ABN MEDALLIST

The ABN Medal is awarded annually to recognise outstanding contributions by British neurologists or neuroscientists to the science or practice of neurology, or for contributions to the Association.

For over 100 years, the prestige of British neurology depended on charismatic clinical skills and leadership. But from the 1960s, the breeze of change could be felt as new methodologies from which many other specialities took advantage started to inform the pathogenesis of neurological disorders, and the rituals of descriptive neurology were no longer seen as sufficient; disease mechanisms had also to be understood. The seeds of this brave new clinical neuroscience were sown sparingly; and few individuals had the confidence and ability to embrace the new methodologies and use these to illuminate the nature of neurological disease.

In honouring Angela Vincent as the 2009 ABN medallist, we recognise someone who has played an important role in the evolution of experimental neurology in the run-up to this millennium, and who remains active particularly in neuroimmunology. Angela qualified at the Westminster Hospital Medical School in 1966. She worked first with Ricardo Miledi at University College London. And with John Newsom Davis she established a neuroimmunology group at the Royal Free Hospital School of Medicine from 1977. This was a formidable combination: the talented and energetic clinician-scientist complementing these same qualities in the imaginative and technically versatile scientist-clinician. In Oxford, Angela, John and their loyal team, systematically unravelled an understanding of immunological and molecular disease mechanisms in neurology. In time, no autoantibody could hope to lurk undisturbed in the nooks and crannies of brain, nerve, neuromuscular junction or muscle without danger of exposure from the searchlight of Angela’s ever more sophisticated and intuitive assays: the acetylcholine receptor, alone and clustered; MuSK; rapsyn; potassium channels in nerve and brain; glutamate and glycine receptors; aquaporin-4; and acid sensing ion channels have all come under her scrutiny and had their pathogenicity laid bare.

Angela has held personal or honorary professorships in Oxford, here in Liverpool, and now in London; she is a Fellow of the Academy of Medical Sciences; and of the Royal Colleges of Pathologists and of Physicians; she is past-president of the International Society for Neuroimmunologists. As one of that distinguished group of academics to have made her mark without pausing to collect a domestic higher degree on the way, she does nevertheless hold an honorary doctorate from Bergen University in Norway; she is currently an associate editor of Brain; and has been a member of the Association of British Neurologists since 1994.

We are not the first institution to honour Angela but in pioneering the establishment of a new branch of neurological medicine; in recognising her fundamental contributions to explaining a whole host of disorders having an immunological basis; in training a generation of clinical investigators in the arts of laboratory medicine; and in providing scientific excellence and infrastructure in the two outstanding clinical neuroscience departments where she has worked – the Royal Free and Oxford – with modesty and self-effacing lack of personal promotion, we have served the spirit of this award well in awarding the 2009 ABN medal to Angela Vincent.

Alastair Compston

THE EPIDEMIOLOGY OF MOTOR NEURONE DISEASE IN TWO COUNTIES IN THE SOUTH WEST OF ENGLAND

I. Imam, S. Ball, D. Wright, O. Hanemann, J. Zajicek. Neurology Department, Derriford Hospital, Plymouth, Plymouth, UK, School of Mathematics and Statistics, University of Plymouth, Plymouth, UK

Introduction The epidemiology of motor neurone disease (MND) in the counties of Devon and Cornwall in England has not previously been studied. A previous study of England and Wales has however reported a very high death certification rate of MND in Devon.

Methodology We attempted to identify all cases of MND diagnosed in Devon and Cornwall between 2002 and 2007. The capture–recapture technique was used to assess completeness of case ascertainment. Results: The overall crude incidence rate as 2.98 per 100 000 (95% CI 2.61 to 3.36). The incidence rate standardised to the 2001 UK population was 2.52 per 100 000 (CI 2.20 to 2.84). The crude incidence rate in Cornwall was 3.78 per 100 000 (CI 3.03 to 4.53) and this was significantly higher (p = 0.011) than the rate in Devon, which was 2.61 per 100 000 (CI 2.19 to 3.04). The standardised point prevalence rate was 5.66 per 100 000 (CI 4.49 to 6.83).

Conclusions The incidence rate of MND in our study is similar to reported findings in large prospective studies of the disease. There is a significant difference between the incidence rates in Devon and Cornwall. There is a need to establish a prospective MND Register to accurately document the epidemiological characteristics of the disease.

Email: ibrahimimam2000@yahoo.com

HOW DOES A DYNEIN MUTATION SLOW MOTOR NEURONE DISEASE?

J. C. Stevens, V. Bros-Facer, W. Hendriks, J. van Minnen, L. Greensmith, J. E. Martin, E. M. C. Fisher. Institute of Neurology, Queen Square, London, UK, Center for Regenerative Medicine, MGH Boston, USA, Vrije Universiteit, Amsterdam, The Netherlands, Queen Mary, London University, London, UK, Cancer Research UK, London, UK

Approximately 10% of motor neurone disease (MND) is familial, of which 10–25% is due to mutations in superoxide dismutase 1 (SOD1). Mice possessing human mutant SOD1G93A develop MND. However, the mechanism of mutant SOD1 toxicity remains unexplained.

“Loa” mice possess a mutation in the transport protein dynein. Crossing Loa and SOD1G93A strains produces four offspring genotypes: wild-type (WT), Loa (heterozygotes), SOD1G93A (heterozygotes) and Loa/SOD1G93A (double heterozygotes).

Our previous results show that the Loa mutation in Loa/SOD1G93A motor neurons rescues retrograde axonal transport defects observed in SOD1G93A motor neurons and increases the lifespan of SOD1G93A mice.

Using lentiviruses, we expressed green fluorescent protein (GFP)-tagged SOD1 in cultured spinal motor neurons. We compared localisation and transport of GFP-OD1G93A between motor neurons of WT, Loa, SOD1G93A and Loa/SOD1G93A mice. We compared localisation and transport of mutant and wild-type GFP-SOD1 in wild-type motor neurons.

Localisation and axonal movement of GFP-SOD1G93A was indistinguishable between motor neurons of all four genotypes. Furthermore, GFP-SOD1WT showed localisation and axonal movement indistinguishable from GFP-SOD1G93A.

The lack of differences in localisation and transport of SOD1 between SOD1G93A and Loa/SOD1G93A neurons suggested that the effects of the dynein mutation are mediated through an alternative mechanism.

Email: jamescstevens@talk21.com

TRANSCRIPTIONAL PROFILING OF SPINAL MOTOR NEURONES IN THE VEGF^δ/δ MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS

A. Brockington, P. Heath, H. Holden, P. Kasher, M. Autiero, F. Claes, D. Lambrechts, P. Carmeliet, P. J. Shaw. Academic Neurology Unit, University of Sheffield, Sheffield, UK, Vesalius Research Centre, Katholieke Universiteit Leuven, Leuven, Belgium

Deletion of the hypoxia response element of the promoter region of the gene encoding vascular endothelial growth factor (VEGF) in mice causes a reduction in neural VEGF expression, and results in adult-onset motor neurone degeneration that resembles amyotrophic lateral sclerosis (ALS). Understanding the molecular pathways to neurodegeneration in the VEGF^δ/δ mouse model of ALS may improve understanding of the mechanisms of motor neurone death in the human disease.

The mechanisms of neurodegeneration in the VEGF^δ/δ mouse were investigated using transcriptional profiling of spinal motor neurones, isolated by laser capture icrodissection from 3 pairs of transgenic mice and wild-type littermates at 3 time points of disease. Extracted RNA was amplified, and gene expression profiles determined by microarray analysis, on the Affymetrix platform.

324 genes were significantly differentially expressed in motor neurones of presymptomatic VEGF^δ/δ mice, 384 genes at disease onset, and 689 genes at late stage disease. In early disease, there was transcriptional upregulation, with a switch to major transcriptional downregulation at late stage disease, associated with downregulation of genes involved in RNA processing. At symptom onset, the reduction in neural expression of VEGF observed in VEGF^δ/δ mice was accompanied by downregulation of genes involved in the maintenance of neuronal processes and synapses: genes encoding cholesterol synthesis enzymes, synaptic proteins, reelin, and proteins involved in axonogenesis. These findings suggest a hitherto unrecognised role of VEGF in the maintenance of synaptic circuitry, and suggest that its dysregulation could result in a dying-back axonopathy.

Email: alicebrockington@yahoo.co.uk

AN AUDIT OF NEUROPHYSIOLOGICAL CRITERIA USED IN THE DIAGNOSIS OF MOTOR NEURONE DISEASE

C. P. Douglass, R. H. Kandler, P. J. Shaw, C. J. McDermott. Royal Hallamshire Hospital, Sheffield, UK

Introduction New criteria for the neurophysiological diagnosis of amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) were recently proposed at an international symposium in Awaji-Shima. They differ from the accepted revised El-Escorial criteria by considering fasciculation potentials to be evidence of acute denervation. In addition when assessing diagnostic certainty the Awaji-Shima criteria equate electrodiagnostic evidence of denervation with clinical examination findings.

Aim To establish if the Awaji-Shima criteria enable an earlier diagnosis of MND to be made without increasing the number of false positives.

Methods A retrospective review was performed of 205 consecutive sets of notes, from patients who underwent neurophysiological assessment for suspected MND. The diagnoses reached using the two sets of criteria were compared to the final clinical diagnosis.

Results 110 patients of 205 had a final clinical diagnosis of MND. Awaji-Shima criteria increased the sensitivity of diagnosis without affecting the specificity or the false positive rate. Accepting fasciculations as evidence of acute denervation increased the diagnostic certainty of MND.

Discussion The new criteria may allow earlier diagnosis of MND without increasing the false positive rate.

Email: chris_douglass@hotmail.com

SOD1 MUTATIONS IN FAMILIAL MOTOR NEURONE DISEASE – DISCORDANT D90A GENOTYPE IN AFFECTED TWINS

K. E. Morrison, Y-Y. Dong, P. Renwick, J. McCauley. School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Bigmingham, UK, Guy’s and St Thomas’ Hospital, London, UK

Approximately 10% of patients with motor neurone disease (MND) have a family history of disease, and of these cases around 20% harbour dominant mutations in the Cu/Zn superoxide dismutase gene, SOD1. Unique among the over 130 SOD-1 mutations identified is the D90A mutation, which is dominant in most populations, but recessive in parts of Scandinavia, where 2–5% of the normal population are heterozygous carriers. In this presentation we will outline the clinical, neurophysiological and genetic features of two English dizygotic twin brothers, both with MND. There is no other history of MND in this family, and the parents were not consanguineous. Sequence analysis shows a heterozygous D90A SOD1 mutation in one twin, while screening of archived DNA from his deceased twin brother reveals normal SOD1. Haplotype analysis with markers flanking SOD1 shows neither twin has inherited the haplotype common to Scandinavian D90A recessive cases. One explanation of these results is that the heterozygous D90A mutation is of no relevance to the MND phenotype in the live brother. Both brothers may harbour an identical mutation in another, as yet unidentified, gene. The disease is less aggressive in the D90A brother, in keeping with theories that D90A is linked to a protective factor.

Email: k.morrison@bham.ac.uk

DIAGNOSTIC DELAYS IN PATIENTS WITH MOTOR NEURONE DISEASE – THE EFFECTS OF SOCIAL CLASS AND OTHER DEMOGRAPHIC FACTORS

A. Wills, C. Gilmore, T. Owens, N. Evangelou. Nottingham University Hospitals, University of Nottingham, Nottingham, UK

In spite of improvements in outpatient waiting times over the last 10 years the lag time between symptom onset and diagnosis in patients with motor neurone disease (MND) remains considerable. We retrospectively analysed the case notes and GP referral letters of 170 patients attending the MND clinic. The average wait between symptom onset and diagnosis was 15 months; this delay has not improved between 2000 and 2009. The major contributor to this lengthy delay was failure to refer to the appropriate specialist (a neurologist!) by primary care physicians (12 months). In this cohort of patients 81 patients (48%) were initially referred to other specialties (ENT, neurosurgery, orthopaedics, gastroenterology, respiratory) and referral to another specialist was associated with a 2-month average increase in diagnostic delay per referral. The diagnosis of MND was considered in primary care in only 10 cases (6%) and by other secondary care physicians/surgeons in 9 cases (5%). Interestingly, in contrast with other chronic neurological diseases such as multiple sclerosis, there was no correlation between social deprivation indices based on post code (Townsend, Carstairs and IMD score) and diagnostic delay suggesting that the NHS is chronically inefficient but ruthlessly egalitarian.

