home » department of neurology » peer reviewed publications 2009

1. Mult Scler. 2009 Dec;15(12):1528-31. Epub 2009 Dec 7.

Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we
stop what we have started?

Lonergan R, Kinsella K, Duggan M, Jordan S, Hutchinson M, Tubridy N.

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

Disease-modifying therapy is ineffective in disabled patients (Expanded
Disability Status Scale [EDSS] > 6.5) with secondary progressive multiple
sclerosis (MS) without relapses, or in primary progressive MS. Many patients with
secondary progressive MS who initially had relapsing MS continue to use
disease-modifying therapies. The enormous associated costs are a burden to health
services. Regular assessment is recommended to guide discontinuation of
disease-modifying therapies when no longer beneficial, but this is unavailable to
many patients, particularly in rural areas. The objectives of this study are as
follows: 1. To observe use of disease-modifying therapies in patients with
progressive multiple sclerosis and EDSS > 6.5. 2. To examine approaches used by a
group of international MS experts to stopping-disease modifying therapies in
patients with secondary progressive MS without relapses. During an
epidemiological study in three regions of Ireland (southeast Dublin city, and
Wexford and Donegal Counties), we recorded details of disease-modifying therapies
in patients with progressive MS and EDSS > 6.5. An e-questionnaire was sent to 26
neurologists with expert knowledge of MS, asking them to share their approach to
stopping disease-modifying therapies in patients with secondary progressive MS.
Three hundred and thirty-six patients were studied: 88 from southeast Dublin, 99
from Wexford and 149 from Donegal. Forty-four had EDSS > 6.5: 12 were still using
disease-modifying therapies. Of the surveyed neurologists, 15 made efforts to
stop disease-modifying therapies in progressive multiple sclerosis, but most did
not insist. A significant proportion (12 of 44 patients with progressive MS and
EDSS > 6.5) was considered to be receiving therapy without benefit. Eleven of the
12 were from rural counties, reflecting poorer access to neurology services. The
costs of disease-modifying therapies in this group (>170,000 euro yearly) could
be re-directed towards development of neurology services to optimize their

PMID: 19995848 [PubMed - indexed for MEDLINE]

2. J Immunol. 2009 Dec 1;183(11):7602-10. Epub 2009 Nov 16.

CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in
multiple sclerosis.

Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O'Farrelly C, Tubridy
N, Mills KH.

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

Despite the fact that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells) play
a central role in maintaining self-tolerance and that IL-17-producing CD4(+) T
cells (Th17 cells) are pathogenic in many autoimmune diseases, evidence to date
has indicated that Th17 cells are resistant to suppression by human Foxp3(+) Treg
cells. It was recently demonstrated that CD39, an ectonucleotidase which
hydrolyzes ATP, is expressed on a subset of human natural Treg cells. We found
that although both CD4(+)CD25(high)CD39(+) and CD4(+)CD25(high)CD39(-) T cells
suppressed proliferation and IFN-gamma production by responder T cells, only the
CD4(+)CD25(high)CD39(+), which were predominantly FoxP3(+), suppressed IL-17
production, whereas CD4(+)CD25(high)CD39(-) T cells produced IL-17. An
examination of T cells from multiple sclerosis patients revealed a normal
frequency of CD4(+)CD25(+)CD127(low)FoxP3(+), but interestingly a deficit in the
relative frequency and the suppressive function of
CD4(+)CD25(+)CD127(low)FoxP3(+)CD39(+) Treg cells. The mechanism of suppression
by CD39(+) Treg cells appears to require cell contact and can be duplicated by
adenosine, which is produced from ATP by the ectonucleotidases CD39 and CD73. Our
findings suggest that CD4(+)CD25(+)Foxp3(+)CD39(+) Treg cells play an important
role in constraining pathogenic Th17 cells and their reduction in multiple
sclerosis patients might lead to an inability to control IL-17 mediated
autoimmune inflammation.

PMID: 19917691 [PubMed - indexed for MEDLINE]

3. Ir Med J. 2009 Oct;102(9):292-4.

A pernicious leucoencephalopathy.

Molloy A, Cawley N, Ali E, Connolly S, Tubridy N, Hutchinson M.

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

Pernicious anaemia may manifest various neurological symptoms and signs ranging
from the subtle to the dramatic. We describe a young man with cobalamin
deficiency presenting with sensorimotor deficits, ataxia, dysarthria, mild
cognitive deterioration and altered mood of insidious onset. The MRI brain
findings were in keeping with a leucoencephalopathy without evidence of MRI
changes in the spinal cord. This constellation of features has been reported
rarely. His response to treatment as well as the marked improvement of the
leucoencephalopathy on imaging suggests at least partial reversibility of the
neurological deficits.

