinical characteristics; (ii) compare HSUVs of people with HD in the UK with population norms; (iii) identify the relative strength of demographic and clinical characteristics in predicting HSUVs. METHODS: European Huntington's Disease Network REGISTRY study data were used for analysis. This is a multi-centre, multi-national, observational, longitudinal study, which collects six-monthly demographic, clinical, and patient-reported outcome measures, including the SF-36. SF-36 scores were converted to SF-6D HSUVs and described by demographic and clinical characteristics. HSUVs from people with HD in the UK were compared with population norms. Regression analysis was used to estimate the relative strength of age, gender, time since diagnosis, and disease severity (according to the Total Function Capacity (TFC) score, and the UHDRS's Motor score, Behavioural score, and Cognition score) in predicting HSUVs. RESULTS: 11,328 questionnaires were completed by 5560 respondents with HD in 12 European countries. Women generally had lower HSUVs than men, and HSUVs were consistently lower than population norms for those with HD in the UK, and dropped with increasing disease severity. The regression model significantly accounted for the variance in SF-6D scores (n = 1939; F [7,1931] = 120.05; p
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Lennox B, Yeeles K, Jones PB, Zandi M, Joyce E, Yu LM, Tomei G, Pollard R, Vincent SA, Shimazaki M, et al (2019). Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: Study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2).
Trials,
20(1).
Abstract:
Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: Study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2)
Background: Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods: We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2-4 consecutive days no later than 7 days from baseline. It will continue 4-5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2-3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion: the SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration: ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.
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Nicholas R, Harrower T, Jiang X, Licata S, Vonsy J (2019). NATALIZUMAB TREATMENT FOR MS: UK AND GLOBAL RESULTS FROM TOP.
Author URL.
Young CA, Ealing J, McDermott C, Williams T, Al-Chalabi A, Majeed T, Burke G, Pinto A, Dick D, Talbot K, et al (2019). The relationships between symptoms, disability, perceived health and quality of life in amyotrophic lateral sclerosis/motor neuron disease.
Amyotroph Lateral Scler Frontotemporal Degener,
20(5-6), 317-327.
Abstract:
The relationships between symptoms, disability, perceived health and quality of life in amyotrophic lateral sclerosis/motor neuron disease.
Objectives: Using the Wilson and Cleary model linking clinical variables to quality of life, we explored the associations between physical and psychological factors, disability, perceived health and quality of life in ALS/MND. Methods: the ongoing UK study of Trajectories of Outcomes in Neurological Conditions (TONiC) recruited participants with ALS/MND to complete a questionnaire pack including demographic factors and several patient reported outcome measures (PROMs); a clinician provided data on disease onset type and duration since diagnosis. All PROMs were transformed from ordinal raw scores to interval-scaled latent estimates via the Rasch measurement model. Results: Data from 636 patients were analyzed; mean age 65.1 years (SD 10.7), 61.3% male. Median duration since diagnosis was 11.2 months (IQR 4.6-29.9; range 0.4-295.9 months); 67.3% had limb and 27.3% bulbar onset disease. Symptoms such as breathlessness and fatigue, along with most domains of activity limitations, were shown to vary by onset type. A series of models illustrated the importance of physical functioning and anxiety upon quality of life, with breathlessness and fatigue having indirect effects. The models were invariant for gender and onset type. Conclusions: This large study highlights the importance of functional status and anxiety as key variables influencing quality of life in ALS/MND. The nature and diversity of factors, both physical and psychological, which have been shown to influence the quality of life of people with ALS/MND provide strong evidence in support of the widespread implementation of multidisciplinary care.
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2018
Milinis K, Tennant A, Mills RJ, Al-Chalabi A, Burke G, Dick DJ, Ealing J, Hanemann CO, Harrower T, McDermott CJ, et al (2018). Development and validation of Spasticity Index-Amyotrophic Lateral Sclerosis.
Acta Neurol Scand,
138(1), 47-54.
Abstract:
Development and validation of Spasticity Index-Amyotrophic Lateral Sclerosis.