Email: adewills61@hotmail.com

EARLY AND CONTINUED TREATMENT OF N-METHYL D-ASPARTATE RECEPTOR-ANTIBODY ENCEPHALITIS OPTIMISES OUTCOME OF A PREDOMINANTLY NON-PARANEOPLASTIC DISEASE

S. R. Irani, K. Bera, S. Maxwell, D. M. Kullman, P. Waters, I. Galea, M. Allen, D. Beeson, B. Lang, A. Vincent. Department of Clinical Neurology, Oxford University, Oxford, UK

To define N-methyl d-aspartate receptor-antibody (NMDARAb), we established a sensitive serological assay and here present the first European case series of 55 patients diagnosed with NMDARAb encephalitis. In striking comparison to the only previous series (Dalmau et al 2008), one-third of cases were male and a neoplasm was detected in only 17% of cases. Ages ranged from 2 to 71 years. Most patients presented with encephalopathy, psychiatric manifestations, and seizures and progressed within 3 weeks to dyskinaesias, reduction in conscious level, and dysautonomia. There were important clinical differences between paraneoplastic and non-paraneoplastic cases, and between children and adults. Cerebrospinal fluid lymphocytosis was seen early whereas oligoclonal bands appeared later in the disease. Notably, magnetic resonance imaging was normal in 76% of cases.

Early immunotherapy predicted improved clinical outcomes (p = 0.019) as did early tumour removal (p = 0.047). There was a correlation between antibody levels and clinical outcome in individuals. However, in non-paraneoplastic patients many had residual NMDARAbs and this may account for the 36% relapse rate in the cohort followed up for over 1 year.

The results suggest that NMDARAb encephalitis is an important disease to identify in both sexes and all age groups. Cases without associated tumours may require ongoing immunotherapies to prevent relapse.

Email: saroshirani@doctors.net.uk

CHARACTERISTICS OF FEBRILE SEIZURES IN A STUDY OF INTERLEUKIN-1 AND OTHER INFLAMMATION-RELATED GENE POLYMORPHISMS

C. L. Deed, J. E. Martin, S. M. Allan, W. Ollier, H. C. A. Emsley. Royal Preston Hospital, Preston, UK, University of Liverpool, Liverpool, UK, University of Manchester, Manchester, UK

Background Febrile seizures (FS) are an important neurological problem because of their association with hippocampal sclerosis. We are investigating the endogenous pyrogen and pro-inflammatory cytokine interleukin-1 (IL-1) and other inflammation-related gene polymorphisms in FS.

Methods Cases aged 6 months to 5 years, with peak aural temperature >38°C, simple or complex FS, consent from parent/guardian, and no history of any neurological condition or evidence of acute symptomatic seizure, and matched controls with an acute febrile illness but no associated FS.

Results 133 cases and 121 controls were recruited, with an overall mean age of 1.8 years. Mean (±SD) peak aural temperature was 39.0°C (±0.6°C) (cases) and 38.9°C (±0.6°C) (controls). FS were simple in 102 (77%), complex in 30 (23%) and sporadic in 81 (61%) cases. The commonest cause of febrile illness in cases (43%) and controls (30%) was an upper respiratory tract infection, and other identified causes were similar among cases and controls.

Conclusions The similarity in peak aural temperature and cause of febrile illness among cases and controls points to host factors being important determinants of FS, in keeping with the concept of genetic susceptibility. This supports the study of IL-1 and other inflammation-related genes in this population.

Email: h.emsley@liv.ac.uk

ALEMTUZUMAB (CAMPATH-1H) TREATMENT FOR MULTIPLE SCLEROSIS REDUCES PRO-INFLAMMATORY CYTOKINE SECRETION FROM PERIPHERAL BLOOD MONONUCLEAR CELLS

C. L. Helliwell, S. A. J. Thompson, J. Jones, J. A. Somerfield, M. Zandi, A. Compston, A. J. Coles. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

Background Alemtuzumab (Campath-1H) is a humanised monoclonal antibody that causes prolonged lymphocyte depletion and is being tested in phase 3 trials as a treatment of multiple sclerosis. The mechanism of its therapeutic effect is unknown. Here we test the hypothesis that reconstitution after alemtuzumab alters the activity of pro-inflammatory Th17 activity lymphocytes.

Methods Peripheral blood mononuclear cells (PBMC) and CD4+ cells from controls, or MS patients (n = 15), untreated or 12 months after alemtuzumab, were cultured with CD3/CD28 coated beads and rhIL-23. Day 3 supernatant cytokine concentration was assessed by ELISA (IL-22) or Luminex (IL-1β IL4, IL6, IL12p70, IL17A, IFNγ, TNFα) and mRNA was measured by sq-rt PCR in the cultured cells.

Results After alemtuzumab, there was a significant reduction in the secretion of IL1β, IL4, IL6, IL12p70, IL17A, IL22, IFNγ and TNFα in PBMC and CD4+ supernatants.

Conclusion Secretion of “pro-inflammatory” cytokines, especially IL17 and IL22 (two cytokines produced by the recently described “Th17” cell) is reduced after alemtuzumab. This is a potential mechanism of alemtuzumab’s therapeutic effect.

Email: c.helliwell@doctors.org.uk

MAINTENANCE TREATMENT WITH GLATIRAMER ACETATE FOLLOWING MITOXANTRONE INDUCTION THERAPY IN VERY ACTIVE RELAPSING REMITTING MS: EXTENDED PROSPECTIVE FOLLOW UP

I. Karpha, J. Ramtahal, M. Boggild. The Walton Centre for Neurology and Neurosurgery NHS Trust, Liverpool, UK

Background In very active relapsing remitting multiple sclerosis (VA-RRMS) a number of groups have now reported treatment protocols based on an initial period of immunosuppression (induction) followed by immunomodulation (maintenance). We report extended experience using mitoxantrone as induction therapy before maintenance treatment with glatiramer acetate (GA).

Aims To assess the effect of mitoxantrone induction therapy followed by GA on annualised relapse rate (ARR) and EDSS, and explore predictive factors for treatment outcome.

Methods 76 (24 M, 52 F) patients with VA-RRMS were treated with mitoxantrone (generally 48 mg/m²) followed by GA. All patients were followed prospectively at 6 monthly intervals and assessed acutely at relapse.

Results Mean follow-up was 56.4 months, minimum 1 year on GA alone. Mean pre-treatment ARR was 1.915, post-treatment ARR was 0.139 (mean difference 1.775, p<0.001, 95% CI 1.580 to 1.970). Mean pre-treatment EDSS was 4.2, mean post-treatment EDSS 3.127 (p<0.001). Disability (change of 1 point to EDSS 5.5 and 0.5 over 5.5) was improved in 56%, stable in 35% and worse in 9%. Baseline factors influencing outcome and adverse effect will also be reported.

Conclusion Results suggest sustained clinical benefit at almost 5 years post-mitoxantrone therapy, with ARR remaining suppressed, and disability stabilised or improved in 91%.

Email: i.karpha@student.liv.ac.uk

REASSESSING THE USE OF MITOXANTRONE IN MULTIPLE SCLEROSIS

B. R. Wakerley, M. Hanspall, O. Malik, R. Nicholas, C. McGuigan. Imperial College Healthcare Trust, Charing Cross Hospital, Fulham Palace Road, London, UK

Background Mitoxantrone is a synthetic anthracenedione used in the treatment of aggressive relapsing remitting and secondary progressive multiple sclerosis. Early introduction of mitoxantrone in naïve patients and those sub-optimally controlled by first line disease-modifying therapies (DMTs) has been advocated.

Aim We aimed to identify prescribing habits and assess impact on disease characteristics of patients treated with mitoxantrone by performing a retrospective audit of patients treated with mitoxantrone and a control group of untreated MS patients at Imperial College Healthcare Trust.

Results Prior to treatment, the mitoxantrone treated group had higher annualised relapse rates (ARR, mean±SE) over the first 3 years from disease onset (0.47±0.02) compared to the untreated group (0.20±0.2, p = 0.0005) and higher disability at 2 years (EDSS 1.92±0.31 vs 0.94±0.07, p<0.05). Mitoxantrone was started 11.2 yrs (3.0–30.6 yrs) after disease onset, following failure of first line DMTs, duration 3.2 yrs (0.4–12.5 yrs). Initiation of mitoxantrone resulted in a reduction in ARR (0.43±0.07 vs 0.22±0.08, p = 0.12) and apparent EDSS stabilization.

Conclusions Mitoxantrone treatment showed a trend towards reduced relapse rates and stabilised EDSS progression but these subjects still had more severe disability compared to the control population so may have benefited from earlier introduction of mitoxantrone treatment based on early markers of disease activity.

Email: cmcguigan@doctors.org.uk

LONG TERM OUTCOME IN NEUROMYELITIS OPTICA: LESSONS FROM 6 YEARS OF THE UK NMO STUDY

A. Jacob, J. Palace, P. Waters, S. Jarius, E. Littleton, M. Malik, R. Nicholas, T. Solomon, E. Silber, C. Constantinescu, A. Vincent, M. Boggild. The Walton Centre for Neurology and Neurosurgery, Liverpool, UK, John Radcliffe Hospitals, Oxford, UK

Background Neuromyelitis optica (NMO) is established as a disease entity separate from MS. It is thought to be a more severe disease than MS and that it responds better to immunosuppression than immunomodulation. However, it is uncertain if all patients should be treated or indeed if patients with a single clinical episode and positive NMO antibodies should be treated. The UK NMO study charted the outcome of patients with NMO/NMO spectrum disorders over a six-year period and offers insight into the longer-term outcomes.

Results 41 patients were identified. 34 (83%) were NMO IgG/anti-AQP4 antibody positive during the course of the disease. At a median follow up of 35 months (4–71), 10 patients (23%) had died. The median EDSS was 7.2 (1.5–10). Immunosuppressants were used in all (with reduction in post treatment relapse rates) but at variable durations from the index event often after acquiring residual disability. 70% of patients had acquired residual disability after their first episode itself; the remainder by the third.

Conclusions NMO remains a disabling illness with high mortality and early preventative treatment is needed to prevent relapses. However, early, effective acute treatment of both the index events and relapses is required to avoid disability.

Email: anu.jacob@thewaltoncentre.nhs.uk

NEUROMYELITIS OPTICA SPECTRUM AND RELATIONSHIP WITH AQUAPORIN-4 ANTIBODY DISEASE: THE OXFORD COHORT

M. I. Leite, A. Fitzpatrick, D. Lashley, A. Weir, P. Waters, A. Vincent, J. Palace. Department of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK

The identification of neuromyelitis optica (NMO) antibodies to aquaporin-4 (AQP4abs) has widened the diagnostic criteria and recognised a broader NMO spectrum. We investigated whether these antibodies define specific disease syndromes and report details of patients followed in Oxford. 14/15 NMO patients had AQP4abs and all had relapsing disease, 5/13 had CSF oligoclonal bands and onset brain MRIs were normal in 7 and showed “MS-like” lesions in 3. None presented with simultaneous myelitis and optic neuritis. All responded to immunosuppression. Of 10 patients with longitudinally extensive transverse myelitis (LETM) 4 were AQP4ab+ve, 1/4 was monophasic (with short follow-up). Six LETM patients were AQP4ab–ve and 1/6 was relapsing. Two of four chronic relapsing inflammatory optic neuropathy patients were AQP4+ve. AQP4abs were not identified in monophasic ON or short lesion myelitis patients. One patient with clinical monophasic Devic’s disease but brain MRI lesions was AQP4-ve and classified as acute disseminated encephalomyelitis. True AQP4ab–ve NMO appears less frequent than previously reported from studies which have included remote cohort data. LETM and response to treatment remain the main distinguishing features between MS and AQP4+ve NMO. AQP4ab+ve LETM and ON appear chronic relapsing conditions and may be aetiologically distinct from acute monophasic TM and ON.