PMID: 19902649 [PubMed - in process]

4. Lancet Neurol. 2009 Oct;8(10):889-97. Epub 2009 Sep 2.

250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in
relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre

O'Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, Hartung HP, Jeffery
D, Kappos L, Boateng F, Filippov V, Groth M, Knappertz V, Kraus C, Sandbrink R,
Pohl C, Bogumil T; BEYOND Study Group, O'Connor P, Filippi M, Arnason B, Cook S,
Goodin D, Harung HP, Kappos L, Jeffery D, Comi G.

Collaborators: Abramsky O, Achiron A, Agius M, Aichner F, Altenkirch H, Amato MP,
Anten B, Arbizu T, Ash P, Ballario C, Bashir K, Baum K, Baumhackl U, Beaver G,
Belova A, Berger J, Berger T, Berlit P, Beuche W, Bhan V, Bigley K, Bissay V,
Blake C, Bö L, Boyko A, Brochet B, Brown M, Callegaro D, Carra A, Carroll W,
Cascione M, Christie S, Clanet M, Clavelou P, Clementino VI, Confavreux C, Cooper
J, Cross A, Csanyi A, Czlonkowska A, D'Hooghe M, Damier P, Debouverie M, Defer G,
Demina T, Deri N, Diem R, Dressel A, Dubois B, Dunne P, Duquette P, Durelli L,
Edan G, Elias S, Elovaara I, Esfahani F, Evtushenko S, Fabijan TH, Fernández O,
Ferreira ML, Fink A, Flechter S, Ford C, Francesconi C, Freedman M, Fryze W,
Gabbai A, Gács G, Gallo P, Gazda S, Gerloff C, Glyman S, Goodman A, Gottesman M,
Grand'Maison F, Guarnaccia J, Gutierrez A, Haas J, Hansen HJ, Hardiman O, Heard
R, Heidenreich F, Herbert J, Herminia Scola R, Hodgkinson S, Hoffmann F, Holub R,
Huddlestone J, Hughes B, Hughes M, Hunter S, Hurwitz B, Izquierdo G, Jacobasch E,
Jacques F, Jakab G, Jongen P, Karageorgiou C, Karni A, Kasper L, Kaufman M,
Keidel M, Khatri B, Kiefer R, Kirzinger S, Kita M, Komoly S, Kotov S, Kozubski W,
Kumlien E, Kwiecinski H, Labouge P, LaGanke C, Lapierre Y, Lebrun-Frenay C, Leist
T, Leon SA, Luetic G, Lynch S, Lynch T, Malkova N, Maltezou M, Markowitz C,
Martin C, Mattle H, Mattson D, Metra M, Meyding-Lamadé U, Milo R, Milonas I,
Miller A, Miller T, Minagar A, Mitchell G, Moreau T, Mosberg R, Murphy R, Nehrych
T, Nikl J, Odinak M, Oschmann P, Owen King J, Pagani L, Pereira Damasceno B,
Podemski R, Pöhlau D, Pozzilli C, Rammohan K, Reunanen M, Rice G, Richardson P,
Rivera V, Rizvi S, Rogozhyn V, Rolak L, Rosenkranz T, Rotta R, Sanders E, Sater
R, Satgur Gupta A, Schwartz R, Sedal L, Sega-Jazbec S, Selchen D, Selmaj K,
Sheremata W, Shvets T, Silver D, Simsarian J, Skoromets A, Smiroldo J, Sokolova
L, Solovyova Y, Sommer N, Spirin N, Stangel M, Stark E, Steinbrecher A, Stemper
B, Stolyarov I, Strasser-Fuchs S, Sweeney B, Tettenborn B, Thrower B, Tilbery CP,
Traboulsee A, Trojano M, Tubridy N, Tyor W, Valikovics A, Vermersch P, Vollmer T,
Voloshyna N, Vrech C, Wajgt A, Weller B, Wendt J, Yakhno N, Yeung M, Zavalishin

St Michael's Hospital, Toronto, Canada. oconnorp@smh.toronto.on.ca

Erratum in:
    Lancet Neurol. 2009 Nov;8(11):981.

Comment in:
    Lancet Neurol. 2009 Oct;8(10):870-1.
    Lancet Neurol. 2009 Dec;8(12):1085-6; author reply 1086-7.

