Publications by authors named "Timothy Harrower"

20 Publications

  • Page 1 of 1

Quality of life in multiple sclerosis is dominated by fatigue, disability and self-efficacy.

J Neurol Sci 2021 Apr 9;426:117437. Epub 2021 Apr 9.

Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, UK. Electronic address:

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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http://dx.doi.org/10.1016/j.jns.2021.117437DOI Listing
April 2021

Measuring quality of life in ALS/MND: validation of the WHOQOL-BREF.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Jun 27:1-9. Epub 2020 Jun 27.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

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? 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. 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. 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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http://dx.doi.org/10.1080/21678421.2020.1752244DOI Listing
June 2020

Clinical features and genetic risk of demyelination following anti-TNF treatment.

J Crohns Colitis 2020 Jun 4. Epub 2020 Jun 4.

IBD Pharmacogenetics Group, University of Exeter, Exeter, UK.

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 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. We compared genetic risk scores (GRS), calculated using carriage of 43 susceptibility loci for MS, in 48 cases to 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 9 (17%), progressive symptoms in 3 (6%): 2 (4%) patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 x 10-4, 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 were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa104DOI Listing
June 2020

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 2019 Dec 13;20(9):1335-1347. Epub 2019 Aug 13.

Neurology, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, Devon, EX2 5DW, UK.

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 < 0.001; adjusted R-squared 0.3007), with TFC score, Behavioural score, and male gender significant predictors of SF-6D values (p < 0.001).

Conclusion: To our knowledge, this is the first report of HSUVs for HD for countries other than the UK, and the first report of SF-6D HSUVs described for 12 European countries, according to demographic and clinical factors. Our analyses provide new insights into the relationships between HD disease characteristics and assessment of health-related quality of life in a form that can be used in policy-relevant economic evaluations.
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http://dx.doi.org/10.1007/s10198-019-01092-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856291PMC
December 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 2019 Jun 7;20(1):331. Epub 2019 Jun 7.

Department of Clinical Neurosciences, University of Cambridge, Box 165, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.

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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http://dx.doi.org/10.1186/s13063-019-3336-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555751PMC
June 2019

The relationships between symptoms, disability, perceived health and quality of life in amyotrophic lateral sclerosis/motor neuron disease.

Amyotroph Lateral Scler Frontotemporal Degener 2019 08 22;20(5-6):317-327. Epub 2019 May 22.

n Swiss Paraplegic Research , Nottwil , Switzerland.

: 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. : 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. : 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. : 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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http://dx.doi.org/10.1080/21678421.2019.1615951DOI Listing
August 2019

Outcome of cell suspension allografts in a patient with Huntington's disease.

Ann Neurol 2018 12 25;84(6):950-956. Epub 2018 Oct 25.

Centre de Recherche du CHU de Québec (CHUQ), Axe Neurosciences, Québec, QC, Canada.

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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http://dx.doi.org/10.1002/ana.25354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587549PMC
December 2018

Cost-effectiveness analysis of abobotulinumtoxinA for the treatment of cervical dystonia in the United Kingdom.

Clinicoecon Outcomes Res 2017 15;9:211-229. Epub 2017 Apr 15.

Health Economics and Outcomes Research (Global), Ipsen Pharma, Boulogne-Billancourt, France.

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.
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http://dx.doi.org/10.2147/CEOR.S112254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402907PMC
April 2017

A multicentre evaluation of oropharyngeal secretion management practices in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2017 02 31;18(1-2):1-9. Epub 2016 Aug 31.

a Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, & Academic Directorate of Neurosciences, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield.

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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http://dx.doi.org/10.1080/21678421.2016.1221433DOI Listing
February 2017

AbobotulinumtoxinA in the management of cervical dystonia in the United Kingdom: a budget impact analysis.

Clinicoecon Outcomes Res 2015 9;7:441-9. Epub 2015 Sep 9.

Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

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.
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http://dx.doi.org/10.2147/CEOR.S86355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573201PMC
September 2015

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Nat Genet 2013 Nov 29;45(11):1353-60. Epub 2013 Sep 29.

1] John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA. [2].

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.
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http://dx.doi.org/10.1038/ng.2770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832895PMC
November 2013

Management of sialorrhoea in motor neuron disease: a survey of current UK practice.

Amyotroph Lateral Scler Frontotemporal Degener 2013 Dec 7;14(7-8):521-7. Epub 2013 May 7.

Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, & Academic Directorate of Neurosciences, Royal Hallamshire Hospital , Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield.

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.
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http://dx.doi.org/10.3109/21678421.2013.790452DOI Listing
December 2013

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

J Neurol Neurosurg Psychiatry 2013 Jun 23;84(6):657-65. Epub 2013 Jan 23.

Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.
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http://dx.doi.org/10.1136/jnnp-2012-302441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646287PMC
June 2013

TB or not TB?

Am J Med 2008 Aug;121(8):684-6

Department of Neurology, Essex Centre for Neurological Sciences, Romford, United Kingdom.

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http://dx.doi.org/10.1016/j.amjmed.2008.01.018DOI Listing
August 2008

Stent placement for management of a small parasagittal meningioma. Technical note.

J Neurosurg 2008 Feb;108(2):377-81

Academic Neurosurgical Unit, Department of Neurosciences, University of Cambridge, and Department of Oncology, Addenbrooke's Hospital, Cambridge, United Kingdom.

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.
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http://dx.doi.org/10.3171/JNS/2008/108/2/0377DOI Listing
February 2008

POLG1 mutations manifesting as autosomal recessive axonal Charcot-Marie-Tooth disease.