Email: maria.leite@imm.ox.ac.uk

THE USE OF RITUXIMAB IN MYASTHENIA GRAVIS AND LAMBERT–EATON MYASTHENIC SYNDROME: UK EXPERIENCE

H. El-Naggar, P. Maddison. Nottingham University Hospitals NHS Trust, Nottingham, UK

Originally used to treat B-cell malignancies, the monoclonal anti-CD20 antibody rituximab has since been used successfully as a therapy for B cell-mediated autoimmune disorders such as rheumatoid arthritis. There is limited experience worldwide in the use of this treatment in other organ-specific autoimmune disorders such as myasthenia gravis. In an attempt to broaden our knowledge of the effects of rituximab in patients with autoimmune disorders of neuromuscular transmission, we collected data from members of the UK myasthenia interest group from all patients treated with rituximab.

Over the last 3 years, 10 patients with generalised myasthenia gravis (acetylcholine receptor antibodies detected in seven, MuSK antibodies in three), and two with Lambert–Eaton myasthenic syndrome have been treated with rituximab in the UK. Almost all (11/12, 92%) were women, with a median age at disease onset of 21 years. All patients had previously been treated with prednisolone, second line oral immunosuppressants, and either intravenous immunoglobulin or plasma exchange. Rituximab treatment resulted in an excellent response (remission) in 3/12 (25%), with a good response seen in 5 others (42%). Only one patient developed worsening of their myasthenia following treatment. There was no correlation between treatment success and pre-treatment disease duration, or antibody status.

Email: dr.hany@doctors.org.uk

HETEROZYGOSITY AT POLYMORPHIC CODON 219 IN TWO VARIANT CREUTZFELDT–JAKOB DISEASE PATIENTS

¹A. Lukic, ²J. A. Beck, ²J. D. F. Wadsworth, ³S. Brandner, J. Collinge, S. Mead. ¹National Prion Clinic, National Hospital for Neurology and Neurosurgery, London, UK, ²MRC Prion Unit, Department of Neurodegenerative Disease, National Hospital for Neurology and Neurosurgery, London, UK, ³Department of Neuropathology, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK

Genetic variants of the prion protein gene (PRNP) strongly determine susceptibility to prion diseases. All tested patients with definite variant Creutzfeldt–Jakob disease (vCJD) are homozygous for methionine at PRNP codon 129. Heterozygosity at codon 219 (E219K), a common variant in Asians, confers resistance to sporadic CJD (sCJD). We report heterozygosity at codon 219 in 2 patients with diagnoses of probable and definite vCJD. The first patient was a 34-year-old white Caucasian who presented in 2004 with a 14-month history of personality and behavioural change progressing to ataxia, dysarthria, choreiform movements and cognitive impairment. Investigations were consistent with a diagnosis of probable vCJD. The second patient was a 31-year-old Afro-Caribbean female who over 18 months developed ataxia, choreiform movement disorder, myoclonic jerks and cognitive decline. Tonsillar biopsy confirmed a diagnosis of vCJD. RNP sequencing showed a methionine homozygous codon 129 genotype and E219K polymorphism in both patients. This polymorphism has not previously been reported in a white Caucasian individual. We found only 11 patients, all with Asian ethnicity or ancestry, in our heterogenous diagnostic referral series totalling over 1800 samples. The E219K polymorphism is protective against sCJD but appears to be neutral or may even confer susceptibility to vCJD.

Email: ana.lukic@uclh.nhs.uk

INHERITED PRION DISEASE WITH 4-OCTAPEPTIDE REPEAT INSERTION – A DISEASE THAT REQUIRES THE INTERACTION OF MULTIPLE GENETIC RISK FACTORS

D. Kaski, C. Pennington, J. Beck, M. Poulter, J. Uphill, M. Bishop, J. Lineham, C. Powell, S. Brandner, R. Knight, J. Collinge, S. Mead. ¹MRC Prion Unit, UCL Institute of Neurology, Queen Square, London, UK, ²National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

Genetic factors are implicated in the aetiology of sporadic late-onset neurodegenerative diseases. Whether these genetic variants are predominantly common or rare, and how multiple genetic factors interact with each other to cause disease is poorly understood. Inherited prion diseases are highly heterogenous and may be clinically mistaken for sporadic Creutzfeldt-Jakob disease because of a negative family history. Here we report our investigation of 10 UK patients with four extra octapeptide repeats (4-OPRI) in prion protein gene (PRNP). The predominant clinical syndrome is a progressive cortical dementia with pyramidal signs, myoclonus and cerebellar abnormalities which closely resemble sporadic CJD (sCJD). Autopsy shows perpendicular deposits of PrP in the molecular layer of the cerebellum. Identity testing, PRNP microsatellite haplotyping and genealogical work confirm no cryptic close family relationships and multiple progenitor disease haplotypes. All patients were homozygous for methionine at polymorphic codon 129 (p = 0.01). In addition, at a SNP upstream of PRNP thought to confer susceptibility to sCJD (rs1029273C), all patients were homozygous for the risk allele (P<0.001). These analyses suggest that manifestation of the clinical disease requires a combination of a rare mutation with multiple common risk alleles. These families demonstrate a classical example of epistasis, which may provide a valuable precedent for the understanding of sporadic neurodegenerative disease more generally.

Email: diego.kaski@uclh.nhs.uk

TG6 ATAXIA

M. Hadjivassiliou, P. Aeschlimann, D. P. Aeschlimann. Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK, School of Dentistry, Cardiff University, Cardiff, UK

We have demonstrated that autoantibodies in gluten ataxia recognise a novel neuronal transglutaminase, TG6. TG6 is primarily expressed in neural tissue. We have postulated that anti-TG6 antibodies may prove to be a more sensitive and specific marker for gluten related neurological dysfunction. We investigated if TG6 antibodies can be the sole marker of gluten related neurological dysfunction. We tested 12 consecutive patients with sporadic idiopathic ataxia and no serological evidence of gluten sensitivity (negative for TG2, EMA and IgG and IgA anti-gliadin antibodies) for the presence of anti-TG6. All 12 patients underwent duodenal biopsy for routine histological examination as well as for evidence of IgA deposits against TG in the gut (a specific test for gluten sensitivity). Seven out of the 12 patients had antibodies against TG6. Four had both IgG and IgA, two had only IgG and one had only IgA antibodies. In 3 out of the 7 patients there was evidence of small bowel involvement (one had enteropathy, 2 had increased intraepithelial lymphocytes and all 3 had deposits against TG). These results suggest that anti-TG6 may be the only marker of gluten sensitivity in patients presenting with ataxia even in the presence of an enteropathy.

Email: m.hadjivassiliou@sheffield.ac.uk

OCULOMOTOR IMPULSIVITY IN PARKINSON’S DISEASE

R. J. Adam, P. M. Bays, V. Singh-Curry, P. G. Bain, M. Husain. Institute of Neurology, University College London, London, UK, The National Hospital for Neurology and Neurosurgery, UCLH NHS Trust, Imperial College London, London, UK

Impulse control disorders are recognised as part of the phenotype of Parkinson’s disease (PD). It is difficult to predict which patients might develop impulsive behaviours and thereby avoid precipitants. Eye movements have proven to be a sensitive index of decision making in non-human primates. We developed an oculomotor paradigm to probe impulsivity in humans: a rewarded, “traffic light” task in which healthy volunteers (n = 43) and PD patients (n = 18) were asked to hold fixation when the stimulus was red or amber. When the signal turned green they had to saccade to a target as swiftly as possible. Faster responses yielded higher rewards. Crucially, the amber durations were randomly drawn from a normal distribution such that subjects might learn to anticipate. A simple model was used to fit the distributions of saccadic reaction times. Parameters of best fit for the model were used to compare performance between individuals and groups. In a proof-of-principle study we also attempted to modulate oculomotor impulsivity in healthy volunteers using dopaminergic medications. There is a marked reduction in oculomotor impulsivity with increasing age. PD patients without impulse control disorders performed similarly to age matched controls. Ongoing studies are examining the effects in PD patients with impulse control difficulties.

Email: r.adam@ion.ucl.ac.uk

DEEP BRAIN STIMULATION OF THE SUBTHALAMIC NUCLEUS; THE WALTON CENTRE EXPERIENCE

H. L. Tyne, J. Osman-Farah, S. Alusi, M. J. Steiger, P. Eldridge, N. A. Fletcher, T. K. Varma. The Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Deep brain stimulation of the subthalamic nucleus (DBS-STN) has become an accepted treatment in selected cases of advanced Parkinson’s disease.

A total 64 patients have undergone DBS-STN at the Walton Centre for Neurology and Neurosurgery. The average age at surgery was 59 years (range 35–71 years) with average disease duration of 11.7 years (range 6–26 years). UPDRS “ON” part III total was 26.1 (SD ±17.3), “OFF” part III total was 53.4 (SD± 14). At baseline mean levodopa dosage was 679 mg (SD± 397.8), and levodopa equivalence was 1456 (SD±733). Apomorphine infusion pumps were being used by 24 patients.

Patients were reassessed at 12 months (n = 48), 3 years (n = 38) and 5 years (n = 19). A reduction in both levodopa and levodopa equivalent dose was seen at all assessments, compared to baseline. At all assessments, including 5 years, significant reduction (p<0.01) in UPDRS part III total was seen “off medication/on stimulator” compared to the “off” state preoperatively. There was a significant sustained improvement in dyskinesia and “off” scores on the UPDRS.

The Walton Centre experience of DBS-STN shows significant and sustained improvement in UPDRS part III scores, dyskinesia, “off” scores and medication reduction up to 5 years post operatively.

Email: htyne@ukonline.co.uk

PROGRESSIVE SUPRANUCLEAR PALSY IMPAIRS THEORY OF MIND

B. C. P. Ghosh, J. R. Hodges, J. B. Rowe. University of Cambridge, Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK, Prince of Wales Medical Research Institute, Sydney, Australia

Background Progressive supranuclear palsy (PSP) is characterised by falls, akinetic-rigidity, oculomotor paresis and cognitive impairments such as apathy, poor executive function and non-fluency. The cognitive syndrome also includes impaired emotional and social cognition. Here we examined the ability of patients with PSP to infer the mental state or intentions of other people.

Methods Seventeen patients with probable PSP and 22 matched controls performed the Mind in the Eyes test (MIE) and the TASIT test of social inference (TASIT). MIE requires participants to select one of four option words to describe the thoughts or feelings (and gender) of a photographed person. TASIT assesses participants’ comprehension of videos of social situations, including sincerity, sarcasm or paradoxical sarcasm.

Results Patients were not impaired at gender decisions on MIE, but were worse identifying the correct mental state (t = 5.1, df = 37, p<0.001). In the TASIT, patients were equivalent to controls assessing sincere scenarios (t<1), but worse identifying sarcasm (t = 2.4, df = 20.4, p = 0.028) and paradoxical sarcasm (t = 2.8, df = 36, p = 0.008).

Discussion PSP impairs the ability to understand other people’s thoughts, intentions and beliefs, in addition to impairment of emotion recognition. These deficits may contribute to the behavioural and neuropsychiatric problems associated with PSP, with implications for patient management by carers and professional services alike.

