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G V McDonnell

Publications and source records attributed to G V McDonnell.

At least 19 recordsLinked to original sources
PubMed2006

Mapping candidate non-MHC susceptibility regions to multiple sclerosis.

Understanding the genetic basis of multiple sclerosis (MS) remains a major challenge, despite decades of intensive research. In order to identify candidate non-MHC susceptibility regions to MS, the results of whole genome screens for linkage or association and follow-up studies in 18 different populations were superimposed together in a combined genomic map. Analysis of this map led to the prediction of at least 38 potential susceptibility regions, each showing linkage and/or association in several populations. Among these, 17 regions were the most reproducibly reported in these studies, thus representing top predicted candidates for MS. This non-formal approach to meta-analysis demonstrated the ability to verify results and retrieve lost information in an association study. Assessment of the map in a Northern Irish refined screen (n=415 cases, n=490 controls) revealed association in 15 regions (P<0.05), including 10 promising candidates on chromosomes 1p13, 2p13, 2q14, 3p23, 7q21, 13q14, 15q13, 17p13, 18q21 and 20p12 (P<0.0025). Seven of these regions were previously overlooked in the Northern Irish whole genome association study. Collating results from numerous studies, this draft map represents a tool that should facilitate the analysis of the genetic backgrounds of MS in many populations.

Adult↗
PubMed2006

A systematic review of oral methotrexate for multiple sclerosis.

Oral methotrexate is a potent immunosuppressant, which could have a beneficial effect on relapse rates and delay disease progression in multiple sclerosis (MS). We performed a systematic review of all randomized controlled trials of oral methotrexate for MS. Of the two randomized controlled trials identified, one was excluded due to its allocation concealment and definition of a relapse and time to sustained disease progression. The other trial studied 60 participants with progressive MS only. This trial reported a non-significant reduction in sustained Expanded Disability Status Scale (EDSS) progression and number of relapses in favour of methotrexate therapy. There were no data on relapse rate and no difference in time to first relapse. Minor side-effects were reported in both methotrexate (87.1%) and placebo groups (89.7%), but there were no major side-effects. Further trials are required in both relapsing-remitting and progressive groups to establish the role of oral methotrexate in MS.

Administration, Oral↗
PubMed2005

Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity.

BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Adult↗
PubMed2004

Methotrexate for multiple sclerosis.

BACKGROUND: Methotrexate is a potent immunosuppressant which in theory could reduce relapse rates and delay disease progression in multiple sclerosis (MS). Subsequently, clinical trials of methotrexate have been conducted in people with MS. OBJECTIVES: To identify and summarise the evidence that methotrexate is beneficial and safe for people with MS. SEARCH STRATEGY: We searched the Cochrane MS Group trials register (searched December 2003), the Cochrane Central Register of Controlled Trails (The Cochrane Library Issue 4, 2003), MEDLINE (Pub Med) (January 1966 to June 2001), EMBASE (January 1988 to June 2001), and reference lists of articles. We also contacted trialists and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials of methotrexate for the prevention of relapses and disease progression in MS. DATA COLLECTION AND ANALYSIS: Two reviewers (OG, GM, ) independently selected articles for inclusion, assessed the trials' quality and extracted the data. Authors of one trial were contacted to obtaining missing information. MAIN RESULTS: One trial involving 60 participants with chronic progressive multiple sclerosis was included. The trial showed a non-significant reduction in sustained EDSS progression and number of relapses in favour of methotrexate therapy. There was no difference in time to first relapse and no data on relapse rate. Minor side-effects were reported frequently in both methotrexate (87.1%) and placebo groups (89.7%), but there were no major side-effects. REVIEWERS' CONCLUSIONS: In progressive MS, the single included trial reveals a non-significant trend in reduction of sustained EDSS progression and number of relapses in favour of methotrexate. A trial of methotrexate in relapsing remitting MS showed non-significant trends in favour of methotrexate but was excluded on methodological grounds. Before drawing further conclusions regarding the efficacy of methotrexate in MS, further trials are required.