BACKGROUND: The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose
(BEYOND) trial was to compare the efficacy, safety, and tolerability of 250
microg or 500 microg interferon beta-1b with glatiramer acetate for treating
relapsing-remitting multiple sclerosis. METHODS: Between November, 2003, and
June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were
screened and 2244 patients were enrolled in this prospective, multicentre,
randomised trial. Patients were randomly assigned 2:2:1 by block randomisation
with regional stratification to receive one of two doses of interferon beta-1b
(250 microg or 500 microg) subcutaneously every other day or 20 mg glatiramer
acetate subcutaneously every day. The primary outcome was relapse risk, defined
as new or recurrent neurological symptoms separated by at least 30 days from the
preceding event and that lasted at least 24 h. Secondary outcomes were
progression on the expanded disability status scale (EDSS) and change in
T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for
2.0-3.5 years; MRI was done at screening and annually thereafter. Analysis was by
per protocol. This study is registered, number NCT00099502. FINDINGS: We found no
differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or
normalised brain volume among treatment groups. Flu-like symptoms were more
common in patients treated with interferon beta-1b (p<0.0001), whereas
injection-site reactions were more common in patients treated with glatiramer
acetate (p=0.0005). Patient attrition rates were 17% (153 of 888) on 250 microg
interferon beta-1b, 26% (227 of 887) on 500 microg interferon beta-1b, and 21%
(93 of 445) for glatiramer acetate. INTERPRETATION: 500 microg interferon beta-1b
was not more effective than the standard 250 microg dose, and both doses had
similar clinical effects to glatiramer acetate. Although interferon beta-1b and
glatiramer acetate had different adverse event profiles, the overall tolerability
to both drugs was similar. FUNDING: Bayer HealthCare Pharmaceuticals.

PMID: 19729344 [PubMed - indexed for MEDLINE]

5. J Neurovirol. 2009 Dec;15(5-6):351-9.

Reactivation of BK polyomavirus in patients with multiple sclerosis receiving
natalizumab therapy.

Lonergan RM, Carr MJ, De Gascun CF, Costelloe LF, Waters A, Coughlan S, Duggan M,
Doyle K, Jordan S, Hutchinson MW, Hall WW, Tubridy NJ.

Department of Neurology, St Vincent's University Hospital, Elm Park, Dublin,
Ireland. roisin.lonergan@st-vincents.ie

Natalizumab therapy in multiple sclerosis has been associated with JC
polyomavirus-induced progressive multifocal leucoencephalopathy. We hypothesized
that natalizumab may also lead to reactivation of BK, a related human
polyomavirus capable of causing morbidity in immunosuppressed groups. Patients
with relapsing remitting multiple sclerosis treated with natalizumab were
prospectively monitored for reactivation of BK virus in blood and urine samples,
and for evidence of associated renal dysfunction. In this cohort, JC and BK DNA
in blood and urine; cytomegalovirus (CMV) DNA in blood and urine; CD4 and CD8
T-lymphocyte counts and ratios in peripheral blood; and renal function were
monitored at regular intervals. BK subtyping and noncoding control region
sequencing was performed on samples demonstrating reactivation. Prior to
commencement of natalizumab therapy, 3 of 36 patients with multiple sclerosis
(8.3%) had BK viruria and BK reactivation occurred in 12 of 54 patients (22.2%).
BK viruria was transient in 7, continuous in 2 patients, and persistent viruria
was associated with transient viremia. Concomitant JC and CMV viral loads were
undetectable. CD4:CD8 ratios fluctuated, but absolute CD4 counts did not fall
below normal limits. In four of seven patients with BK virus reactivation,
transient reductions in CD4 counts were observed at onset of BK viruria: these
resolved in three of four patients on resuppression of BK replication. No renal
dysfunction was observed in the cohort. BK virus reactivation can occur during
natalizumab therapy; however, the significance in the absence of renal
dysfunction is unclear. We propose regular monitoring for BK reactivation or at
least for evidence of renal dysfunction in patients receiving natalizumab.

PMID: 19670070 [PubMed - indexed for MEDLINE]

6. Neurology. 2009 Aug 11;73(6):e25-9.

Clinical reasoning: an unusual case of papilledema after orthotopic liver

Gorman GS, Tubridy NJ, Hutchinson M.

Mitochondrial Research Group, 4th Floor, The Medical School, Newcastle
University, Newcastle upon Tyne, UK. grainne.gorman@ncl.ac.uk

PMID: 19667314 [PubMed - indexed for MEDLINE]

7. J Med Genet. 2009 Nov;46(11):786-91. Epub 2009 Jul 7.

Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic
migraine: implications for diagnostic testing.

Labrum RW, Rajakulendran S, Graves TD, Eunson LH, Bevan R, Sweeney MG, Hammans
SR, Tubridy N, Britton T, Carr LJ, Ostergaard JR, Kennedy CR, Al-Memar A,
Kullmann DM, Schorge S, Temple K, Davis MB, Hanna MG.

MRC Centre for Neuromuscular Diseases, Institute of Neurology, UCL, London WC1N
3BG, UK.