OBJECTIVES: Spasticity is a common and disabling feature of amyotrophic lateral sclerosis (ALS). There are currently no validated ALS-specific measures of spasticity. The aim of this study was to develop and use a self-report outcome measure for spasticity in ALS. METHODS: Following semi-structured interviews with 11 ALS patients, a draft scale was administered across ALS clinics in the UK. Internal validity of the scale was examined using the Rasch model. The numerical rating scale (NRS) for spasticity and Leeds Spasticity scale (LSS) were co-administered. The final scale was used in a path model of spasticity and quality of life. RESULTS: a total of 465 patients (mean age 64.7 years (SD 10), 59% male) with ALS participated. Spasticity was reported by 80% of subjects. A pool of 71 items representing main themes of physical symptoms, negative impact and modifying factors was subject to an iterative process of item reduction by Rasch analysis resulting in a 20-item scale-the Spasticity Index for ALS (SI-ALS)-which was unidimensional and free from differential item functioning. Moderate correlations were found with LSS and NRS-spasticity. Incorporating the latent estimate of spasticity into a path model, greater spasticity reduced quality of life and motor function; higher motor function was associated with better quality of life. CONCLUSIONS: the SI-ALS is a disease-specific self-report scale, which provides a robust interval-level measure of spasticity in ALS. Spasticity has a substantial impact on quality of life in ALS.
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Kapoor R, Ho P-R, Campbell N, Chang I, Deykin A, Forrestal F, Lucas N, Yu B, Arnold DL, Freedman MS, et al (2018). Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. The Lancet Neurology, 17(5), 405-415.
Maxan A, Mason S, Saint-Pierre M, Smith E, Ho A, Harrower T, Watts C, Tai Y, Pavese N, Savage JC, et al (2018). Outcome of cell suspension allografts in a patient with Huntington's disease.
Ann Neurol,
84(6), 950-956.
Abstract:
Outcome of cell suspension allografts in a patient with Huntington's disease.
For patients with incurable neurodegenerative disorders such as Huntington's (HD) and Parkinson's disease, cell transplantation has been explored as a potential treatment option. Here, we present the first clinicopathological study of a patient with HD in receipt of cell-suspension striatal allografts who took part in the NEST-UK multicenter clinical transplantation trial. Using various immunohistochemical techniques, we found a discrepancy in the survival of grafted projection neurons with respect to grafted interneurons as well as major ongoing inflammatory and immune responses to the grafted tissue with evidence of mutant huntingtin aggregates within the transplant area. Our results indicate that grafts can survive more than a decade post-transplantation, but show compromised survival with inflammation and mutant protein being observed within the transplant site. Ann Neurol 2018;84:950-956.
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Middleton RM, Rodgers WJ, Chataway J, Schmierer K, Rog D, Galea I, Akbari A, Tuite-Dalton K, Lockhart-Jones H, Griffiths D, et al (2018). Validating the portal population of the United Kingdom Multiple Sclerosis Register.
Mult Scler Relat Disord,
24, 3-10.
Abstract:
Validating the portal population of the United Kingdom Multiple Sclerosis Register.
The UK Multiple Sclerosis Register (UKMSR) is a large cohort study designed to capture 'real world' information about living with multiple sclerosis (MS) in the UK from diverse sources. The primary source of data is directly from people with Multiple Sclerosis (pwMS) captured by longitudinal questionnaires via an internet portal. This population's diagnosis of MS is self-reported and therefore unverified. The second data source is clinical data which is captured from MS Specialist Treatment centres across the UK. This includes a clinically confirmed diagnosis of MS (by Macdonald criteria) for consented patients. A proportion of the internet population have also been consented at their hospital making comparisons possible. This dataset is called the 'linked dataset'. The purpose of this paper is to examine the characteristics of the three datasets: the self-reported portal data, clinical data and linked data, in order to assess the validity of the self-reported portal data. The internet (n = 11,021) and clinical (n = 3,003) populations were studied for key shared characteristics. We found them to be closely matched for mean age at diagnosis (clinical = 37.39, portal = 39.28) and gender ratio (female %, portal = 73.1, clinical = 75.2). The Two Sample Kolmogorov-Smirnov test was for the continuous variables to examine is they were drawn from the same distribution. The null hypothesis was rejected only for age at diagnosis (D = 0.078, p
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Author URL.