Arch Neurol 2008 Jan;65(1):133-6

Department of Neurology, Essex Center for Neurological Sciences, Queen's Hospital, Romford, England.

Background: Although a molecular diagnosis is possible in most patients having Charcot-Marie-Tooth disease (CMT), recessively inherited and axonal neuropathies still present a diagnostic challenge.

Objective: To determine the cause of axonal CMT type 2 in 3 siblings.

Design: Case report.

Setting: Academic research.

Participants: Three siblings who subsequently developed profound cerebellar ataxia.

Main Outcome Measures: Muscle biopsy specimen molecular genetic analysis of the POLG1 (polymerase gamma-1) gene, as well as screening of control subjects for POLG1 sequence variants.

Results: Cytochrome c oxidase deficient fibers and multiple deletions of mitochondrial DNA were detected in skeletal muscle. Three compound heterozygous substitutions were detected in POLG1.

Conclusion: Even in the absence of classic features of mitochondrial disease, POLG1 should be considered in patients having axonal CMT that may be associated with tremor or ataxia.
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http://dx.doi.org/10.1001/archneurol.2007.4DOI Listing
January 2008

Lewy bodies in Parkinson's disease: protectors or perpetrators?

Exp Neurol 2005 Sep;195(1):1-6

Cambridge Centre for Brain Repair, Robinson Way, Cambridge CB22PY, UK.

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http://dx.doi.org/10.1016/j.expneurol.2005.06.002DOI Listing
September 2005

Cell therapies for neurological disease--from bench to clinic to bench.

Expert Opin Biol Ther 2005 Mar;5(3):289-91

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.
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http://dx.doi.org/10.1517/14712598.5.3.289DOI Listing
March 2005

Is there a future for neural transplantation?

BioDrugs 2004 ;18(3):141-53

Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK.

Traditionally neural transplantation has had as its central tenet the replacement of missing neurons that have been lost because of neurodegenerative processes, as exemplified by diseases such as Parkinson disease (PD). However, the effectiveness and widespread application of this approach clinically has been limited, primarily because of the poor donor supply of human fetal neural tissue and the incomplete neurobiological understanding of the circuit reconstruction required to normalize function in these diseases. So, in PD the progress from promising neural transplantation in animal models to proof-of-principle, open-labeled clinical transplants, to randomized, placebo-controlled studies of neural transplantation has not been straightforward. The emergence of previously undescribed adverse effects and lack of significant functional advantage in recent clinical studies has been disappointing and has served to cast a new, and perhaps more realistic, perspective on this treatment approach. In fact, there have been calls by some involved in neural transplantation to return to the drawing board before pressing on with further clinical trials, and the return to basic experimentation. This therefore precipitates the question - is there a future for neural transplantation? It is important to remember that there are a number of possible explanations for the disappointing results from the recent clinical trials in PD, ranging from the mode of transplantation to patient selection. Nevertheless, almost irrespective of these reasons for the current trial results, there have always been significant practical and ethical problems with using human fetal tissue, and so a number of alternative cell sources have been investigated. These alternative sources include stem cells, which are attractive for cell-based therapies because of their potential ease of isolation, propagation and manipulation, and their ability in some cases to migrate to areas of pathology and differentiate into specific and appropriate cell types. Furthermore, the availability of stem cells derived from non-embryonic sources (e.g. adult stem cells derived from the sub-ventricular zone) has removed some of the ethical limitations associated with the use of embryonic human tissue. These potentially beneficial aspects of stem cells means that there is a future for neural transplantation as a means of treating patients with a range of neurological disorders, although whether this will ever translate into a truly effective, widely available therapy remains unknown.
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http://dx.doi.org/10.2165/00063030-200418030-00001DOI Listing
August 2004

The emerging technologies of neural xenografting and stem cell transplantation for treating neurodegenerative disorders.

Drugs Today (Barc) 2004 Feb;40(2):171-89

Cambridge Center for Brain Repair, Cambridge, UK.

Neural transplantation has normally been considered in the context of the neurodegenerative disorders, Parkinson's and Huntington's disease, which are characterized pathologically by the predominant loss of specific cells in the basal ganglia. This approach has now emerged from the experimental arena into the level of clinical trial, at least with respect to fetal human allografts. However the ethical and practical problems with using such tissue has led to the search for alternative sources of cells of which two of the most promising are cells from another species, such as the pig (xenografts), and stem cells. Neural transplantation using cells derived from the developing pig brain offers many advantages. Firstly, time-mated litters will overcome the issue of donor tissue supply. Secondly, advances in genetic technology have led to the development of pigs which have a reduced rejection potential. Thirdly, xenografted neural fiber outgrowth may be superior to that from neural grafts derived from the same species (allografts) which may increase the potential for circuit reconstruction. Disadvantages with this tissue source include concerns about transmission of zoonotic infections and the immunological rejection of the xenograft. Stem cells are defined as cells capable of division (self-renewal) and differentiation into a range of different cell types (differentiation). A variety of such cells exist including embryonic stem cells, neural stem cells derived from the developing fetal brain (neural progenitor cells), adult neural stem cells and adult stem cells originating from outside of the central nervous system. Each of these different types of stem cell have their own unique benefits but also disadvantages, and access to each type is constrained by a number of limiting factors. All of this means that the translation of these cell therapies into practice is not straightforward and must be done at a pace dictated by laboratory-based research rather than corporate share price.
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http://dx.doi.org/10.1358/dot.2004.40.2.799428DOI Listing
February 2004