BACKGROUND: Episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1
(FHM1) are autosomal dominant disorders characterised by paroxysmal ataxia and
migraine, respectively. Point mutations in CACNA1A, which encodes the neuronal
P/Q-type calcium channel, have been detected in many cases of EA2 and FHM1. The
genetic basis of typical cases without CACNA1A point mutations is not fully
known. Standard DNA sequencing methods may miss large scale genetic
rearrangements such as deletions and duplications. The authors investigated
whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1.
METHODS: The authors used multiplex ligation dependent probe amplification (MLPA)
to screen for intragenic CACNA1A rearrangements. RESULTS: The authors identified
five previously unreported large scale deletions in CACNA1A in seven families
with episodic ataxia and in one case with hemiplegic migraine. One of the
deletions (exon 6 of CACNA1A) segregated with episodic ataxia in a four
generation family with eight affected individuals previously mapped to 19p13. In
addition, the authors identified the first pathogenic duplication in CACNA1A in
an index case with isolated episodic diplopia without ataxia and in a first
degree relative with episodic ataxia. CONCLUSIONS: Large scale deletions and
duplications can cause CACNA1A associated channelopathies. Direct DNA sequencing
alone is not sufficient as a diagnostic screening test.

PMID: 19586927 [PubMed - indexed for MEDLINE]

8. Nat Genet. 2009 Jul;41(7):824-8. Epub 2009 Jun 14.

Genome-wide association study identifies new multiple sclerosis susceptibility
loci on chromosomes 12 and 20.

Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene).

Collaborators: Bahlo M, Booth DR, Broadley SA, Brown MA, Foote SJ, Griffiths LR,
Kilpatrick TJ, Lechner-Scott J, Moscato P, Perreau VM, Rubio JP, Scott RJ,
Stankovich J, Stewart GJ, Taylor BV, Wiley J, Brown MA, Booth DR, Clarke G, Cox
MB, Csurhes PA, Danoy P, Drysdale K, Field J, Foote SJ, Greer JM, Griffiths LR,
Guru P, Hadler J, McMorran BJ, Jensen CJ, Johnson LJ, McCallum R, Merriman M,
Merriman T, Pryce K, Scott RJ, Stewart GJ, Tajouri L, Wilkins EJ, Rubio JP, Bahlo
M, Brown MA, Browning BL, Browning SR, Perera D, Rubio JP, Stankovich J, Broadley
S, Butzkueven H, Carroll WM, Chapman C, Kermode AG, Marriott M, Mason D, Heard
RN, Pender MP, Slee M, Tubridy N, Lechner-Scott J, Taylor BV, Willoughby E,
Kilpatrick TJ.

To identify multiple sclerosis (MS) susceptibility loci, we conducted a
genome-wide association study (GWAS) in 1,618 cases and used shared data for
3,413 controls. We performed replication in an independent set of 2,256 cases and
2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified
risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11);
rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40
on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)).
Both loci are also associated with other autoimmune diseases. We also replicated
several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x
10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x
10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a
statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

PMID: 19525955 [PubMed - indexed for MEDLINE]

9. Tissue Antigens. 2009 Jul;74(1):17-21. Epub 2009 Apr 21.

HLA-DRB1 associations with disease susceptibility and clinical course in
Australians with multiple sclerosis.

Stankovich J, Butzkueven H, Marriott M, Chapman C, Tubridy N, Tait BD, Varney MD,
Taylor BV, Foote SJ; ANZgene Consortium, Kilpatrick TJ, Rubio JP.

Collaborators: Booth DR, Broadley S, Greer JM, Grifffiths LR, Heard RN,
Lechner-Scott J, Pender MJ, Scott RJ, Stewart GJ.

The Menzies Research Institute, Hobart, Tasmania, Australia.

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence
susceptibility to multiple sclerosis (MS), but their contribution if any to the
clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles
in a large sample of 1230 Australian MS cases, with some enrichment for subjects
with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls.
Using logistic regression, we found that DRB1*1501 was strongly associated with
risk (P = 7 x 10(-45)), as expected, and after adjusting for DRB1*1501, a
predisposing effect was also observed for DRB1*03 (P = 5 x 10(-7)). Individuals
homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS
than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15
genotype combination, respectively, protected against PPMS in comparison to
subjects with relapsing disease. Together, these data provide further evidence of
heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the
phenotypic expression of MS.

PMID: 19392788 [PubMed - indexed for MEDLINE]

10. Neurology. 2009 Jan 20;72(3):e11-4.

Clinical reasoning: a case of Wegener granulomatosis complicated by seizures and
headaches: curiouser and curiouser.

Gorman G, Hutchinson M, Tubridy N.

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

PMID: 19153367 [PubMed - indexed for MEDLINE]