2017
Shivane A, Edwards P, Hilton D, Cunningham R, Nabarro L, Harrower T (2017). A case of meningo-encephalitis with unusual neuropathology.
Author URL.
McGeachan AJ, Hobson EV, Al-Chalabi A, Stephenson J, Chandran S, Crawley F, Dick D, Donaghy C, Ellis CM, Gorrie G, et al (2017). A multicentre evaluation of oropharyngeal secretion management practices in amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Frontotemporal Degener,
18(1-2), 1-9.
Abstract:
A multicentre evaluation of oropharyngeal secretion management practices in amyotrophic lateral sclerosis.
Failure to clear oral secretions can be debilitating for patients with amyotrophic lateral sclerosis (ALS), but the treatment of this symptom is poorly defined and there is no consensus on best practice. The objective of this study was to identify the treatments that are commonly prescribed, and to describe how experienced clinicians manage a patient with treatment resistant symptoms. Twenty-three clinicians were approached, of which 19 from 16 centres across the UK provided case report forms for a total of 119 ALS patients identified as having problematic oral secretions. The use of five anticholinergics, salivary gland botulinum toxin injections, conservative management approaches and carbocisteine were reported. of the 72 patients who were evaluated following the initiation of a first anticholinergic, 61% had symptomatic improvement. Only 19% of patients achieved symptomatic improvement with the use of an alternative anticholinergic when an initial anticholinergic achieved no symptomatic improvement. Problems with thick and thin secretions often coexisted, with 37% of patients receiving treatment for both types of problem. In conclusion, a variety of treatment options are employed by expert clinicians for problematic oral secretions in ALS patients. The variation in management highlights the need for further prospective research in this area.
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Author URL.
Muthukumar M, Desai K, Abogunrin S, Harrower T, Gabriel S, Dinet J (2017). Cost-effectiveness analysis of abobotulinumtoxinA for the treatment of cervical dystonia in the United Kingdom.
Clinicoecon Outcomes Res,
9, 211-229.
Abstract:
Cost-effectiveness analysis of abobotulinumtoxinA for the treatment of cervical dystonia in the United Kingdom.
BACKGROUND: Cervical dystonia (CD) involves painful involuntary contraction of the neck and shoulder muscles and abnormal posture in middle-aged adults. Botulinum neurotoxin type a (BoNT-A) is effective in treating CD but little is known about its associated cost-effectiveness. OBJECTIVE: to evaluate the cost-effectiveness of abobotulinumtoxinA for treating CD from the UK payer perspective. METHODS: a Markov model was developed to evaluate the cost-effectiveness of abobotulinum-toxinA versus best supportive care (BSC) in CD, with a lifetime horizon and health states for response, nonresponse, secondary nonresponse, and BSC in patients with CD (mean age: 53 years; 37% male). Clinical improvement measured using Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was mapped to utility using data from a randomized trial of abobotulinumtoxinA. Health care resource use, costs, and other inputs were from the British National Formulary, Personal Social Services Research Unit, published literature, or expert opinion. Costs and outcomes were discounted at 3.5% per annum. RESULTS: in the base case, the incremental lifetime quality-adjusted life-years (QALYs) gained from abobotulinumtoxinA arm versus BSC was 0.253 per patient, whereas the incremental cost was £7,160, leading to an incremental cost-effectiveness ratio (ICER) of £30,468 per QALY. One-way sensitivity analyses showed that these results were sensitive to the proportion of responders to abobotulinumtoxinA at first injection, duration between injections, the number of reinjections allowed among primary nonresponders, and any difference in baseline TWSTRS value between the BSC and abobotulinumtoxinA arms. Probabilistic sensitivity analysis showed that abobotulinumtoxinA was cost-effective 46% and 49% of times at thresholds of £20,000 and £30,000 per QALY, respectively. Scenarios are considered including vial-sharing, productivity losses, secondary response/nonresponse at subsequent injections, 5-year time horizon, and alternative reinjection intervals for BoNT-As produced ICERs ranging from cost-saving to £40,777 per QALY, versus BSC. CONCLUSION: AbobotulinumtoxinA was found to be cost-effective in treating adults with CD, at acceptable willingness-to-pay thresholds in the UK.
