home » department of neurology » peer reviewed publications 2011


1. J Neurol Neurosurg Psychiatry. 2011 Jan 19. [Epub ahead of print]

Multiple sclerosis prevalence in Ireland: relationship to vitamin D status and
HLA genotype

Lonergan R, Kinsella K, Fitzpatrick P, Brady J, Murray B, Dunne C, Hagan R,
Duggan M, Jordan S, McKenna M, Hutchinson M, Tubridy N.

Department of Neurology, St Vincent's University Hospital and University College
Dublin, Ireland.

Background The relationship between prevalence of multiple sclerosis (MS) and
latitude may be due to both genetic and environmental factors. The hypothesis
that, in Ireland, MS prevalence is increasing and that north-south differences
relate to variation in serum 25-hydroxyvitamin D (25(OH)D) levels was tested in
this study. Patients and methods Patients and matched control subjects were
identified in counties Donegal, Wexford and South Dublin through multiple
sources. Prevalence was determined. Blood samples were taken for serum 25(OH)D
and serum intact parathyroid hormone measurement, and DNA was extracted. Results
Prevalence in 2007 was significantly greater in Donegal (northwest) (290.3/105,
95% CI 262.3 to 321.7) compared with 2001 (184.6/105; 162 to 209.5). In Wexford
(southeast), there was a non-significant increase in prevalence in 2007 compared
with 2001. Prevalence was significantly higher in Donegal than in Wexford
(144.8/105; 126.7 to 167.8, p<0.0001) and South Dublin (127.8/105; 111.3 to
148.2, p<0.0001). Overall, mean 25(OH)D levels were low and did not differ
between patients (38.6 nmol/l) and controls (36.4 nmol/l) However, significantly
more patients than controls had 25(OH)D levels <25&emsp14;nmol/l (deficiency)
(p=0.004). Levels of 25(OH)D (mean 50.74&emsp14;nmol/l) were significantly higher
in South Dublin (area with lowest prevalence) (p<0.0001) than in Donegal or
Wexford. HLA DRB1*15 occurred most frequently in Donegal (greatest MS prevalence)
and least frequently in South Dublin. Conclusion Vitamin D deficiency is common
in Ireland. Latitudinal variation in MS probably relates to an interaction
between genetic factors and environment (25(OH)D levels), and MS risk may be
modified by vitamin D in genetically susceptible individuals.

PMID: 21248317 [PubMed - as supplied by publisher]



2. Brain Behav Immun. 2011 Mar 21. [Epub ahead of print]

IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells.

Sweeney CM, Lonergan R, Basdeo SA, Kinsella K, Dungan LS, Higgins SC, Kelly PJ
, Costelloe L, Tubridy N, Mills KH, Fletcher JM.

School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.


Interferon (IFN)-β is a commonly used therapy for relapsing remitting multiple sclerosis (RRMS). However its protective mechanism is still unclear and the failure of many patients to respond has not been explained. We have found that IFN-β suppressed IL-23 and IL-1β production and increased IL-10 production by human dendritic cells (DC) activated with the TLR2 and dectin-1 agonist zymosan. Furthermore, IFN-β impaired the ability of DC to promote IL-17 production by CD4(+) T cells, but did not affect IFN-γ production. IFN-β induced IL-27 expression by DC, and neutralisation of IL-27 abrogated the suppressive effects of IFN-β on zymosan-induced IL-1 and IL-23 production and the generation of Th17 cells in vitro. Complementary in vivo studies in a mouse model showed that treatment with IFN-β enhanced expression of IL-27, and reduced IL-17 in the CNS and periphery and attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE). In addition, the significant suppressive effect of IFN-β on the ability of DC to promote Th17 cells was lost in cells from IL-27 receptor deficient mice. Finally, we showed that PBMC from non-responder RRMS patients produced significantly less IL-27 in response to IFN-β than patients who responded to IFN-β therapy. Our findings suggest that IFN-β mediates its therapeutic effects in MS at least in part via the induction of IL-27, and that IL-27 may represent an alternative therapy for MS patients that do not respond to IFN-β.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 21420486 [PubMed - as supplied by publisher]


3. J Neurol Sci. 2011 Mar 30. [Epub ahead of print]

Change in PASAT performance correlates with change in P3 ERP amplitude over a 12-month period in multiple sclerosis patients.

Kiiski H, Reilly RB, Lonergan R, Kelly S, O'Brien M, Kinsella K, Bramham J, Burke T
, O'Donnchadha S, Nolan H, Hutchinson M, Tubridy N, Whelan R.

Trinity Centre for Bioengineering, Trinity College Dublin, College Green, Dublin 2, Ireland.


OBJECTIVE: To examine the correlation between the change in PASAT and the change in P3 event-related potentials (ERPs) over a 12-month period in multiple sclerosis (MS) patients, and to compare the 12-month change in the P3 ERP between MS patients and controls.

METHODS: Forty-four subjects (27 MS patients, 17 controls) completed visual and auditory two-stimulus oddball and three-stimulus oddball tasks at Month 0 and Month 12. Data were recorded from a 128-scalp channel electroencephalography array. Data from scalp channels were converted into continuous interpolated images (incorporating the entire scalp and time). Amplitude, topographical differences and correlations were then tested using statistical parametric mapping.

RESULTS: The change in visual and auditory P3a correlated significantly with the change in PASAT score (r=0.56, p<0.001 and r=0.48, p=0.003, respectively). Visual P3b and P3a showed greater decrease in 12months in MS patients relative to controls. Visual P3b, auditory P3b and auditory P3a amplitudes had significantly decreased in MS patients after 12-month period.

CONCLUSIONS: Change in visual and auditory P3a ERP amplitudes correlate with change in PASAT scores in MS patients. Visual modality is more sensitive to changes in P3 ERP amplitudes over 12-month period.

