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Peer Reviewed Publications 2010 

1. Ir J Med Sci. 2010 Dec;179(4):599-601. Epub 2010 Oct 1. 

Late-onset progressive visual loss in a man with unusual MRI findings: MS,
Harding's, Leber's or Leber's Plus?

Cawley N, Molloy A, Cassidy L, Tubridy N.

Department of Neurology, St. Vincent's University Hospital, Elm Park, Dublin 4,

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder,
typically presenting in the second and third decade. We report the case of an
elderly gentleman with significant vascular risk factors, presenting with slowly
progressive, bilateral, visual loss with high signal lesions in the pericallosal
and periventricular deep white matter on MRI brain studies. Possible diagnoses
included late-onset MS, ischaemic optic neuropathies, a mitochondrial disorder or
an overlap syndrome such as Harding's disease.

PMID: 20882363 [PubMed - in process]

2. Clin Exp Immunol. 2010 Oct;162(1):1-11. doi: 10.1111/j.1365-2249.2010.04143.x.

T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH.

Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity
College, St Vincent's University Hospital, Dublin, Ireland.

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central
nervous system (CNS), which involves autoimmune responses to myelin antigens.
Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for
MS, have provided convincing evidence that T cells specific for self-antigens
mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells
were thought to be the main effector T cells responsible for the autoimmune
inflammation. However more recent studies have highlighted an important
pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17,
but also IL-17-secreting γδ T cells in EAE as well as other autoimmune and
chronic inflammatory conditions. This has prompted intensive study of the
induction, function and regulation of IL-17-producing T cells in MS and EAE. In
this paper, we review the contribution of Th1, Th17, γδ, CD8(+) and regulatory T
cells as well as the possible development of new therapeutic approaches for MS
based on manipulating these T cell subtypes.

PMID: 20682002 [PubMed - indexed for MEDLINE]

3. Neurology. 2010 Aug 3;75(5):411-8.

OAS1: a multiple sclerosis susceptibility gene that influences disease severity.

O'Brien M, Lonergan R, Costelloe L, O'Rourke K, Fletcher JM, Kinsella K, Sweeney
C, Antonelli G, Mills KH, O'Farrelly C, Hutchinson M, Tubridy N.

Education & Research Centre, St. Vincent's University Hospital, Elm Park, Dublin
4, Ireland. margaretobrien@physicians.ie

Comment in:
    Nat Rev Neurol. 2010 Oct;6(10):526.

BACKGROUND: Type 1 interferons upregulate oligoadenylate synthetase 1 (OAS1). A
single nucleotide polymorphism (SNP) in exon 7 of OAS1 results in differential
RNAseL enzyme activity, the A allele coding for a truncated form with low
activity and the G conferring high activity. We hypothesized that OAS1 genotypes
would influence both susceptibility to multiple sclerosis (MS) and disease
activity with the AA genotype being overrepresented and the GG genotype
underrepresented in relapsing-remitting MS (RRMS) with increased disease
METHODS: We examined OAS1 genotype distribution in 401 patients with MS, 394
healthy controls, and 178 patients with RRMS receiving interferon-beta (IFNbeta)
assessed as 1) having no or minimal disease activity on IFNbeta, 2) having
disease activity despite IFNbeta, and 3) 65 patients with RRMS with highly active
RESULTS: The OAS1 genotype distribution differed between patients with MS and
controls (p = 0.000003), with lower frequency of GG homozygotes in patients with
MS (6%) compared with controls (17%). In relation to disease severity, 34 (32%)
patients with no or minimal disease activity on IFNbeta had the AA and 8 (8%) the
GG genotype; of patients with disease activity despite IFNbeta, 27 (51%) were AA,
while only 1 (2%) was GG (p = 0.03). Median time to first relapse on IFNbeta was
24 months in patients with RRMS with AA genotype and 33 months with AG or GG
genotype (p = 0.04). The GG genotype was absent in 65 patients with highly active
RRMS (p = 0.03).
CONCLUSIONS: A functional OAS1 SNP, AA genotype, confers susceptibility to MS and
the GG genotype may protect against increased disease activity.

PMID: 20679634 [PubMed - indexed for MEDLINE]

4. Eur J Neurol. 2010 Jul 28. [Epub ahead of print]

Preliminary evidence for correlation between PASAT performance and P3a and P3b
amplitudes in progressive multiple sclerosis.

Kiiski H, Whelan R, Lonergan R, Nolan H, Kinsella K, Hutchinson M, Tubridy N,
Reilly RB.