Email: bcpg1@cam.ac.uk

HEREDITARY MYOCLONUS-DYSTONIA (DYT11) DUE TO EPSILON SARCOGLYCAN MUTATION: THE WALTON CENTRE EXPERIENCE

S. H. Wong, M. J. Steiger, A. J. Larner, N. A. Fletcher. The Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Myoclonus-dystonia (MD) associated with SGCE mutations (DYT11) is characterised by alcohol-sensitive myoclonus and dystonia, especially writer’s cramp and torticollis. The majority of familial cases are caused by mutations in the epsilon sarcoglycan (SGCE) gene on chromosome 7q21, first reported in 2001. We describe three families with autosomal dominant disease inheritance and variable penetrance, and one sporadic case with SGCE mutations, highlighting the spectrum of presentation and severity of MD with SGCE mutations. One family had a novel mutation in exon 5 of the SGCE gene: n.539_593del (p.Leu180ProfsX2). In this family, the proband first became symptomatic with retrocollis and axial dystonia at the age of 47 years, a late onset; the symptoms were severe enough to require treatment with bilateral pallidal deep brain stimulation. Intra-familial phenotypic variability was seen, with members of the same family presenting with predominantly myoclonus or dystonic movements and fixed postures. Another family gave an interesting history of affected members having a tendency to walk backwards and to pirouette. Neuropsychiatric symptoms of anxiety, depression and bipolar disorder were present in many affected patients. In conclusion, MD resulting from SGCE mutations has a variable phenotype with intrafamilial heterogeneity, with neuropsychiatric symptoms commonly seen in addition to the movement disorder.

Email: suiwong@doctors.org.uk

TEMPORAL DISCRIMINATION THRESHOLDS IN ADULT ONSET PRIMARY TORSION DYSTONIA – VOXEL BASED MORPHOMETRY IN UNAFFECTED RELATIVES VALIDATES A NEW ENDOPHENOTYPE

R. Whelan, D. Bradley, R. Walsh, R. B. Reilly, S. Hutchinson, F. Molloy, M. Hutchinson. Department of Neurology, St. Vincent’s Hospital, Dublin, Ireland, Trinity Centre for BioEngineering, Trinity College Dublin, Dublin, Ireland, Department of Neurophysiology, Beaumont Hospital, Dublin, Ireland

Background Familial adult onset primary torsion dystonia (AOPTD) is autosomal dominant with markedly reduced penetrance. Sensory abnormalities in unaffected relatives of AOPTD patients may indicate non-manifesting gene carriage. We found abnormal temporal discrimination thresholds (TDTs) in AOPTD patients and relatives. Voxel-based morphometry (VBM) is an MRI technique used to demonstrate grey-matter change.

Objective To validate abnormal TDTs in AOPTD relatives using VBM.

Patients and Methods TDTs were examined in 32 AOPTD patients, 40 first degree relatives, 17 second degree relatives and 43 controls using visual and tactile stimuli. In 33 unaffected relatives VBM was used to compare putaminal volumes between relatives with abnormal and normal TDTs.

Results The mean TDT in controls <50 years was 22.85 ms and >50 years was 30.87 ms. The upper limit of normal was defined as control mean +2.5 SD. Abnormal TDTs were found in 27/32 (85%) patients had, 20/40 (50%) first degree relatives and 7/17 (41%) second degree relatives. VBM compared 13 unaffected relatives with abnormal TDTs (mean Z-Score 0.52) and 20 with normal TDTs (mean z-score 5.9). Relatives with abnormal TDTs had significantly greater putaminal grey matter volume bilaterally.

Conclusion A structural correlate of abnormal TDTs was demonstrated. VBM findings indicate that putaminal enlargement in AOPTD is a primary phenomenon.

Email: david.bradley@ucd.ie

TEST YOUR MEMORY

J. Brown, G. Pengas, P. Clatworthy, K. Dawson. Department of Neurology, Addenbrookes, Cambridge, UK

Neurologists and their patients would benefit from having a cognitive test which was quick to use, tested a reasonable number of cognitive domains and was sensitive to mild Alzheimer’s disease. The Test Your Memory ( TYM ) was designed to fulfil these criteria. The paradox of thorough testing in minimal operator time was achieved by asking the patient to fill in the TYM sheet themselves supervised by a receptionist or nurse.

The TYM test was given to 125 patients with degenerative dementia in the Cambridge memory clinic and 540 normal controls.

Normal controls scored an average of 47/50 on the TYM, patients with Alzheimer’s disease (AD) scored an average of 33/50. The TYM showed excellent correlation with the Addenbrooke’s cognitive examination revised (ACE-R) and mini-mental state examination (MMSE). The TYM detected 93% of patients with AD in our cohort using a cut-off of 42/50, the MMSE detected 52%. Patients with non-AD dementias scored an average of 39/50.

The TYM is a powerful and valid screening test for AD which is simple and quick to use.

Delegates will be able to complete and mark their own TYM sheet – should they wish.

Email: jmb75@medschl.cam.ac.uk

REACTIVATION OF BK VIRUS IN PATIENTS WITH MULTIPLE SCLEROSIS ON NATALIZUMAB THERAPY

R. Lonergan, C. F. De Gascun, M. J. Carr, L. Costelloe, J. Fletcher, A. Waters, S. Coughlan, M. Duggan, K. Doyle, S. Jordan, W. W. Hall, M. Hutchinson, N. Tubridy. Department of Neurology, St. Vincent’s University Hospital, Dublin, Ireland

Background Natalizumab therapy has been associated with JC virus-induced PML. Reactivation of BK, another polyomavirus, during immunosuppression can be pathogenic (BK virus-associated nephropathy).

Hypothesis If JC virus can reactivate during natalizumab therapy, so could BK virus (BKV).

Objective To prospectively monitor for BK reactivation in RRMS patients receiving natalizumab.

Methods Blood and urine samples of 56 patients treated for a mean of 15 months (1–29) with natalizumab had polyomavirus screen (JC and BK PCR) at enrolment, monthly for 3 months, and 3-monthly thereafter. CD4 counts in peripheral blood were monitored. Baseline renal profile was recorded, and monitored monthly in patients with BKV reactivation. BKV subtyping was also performed.

Results Reactivation occurred in 12 patients (at mean dose 9.9). Viruria was transient in 10 patients and persistent in two. Persistent viruria was associated with transient viraemia. Concomitantly JC viral-loads were undetectable. Reactivating BKV subtypes were heterogeneous. CD4 counts fluctuated but remained within normal limits: in 5 of the 12 patients with BKV reactivation, transient reductions were observed prior to onset of viruria. Renal function remains normal in all 12.

Conclusions BK virus reactivation can occur during natalizumab therapy, but the significance of viruria or transient viraemia, in the absence of renal dysfunction, is unclear.

Email: roisin.lonergan@st-vincents.ie

SEASONAL VARIATION OF ONSET OF RELAPSES IN MULTIPLE SCLEROSISIN THE NORTHERN AND SOUTHERN HEMISPHERES: RESULTS FROM THE MSBASE REGISTRY

O. M. Gray, D. Jolley, H. Butzkueven. MSBase Foundation, Royal Melbourne Hospital, Parkville, Victoria, Australia

Background Previous studies into time of onset of relapses have had conflicting results; a meta-analysis suggests that relapses are seasonal, with more in spring and fewest in winter. However, small numbers, differing diagnostic criteria and the involvement of single regions limited these studies.

Objective To determine if there is a temporal variation in onset of relapses using the MSBase registry, a large, multi-centre cohort study of MS outcomes.

Methods Data was extracted on 16^th July 2008. The dataset comprised 7860 cases with all forms of MS from 33 centres in 16 countries, including 25 784 documented relapses. Relapses with 1st or 15th of any month recorded as day of onset were excluded, as these were common default dates. Statistical analysis was performed using log-linear regression analysis.

Results 10 887 relapses (9478 northern, 1409 southern) including 1645 first demyelinating events were analysed. Relapse onset followed a cyclical pattern with peaks in early spring and troughs in autumn in both hemispheres. Relapse onset was commonest in April in the northern hemisphere and October in the southern hemisphere.

Conclusions A seasonal variation in onset of relapses is present with a spring peak and an autumn trough in both northern and southern hemispheres.

Email: orlagray@hotmail.com

INAPPROPRIATE USE OF DISEASE-MODIFYING THERAPY IN SEVERELY DISABLED PATIENTS WITH PROGRESSIVE MULTIPLE SCLEROSIS

R. Lonergan, K. Kinsella, S. Jordan, M. Duggan, M. Hutchinson, N. Tubridy. Department of Neurology, St. Vincent’s University Hospital, Dublin, Ireland, Department of Immunology and Biochemistry, Trinity College Dublin, Dublin, Ireland

Background Disease-modifying therapy (DMT) is ineffective in disabled patients (EDSS >6.5) with secondary progressive MS (SPMS) without relapses or in primary progressive MS (PPMS). Many SPMS patients who initially had RRMS continue to use immunomodulatory treatment (IMT). Enormous costs of inappropriate IMT burden health services. Regular neurology assessment is recommended to monitor treatment response, but is unavailable to many, particularly in rural areas.

Aim To observe IMT use in patients with progressive MS and EDSS >6.5.

Methods During an epidemiological study in three regions in Ireland (South Dublin city, and Wexford and Donegal Counties, rural areas), we recorded IMT details of patients with progressive MS and EDSS >6.5.

Results 336 patients were seen: 88 from South Dublin city, 99 from Wexford and 149 from Donegal. Forty-four had EDSS >6.5: twelve were still on DMT. Eight had SPMS and 4 had PPMS. Eleven of the 12 were from rural counties.

Conclusion A significant proportion (27%) was receiving inappropriate therapy. Eleven of the twelve were from rural counties, reflecting poorer access to neurology services. Costs of IMT in this group (∼€192 000 yearly) could be redirected towards development of neurology services, to optimise management of these patients. Applied to Ireland as a whole, over €1 000 000 could be saved yearly, by identifying patients on inappropriate DMT.

Email: roisin.lonergan@st-vincents.ie

MELANOCORTIN 1 RECEPTOR GENE POLYMORPHISMS ARE ASSOCIATED WITH MULTIPLE SCLEROSIS OUTCOME

R. Abraham, R. C. Strange, T. V. Raveendran, S. Ramachandran, C. P. Hawkins. University Hospital of North Staffordshire NHS Trust, Stoke-on-Trent, Staffordshire, UK

Previous studies suggest a possible role of melanocortin 1 receptor (MC1R) gene polymorphisms in MS outcome. The relationship is more complex than the obvious influence of this gene on skin colour and thereby modulating vitamin D synthesis. In this study we hypothesised that MC1R gene polymorphisms are associated with higher multiple sclerosis severity score (MSSS); early-life sun exposure modulates the association between these polymorphisms and disease outcome. We determined MSSS in a cohort of 551 unrelated MS patients. MC1R related SNPs were identified using pyrosequencing. Information regarding past sun exposure, tendency to sunburn, skin-type and hair colour was collected using a pre-validated questionnaire. We found significant associations between some of the MC1R variants and MSSS. The MC1R Asp294/His294 and His294/His294 genotypes were associated with lower MSSS when compared to wild type Asp294/Asp294 (median MSSS 3.51 and 5.74; p = 0.0089). Asp84/Glu84 was associated with a more severe disease course than Asp84/Asp84 (median MSSS 8.58 and 5.70; p = 0.005). We did not find any direct association between MSSS and early-life UV exposure. Interestingly, the effect of these polymorphisms on MSSS is retained only in patients with a history of sunburn, pointing towards a complex interaction between skin type, UV exposure and MC1R gene polymorphisms.

Email: robyjabraham@hotmail.com

ESTIMATING THE INCIDENCE AND PREVALENCE OF NEUROMYELITIS OPTICA IN THE UK: EXTRAPOLATING DATA FROM MERSEYSIDE

A. Jacob, K. Das, M. Boggild. The Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Background Neuromyelitis optica (NMO) is a potentially fatal demyelinating neurological condition distinct from MS. Though our knowledge on its pathogenesis has advanced, very little is known about its epidemiology in western populations.

Aims To estimate the incidence and prevalence of NMO in the UK.

Methods Neurology services to all hospitals in Merseyside are provided by the Walton Centre. We searched records of the Centre from 1996 to December 2008, for NMO or NMO spectrum disorders (NMOSD) using the 2006 Wingerchuk criteria and contacted all 26 consultant neurologists. Patients identified were contacted, examined and tested for aquaporin-4 antibodies.