Abstract.
Author URL.
Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung H-P, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, et al (2017). Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. New England Journal of Medicine, 376(3), 221-234.
2015
Dinet J, Desai K, Brand S, Abogunrin S, Gabriel S, Harrower T (2015). 61. AbobotulinumtoxinA in the management of cervical dystonia (CD) in the United Kingdom (UK): a budget impact analysis (BIA). Toxicon, 93
Desai K, Muthukumar M, Abogunrin S, Harrower T, Dinet J, Gabriel S (2015). ABOBOTULINUMTOXIN a IN THE MANAGEMENT OF CERVICAL DYSTONIA IN THE UNITED KINGDOM: a COST-EFFECTIVENESS ANALYSIS.
Author URL.
Abogunrin S, Brand S, Desai K, Dinet J, Gabriel S, Harrower T (2015). AbobotulinumtoxinA in the management of cervical dystonia in the United Kingdom: a budget impact analysis.
Clinicoecon Outcomes Res,
7, 441-449.
Abstract:
AbobotulinumtoxinA in the management of cervical dystonia in the United Kingdom: a budget impact analysis.
BACKGROUND: Cervical dystonia (CD) can be effectively managed by a combination of botulinum neurotoxin a (BoNT-A) and conventional therapy (skeletal muscle relaxants and rehabilitative therapy), but the costs of different interventions in the UK vary. METHODS: a budget impact model was developed from the UK payer perspective with a 5-year time horizon to evaluate the effects of changing market shares of abobotulinumtoxinA, onabotulinumtoxinA, and incobotulinumtoxinA, and best supportive care from the UK payer perspective. Epidemiological and resource use data were retrieved from the published literature and clinical expert opinion. Deterministic sensitivity analyses were performed to determine the parameters most influential on the budgetary findings under base case assumptions. RESULTS: Under base case assumptions, an increased uptake of abobotulinumtoxinA showed an accumulated savings of £2,250,992 by year 5. Treatment per patient per year with onabotulinumtoxinA and incobotulinumtoxinA costs more when compared to treatment with abobotulinumtoxinA. One-way sensitivity analyses showed that the prevalence of CD, dose per injection of each of the BoNT-As, and time to reinjection of incobotulinumtoxinA and abobotulinumtoxinA influenced the base case findings most. CONCLUSION: There is potential for cost savings associated with the greater use of abobotulinumtoxinA rather than other BoNT-A treatments, permitting more patients to benefit more from effective BoNT-A treatment with a fixed budget.
Abstract.
Author URL.
Dharia S, Harrower T (2015). CNS RELAPSE OF NHL MASQUERADING AS MILLER FISHER SYNDROME.
Author URL.
2014
Greaves RF, Woollard GA, Hoad KE, Walmsley TA, Johnson LA, Briscoe S, Koetsier S, Harrower T, Gill JP (2014). Laboratory medicine best practice guideline: Vitamins A, E and the carotenoids in blood.
Clinical Biochemist Reviews,
35(2), 81-113.
Abstract:
Laboratory medicine best practice guideline: Vitamins A, E and the carotenoids in blood
Despite apparent method similarities between laboratories there appear to be confounding factors inhibiting uniform reporting and standardisation of vitamin assays. The Australasian Association of Clinical Biochemists (AACB) Vitamins Working Party, in conjunction with the Royal College of Pathologists of Australasia Quality Assurance Programs, has formulated a guideline to improve performance, reproducibility and accuracy of fat-soluble vitamin results. The aim of the guideline is to identify critical pre-analytical, analytical and post-analytical components of the analysis of vitamins A, E and carotenoids in blood to promote best practice and harmonisation. This best practice guideline has been developed with reference to the Centers for Disease Control and Prevention (CDC) "Laboratory Medicine Best Practices: Developing an Evidence-Based Review and Evaluation Process". The CDC document cites an evaluation framework for generating best practice recommendations that are specific to laboratory medicine. These 50 recommendations proposed herein, were generated from a comprehensive literature search and the extensive combined experience of the AACB Vitamins Working Party members. They were formulated based on comparison between an impact assessment rating and strength of evidence and were classified as either: (1) strongly recommend, (2) recommend, (3) no recommendation for or against, or (4) recommend against. These best practice recommendations represent the consensus views, in association with peer reviewed evidence of the AACB Vitamins Working Party, towards best practice for the collection, analysis and interpretation of vitamins A, E and carotenoids in blood.
