Genome-wide Association Scan Identifies Two Novel MultipleSclerosis Susceptibility Loci. Both Chromosome LocationsIdentified are Associated with Autoimmune Diseases IncreasingEvidence for Common Mechanisms of Pathogenesis for Autoim-mune Diseases

Bruce Taylor

Non-HLA genetic risk factors have recently been identified formultiple sclerosis (MS). To identify additional MS susceptibility lociwe conducted a genome-wide association scan (GWAS) in 1,618 MScases from Australia and New Zealand (ANZ) and used control datafrom the United Kingdom and the United States of America(n = 3,413). Replication was conducted in an independent set of2,256 ANZ MS cases and 2310 ANZ controls, making a total sampleof 3,874 cases and 5,723 controls. We identified risk-associated SNPsat two loci on different chromosomes with p values of 2.2 �10-10,p = 2.7 � 10-10, and 1.4 � 10-7 at the first locus, and p values of1.7 �10-7 and 4.0 � 10-7 at the second locus. Several previouslyreported MS associations were also replicated (HLA-DR15,p = 6.8 � 10-193; CD58, p = 3.4 � 10-7; EV15/RPL5, p = 1.7 � 10-6;IL2RA, p = 7.4 � 10-6, CLEC16A, p = 1.5 � 10-5, IL7R, p = 2.8 � 10-4).Evidence of statistical interaction was identified between SNPs inEV15/RPL5 and HLA-DR15 (p = 0.001).

Both chromosome locations identified are associated with vari-ous organ-specific autoimmune diseases, including rheumatoidarthritis, type 1 diabetes and Grave’s disease. Therefore, this currentstudy of MS confirms a pathogenetic overlap between theseimmune-mediated complex diseases.

doi:10.1016/j.jocn.2009.07.022

The Audio Recorded Cognitive Screen (ARCS): A New Sensitiveand Easy to Administer Tool to Assess Cognition in Patients withMultiple Sclerosis

Jeannette Lechner-Scott 1,3, Susan Agland 1, Tanya Kerr 2, Peter WSchofield 2,3

1 Department of Neurology, John Hunter Hospital, Newcastle, NSW,Australia2 Neuropsychiatry Service, Hunter New England Area Health, Newcastle,NSW, Australia3 Centre for Brain and Mental Health Research, University of Newcastle,NSW, Australia

Background: Cognitive impairment is common (43-65%) inmultiple sclerosis (MS) and often leads to early disability and unem-ployment. However, cognitive impairment in MS may remain unrec-ognised if measured only by Expanded Disability Status Scale (EDSS)or Mini Mental State Examination. Detailed neuropsychological test-ing is time consuming and requires skilled personnel. The ARCS com-prises a battery of cognitive tests administered via CD player andheadphones. Testing lasts 35 minutes. Unsupervised patients recordtheir responses in a booklet that is later scored. Scoring takes aboutthree minutes and is the only clinician time needed to gain the re-sults of the assessment.

Objective: This ongoing study examines the potential ofthe ARCS, which has been validated in other patient groups, as anew cognitive screening tool in the MS population. Here we compareresults of the ARCS and the Paced Auditory Serial Addition Task (PA-SAT 3, a cognitive screening tool, currently used in clinical trials)with the results from ‘gold standard’ formal neuropsychologicaltesting.

Methods: 79 patients with the clinical isolated syndrome or def-inite diagnosis of multiple sclerosis were recruited from the MSclinic in Newcastle. All 79 patients underwent testing with the ARCS,34 were in addition assessed with the PASAT 3 and 30 completedtwo and a half hours of detailed neuropsychological assessment,including tests of new learning and and executive functioning.

Results: Elements of the ARCS assessing memory and executivefunctioning correlated strongly with comparable tests within theformal neuropsychological test battery (NTB): eg ARCS delayed recallwith delayed recall on the Rey Auditory Verbal Learning Test (RAV-LT) (r = 0.75, p < .001). ARCS letter fluency with NTB letter fluency(r = 0.69, p = .001), ARCS category fluency with NTB category fluency(r = 0.71, p < .001), and a novel measure of executive functioning inARCS with Trails B (r = -0.60. p < .001). By contrast, PASAT scorewas not associated with RAVLT (r = .095) and was modestly associ-ated with measures of executive functioning on NTB (category flu-ency r = 0.60, letter fluency r = 0.194, Trails B r = -0.62). Theseresults suggest that the ARCS has good validity for the assessmentboth of memory and executive functioning in patients with multiplesclerosis. By contrast, at least in this sample, PASAT was not informa-tive with respect to memory performance.