Results Eight patients with NMO and four with NMO spectrum disorders were identified. Five patients with NMO and all patients with NMOSD were alive on 31st December 2008. The adult population of Merseyside is 1 145 322 giving a population prevalence of NMO of 4.37 and a combined (NMO +NMOSD) of 7.86/million. Three patients with NMO and six with NMOSD were newly diagnosed giving an incidence of 0.52 and 0.7, respectively, and a combined incidence of 1.22/million/year. The UK has an adult population of 46 930 337 suggesting there are at least 369 patients with NMO or NMOSD and 57 new patients/year.

Email: anu.jacob@thewaltoncentre.nhs.uk

NEUROPSYCHIATRIC PRESENTATION OF MULTIPLE SCLEROSIS

J. Alty, A. Kilsby, M. Johnson, O. Lily, H. Ford. Leeds General Infirmary, Leeds, UK

Introduction The presentation of multiple sclerosis (MS) with predominantly or purely neuropsychiatric symptoms has been rarely described.

Methods We retrospectively reviewed 5 cases referred to the West Yorkshire Regional MS Treatment Programme between 1998 and 2008 who were found to have neuropsychiatric symptoms at onset.

Results Five cases (3 female) with a mean age of 29 years (range 20–37) are described. Their psychiatric diagnoses comprised amnesic syndrome, catatonic depression, bipolar disorder, catatonic psychosis and fronto-temporal dementia. They were consequently diagnosed with MS as per revised MacDonald criteria and subsequent disease progression fulfilled diagnostic criteria of relapsing–remitting MS (2), secondary progressive MS (2), and primary progressive MS (1). The mean follow-up period was 10 years (range 1–15).

Conclusions A neuropsychiatric presentation of MS is rare with only 5 cases recorded out of 1500 new patients seen in this regional MS clinic over a 10-year period. However, the true prevalence is probably underestimated as doctors tend to rely on the presence of physical symptoms before considering the diagnosis of MS. Early recognition of neuropsychiatric manifestations of MS is particularly important in view of making an early diagnosis of MS, limiting morbidity and considering disease-modifying drugs.

Email: altyjane@hotmail.com

STABILITY OF RETINAL NERVE FIBRE LAYER LOSS IN A PROGRESSIVE MS COHORT

A. P. D. Henderson, S. A. Trip, P. G. Schlottmann, D. R. Altmann, D. F. Garway-Heath, G. T. Plant, D. H. Miller. UCL Institute of Neurology, London, UK, Moorfields Eye Hospital, London, UK, London School of Hygeine and Tropical Medicine, London, UK

Several groups have demonstrated axonal loss in the clinically unaffected retinas of patients with multiple sclerosis; however the rate of this loss and the stage at which it occurs is unknown. Using optical coherence tomography, we serially studied sixteen patients with primary progressive multiple sclerosis (10 males and 6 females; mean age at study entry, 51 years; median EDSS, 6; mean disease duration at study entry, 12 years) and eighteen patients with secondary progressive multiple sclerosis (4 males and 14 females; mean age, 50 years; median EDSS at study entry, 6; mean disease duration at study entry, 20 years) on two occasions approximately 1.5 years apart. No patient experienced optic neuritis between the two studies. Eighteen healthy controls (10 males and 8 females; mean age at study entry, 46 years) were also studied twice. While both retinal nerve fibre layer thickness (RNFL thickness) and macular volume declined in all groups, there was no significant difference when comparing the patient and control groups. This suggests that the retinal changes seen in progressive MS patients occur earlier in the course of the disease and are perhaps mediated by subclinical episodes of acute inflammation.

Email: a.henderson@ion.ucl.ac.uk

RADIOLOGICAL BUT NOT CLINICAL CONVERSION TO MULTIPLE SCLEROSIS FOLLOWING A CLINICALLY ISOLATED SYNDROME

D. T. Chard, J. K. Swanton, C. M. Dalton, K. T. Fernando, K. A. Miszkiel, G. T. Plant, A. J. Thompson, D. H. Miller. UCL Institute of Neurology, London, UK

Introduction The 2001 McDonald criteria allow MRI findings to diagnose multiple sclerosis (MS) after a clinically isolated syndrome (CIS). The proportion of CIS patients who convert to MS on radiological findings alone is not known. We investigated this in a cohort of CIS patients who are being prospectively followed up from near CIS onset with planned MRI and clinical assessments at baseline, and after approximately 3 months, 1, 3 and 5–8 years.

Subjects 118 CIS patients (mean age at presentation 32.6 years, 73 females, 45 males) were followed up a mean of 7 years (range 4–12).

Results 55/118 had no further clinical events suggesting MS. Of these, 11 fulfilled the McDonald MRI criteria for MS, while 44 did not. Those developing “MRI-only” MS were older (38.5 {SD 6.2} vs 31.7 {7.1} years), and had higher baseline Gd-enhancing lesion numbers (0.5 {0.7} vs 0.1 {0.5}), T1-hypointense (0.3 ml {0.7} vs 0.0 {0.0}) and T2 (2.4 ml {2.1} vs 0.1 {0.2}) lesion volumes.

Conclusions The development of MS on MRI following a CIS does not mean that further clinical events are inevitable, and reinforces the fact that disease activity may be clinically silent.

Email: d.chard@ion.ucl.ac.uk

COMPLIANCE WITH MCDONALD CRITERIA AND RED FLAG RECOGNITION IN A GENERAL NEUROLOGY PRACTICE IN IRELAND

C. Albertyn, S. O’Dowd, R. Murphy. Department of Neurology, Adelaide and Meath Hospital, Tallaght, Dublin, Ireland

Background The 2005 McDonald criteria aim to simplify and speed the diagnosis of multiple sclerosis (MS) without compromising on specificity. An important caveat of the criteria is no better explanation for the presentation. A recently published consensus statement on the differential diagnosis of MS guides special investigations in the context of red flags.

Objective We aimed to see how many patients with a practice diagnosis of MS, but not fulfilling the McDonald criteria, would go on to satisfy criteria after 30 months of follow-up. We scrutinised the subgroup still not obeying criteria for red flags and clues to alternative diagnoses.

Methods Clinical notes and paraclinical tests were examined retrospectively.

Results Twenty-eight patients were included. Fifteen patients (54%) went on to fulfil criteria. Alternative diagnoses were considered and investigated in 10 of the remaining 13 patients. None of these investigations yielded significantly abnormal results. Seven patients exhibited at least one red flag and these were appropriately investigated in five patients.

Conclusion Just under half of patients persistently defied McDonald criteria. Red flags may be useful in guiding the search for alternative diagnoses, but the yield was low in our cohort. Additional red flags are proposed.

Email: christine.albertyn@amnch.ie

OAS1 GENOTYPE PREDICTS RESPONSE TO BETA INTERFERON THERAPY IN RELAPSING MULTIPLE SCLEROSIS

M. O’Brien, R. Lonergan, L. Costelloe, J. Fletcher, C. O’Farrelly, K. O’ Rourke, M. Hutchinson, N. Tubridy. Department of Neurology, St. Vincent’s University Hospital, Dublin, Ireland, Department of Immunology and Biochemistry, Trinity College Dublin, Dublin, Ireland

Background Of all relapsing MS (RRMS) patients treated with beta-interferons (IFNb), 1/3 has a suboptimal response. IFNb upregulates oligoadenylate synthetase 1 (OAS1), which induces anti-inflammatory activity. A SNP in OAS1 influences enzyme activity; G allele confers high OAS1 activity, and A allele confers low activity.

Hypothesis RRMS patients with AA genotype will have reduced responsiveness to IFNb therapy compared to those with AG or GG.

Patients and Methods 163 RRMS patients treated with IFNb were followed in relation to the time to first relapse (TTFR). Forty patients requiring natalizumab therapy were also assessed. We examined occurrence of a functional SNP at exon 7 of the OAS1 gene.

Results Thirty-four percent had AA genotype, 61% AG genotype, and 5% GG genotype. Mean TTFR on IFNb therapy differed between patients with AA genotype (21 months) and AG or GG genotype (33 months) (p = 0.0496). In the natalizumab cohort, 32.5% had AA, 67.5% AG and none GG genotype; GG was under-represented in patients with highly active RRMS.

Conclusion A functional SNP in the OAS gene, the AA genotype, predicts earlier TTFR on IFNb treatment. Possession of GG genotype is protective against highly active RRMS. OAS genotyping may guide IFNb therapy and could alert the clinician to those less likely to respond.

Email: roisin.lonergan@st-vincents.ie

MOTOR SKILL LEARNING IN MULTIPLE SCLEROSIS

V. Tomassini, H. Johansen-Berg, L. Leonardi, J. Palace, C. Pozzilli, P. M. Matthews. FMRIB Centre, Department of Clinical Neurology, University of Oxford, Oxford, UK, Department Neurological Sciences, La Sapienza University, Rome, Italy, GSK Clinical Imaging Centre and Department of Clinical Neuroscience, Imperial College London, London, UK

Brain functional reorganization mediates recovery in multiple sclerosis (MS). Motor recovery and learning share similar mechanisms of brain plasticity. Short- and long-term learning occurs via different mechanisms in healthy individuals. Here we explore dynamics of learning in MS that may clarify mechanisms of motor recovery after damage. Subjects learned a repeating sequence of hand movements. Short-term learning was assessed in 66 patients and 30 controls. Long-term learning was tested in a subgroup (23 patients, 12 controls) practising the sequence for 2 weeks. Short-term learning occurred in both groups. However, patients showed reduced mean short-term learning changes relative to controls (mean±SD error in sequence: patients vs controls 133.1±69.2 vs 91.1±41.7, p<0.0005). By contrast, long-term learning in patients and controls was comparable (mean±SD error in sequence: patients vs controls 58.3±17.7 vs 49.6±12.2, p<0.1). While in controls there was a correlation between short- and long-term learning (rho = 0.8, p<0.005), in patients this correlation was lost (rho = 0.2, p<0.5). We suggest that MS pathology impairs short-term signal summation and adaptation, but structural adaptive changes and other mechanisms of long- term plasticity can compensate for this. This emphasises a neurobiological basis for neurorehabilitation in MS and suggests that efforts to modulate long-term plasticity may contribute to improving outcomes.

Email: valentt@fmrib.ox.ac.uk

RETINAL NERVE FIBRE LAYER AXONAL LOSS FOLLOWING UNILATERAL ACUTE OPTIC NEURITIS

A. P. D. Henderson, S. A. Trip, P. G. Schlottmann, D. R. Altmann, D. F. Garway-Heath, G. T. Plant, D. H. Miller. UCL Institute of Neurology, London, UK

Axonal loss is thought to be the cause of enduring disability in MS. Retinal nerve fibres are accessible to study with optical coherence tomography (OCT) and can act as a measure of axonal loss following optic neuritis.

We prospectively followed 20 patients with acute unilateral optic neuritis and no history of other eye disease (including previous attacks of optic neuritis), with OCT to establish the mean retinal nerve fibre layer thickness (RNFLT) and macular volume (MV). These measures were performed at less than 1 month following onset, and also at three, six and 12 months following onset.

Affected eye RNFLT was significantly decreased at 12 months (85.3 μm SD 16.3, at 12 months, p<0.001 compared with the fellow eye 101.6 μm SD 11.6). The affected eye developed significant loss of MV compared with the fellow eye (6.34 mm³ SD 0.40 at 12 months, p<0.001 vs fellow eye 6.84 mm³ SD 0.31). 16/20 recovered to normal visual acuity (logMAR<0.1).

There is significant loss of RNFLT (mean −18%) in spite the generally good visual recovery typical for optic neuritis. OCT measuring RNFLT should be a sensitive tool for acute neuroprotection trials in optic neuritis.