Trinity Centre for Bioengineering, Trinity College Dublin, College Green, Dublin,

Background: The no-go P3a event-related potential (ERP) is a measure of
attentional engagement and the P3b is a measure of context updating. The aim of
this study was to compare ERP topographies: (i) to Paced Auditory Serial Addition
Test (PASAT) results, (ii) of visual and auditory P3a and P3b of patients with
primary progressive multiple sclerosis (PPMS) versus patients with
secondary-progressive multiple sclerosis (SPMS) and (iii) of both progressive
subtypes to healthy controls. Methods: Thirty subjects (10 PPMS, 10 SPMS and 10
age-matched controls) completed visual and auditory no-go P3a and P3b tasks
whilst data were recorded from a 128-scalp channel electroencephalography (EEG)
array. Data from scalp channels were converted into continuous interpolated
images (incorporating the entire scalp and time). Topographical differences and
correlations were then tested using statistical parametric mapping. Results: For
the patients with multiple sclerosis (MS), PASAT score correlated significantly
with parietal regions in the auditory P3b, auditory P3a and visual P3b
conditions, and with central regions in the visual P3a condition. Patients with
PPMS had significantly lower amplitude than patients with SPMS in the auditory
P3b condition over the parietal area. The control group had greater amplitude
than the patients with MS in all the P3 tasks, with the exception of the auditory
P3b. Conclusions: These data suggest that PASAT performance and P3 ERPs correlate
for MS progressive subtypes and that PPMS and SPMS differ in electrophysiological
responses during auditory P3b tasks.

PMID: 20666835 [PubMed - as supplied by publisher]

5. BMC Med Educ. 2010 Jun 23;10:49.

Attitudes of US medical trainees towards neurology education: "Neurophobia" - a
global issue.

Zinchuk AV, Flanagan EP, Tubridy NJ, Miller WA, McCullough LD.

Department of Neurology, University of Connecticut Health Center 263 Farmington
Avenue, Farmington, CT 06030, USA.

BACKGROUND: Several studies in the United Kingdom and Asia have suggested that
medical students and residents have particular difficulty in diagnosing and
managing patients with neurological problems. Little recent information is
available for US trainees. We examined whether students and residents at a US
university have difficulty in dealing with patients with neurological problems,
identified the perceived sources of these difficulties and provide suggestions
for the development of an effective educational experience in neurology.
METHODS: A questionnaire was administered to third and fourth year medical
students at a US school of medicine and to residents of an internal medicine
residency program affiliated with that school. Perceived difficulties with eight
medical specialties, including neurology, were examined. Methods considered to be
most useful for learning medicine were documented. Reasons why neurology is
perceived as difficult and ways to improve neurological teaching were assessed.
RESULTS: 152 surveys were completed. Participation rates varied, with medical
students having higher response rates (> 50%) than medical residents (27%-48%).
Respondents felt that neurology was the medical specialty they had least
knowledge in (p < 0.001) and was most difficult (p < 0.001). Trainees also felt
they had the least confidence when dealing with patients with neurological
complaints (p < 0.001). Residents felt more competent in neurology than students
(p < 0.001). The paramount reasons for perceived difficulties with neurology were
the complexity of neuroanatomy, limited patient exposure and insufficient
teaching. Transition from pre-clinical to clinical medicine led to a doubling of
"poor" ratings for neurological teaching. Over 80% of the respondents felt that
neurology teaching could be improved through greater exposure to patients and
more bedside tutorials.
CONCLUSIONS: Medical students and residents at this US medical university found
neurology difficult. Although this is consistent with prior reports from Europe
and Asia, studies in other universities are needed to confirm generalizability of
these findings. The optimal opportunity for improvement is during the transition
from preclinical to clinical years. Enhanced integration of basic neurosciences
and clinical neurology with emphasis on increased bedside tutorials and patient
exposure should improve teaching. Studies are needed to quantify the effect of
these interventions on confidence of trainees when dealing with patients
presenting with neurological complaints.

PMCID: PMC2900283
PMID: 20573257 [PubMed - indexed for MEDLINE]

6. J Neurol Sci. 2010 Jun 15;293(1-2):45-50.

Impaired information processing speed and attention allocation in multiple
sclerosis patients versus controls: a high-density EEG study.

Whelan R, Lonergan R, Kiiski H, Nolan H, Kinsella K, Hutchinson M, Tubridy N,
Reilly RB.