SIGNIFICANCE: P3 ERPs may have utility in monitoring the change in cognitive functioning in MS.

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID: 21457995 [PubMed - as supplied by publisher]


4. Mult Scler. 2011 Apr 5. [Epub ahead of print]

Multiple Sclerosis, from referral to confirmed diagnosis: an audit of clinical practice.

Kelly S, Chaila E, Kinsella K, Duggan M, McGuigan C, Tubridy N, Hutchinson M.

Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland.


Background: The National Institute for Health and Clinical Excellence (NICE) guidelines recommend a timeline of 6 weeks from referral to neurology consultation and then 6 weeks to a diagnosis of multiple sclerosis (MS). Objectives: We audited the clinical management of all new outpatient referrals diagnosed with MS between January 2007 and May 2010. Methods: We analysed the timelines from referral to first clinic visit, to MRI studies and lumbar puncture (LP) (if performed) and the overall interval from first visit to the time the diagnosis was given to the patient. Results: Of the 119 diagnoses of MS/Clinically Isolated Syndrome (CIS), 93 (78%) were seen within 6 weeks of referral. MRI was performed before first visit in 61% and within 6 weeks in a further 27%. A lumbar puncture (LP) was performed in 83% of all patients and was done within 6 weeks in 78%. In total, 63 (53%) patients received their final diagnosis within 6 weeks of their first clinic visit, with 57 (48%) patients having their diagnosis delayed. The main rate-limiting steps were the availability of imaging and LP, and administrative issues. Conclusions: We conclude that, even with careful scheduling, it is difficult for a specialist service to obtain MRI scans and LP results so as to fulfil NICE guidelines within the optimal six-week period. An improved service would require MRI scans to be arranged before the first clinic visit in all patients with suspected MS.

PMID: 21467186 [PubMed - as supplied by publisher]

5. J Neurol Neurosurg Psychiatry. 2011 Aug 17. [Epub ahead of print]




Using atypical symptoms and red flags to identify non-demyelinating disease.

Kelly SB, Chaila E, Kinsella K, Duggan M, Walsh C, Tubridy N, Hutchinson M.


Department of Neurology, St. Vincent's University Hospital, Dublin, Ireland.


Background Red flags and atypical symptoms have been described as being useful in suggesting alternative diagnoses to multiple sclerosis (MS) and clinically isolated syndrome (CIS); however, their diagnostic utility has not been assessed. The aim of this study was to establish the predictive value of red flags and the typicality/atypicality of symptoms at presentation in relation to the final diagnosis of patients referred with suspected MS. Methods All patients referred with suspected MS over a 3-year period were assessed by the typicality of the clinical presentation and the occurrence of red flags in relation to the eventual diagnosis. The extent of agreement of trainee and consultant neurologists as to typicality of clinical presentations was determined. Results Of 244 patients referred, 119 (49%) had MS/CIS and 125 (51%) did not. 41 patients were referred because of an abnormal MRI. Of 203 with clinical symptoms, 96 patients had atypical symptoms of whom, 81 (84%) did not have MS and 15 (16%) had MS/CIS. Typical symptoms occurred in 107 patients; 10% did not have MS/CIS. Atypical symptoms had a sensitivity of 84%, specificity of 90% and positive likelihood ratio (PLR) of 8.4, whereas red flags had a sensitivity of 47%, specificity of 88% and PLR of 3.9 for the exclusion of MS/CIS. Mean percentage agreement between consultants and trainees was 73% with a range of 32-96%. Conclusions Atypical features at presentation are more sensitive, specific and have a higher PLR than red flags to refute a diagnosis of MS/CIS.



[PubMed - as supplied by publisher

6.Brain. 2011 Aug 11. [Epub ahead of print]

Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporal discrimination test.

Kimmich O, Bradley D, Whelan R, Mulrooney N, Reilly RB, Hutchinson S, O'Riordan S, Hutchinson M.


1 Department of Neurology, St Vincent's University Hospital, Dublin 4, Ireland.


Adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance; patients with sporadic adult-onset primary torsion dystonia are much more prevalent than familial. The temporal discrimination threshold is the shortest time interval at which two stimuli are detected to be asynchronous and has been shown to be abnormal in adult-onset primary torsion dystonia. The aim was to determine the frequency of abnormal temporal discrimination thresholds in patients with sporadic adult-onset primary torsion dystonia and their first-degree relatives. We hypothesized that abnormal temporal discrimination thresholds in first relatives would be compatible with an autosomal dominant endophenotype. Temporal discrimination thresholds were examined in 61 control subjects (39 subjects <50 years of age; 22 subjects >50 years of age), 32 patients with sporadic adult-onset primary torsion dystonia (cervical dystonia n = 30, spasmodic dysphonia n = 1 and Meige's syndrome n = 1) and 73 unaffected first-degree relatives (36 siblings, 36 offspring and one parent) using visual and tactile stimuli. Z-scores were calculated for all subjects; a Z > 2.5 was considered abnormal. Abnormal temporal discrimination thresholds were found in 1/61 (2%) control subjects, 27/32 (84%) patients with adult-onset primary torsion dystonia and 32/73 (44%) unaffected relatives [siblings (20/36; 56%), offspring (11/36; 31%) and one parent]. When two or more relatives were tested in any one family, 22 of 24 families had at least one first-degree relative with an abnormal temporal discrimination threshold. The frequency of abnormal temporal discrimination thresholds in first-degree relatives of patients with sporadic adult-onset primary torsion dystonia is compatible with an autosomal dominant disorder and supports the hypothesis that apparently sporadic adult-onset primary torsion dystonia is genetic in origin.



[PubMed - as supplied by publisher]