Email: a.henderson@ion.ucl.ac.uk

THE THALAMUS AND NEUROPATHIC PAIN IN MULTIPLE SCLEROSIS

D. Seixas, J. Palace, S. Jbabdi, K. Miller, B. MacIntosh, M. Donahue, S. Deoni, S. Kolind, A. Weir, I. Tracey. Porto University, Porto, Portugal, Oxford University and Oxford Radcliffe Hospitals NHS Trust, Oxford, UK

Pain in multiple sclerosis (MS) is still poorly understood. Twenty-three MS patients were evaluated, 12 with neuropathic pain and 11 without pain, using a clinical and magnetic resonance imaging protocol. Mean duration of pain was 7.6 years (±2.5). Pain interfered with walking, work and sleep; in 75% depression coexisted. The most common sensory abnormalities were temperature abnormalities. Considering MS lesion location likely responsible for the pain, we found lesions in the spinal cord (n = 8), the medulla (n = 1) and thalamus (n = 1). In two cases lesion position was impossible to determine. Eleven patients had thalamic lesions (bilateral in six cases): five in the pain group and four in the control group, though in only one patient did it explain the pain. The majority of MS lesions in the thalamus were medially situated.

Discussion of the individual lesion location within the thalamus will be provided, using diffusion tractography. Pain was a debilitating symptom in MS, and mostly caused by spinal cord plaques. Thalamic lesions were common, but largely not associated with pain. This knowledge is important for future research. Our findings may also have an impact in the use of deep brain stimulation for pain treatment in MS.

Email: dseixas@med.up.pt

VALIDITY OF RETROSPECTIVE QUESTIONNAIRE DERIVED DISABILITY AND CLINICAL DATA IN MULTIPLE SCLEROSIS

G. Ingram, E. Colley, Y. Ben-Shlomo, M. Cossburn, C. Hirst, T. Pickersgill, N. Robertson. University Hospital of Wales, Cardiff, UK, University of Bristol, Bristol, UK

Clinical information in MS is commonly restricted to cross-sectional analysis. Detailed longitudinal phenotypic data are scarce and valuable resources enabling contributions to a range of epidemiological, genetic and interventional studies. We describe the utility and validity of a novel patient administered questionnaire designed to ascertain current disability and retrospective information in a cohort of 79 patients for whom comparable clinician derived data has been amassed regularly over a period of more than 10 years.

Reliability analysis for current EDSS showed an intraclass correlation coefficient (ICC) of 0.79 between questionnaire (both via post or telephone) and clinician derived data with agreement in 75.9%. Good ICC was also shown for year of disease onset (0.86), diagnosis (0.91) and time to secondary progression (0.88) as well as time to EDSS >4, 6 and 8 (all >0.9). The postal questionnaire accurately determined current disease course (Kappa coefficient 0.89), with only 2 patients disagreeing with contemporary clinician assessment.

This questionnaire provides accurate current and retrospective data on time to well-recognised disability milestones. We aim to extend this work by obtaining more data and using covariates to model measurement error so that we can impute missing time to event data. This maximises power and reduces bias producing more accurate natural history data.

Email: drgillianingram@hotmail.com

TEMPORAL DISCRIMINATION THRESHOLDS IN ADULT ONSET PRIMARY TORSION DYSTONIA – VOXEL BASED MORPHOMETRY IN UNAFFECTED RELATIVES VALIDATES A NEW ENDOPHENOTYPE

R. Whelan, D. Bradley, R. Walsh, R. B. Reilly, S. Hutchinson, F. Molloy, M. Hutchinson. Department of Neurology, St. Vincent’s Hospital, Dublin Ireland, Trinity Centre for BioEngineering, Trinity College Dublin, Dublin, Ireland, Department of Neurophysiology, Beaumont Hospital, Dublin, Ireland

Background Familial adult onset primary torsion dystonia (AOPTD) is autosomal dominant with markedly reduced penetrance. Sensory abnormalities in unaffected relatives of AOPTD patients may indicate non-manifesting gene carriage. We found abnormal temporal discrimination thresholds (TDTs) in AOPTD patients and relatives. Voxel-based morphometry (VBM) is an MRI technique used to demonstrate grey-matter change.

Objective To validate abnormal TDTs in AOPTD relatives using VBM.

Patients and Methods TDTs were examined in 32 AOPTD patients, 40 first degree relatives, 17 second degree relatives and 43 controls using visual and tactile stimuli. In 33 unaffected relatives VBM was used to compare putaminal volumes between relatives with abnormal and normal TDTs.

Results The mean TDT in controls <50 years was 22.85 ms and >50 years was 30.87 ms. The upper limit of normal was defined as control mean +2.5 SD. Abnormal TDTs were found in 27/32 (85%) patients had, 20/40 (50%) first degree relatives and 7/17 (41%) second degree relatives. VBM compared 13 unaffected relatives with abnormal TDTs (mean Z-Score 0.52) and 20 with normal TDTs MEAN z-Score 5.9). Relatives with abnormal TDTs had significantly greater putaminal grey matter volume bilaterally.

Conclusion A structural correlate of abnormal TDTs was demonstrated. VBM findings indicate that putaminal enlargement in AOPTD is a primary phenomenon.

Email: drranjuygc@yahoo.co.uk

AUDITORY GAMMA-BAND OSCILLATION AS A NEUROLOGICAL BASIS FOR TINNITUS

W. Sedley, K. Alter, S. Kumar, G. Barnes, H. Ashton, R. Marsh, I. Johnson, M. A. Howard, T. D. Griffiths. Auditory Group, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK, Functional Imaging Laboratory, University College London, London, UK, Department of Neurosurgery, University of Iowa, Iowa City, IA, USA

Tinnitus is common in both the general population and neurological disorders; our work examines neural activity underlying the tinnitus percept as a means of understanding pathogenesis and aiding treatments. fMRI and PET studies in tinnitus patients implicate networks of overactivity including the auditory cortex, but do not directly demonstrate the responsible neural activity.

The present studies from our group explore electrical oscillations in the gamma band (>40 Hz) as a biomarker of the tinnitus percept. The hypothesis is suggested by depth electrode recordings from neurosurgical patients, which demonstrate gamma oscillations in primary and secondary auditory cortex as a correlate of normal pitch perception.

Our surface EEG recordings from tinnitus patients demonstrate focal areas of increased temporal lobe gamma activity in individual patients with tinnitus. Surface EEG recordings from patients able to increase their tinnitus using jaw movements also demonstrate gamma power increases over the temporal lobes. MEG recordings using synthetic aperture magnetometry are under evaluation to place “virtual electrodes” in the auditory cortex that allow anatomically precise measurement of correlates of the tinnitus percept.

This approach has identified a biomarker for tinnitus that can be measured non-invasively, with anatomical and temporal precision, in individual patients for neuroscientific and clinical studies.

Email: willsedley@gmail.com

THE NEUROLOGICAL SLEEP CLINIC – HOW TO DEVELOP A SERVICE FOR THOSE WHO DO NOT SNORE

A. Dayal, K. N. Anderson. Regional Sleep Service, Freeman Hospital, University of Newcastle upon Tyne, Newcastle upon Tyne, UK

Few neurologists in the UK specialise in sleep medicine despite many common sleep disorders, eg narcolepsy, restless legs syndrome, REM sleep behaviour disorder having a clear neurological origin. Sleep medicine in many other countries is better established with neurologists, psychiatrists and respiratory physicians all investigating patients. The American Academy of Sleep Medicine (AASM) have practice parameters for the investigation and treatment of the conditions within the International Classification of Sleep Disorders (ICSD). The expansion of the Regional Sleep Service in Newcastle, with the appointment of a consultant neurologist to the service led to a review of the process for investigating and managing the neurological sleep disorders. A comprehensive database was established to document the patient pathway for all those seen within the newly established neurological sleep clinic. This has allowed a prospective audit of all patients seen with diagnosis, investigations including polysomnography, treatment and patient outcomes including patient satisfaction scores and validated sleep questionnaires all being recorded. The data for the first 200 patients is presented here and compared to the AASM standards. 95% of patients completed the 18-week RTT pathway, but 19% patients had diagnoses revised following polysomnography highlighting the need for appropriate patient pathways in sleep medicine.

Email: kirstie.anderson@nuth.nhs.uk

OCCURRENCE OF WAKE SEIZURES AFTER PURE SLEEP EPILEPSY: A SYSTEMATIC REVIEW AND IMPLICATIONS FOR DRIVING LAW

R. H. Thomas, W. H. King, J. A. Johnston, P. E. M. Smith. Wales Epilepsy Research Network, Swansea University, Swansea, UK, Department of Neurology, University Hospital of Wales, Cardiff, UK, National Public Health Service, Pontypool, Gwent, UK

Who with sleep seizures is safe to drive? Driving law is controversial; ineligibility varies between individual US states and EU countries. Current UK driving law is based on a single-centre study from 1974 where most participants were untreated. However, medication often controls pure sleep-related epilepsy (PSE) and medication withdrawal often provokes wake seizures.

This systematic review asked, “What is the risk of awake seizures in PSE?” 9885 titles were identified; 2312 excluded (not human or adult); 40 full text review; six papers met our inclusion criteria; each had a different PSE definition.

Using the largest prospective study (D’Alessandro 2004), we could calculate next year’s wake seizure chance (treated): maximal in second year; 5.7% 95% CI (3.0 to 10.4%), relative risk (RR) 1.3. The DVLA broadly accepts RR of <2.0 for Group 1 licensing. However, this study excluded frontal lobe epilepsies. Furthermore, follow-up (n = 160) varied from 2–6 years, yet new awake seizures may occur even after 10–20 years of PSE.

A paucity of evidence underpins licensing law; current rulings would be difficult to defend if legally challenged. We may be both penalising people with PSE without increased risk of wake seizures, while failing to identify subgroups at unacceptable risk of an awake seizure at the wheel.

Email: Rhys-Thomas@doctors.org.uk

EFFECTIVENESS OF DOSE ESCALATION OF LAMOTRIGINE BASED ON SERUM LEVELS COMPARED TO DOSE MAINTENANCE IN PREGNANCY: A SYSTEMATIC REVIEW

D. McCorry, M. Bagary, L. Greenhill, K. Hard, K. S. Khan, A. Pirie, S. Thangaratinam. University Hospital Birmingham, Birmingham Women’s Hospital, Birmingham, UK, Queen Elizabeth Psychiatric Hospital, Birmingham, UK

Background Epilepsy is one of the significant causes of indirect maternal deaths in pregnancy. In pregnancy, plasma levels of lamotrigine (LTG) fall significantly and this may result in a loss of seizure control. We wished to review the available evidence assessing the effectiveness of dose escalation of LTG in response to falling serum levels compared to dose maintenance and the associated maternal and foetal outcomes.

Methods We searched MEDLINE (1966–2008) and EMBASE (1980–2008), for relevant citations on the effectiveness of different dose regimes of LTG in pregnancy. Study selection, quality assessment and data extraction was carried out by 2 independent reviewers. We calculated the relative risk (RR) and the rates of seizures in both regimes and maternal and foetal outcomes.

Results Five studies studying 97 women only were assessed for the effects of the different LTG regimes on seizures. The combined rate of seizure deterioration was 0.40 (95% CI 0.26 to 0.55) in dose escalation group, compared to 0.73 (95% CI 0.56 to 0.86) in dose maintenance group.

Discussion There are very few observational studies and no randomised controlled trials informing clinical practice on LTG management in pregnancy. A prospective randomised controlled trial is needed to inform best practice.

Email: dougallmccorry@yahoo.com

SELF REPORTED SIDE EFFECTS OF ANTI EPILEPTIC DRUGS IN MONOTHERAPY

U. C. Wieshmann, G. M. Tan, G. Baker. The Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Aim To ascertain the frequency of self-reported antiepileptic drug (AED) side effects.

Methods One hundred epilepsy patients on monotherapy with carbamazepine (CBZ, n = 36, median dose (MD) 800 mg/day), sodium valproate (VPA, n = 21, MD 1000 mg/day), levetiracetam (LEV, n = 12, MD 1875 mg/day), phenytoin (PHT, n = 11, MD 300 mg/day) or lamotrigine (LTG, n = 20, MD 237.5 mg/day) completed the Liverpool Adverse Event Profile, a 19 items questionnaire. The results were compared with 41 healthy control subjects (CTRL).