Department of Neurology, St. Vincent's University Hospital, University College
Dublin, Dublin, Ireland. Robert.whelan@tcd.ie

BACKGROUND: The no-go P3a is a variant of the P300 event-related potential (ERP)
that indexes speed of information processing and attention allocation. The aim of
this study was to compare ERP findings with results from the paced auditory
serial addition test (PASAT) and to quantify latency, amplitude and topographical
differences in P3a ERP components between multiple sclerosis (MS) patients and
PATIENTS AND METHODS: Seventy-four subjects (20 relapsing remitting (RRMS)
patients, 20 secondary progressive (SPMS) patients and 34 controls) completed a
three-stimulus oddball paradigm (target, standard, and non-target). Subjects
participated in separate visual and auditory tasks while data were recorded from
134 EEG channels. Latency differences were tested using an ANCOVA. Topographical
differences were tested using statistical parametric mapping.
RESULTS: Visual P3a amplitude correlated with PASAT score in all MS patients over
frontal and parietal areas. There were significant differences in latency,
amplitude, and topography between MS patients and controls in the visual
condition. RRMS and SPMS patients differed in visual P3a latency and amplitude at
frontal and parietal scalp regions. In the auditory condition, there were latency
differences between MS patients and controls only over the parietal region.
CONCLUSION: The present results demonstrate that information processing speed and
attention allocation are impaired in MS.

PMID: 20399448 [PubMed - indexed for MEDLINE]

7. Clin Neurophysiol. 2010 Sep;121(9):1420-6. Epub 2010 Apr 8.

A high-density ERP study reveals latency, amplitude, and topographical
differences in multiple sclerosis patients versus controls.

Whelan R, Lonergan R, Kiiski H, Nolan H, Kinsella K, Bramham J, O'Brien M, Reilly
RB, Hutchinson M, Tubridy N.

Department of Neurology, St. Vincent's University Hospital/University College
Dublin, Ireland. Robert.whelan@tcd.ie

OBJECTIVE: To quantify latency, amplitude and topographical differences in
event-related potential (ERP) components between multiple sclerosis (MS) patients
and controls and to compare ERP findings with results from the paced auditory
serial addition test (PASAT).
METHODS: Fifty-four subjects (17 relapsing remitting (RRMS) patients, 16
secondary progressive (SPMS) patients, and 21 controls) completed visual and
auditory oddball tasks while data were recorded from 134 EEG channels. Latency
and amplitude differences, calculated using composite mean amplitude measures,
were tested using an ANOVA. Topographical differences were tested using
statistical parametric mapping (SPM).
RESULTS: In the visual modality, P2, P3 amplitudes and N2 latency were
significantly different across groups. In the auditory modality, P2, N2, and P3
latencies and N1 amplitude were significantly different across groups. There were
no significant differences between RRMS and SPMS patients on any ERP component.
There were topographical differences between MS patients and controls for both
early and late components for the visual modality, but only in the early
components for the auditory modality. PASAT score correlated significantly with
auditory P3 latency for MS patients.
CONCLUSIONS: There were significant ERP differences between MS patients and
SIGNIFICANCE: The present study indicated that both early sensory and later
cognitive ERP components are impaired in MS patients relative to controls.

PMID: 20381418 [PubMed - indexed for MEDLINE]

8. Eur J Neurol. 2010 Apr;17(4):e28-32. Epub 2009 Dec 29.

The 'hidden work' of a hospital neurologist: 1000 consults later.

Ali E, Chaila E, Hutchinson M, Tubridy N.

Department of Neurology, St Vincent's University Hospital, Elm Park, Dublin,

Comment in:
    Eur J Neurol. 2010 Apr;17(4):e26-7.

BACKGROUND: A new Web-based, internal neurology referral service was introduced
in our department to expedite inpatient review for other departments and to allow
assessment of the impact of neurology consults on patient care throughout the
hospital, especially in the emergency department (ED). The results of the
analysis of the first 1000 referrals using the new system are presented. Methods:
An intranet referral system was designed by the consultant neurologists. The
previous method of referral was by handwritten letter. The electronic template
included 'drop-down' menus and mandatory fields to help guide referring teams. An
outcome section is completed by the neurology team. Results: An average of 17
referrals was seen weekly. Seventy-seven per cent were seen within 24 h of
referral. A consultant neurologist saw 87% of the referrals directly; 13% were
first seen by a registrar and later discussed with a consultant. Forty per cent
were seen in the ED of which a one-third of the patients were discharged
following assessment. The most common reason for referral was seizure(s) or an
episode of collapse (28%). Patients presenting with stroke/transient ischaemic
attack represented 13.5%, and 12.5% presented with headaches. The management of
79% of referred cases was deemed to have been significantly changed after
neurology review. Discussion: The introduction of a neurology consultant-designed
and consultant-led intranet referral service has greatly enhanced the delivery of
the consult service to patients in our hospital. This referral system contributes
significantly to hospital efficiency and to access for patients to specialist

PMID: 20050903 [PubMed - indexed for MEDLINE]

9. Mol Syndromol. 2010 Sep;1(3):121-126. Epub 2010 Sep 14.

Expansion of the Spectrum of FLNA Mutations Associated with Melnick-Needles

Foley C, Roberts K, Tchrakian N, Morgan T, Fryer A, Robertson SP, Tubridy N.