Abstract.
PD Med Collaborative Group, Gray R, Ives N, Rick C, Patel S, Gray A, Jenkinson C, McIntosh E, Wheatley K, Williams A, et al (2014). Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial.
Lancet,
384(9949), 1196-1205.
Abstract:
Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial.
BACKGROUND: Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease. METHODS: in this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316. FINDINGS: Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5-3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0-2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01-0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0·81, 95% CI 0·61-1·08, p=0·14), admissions to institutions (0·86, 0·63-1·18; p=0·4), and death (0·85, 0·69-1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p
Abstract.
Author URL.
2013
Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C, Shah TS, Spencer C, Booth D, Goris A, et al (2013). Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
Nature Genetics,
45(11), 1353-1362.
Abstract:
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10 -4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10 -8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals. © 2013 Nature America, Inc. All rights reserved.
Abstract.
Hobson EV, McGeachan A, Al-Chalabi A, Chandran S, Crawley F, Dick D, Donaghy C, Ealing J, Ellis CM, Gorrie G, et al (2013). Management of sialorrhoea in motor neuron disease: a survey of current UK practice.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration,
14(7-8), 521-527.
Abstract:
Management of sialorrhoea in motor neuron disease: a survey of current UK practice
Our objective was to better understand UK-wide practice in managing sialorrhoea in motor neuron disease among specialist clinicians. We used a survey of neurologists in the UK with a special interest in motor neuron disease designed to establish clinicians' attitudes towards treatment options and resources for sialorrhoea management. Twenty-three clinicians replied, representing 21 centres. Sixteen centres were specialist MND Care Centres. Clinicians estimated seeing a total of 1391 newly diagnosed patients with MND in 2011. One hundred and ninety-three patients were described. Forty-two percent of patients reviewed in clinicians' last clinic had sialorrhoea and 46% of those with sialorrhoea had uncontrolled symptoms. Clinicians' preferred drugs were hyoscine patches, amitriptyline, carbocisteine and botulinum toxin. Botulinum toxin was used in 14 centres. Risk of dysphagia and staff skills were identified as the main barriers to botulinum toxin use. This survey suggests that there may be as many as 1700 patients with MND in the UK who have symptoms of sialorrhoea and that symptoms may be poorly controlled in nearly half. Treatment strategies varied, reflecting the lack of evidence based guidelines. The use of specialist treatments was influenced by local infrastructure. This study highlights the need for further work to develop evidence based guidance. © 2013 Informa Healthcare.
Abstract.
Alkufri F, Harrower T, Rahman Y, Hughes E, Mundy H, Knibb JA, Moriarty J, Connor S, Samuel M (2013). Molybdenum cofactor deficiency presenting with a parkinsonism-dystonia syndrome.
MOVEMENT DISORDERS,
28(3), 399-400.
Author URL.
Barker RA, Mason SL, Harrower TP, Swain RA, Ho AK, Sahakian BJ, Mathur R, Elneil S, Thornton S, Hurrelbrink C, et al (2013). The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY,
84(6), 657-665.
Author URL.
2012
Lashley D, Gormley K, Harrower T (2012). Natal Natalizumab.
Author URL.
2011
Orth M, Handley OJ, Schwenke C, Dunnett S, Wild EJ, Tabrizi SJ, Landwehrmeyer GB, Bachoud-Levi A-C, Bentivoglio AR, Biunno I, et al (2011). Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY,
82(12), 1409-+.
Author URL.
2008
Ganesan D, Higgins JNP, Harrower T, Burnet NG, Sarkies NJC, Manford M, Pickard JD (2008). Stent placement for management of a small parasagittal meningioma. Technical note.
J Neurosurg,
108(2), 377-381.
Abstract:
Stent placement for management of a small parasagittal meningioma. Technical note.