Results The mean total scores were CBZ/VPA/LEV/PHT/LTG/CTRL = 45/42/42/42/36/31. Twelve of 19 items were significantly more frequent in patients than in control subjects: poor memory 38%, tiredness 37%, sleepiness 25%, difficulties concentrating 23%, shaky hands 21%, headache 22%, depression 19%, nervousness 19%, anger 17%, restlessness 17%, weight gain 15%, dizziness 12%. Seven items were not significantly more frequent: disturbed sleep 23%, skin problems 9%, hair loss 9%, trouble with gums 8%, unsteadiness 5%, upset stomach 8%, blurred vision 3%.

Conclusion All AED included in this study were associated with frequent self-reported side effects, lamotrigine appeared to be slightly better tolerated than the other drugs.

Email: udo.wieshmann@thewaltoncentre.nhs.uk

MEMBERSHIP OF DISEASE SPECIFIC PATIENT ORGANISATIONS – FACTORS INFLUENCING MEMBERSHIP AND BIASES IN PATIENT REPRESENTATION

M. Calabresi, J. Redfern, A. Stewart, C. A. Young. The Walton Centre for Neurology and Neurosurgery, University of Liverpool, Liverpool, UK, University of Barcelona, Barcelona, Spain

Whether the membership of disease specific societies reflects the population with the disease is not well studied. We investigated whether MS Society members (MSS+) and non-members (MSS-) share similar characteristics, and factors determining membership.

A sample of patients randomly selected from a MS research database participated in a postal survey.

Of 314 patients, 224 completed (72%) the questionnaire. A further 20 patients were approached in clinic (N = 244). Prevalence of MSS+ among the responders was 56%. MSS+ were older than MSS- (p<0.05) with longer disease duration (>10 yrs) (p = 0.03); more likely to: consider themselves disabled (p<0.01), receive regular medical care (p<0.01), be members of another club (p = 0.01) and less likely to work (p<0.01).

MSS+ valued information (78%) and support (59%) as motivations for joining. MSS+ found research updates (74%) as the main benefit of continued membership, the main disadvantage being meeting people more seriously affected (55%). MSS- affirmed that not wanting to be reminded about their illness (46%) was the main reason not to join.

Patient societies attract more seriously affected patients. Information and research are powerful drivers for membership. Patient societies may want to ascertain the information needs of less disabled, younger and working patients to increase their breadth of representation.

Email: carolyn.young@thewaltoncentre.nhs.uk

MAKING THE MOST OF OLNS DATA: CAN WE GET MORE OUT OF WHAT WE PUT IN?

A. A. Pace, R. A. C. Hughes, I. N. Van Schaik, J. C. Hobart. Clinical Neurology Research Group, University of Plymouth, Plymouth, UK, King’s College London School of Medicine, Guy’s Hospital, London, UK, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

Background In the Overall Neuropathy Limitations Scale (ONLS), item responses are condensed to generate rank-ordered categories that measure functional limitations caused by peripheral neuropathy. This practice does not use all available information provided by each item, potentially reducing the scale’s sensitivity to individual differences and change.

Aim To explore the possibility of achieving more than ordinal grades from an empirically-modified ONLS.

Methods Item categories were graded sequentially and item scores summed into a total. The resultant scale was tested on re-scored data from the Randomised trial of Methotrexate in CIDP (RMC) study using Rasch analysis.

Results Items locations mapped a measurable continuum for limitations well-targeted to the sample. Items worked cohesively to define a single variable. Scoring categories generally worked as intended. People’s scoring patterns fit Rasch-derived predictions, supporting measurement validity. Person separation reliability was 0.78 with no scoring bias. Interval-level estimates were derived for most people. However, gaps in the measurement continuum reduced measurement precision.

Conclusions Rasch analysis indicated that if ONLS data are scored and combined differently, the resulting scale satisfies many psychometric criteria, and linear measurements of functional limitations can be estimated. Nevertheless, we identified problems that if overcome, will further improve the measurement of functional limitations in CIDP.

Email: adrian.pace@pms.ac.uk

PROSPECTIVE EVALUATION OF THE EFFECT OF WEIGHT LOSS ON INTRACRANIAL PRESSURE IN IDIOPATHIC INTRACRANIAL HYPERTENSION

A. J. Sinclair, M. A. Burdon, A. K. Ball, N. G. Nightingale, P. Good, T. D. Matthews, A. Jacks, M. Lawden, C. E. Clarke, E. A. Walker, J. Tomlinson, P. M. Stewart, S. Rauz. College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK, Neuro-ophthalmology Unit, University Hospitals Birmingham, Birmingham, UK, Department of Neurology, Leicester General Hospital, Leicester, UK

Idiopathic intracranial hypertension (IIH) is characterised by elevated intracranial pressure (ICP) leading to visual loss and disabling headaches affecting predominantly obese females. Weight loss remains a therapy, although evidence of efficacy is limited. We describe the first prospective weight reduction trial in adults with chronic active IIH.

25 female subjects (age 36 (19–54) years, disease duration 21 (4–189) months, body mass index (BMI) 37.4 (28.4–50.2) kg/m² and ICP 39.5±4.6 cm H₂O) were prospectively enrolled into a multicentre, two stage cross over study initially being assigned to no intervention (stage 1) followed by a low calorie meal replacement diet (stage 2) each for 3 months. Outcomes were assessed at baseline and following each stage. No significant changes were noted over stage 1. During stage 2, there were significant reductions in: weight −15.2 (−30.0–−5.6) kg (p<0.001), BMI −5.4(−10.3–−2.0) kg/m₂ (p<0.001), ICP −8.25(−18.0–−2.0) cm H₂O (p<0.001), Headache Impact Test −7(−28–10) (p = 0.004), ultrasonographic measurement of optic disc elevation −0.15(−0.74–0.28) mm (p = 0.002) and nerve sheath diameter −0.73(−5.5–0.6) mm (p = 0.004). LogMAR visual acuity and Humphrey visual field mean deviations did not significantly improve. Symptoms including tinnitus, diplopia and obscurations significantly improved (p<0.05).

This is the first study to conclusively show that weight loss is effective at reducing not only ICP and headaches, but also papilloedema in patients with IIH.

Email: a.b.sinclair@bham.ac.uk

RANDOMISED CONTROLLED TRIAL OF TREATMENTS FOR IDIOPATHIC INTRACRANIAL HYPERTENSION (THE IIH PILOT TRIAL)

A. K. Ball, A. J. Howman, K. Wheatley, M. Lawden, A. Sivaguru, A. Furmston, S. Howell, B. Sharrack, M. B. Davies, M. A. Burdon, T. D. Matthews, A. S. Jacks, A. J. Sinclair, C. E. Clarke. Deaprtment of Neurology, School of Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK, Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK, Midlands Eye Centre, Sandwell and Birmingham NHS Trust, West Midlands, UK, Department of Neurology, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK, Department of Neurology, City Hospital, Sandwell and Birmingham NHS Trust, West Midlands, UK, Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK, Department of Neurology, North Staffordshire Royal Infirmary, University Hospital of North Staffordshire NHS Trust, Staffordshire, UK

The cause of idiopathic intracranial hypertension (IIH) remains unknown and its management lacks an evidence base. Acetazolamide is a common treatment, but has never been examined in a randomised controlled trial. We performed a pilot trial and evaluated various outcome measures to monitor IIH.

50 patients were recruited from five UK centres and randomised to receive acetazolamide (n = 25) or no acetazolamide (n = 25). Symptoms, body weight, visual function measures and novel composite scores of IIH clinical status were recorded over a 12-month period.

The pilot was not powered to detect a treatment effect and no differences in outcome were seen between the groups. Weight loss was observed overall but was not associated with clinical outcome. Non-compliance with acetazolamide was observed in 12 patients. Exploration of the use of commonly measured variables in IIH showed that visual fields (Humphrey perimetry) and optic disc appearance had the strongest concordance with disease status (Somer’s D = 0.66 and D = 0.59, respectively.).

We report the first randomised controlled trial in IIH and highlight issues of recruitment, compliance and outcome measurement to inform future large scale studies. A composite score of disease status may be the most appropriate way to monitor IIH and requires further evaluation.

Email: alexball@doctors.org.uk

DOCUMENTATION OF CSF OPENING PRESSURE AND OTHER ASPECTS OF LUMBAR PUNCTURE PROCEDURE FOR ACUTE HEADACHE

R. M. Hewett, C. E. Counsell. Aberdeen Royal Infirmary, Aberdeen, UK

Background Measuring CSF opening pressure by lumbar puncture is important in patients with acute headache, eg it may be the only indication of cerebral venous sinus thrombosis.

Aim To assess documentation of CSF opening pressure in those with acute headache undergoing lumbar puncture (LP). General documentation of the procedure and CSF investigations were also assessed.

Methods Retrospective review of medical records of patients admitted to a teaching hospital Acute Medical Admissions Unit (AMAU) over a 3-three month period with a presenting complaint of headache.

Results 106 patients presented to AMAU with headache of whom 48 patients had at least one LP attempted. 41 patients (85%) had the LP documented. 39 patients that had a successful documented LP, 22 (56%) had a recorded opening pressure with patient position recorded in seven. No further action taken in the four patients with opening pressure over 25 cm CSF. 20 patients had appropriate results documented (51%). 12 patients (31%) had paired venous blood glucose measured.

Conclusions Documentation of a lumbar puncture for headache in the acute setting was generally poor. CSF opening pressure measurement was frequently omitted and no appropriate action taken if high. Paired venous blood glucose was rarely measured. Acute physicians may benefit from a protocol.

Email: russellhewett@gmail.com

MIGRAINE SUSCEPTIBILITY AND MUTATIONS IN TRESK

M. Z. Cader, S. R. Rajagopolan, R. Lafrenie, G. Rouleau, G. C. Ebers, O. Ansorge, S. Tucker. University of Oxford, Oxford, UK

Migraine is a common and disabling disorder with a strong genetic component. Although the genes underlying the rare familial hemiplegic migraine have been identified, genes causing more common forms of migraine have been elusive. An ion channel candidate gene sequencing in migraine probands revealed mutations in the gene encoding the background potassium channel, TRESK. A frameshift mutation was found in a family segregating migraine with visual aura. A separate missense mutations has also been found to be underrepresented in migraneurs. Electrophysiological studies in Xenopus oocytes reveal that the former causes a complete loss of function while the latter leads to a gain of function. Immunohistochemistry also reveals specific expression of this ion channel in the trigeminal ganglion. Mutations in this ion channel are likely to alter excitability of trigeminal ganglion neurons. TRESK therefore represents an important new mediator of migraine susceptibility.

Email: zameel.cader@dpag.ox.ac.uk

OCCIPITAL NERVE AND DEEP BRAIN STIMULATION FOR MEDICALLY INTRACTABLE CHRONIC CLUSTER HEADACHE

B. Burns, P. J. Goadsby. Headache Group, Institute of Neurology, Queen Square, London, UK, Department of Neurology, University of California, San Francisco, CA, USA

Medically intractable chronic cluster headache (CCH) is a devastating neurological problem for which both deep brain stimulation (DBS) and occipital nerve stimulation (ONS) are being investigated. ONS and DBS for medically intractable CCH may be considered in terms of their efficacy and safety from published data collected in, thus far, almost exclusively open label studies.

For ONS 23/43 (53%) patients reported a >50% improvement, whereas for DBS 33/45 (73%) were similarly improved. Those who have become pain free or almost pain free include 6/43 (14%) with ONS and 21/45 (47%) after DBS. In the only double-blind study of DBS for 11 patients, no improvement was demonstrated, but the 1-month crossover period may have been insufficient to allow improvement.

In terms of safety, DBS has potentially serious side effects, including an asymptomatic ventricular haemorrhage, a transient ischaemic attack and one death due to an intraventricular haemorrhage. Adverse events for ONS are milder and predominantly limited to lead migration, infection and battery depletion.

While it may be argued that DBS should be preferred over ONS for efficacy reasons, when safety is factored in, most headache experts would argue that ONS should be used first to avoid harm. Neurologists should be aware of neuromodulatory options under investigation for medically intractable CCH.