Conclusions: The ARCS may have significant advantages over PA-SAT in screening and monitoring of cognitive impairment in patientswith multiple sclerosis.

doi:10.1016/j.jocn.2009.07.023

Paraclinical Correlates of Visual Acuity Loss in Multiple Sclerosis

Marriott Mark PhD 1,2,3,*, Kolbe Scott C BSc 1,2,*, Butzkueven HelmutPhD 1,2,3, Kilpatrick Trevor J PhD 1,2,3, Egan Gary F PhD 1,2

1 Florey Neuroscience Institutes2 Centre for Neuroscience, University of Melbourne3 Department of Neurology, Royal Melbourne Hospital, Melbourne,Australia

Background: Objective measures of disability in Multiple Sclero-sis are essential for the development and testing of novel therapeuticagents. Whilst neuroprotective agents show promise in limitingdamage in animal models of MS, the lack of paraclinical measuresof such damage (specifically axonal loss and demyelination) is a lim-iting factor in the translation of testing of these agents to humanstudies. Measures such as MRI, OCT and MF VEP are potential toolsthat could prove useful in redressing this need. The aim of this studywas to examine the performance of these paraclinical patients withestablished optic neuritis and persistent abnormalities of visualacuity.

Methods: Twenty-two patients with clinically definite MS and ahistory of unilateral optic neuritis without complete recovery (Snel-len P 6/7.5) underwent optic nerve magnetic resonance imaging(MRI) using a number of sequences including magnetisation transferimaging. In addition, 15 patients had multifocal visual evoked poten-tials (mfVEP) and retinal nerve fibre layer (RNFL) thickness mea-sured for both eyes. The average magnetisation transfer ratio(MTR), mfVEP latency, mfVEP amplitude and RNFL thickness werecalculated for each eye in each patient. Low contrast visual acuitywas measured as the total number of letters read for two contrastlevels (2.5 and 1.25%) for both eyes. Correlation analyses were usedto study the relationships between paraclinical measures and lowcontrast acuity for affected and unaffected eyes separately.

* These authors contributed equally to this work.

Abstracts / Journal of Clinical Neuroscience 16 (2009) 1514–1546 1521

Results: We observed significant differences in mfVEP latency(p = 0.001) and amplitude (p = 0.02), and RNFL thickness(p = 0.0003) between the affected (Snellen P 6/7.5) and unaffectedeyes but no difference in optic nerve MTR. In clinically affected eyesthere were no significant correlations between low contrast acuityand any paraclinical measures. In clinically unaffected eyes, low con-trast acuity was significantly correlated with optic nerve MTR (2.5%:r = 0.48, p = 0.04; 1.25%: r = 0.65, p = 0.003) and mfVEP latency (2.5%:r = -0.62, p = 0.01; 1.25%: r = -0.55, p = 0.03) where both measureshave been previously postulated to represent surrogate measuresof demyelination. However low contrast letter acuity did not corre-late with mfVEP amplitude or RNFL thickness (potential surrogatemeasure of axonal degeneration).

Interpretation: In patients with MS and unilateral opticneuritis, abnormalities were noted in affected and unaffected eyesusing a variety of paraclinical measures. The data reveal complexrelationships between visual acuity and paraclinical measures thatappear to become more complex after an overt attack of opticneuritis.

doi:10.1016/j.jocn.2009.07.024

Bone Health and Age of Commencement of Anti-epileptic Medi-cation: An AED-Discordant Twin and Sibling Pair Study

Petty Sandra 1, Paton Lynda 1, Sakellarides Mary 1, Lawrence Kate 2,Berkovic Samuel 2, Fedorova Tanya 3, Sambrook Phillip 3, O’BrienTerence 1,4, Wark John 1,5

1 Department of Medicine RMH, The University of Melbourne, Parkville,VIC, Australia2 Epilepsy Research Centre, Austin Health, The University of Melbourne,Heidelberg, VIC, Australia3 The Kolling Institute of Medical Research, Sydney, NSW, Australia4 Department of Neurosciences, The Royal Melbourne Hospital, Parkville,VIC, Australia5 Bone and Mineral Service, The Royal Melbourne Hospital, Parkville,VIC, Australia

Background: Patients taking anti-epileptic drugs (AEDs) have in-creased fracture risk. Data is limited regarding effects of age of com-mencement of AEDs, particularly with respect to AED-use at youngerages and achievement of peak bone mass.