Humans↗
PubMed2004

Influence of CCR5 delta32 polymorphism on multiple sclerosis susceptibility and disease course.

The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). We carried out an allelic association study using a deletion polymorphism in the coding region of the CCR5 gene in 331 relapsing-remitting (RR) and secondary progressive (SP) MS patients, 108 primary progressive (PP) MS patients and 230 healthy controls. Of the 331 RR and SPMS patients, 172 were recruited from specialist clinics and 159 from a population survey. Disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS) and used to calculate a progression index for each patient (defined as EDSS divided by duration of disease). No significant difference in distribution of the CCR5 delta32 allele was observed between the 331 RR/SPMS patients and controls, between the 108 PPMS patients and controls or between the PPMS and RR/SPMS groups. Furthermore, no differences in rate of disease progression were detected between carriers and noncarriers of the delta32 allele. In the population-based group of RR/SPMS patients, carriage of the CCR5 delta32 polymorphism was associated with a lower age at disease onset (mean age 26.562 versus 31.065 years, P = 0.003). However, no significant differences in age of onset were present in the PPMS group or in a second RRMS population. These results suggest that the CCR5 delta32 polymorphism is not a major determinant of susceptibility to develop MS in the population under study, and conflict with a previously reported association between CCR5 delta32 carriage and a better prognosis.

Adult↗
PubMed2003

Intravenous immunoglobulins for multiple sclerosis.

BACKGROUND: From animal experiments, there is evidence to suggest that intravenous immunoglobulins can reverse some of the disease process of central nervous system demyelination. Subsequently, clinical trials of intravenous immunoglobulins have been conducted in people with multiple sclerosis (MS). OBJECTIVES: To identify and summarise the evidence that intravenous immunoglobulins are safe and beneficial for people with MS. SEARCH STRATEGY: We searched the Cochrane Multiple Sclerosis Group trials Register( January 2003) The Cochrane Central Register of Controlled Trials (The Cochrane Library issue 4, 2002), MEDLINE (January 1966 to April 2001), EMBASE (January 1988 to April 2001) and reference lists of articles. We also contacted relevant pharmaceutical companies and authors of identified trials. SELECTION CRITERIA: Randomised controlled trials of intravenous immunoglobulins for the secondary prevention of relapses and disease progression in MS. DATA COLLECTION AND ANALYSIS: 913 titles and abstracts were obtained from the literature search, and we eventually identified 10 clinical trials. All reviewers agreed on the final dataset for entry into RevMan 4.1, and summarised the results. Study authors were contacted for additional information but no response was obtained. MAIN RESULTS: Of 913 potential studies, 10 trials were identified with a total of 918 participants, four of which are in progress or awaiting publication. The remaining six trials were suitable for consideration by this review (344 participants). Only two trials met our protocol's inclusion criteria. The four remaining trials were excluded as they did not use outcome measures specified in our review (2 trials, 122 participants), or were of insufficient methodological quality (2 trials, 34 participants). From the two included trials (168 participants) there was a reduction in relapse rate and increased time to first relapse during treatment with intravenous immunoglobulins, but reliable disease progression outcomes were not reported, nor were magnetic resonance imaging (MRI) data available to support clinical information. There may be as many as 574 participants in ongoing or yet to be published trials. REVIEWER'S CONCLUSIONS: There is some evidence to support use of intravenous immunoglobulins as a preventative treatment for relapses in relapsing remitting MS, but further studies should be performed using MRI and disease progression endpoints. It may be possible to draw more robust conclusions when ongoing or recently completed trials make their data available for review. Two rigorously conducted trials with a total of 122 participants did not demonstrate a positive clinical benefit, but were excluded from this review as they employed outcome measures not specified in our protocol. Immunoglobulins were well tolerated with a less than 5% risk of adverse events in participants in included trials.

Humans↗
PubMed2003

Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions: the subclinical stage of primary progressive multiple sclerosis may last 10 years.