The patient in this report had a parasagittal meningioma with an intrasinus extension that presented with features of benign intracranial hypertension and no focal neurological deficit or seizure. The meningioma was managed with a combination of endovascular stent placement and radiotherapy. The authors describe the investigation and technical aspects of stent placement for the stenosed sinus. Good symptomatic relief in the patient was achieved.
Abstract.
Author URL.
2006
Harrower TP, Tyers P, Hooks Y, Barker RA (2006). Long-term survival and integration of porcine expanded neural precursor cell grafts in a rat model of Parkinson's disease. Experimental Neurology, 197(1), 56-69.
2005
Harrower T, Barker RA (2005). Cell therapies for neurological disease--from bench to clinic to bench.
Expert Opin Biol Ther,
5(3), 289-291.
Abstract:
Cell therapies for neurological disease--from bench to clinic to bench.
The lack of any meaningful regeneration in the adult central nervous system (CNS) subsequent to damage or degeneration stimulated the concept of replacement of the deficient cells by transplantation. Thus, much time and effort has been spent on investigating the potential of cell replacement therapy for repair in a range of conditions of the CNS over the last 25 years. As promising proof of principle basic science results were slowly converted to success in clinical transplantation trials in Parkinson's disease (PD), the future seemed very encouraging for cell therapy. However, the recent randomised, double-blind, placebo-controlled studies of fetal neural transplantation in PD have produced more equivocal results, which has dampened enthusiasm for this approach. However, whilst the translation of cell therapies to the clinic is in limbo, the emergence of stem cells as a source of the replacement tissue has revitalised the laboratory-based studies. This paper attempts to reconcile these disparate views and put forward the authors' view on the future of this form of biological therapy and its implications for related therapies.
Abstract.
Author URL.
2004
Harrower TP, Barker RA (2004). Is There a Future for Neural Transplantation?. BioDrugs, 18(3), 141-153.
2002
Harrower T, Ratcliffe E, Richards A, Dunnett S, Bark R (2002). Long-Term Survival of Porcine Expanded Neural Precursors in the Rat Model of Parkinson's Disease. Clinical Science, 103(s47), 67p-67p.
Rosser AE, Barker RA, Harrower T, Watts C, Farrington M, Ho AK, Burnstein RM, Menon DK, Gillard JH, Pickard J, et al (2002). Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475.
J Neurol Neurosurg Psychiatry,
73(6), 678-685.
Abstract:
Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475.
OBJECTIVES: Huntington's disease (HD) is an inherited autosomal dominant condition in which there is a CAG repeat expansion in the huntingtin gene of 36 or more. Patients display progressive motor, cognitive, and behavioural deterioration associated with progressive cell loss and atrophy in the striatum. Currently there are no disease modifying treatments and current symptomatic treatments are only partially effective in the early to moderate stages. Neural transplantation is effective in animal models of HD and offers a potential strategy for brain repair in patients. The authors report a safety study of unilateral transplantation of human fetal striatal tissue into the striatum of four patients with HD. SUBJECTS AND METHODS: Stereotaxic placements of cell suspensions of human fetal ganglionic eminence were made unilaterally into the striatum of four patients with early to moderate HD. All patients received immunotherapy with cyclosporin A, azathioprine, and prednisolone for at least six months postoperatively. Patients were assessed for safety of the procedure using magnetic resonance imaging (MRI), regular recording of serum biochemistry and haematology to monitor immunotherapy, and clinical assessment according to the Core Assessment Protocol for Intrastriatal Transplantation in HD (CAPIT-HD). RESULTS: During the six month post-transplantation period, the only adverse events related to the procedure were associated with the immunotherapy. MRI demonstrated tissue at the site of implantation, but there was no sign of tissue overgrowth. Furthermore, there was no evidence that the procedure accelerated the course of the disease. CONCLUSIONS: Unilateral transplantation of human fetal striatal tissue in patients with HD is safe and feasible. Assessment of efficacy will require longer follow up in a larger number of patients.
Abstract.
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2001
Harrower T, Cruz G, Copeman L, Richards A, Dunnett S, Barker R (2001). MHC and α Gal Expression in Porcine Fetal Neural Tissue. Clinical Science, 100(s44), 13p-13p.