Aim: To investigate:

(1) bone health in gender-matched, AED-discordant twin/siblingpairs;

(2) associations of age of onset of epilepsy with bone mineraldensity (BMD), stratifying pairs where AED-user commencedAED before or after 18 years, when majority of bone mass isattained.

Method: Fifty AED (and epilepsy)-discordant pairs were studied.DXA scans were acquired (Hologic 4500A/1000W), measuring BMDat lumbar spine (LS), total hip (TH), femoral neck (FN), total forearm(FA) and total body bone mineral content (TBBMC). Data wasadjusted for age, height, weight. Paired t-tests calculated meanwithin-pair differences (MWPD). Independent t-tests comparedwithin-pair differences of pairs where the AED-user commencedAED under versus over 18 years.

Results: 40 female, 10 male pairs (17monzygous, 15 dizygoustwins and 18 sib pairs), mean (SD) age 44.5 (15.8) years were stud-ied. For the 27 pairs where the AED-user commenced AED before

18 years of age, there was a significant MWPD in height(�0.02m, p = 0.021). There were no significant MWPDs in age,height, BMI, calcium intake, total fat mass or total lean mass. For23 pairs where the AED-user commenced AED P18 years of age,there was a significant MWPD in calcium intake (=278mg,p = 0.021). Comparing MWPDs of pairs where AED-user com-menced AED after age 18y versus under 18y, there were significantdifferences in the MWPDs between the groups at the TH, FN and inTBBMC (see Table):

Conclusion: Commencement of AED therapy at a younger age isassociated with shorter stature, reduced BMD at total hip, femoralneck and reduced TBBMC. Whether this is primarily attributable toan AED-associated reduction in peak bone mass or is influenced byduration of the epileptic disorder requires further, longitudinalstudies.

doi:10.1016/j.jocn.2009.07.025

Posters:1. A case of cyclospirin-induced isolated bilateral deep cerebellarnuclei toxicity

David J. Szmulewicz 1, Storey Elsdon 2

1 Department of Neuroscience, Alfred Hospital, Victoria, Australia2 Department of Neuroscience (Medicine), Monash University (AlfredHospital Campus), Victoria, Australia

Cyclosporin A belongs to the calcineurin inhibitor class ofimmuno-modulators. It effects suppression of both the cell mediatedand humoral arms of the immune system. Cyclosporin-based immu-notherapy heralded the beginning of successful cardiac transplanta-tion and remains a core component of contemporary allografttolerance.

We present a case of isolated bilateral deep cerebellar nuclei tox-icity in a 61 year old man, six weeks following an orthotopic cardiactransplant managed with cyclosporin. Clinically he demonstratedsigns consistent with pan-cerebellar involvement. These includedtruncal ataxia (anterior/posterior vermis; fastigial nucleus),markedly hypometric saccades to target (dorsal vermis), dysarthria(anterior paravermis; interposed nuclei), appendicular ataxia (inter-mediate and mid-lateral hemispheres (particularly anterior lobe);interposed and dorsal dentate nuclei), and impairment of the

Age AEDOnset inAED-User

MWPD(AED-user– non-user)

SD MeanDifferencebetween agegroups

SE pvalue

TH (g/cm2) P18y 0.0196 0.1185 0.0904 0.0356 0.014*<18y �0.0708 0.1312

FN (g/cm2) P18y 0.0293 0.0996 0.1180 0.0294 0.000*<18y �0.0887 0.1067

LS (g/cm2) P18y �0.0066 0.1356 0.0643 0.0384 0.101<18y �0.0709 0.1351

FA (g/cm2) P18y 0.0058 0.0573 0.0115 0.0132 0.386<18y �0.0058 0.0349

TBBMC(grams)

P18y 81.32 350.41 220.43 100.85 0.034*

<18y �139.22 353.96

KEY:g = grams; cm = centimetres; n = number of pairs; MWPD = mean within-pairdifference; SD = standard deviation; SE = standard error; y = years; p set at <0.05.There was no significant difference in AED duration [Mean (SD) AED use: <18y: 20.5(14.6)y; P18y: 15.2 (12.1)y, p = 0.170.]

1522 Abstracts / Journal of Clinical Neuroscience 16 (2009) 1514–1546