BACKGROUND: Subclinical multiple sclerosis (MS) has been identified incidentally at autopsy; apparently unaffected individuals with an affected twin have demonstrated magnetic resonance imaging (MRI) changes consistent with MS, and 'MRI relapses' are several times more common than clinical relapses. CASE DESCRIPTION: A 39-year-old, right-handed man underwent MRI and PET scanning in 1986 as a 'normal' control in a Parkinson's disease study, where his father was the proband. MRI indicated multiple areas of abnormal signal intensity in a periventricular and grey-white matter junction distribution. Repeated clinical evaluations over the next 10 years were unchanged until 1996, when he complained of progressive weakness of the right foot and clumsiness in the right hand. MRI now indicated a further area of high signal intensity in the right posterior cord at the level of C5/C6. There was mild pyramidal distribution weakness in the right leg with an extensor plantar response on the same side. Over the next five years there has been mild progression in weakness and fatigue and intermittent Lhermitte's phenomenon. At no stage has there been a history of relapse, cerebrospinal fluid examination was normal and evoked responses (visual and somatosensory) are normal. CONCLUSION: This case demonstrates the phenomenon of subclinical MS, unusually supported by prolonged clinical and MRI follow-up. The patient eventually became symptomatic nine years after MRI diagnosis and is following a primary progressive course. Although MRI is known to be sensitive in identifying subclinical 'attacks', the pattern illustrated here may actually be quite typical of primary progressive MS and is compatible with the later onset seen in this subgroup of patients.

Adult↗
PubMed2002

Primary progressive multiple sclerosis: increasing clarity but many unanswered questions.

Heterogeneity in the clinical course of multiple sclerosis (MS) is well recognised and patients following a primary progressive course, 10-15% of the MS population, have a distinct clinical and paraclinical phenotype. This review examines recent advances in our understanding of this subgroup of patients and examines the new criteria to be applied in diagnosis. It also highlights developments in genetic, immunological, magnetic resonance and pathological aspects of the disease, whilst also outlining the results of recent therapeutic trials.

Controlled Clinical Trials as Topic↗
PubMed2002

Evidence for the role of demyelination, HLA-DR alleles, and cytokines in the pathogenesis of parvovirus B19 meningoencephalitis and its sequelae.

OBJECTIVE: To review the clinical and pathological features of parvovirus B19 meningoencephalitis and its sequelae in 12 previously published cases, and to perform additional tests to determine the pathogenesis of the disease. METHODS: Cases were reviewed and available serum and cerebrospinal fluid (CSF) tested for antiganglioside antibodies and a range of cytokines. In situ hybridisation for parvovirus B19 DNA was performed on postmortem brain tissue in two cases. HLA-DRB1 typing was undertaken on genomic DNA extracted from peripheral blood leucocytes. RESULTS: Cerebellar involvement was suggested either clinically or pathologically in four cases. In the two cases with postmortem histology, there was marked atrophy of the molecular and granular layers of the cerebellum with focal loss of Purkinje cells. Brain scanning by MRI or CT was done in six cases during the acute phase. Three were abnormal with evidence of demyelination. Three had markedly enlarged ventricles, in two of which there was high signal intensity from the white matter on both T1 and T2 weighted images. The three cases with abnormal brain scans had long term neurological sequelae (mental retardation, personality change, altered affect). In situ hybridisation on available postmortem brain tissue was negative in the two cases tested. All cases in which HLA-DR alleles were determined carried at least one of the following alleles: HLA-DRB1*01, *04, *07, *09, *15, *16. Available serum and CSF was tested for antiganglioside antibodies (all negative) and for a panel of cytokines, which had a similar profile in both serum (n = 5) and CSF (n = 1) during the acute phase. Cytokines that were consistently detectable were IL-6 (mean 726.20 pg/ml), TNFalpha (50.64 pg/ml), IFNgamma (39.64 pg/ml), GM-CSF (216.12 pg/ml), and MCP-1 (154.43 pg/ml); IL-1beta, IL-5, and IL-13 were undetectable. CONCLUSIONS: HLA-DR associations, an increased cytokine response, and benefit from immunomodulatory treatment (in one case) support a role for the immune response in the pathogenesis of parvovirus B19 meningoencephalitis.