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

Melnick-Needles syndrome (MNS) is a rare X-linked bone dysplasia characterised by
facial dysmorphology and radiographic abnormalities [Melnick and Needles,
1966;97:39-48]. Previously, all published cases of MNS were associated with only
4 mutations [Robertson et al., 2003;33:487-491; Santos et al.,
2010;152A:726-731], all localised within exon 22 of FLNA, the gene encoding the
cytoskeletal protein filamin A. Here we report 3 new mutations in FLNA that are
associated with MNS. One affected member of the first family with the mutation
p.Y1229S presented with a stroke while this patient's daughter, previously known
to be affected from a young age, developed multiple sclerosis. A second unrelated
patient with a typical phenotype is shown to have the mutation c.1054G>T
(p.G352W) within exon 7 of FLNA. A third individual with an atypical presentation
but radiological findings very similar to those seen in classic MNS has a
deletion likely to affect residues within repeat domain 14. These findings
indicate that the mutational spectrum for MNS is wider than previously
appreciated and has implications for genetic testing strategies employed to
confirm a diagnosis of this rare disorder.

PMCID: PMC2957847
PMID: 21031081 [PubMed]

10. J Neurol. 2010 Nov 12. [Epub ahead of print]

'Switching off' SUNCT by sudden head movement: a new symptom.

Chaila E, Ali E, Rawluk D, Hutchinson M.

Department of Neurology, St Vincent's University Hospital, Elm Park, Dublin 4,
Ireland, cholachaila@yahoo.ie.

PMID: 21072534 [PubMed - as supplied by publisher]

11. J Interferon Cytokine Res. 2010 Oct;30(10):787-9.

Natalizumab therapy of multiple sclerosis.

Hutchinson M.

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

Multiple sclerosis (MS) is the commonest disabling neurological disease of young
and middle-aged adults affecting 1 million persons world wide. The illness begins
with a relapsing-remitting MS course in 85%–90% of patients; the other 10%–15%
have a primary progressive onset MS. Our current understanding is that MS is an
autoimmune disorder with an inflammatory T-cell attack on myelin or some
component of the oligodendrocyte--myelin structure. Relapses of disease activity
result in plaques of demyelination with destruction of myelin and, to a lesser,
extent axons. Lymphocytes within the central nervous system tissue recruit more
cells leading to an inflammatory cascade that causes myelin damage, axonal
disruption, and neuronal death. If the plaque occurs in a vocal area of the
central nervous system then symptoms relating to that area result. However,
magnetic resonance imaging shows that approximately 10 times more lesions occur
in asymptomatic areas of the brain. Recovery from an initial relapse may appear
relatively complete but persistent inflammation results in axonal injury and
residual disability results. With time and accumulated lesion load, secondary
degeneration of denuded axons results in the phase of secondary progressive MS
usually 15-20 years after onset.

PMID: 20874255 [PubMed - in process]


12. Mov Disord. 2010 Jan 15;25(1):84-90.

Comparing endophenotypes in adult-onset primary torsion dystonia.

Bradley D, Whelan R, Walsh R, O'Dwyer J, Reilly R, Hutchinson S, Molloy F,
Hutchinson M.

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

Adult-onset primary torsion dystonia (AOPTD) has an autosomal dominant pattern of
inheritance with markedly reduced penetrance; the genetic causes of most forms of
AOPTD remain unknown. Endophenotypes, markers of sub-clinical gene carriage, may
be of use detecting non-manifesting gene carriers in relatives of AOPTD patients.
The aim of this study was to compare the utility of the spatial discrimination
threshold (SDT) and temporal discrimination threshold (TDT) as potential
endophenotypes in AOPTD. Data on other published candidate endophenotypes are
also considered. Both SDT and TDT testing were performed in 24 AOPTD patients and
34 of their unaffected first degree relatives; results were compared with normal
values from a control population. Of the 24 AOPTD patients 5 (21%) had abnormal
SDTs and 20 (83%) had abnormal TDTs. Of the 34 first degree relatives 17 (50%)
had abnormal SDTs and 14 (41%) had abnormal TDTs. Discordant results on SDT and
TDT testing were found in 16 (67%) AOPTD patients and 21 (62%) first degree
relatives. TDT testing has superior sensitivity compared to SDT testing in AOPTD
patients; although false positive TDTs are recognised, the specificity of TDT
testing in unaffected relatives is not determinable. The high level of
discordance between the two tests probably relates methodological difficulties
with SDT testing. The SDT is an unreliable AOPTD endophenotype; TDT testing
fulfils criteria for a reliable endophenotype with a high sensitivity.

PMID: 19938165 [PubMed - indexed for MEDLINE]