Adolescent↗
PubMed2001

Serum and cerebrospinal fluid soluble Fas levels in clinical subgroups of multiple sclerosis.

Elevated sFas levels have been described in multiple sclerosis (MS) patients with active disease. The aim of this study was to assess the diagnostic potential of serum and cerebrospinal fluid (CSF) sFas measurements in differentiating clinically defined MS patient subgroups. Levels of sFas and sFas indices were determined in patients with stable relapsing-remitting MS (RRMS), active RRMS, primary progressive MS (PPMS), secondary progressive MS (SPMS) and patients with inflammatory (IND) and noninflammatory neurological diseases (NIND). Serum sFas modulation over 32 weeks IFN-beta1a therapy was also investigated. Serum and CSF sFas levels and sFas indices were elevated in MS compared to NIND and IND patients. Within the MS group, serum and CSF sFas levels were highest in PPMS, with active RRMS patients demonstrating the highest sFas indices. This may reflect an ongoing disease process which is occurring acutely (active disease) or incessantly (progressive disease). IFN-beta1a induced a transient increase in circulating sFas following initiation of therapy. Whilst evidence was provided for variable sFas expression in clinical subgroups of MS, there was insufficient definition between the respective groups to advocate sFas measurements as a diagnostic marker of clinical subgroups of MS.

Adolescent↗
PubMed2001

Human immunoglobulin for diabetic amyotrophy--a promising prospect?

Diabetic neuropathies are universally recognised and cause significant morbidity. At present improving glycaemic control is the only recognised treatment. A man with type 2 diabetes presented with disabling asymmetric lower limb proximal neuropathy. Rapid clinical, functional, and electrical improvement followed treatment with intravenous immunoglobulin. The aetiology of diabetic amyotrophy remains controversial but there is evidence for an immune mediated process and this case suggests a role for immunoglobulin in the management of this debilitating condition.

Diabetes Mellitus, Type 2↗
PubMed2001

An assessment of the spectrum of disability and handicap in multiple sclerosis: a population-based study.

OBJECTIVES: To establish the spectrum of disability and handicap in a population based sample of multiple sclerosis (MS) patients. BACKGROUND: Much knowledge exists about the epidemiology of MS but, despite its importance for health and social service planning, there remains relatively little data on the extent and nature of disability and handicap in this population. METHODS: In a prevalence study in the north-east of N. Ireland, 288 patients (Poser criteria) were identified. Disability and handicap were assessed using the Incapacity Status Scale and Environmental Status Scale of the Minimal Record of Disability for MS. RESULTS: Both scales were completed for 248 (86%) of patients. Just 71 (29%) are fully independent in all basic ADL's of bathing, dressing, grooming and feeding. Fifty-seven (23%) are unable to climb a flight of stairs and 102 (42%) acknowledge problems with sexual function. Sixty-one (25%) were working essentially full-time and 53 (21%) had no external financial support. Forty-five (18%) had changed residence due to MS, 12 (5%) were institutionalised and 86 (35%) required assistance for at least 1 h/day with ADL's. Eighty-one (33%) were unable to drive a car or use public transport. Forty-two (17%) access community services for at least 1 h/day on average. CONCLUSIONS: This data gives a clear indication of the considerable range of basic health and social issues in a typical MS community. Further work is required to establish patient perceptions of the adequacy of care provision and whether standards of care for MS patients are being met.

Activities of Daily Living↗
PubMed2000

An evaluation of interleukin genes fails to identify clear susceptibility loci for multiple sclerosis.

Differential expression of interleukins may influence susceptibility to inflammatory diseases such as MS. IL-1a production is increased in MS patients during acute relapse, IL-2 receptor (IL-2R) secretion correlates with disease activity in several inflammatory disorders and is variable in MS. Both IL-4 and IL-10 expression vary significantly with relapse/remission in MS and IL-9 is postulated to inhibit steroid-induced apoptosis. To examine the influence of interleukin (IL) genes on MS susceptibility and clinical course, gene association studies using separate polymorphic microsatellite markers for il-1 alpha, il-2, il-2r beta, il-4 il-9 and il-10 were performed, incorporating 150-177 relapsing-remitting or secondary progressive MS (RR/SPMS) patients, 100-110 primary progressive (PPMS) patients and 152-210 controls. No significant differences existed in allele frequencies between either MS group and controls for any of the interleukin microsatellite markers studied, nor were statistically significant differences observed in PPMS vs. RR/SPMS for any marker. These data indicate that the IL-1 alpha, IL-2, IL-2R beta, IL-4, IL-9 and IL-10 genes are unlikely to be susceptibility loci for MS in this population.

Alleles↗
PubMed2000

Issues of medical management in adults with spina bifida.

The objective of this study was to establish the range of medical issues among those attending a clinic for adults with spina bifida (SB) and hydrocephalus (CASBAH). Owing to improvements in medical care in the past 3-4 decades, an increasing number of SB patients go on to prosper in adult life. Since 1990 there has been a CASBAH service in Belfast serving Northern Ireland on a regional basis. There are now 237 patients with SB remaining on the live register at CASBAH. All records were reviewed with regard to site of lesion, ambulatory ability, shunt placement and regularity of attendance. The records of 193 were also reviewed with reference to musculoskeletal problems, bladder function, bowel function, renal impairment and hypertension, skin breakdown, epilepsy and the incidence of clinically significant Chiari/hydrosyringomyelia. Of the patients on the register, 36% are wheelchair dependent, 8% have some ambulatory capacity but are largely wheelchair dependent, 22% are ambulatory with aid and 34% are independently ambulatory. Bladder function is normal in 8%, whilst 32% describe normal bowel function. Renal impairment is present in 48% of patients, and 15% are on anti-hypertensive therapy. Epilepsy is an active issue in 9%, and intraventricular shunts are in situ in 37% of patients. Scoliosis is present in 50% and 70% have joint deformities or contractures. Five patients have become symptomatic from the Chiari/hydrosyringomyelia complex. These data reflect the considerable range of disability in adult SB patients, the challenges presented in long-term management and the need for organised follow-up.

Activities of Daily Living↗
PubMed2000

Evaluation of the clinical utility of cerebrospinal fluid (CSF) indices of inflammatory markers in multiple sclerosis.

OBJECTIVES: Accumulating evidence indicates significant heterogeneity in MS and soluble (s) adhesion molecules are postulated as markers of disease activity. We sought to evaluate intrathecal production of these and other molecules across the clinical spectrum of MS. METHODS: CSF indices of IgG, sICAM-1, sVCAM-1, sE-selectin and sCD30 were calculated in 17 primary progressive (PPMS) patients, 15 secondary progressive patients (SPMS), 28 relapsing-remitting patients in relapse (RRMSR) and 14 RRMS patients in remission (RRMSNR) using commercially available ELISA kits. Patients had not received any immunomodulating therapy within the previous 6 months. MS patients were compared with 44 patients with non-inflammatory neurological diseases (NINDs). RESULTS: The most sensitive CSF index at a 90% level of specificity was for IgG which had 93% sensitivity in RRMSR and 92% sensitivity in RRMSNR. Corresponding sensitivity in PPMS and SPMS was 71% and 73% respectively. None of the other indices had sensitivity >50% apart from sVCAM-1 (64% in RRMSR and 52% RRMSNR) and sCD30 (53% in PPMS). CONCLUSIONS: Unsurprisingly the strongest association in MS was with the intrathecal production of IgG. Similar results in PPMS and SPMS may reflect comparable rates of progression in these 2 groups. Of the other molecules only intrathecal sVCAM-1 production is significantly associated with MS and only in relapsing-remitting disease.

Biomarkers↗