Email: bjburns@doctors.org.uk

THUNDERCLAP HEADACHE: JUNIOR DOCTOR ASSESSMENT IN MINIMISING SUBARACHNOID HAEMORRHAGE MISDIAGNOSIS

V. Apok, J. Chang, K. J. George, B. Davies. North Midlands Regional Headache Clinic, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, UK, Department of Neurology and Neurosurgery, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, UK

Objective To assess the knowledge of thunderclap headache (TCH) and awareness of the pitfalls in assessing of the possibility of subarachnoid haemorrhage (SAH) among junior doctors in A&E.

Methods A telephone survey was carried out. 67 A&Es and 174 doctors across England were surveyed – 92 senior house officers (SHOs), 80 registrars, 2 consultants.

Results 16% of registrars and 19% of SHOs had never heard of TCH. 13% of registrars and 38% of SHOs claimed they had never been called on to assess a patient with TCH. 15% of SHOs rated themselves as “not confident” with assessment of TCH. 14% of SHOs and 9% of SpRs did not know that SAH was the most clinically important diagnosis to exclude for a TCH. Only 39% of registrars and 23% of SHOs indicated that they would use a normal CT and LP to guide safe discharge.

Conclusions There is significant shortfall in knowledge of TCH. Junior doctors also stated that analgesic response ruled out SAH. Assessment of TCH is currently based on experience and junior doctors reported difficulty in knowing when to investigate further (ie CT and LP). This study has highlighted a need for national guidelines on management of TCH in A&E.

Email: vinoapok@doctors.org.uk

SYMPTOMATIC “SUNA” IN THE SETTING OF SEVERE SYMPTOMATIC CAROTID STENOSIS

A. Justin, J. Kinsella, O. Tobin, L. Costelloe, B. Egan, D. J. H. McCabe. The Adelaide and Meath Hospital, Dublin, incorporating the National Children’s Hospital, Trinity College Dublin, Dublin, Ireland

Short-lasting unilateral neuralgiform headache attacks with cranial autonomic features (SUNA) have not been described with symptomatic atherosclerotic carotid stenosis.

A 48-year-old woman presented with a 1-week history of recurrent left retro-orbital stabbing pains, left eye lacrimation, left eye visual blurring, right face, arm and leg numbness, and right arm and leg weakness. These occurred 3–6 times per day, were maximal at onset, lasted 5 minutes, and resolved over 5 minutes. Background history included migraine with aura, diabetes, smoking, hypertension, hyperlipidaemia, peripheral vascular disease, and myocardial infarction.

Brain MRI revealed subtle left middle cerebral artery (MCA) territory ischaemia. Extracranial magnetic resonance angiography (MRA) revealed >70% left internal carotid stenosis. Her symptoms rapidly improved with clopidogrel 75 mg daily, but transcranial Doppler ultrasound detected multiple ongoing left MCA emboli.

The symptoms resolved with therapeutic IV heparin, and she underwent uncomplicated left carotid endarterectomy. She had no further headaches or transient ischaemic attacks (TIAs) at 5 weeks follow up on maintenance treatment with clopidogrel 75 mg daily.

SUNA may occur with symptomatic severe atherosclerotic carotid stenosis. The rapid response to anti-thrombotic therapy, despite ongoing embolisation on transcranial Doppler, suggests that the thrombogenic–inflammatory milieu of a ruptured carotid plaque may contribute to the pathogenesis of SUNA in this setting.

Email: dominick.mccabe@amnch.ie

GREATER OCCIPITAL NERVE BLOCKADE FOR PRIMARY HEADACHE DISORDERS

S. Miller, C. MacKay, S. Ford, M. McKenzie, N. Rasul, G. Gorrie, A. Tyagi. Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, 1345 Govan Road, Glasgow, UK

Greater occipital nerve blocks (GON Blocks) are increasingly used in primary headache disorders. We present our experience with this therapeutic procedure. For 48 consecutive GON Blocks we documented the primary headache conditions, previous treatments, greater occipital nerve tenderness and the outcome of the procedure according to a self reported pain score (0–10). One week following the GON block 25/48 patients reported a significant reduction in headache (pain score reduction more than five).

A significant reduction in headache was seen in 12/24 migraineurs, 7/12 in those with a trigeminal autonomic cephalalgia and in 2/3 with hemicrania continua. Other responders included 1 each with a trigeminal neuropathy, new daily persistent headache and occipital neuralgia. 23/25 patients had tenderness over the greater occipital nerve prior to the procedure. 14 of the 25 reported benefit within 3 days of the procedure. 20 of the 24 migraine sufferers had been tried on at least two prophylactic medications previously.

Greater occipital nerve block is a therapeutic option for patients with headache disorders regardless of classification. It is thought to be most beneficial for trigeminal autonomic cephalalgias but our experience would suggest that it can be used with success in migraineurs not responsive to standard treatments.

Email: smiller4@nhs.net

MALFORMATION RISKS OF ANTIEPILEPTIC DRUGS IN PREGNANCY: UPDATED EXPERIENCE FROM THE UK AND IRELAND EPILEPSY AND PREGNANCY REGISTER

J. I. Morrow, B. Irwin, S. J. Hunt, N. Delanty, B. Liggan, A. J. Russell, W. H. Smithson, I. Robertson, L. Parsons, R. Waddell, P. J. Morrison, J. J. Craig. Royal Victoria Hospital, Belfast, UK

Objective To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AED).

Methods Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first 3 months of life was the main outcome measure.

Results Full outcome data are available on 6086 pregnancies. 4403 (72.3%) were exposed to an AED as monotherapy with 1237 (20.3%) exposed to AEDs as part of a polytherapy regimen. 446 (7.3%) were exposed to no AED during pregnancy. The overall MCM rate for monotherapy exposure was 3.4% (95% CI 2.9 to 4.0). For individual monotherapy exposures to carbamazepine the MCM rate was 2.4% (95% CI 1.7 to 3.3), for lamotrigine 2.3% (95% CI 1.6 to 3.2) and for valproate 6.0% (95% CI 4.7 to 7.6). For those with no AED exposure the MCM rate was 2.5% (95% CI 1.4 to 4.5). For polytherapy exposures the overall MCM rate was 6.0% (95% CI 4.8 to 7.5).

Conclusions Although the numbers remain relatively small the MCM rate for women with epilepsy not taking AEDs may be higher than generally quoted population rates. Regimens containing valproate had significantly more MCMs than those not containing valproate. Data for the other drugs remain reassuring.

*Data through October 31 2008.

Email: jim.morrow@belfasttrust.hscni.net

COGNITIVE ABILITIES OF CHILDREN EXPOSED TO LEVETIRACETAM IN UTERO: PRELIMINARY FINDINGS FROM THE LIVERPOOL AND MANCHESTER NEURODEVELOPMENT GROUP

R. Shallcross, R. L. Bromley, J. Morrow, G. A. Baker. The University of Liverpool & Department of Neurology, Royal Victoria Hospital, Belfast, UK

Purpose The aim of the study is to compare the cognitive abilities of children exposed in utero to levetiracetam (LEV) with a control group of children not exposed to medication in pregnancy, born to mothers without epilepsy at 0–2 years of age.

Methods Children were prospectively enrolled onto the UK pregnancy and epilepsy register before birth. To date, 20 children exposed to LEV in utero have completed the Griffiths Developmental scale documenting the child’s global developmental level. Maternal IQ was also assessed using the National Adult Reading Test. 20 children exposed to LEV were matched by maternal IQ to 20 control children who were prospectively recruited and assessed using the same methods by the Liverpool and Manchester Neurodevelopment Group.

Results No significant differences were found between the groups for Locomotor (p = 0.512), Social (p = 0.391), Hearing & Language (p = 0.691), Performance (p = 0.122) Practical reasoning (p = 0.106) or for the child’s overall development (p = 0.111).

Conclusion The preliminary results suggest that exposure to LEV in utero does not affect the cognitive development of children under 2 years. Caution is needed in interpreting the preliminary results of this study due small sample size and young age of the children. Data collection is ongoing.Acknowledgement: Research was sponsored by UCB Pharma.

Email: r.shallcross@liv.ac.uk

1 IN 8 PATIENTS WITH SYNCOPE ARE MISDIAGNOSED AS EPILEPSY ON LONG TERM CARDIAC RHYTHM MONITORING BY AN IMPLANTABLE ECG LOOP RECORDER

S. Petkar, T. Hamid, S. Rose, A. Clifford, S. Homa, C. Garratt, B. Clarke, P. Cooper, A. Fitzpatrick. Manchester Heart Centre, Manchester Royal Infirmary, Manchester, UK, Greater Manchester Centre for Neurosciences, Hope Hospital, Salford, Greater Manchester, UK

Background Clinical review and tilt testing suggests misdiagnosis of epilepsy occurs in ∼20% of patients. Common alternative diagnosis is convulsive syncope. Epilepsy patients can have bradyarrhythmias and arrhythmias are postulated in sudden unexpected death in epilepsy (SUDEP).

Purpose To determine (a) cardiac rhythm by implantable loop recorder (ILR) during transient loss of consciousness (T-LOC) in patients with “epilepsy”, referred to a tertiary cardiology centre and (b) incidence of misdiagnosis.

Methods Between 1996 and 2006, 357 T-LOC patients underwent ILR (Reveal/Reveal Plus, Medtronic Inc). Review showed “possible” (45/62, 72.6%) or “confirmed” (17/62, 27.4%) “epilepsy” diagnosis in 62/357 (17.4%).

Results N = 62, 25/62(40.3%) males. Age: 50.9±16.9 years (range: 19–80). “Epilepsy” diagnosed by: neurologist 46/62 (74.2%), physician 5/62 (8.1%), paediatrician 6/62 (9.7%), and GP 5/62 (8.1%). Type: partial: 17/62 (27.4%), generalised: 10/62 (16.1%) and unclassified: 35/62 (56.5%). ECG-symptom correlation (ESxC) by ILR 40/62 (64.5%). Key ILR findings: asystole: 11/40 (27.5%), sinus node dysfunction: 4/40 (10%). Permanent pacemakers (PPM) implanted in 15/62 (24.2%). Antiepileptic drug (AEDs) withdrawn in majority (pre PPM: 14/15 (93.3%) vs post: 6/14 (42.9%), p = <0.05). Majority 12/15 (80%) asymptomatic on FU (42±25.6 months) after PPM.

Conclusion First study to show, by ILR, that 8/62 (12.9%) patients with syncope misdiagnosed as epilepsy. Demonstrates difficulties/challenges in diagnosing epilepsy and usefulness of ILR in such patients.

Email: sanjiv.petkar@googlemail.com

INTERICTAL ELECTROCARDIOGRAPHIC ABNORMALITIES AND CARDIAC MORBIDITY IN AN ADULT POPULATION WITH DIFFICULT TO CONTROL EPILEPSY AND LEARNING DISABILITIES

S. Petkar, I. Masih, P. Mitchell, A. Clifford, S. Homa, C. Forrester, H. Thomas, P. Madden, G. Hammonds, P. Cooper, A. Fitzpatrick. Manchester Heart Centre, Manchester Royal Infirmary, Manchester, UK, David Lewis Centre for Epilepsy, Alderley Edge, Cheshire, UK

Purpose Arrhythmias are postulated in sudden unexpected death in epilepsy (SUDEP). Studies have analysed ictal cardiac rhythm. Data on interictal ECGs and cardiac morbidity in epilepsy patients is scarce.

Methods Interictal ECGs in adults with difficult to control epilepsy and learning difficulties, between 2005–2007. Automatic reports compared with interpretation by tertiary care cardiologists. Patients with abnormal ECGs investigated further.

Results n = 214, 136/214 (63.6%) males. Age: 38.1±17.6 years (range: 17–83).

Duration of epilepsy: 33.5±17.7 years (range: 2–73). Comorbid conditions: 3.6±3.7 (median: 3, range: 0–40). Mean AEDs: 5±2.8 (range: 0–15). All in sinus rhythm. No difference (p = ns) in automatically vs manually calculated heart rate, QT/QTc interval. QTc ⩾450 msecs only in 4/214 (1.9%). Minority (85/214, 39.7%) ECGs normal. Most common abnormalities: incomplete RBB and non progression of R: 17/214 (7.9%) each, ST-T changes: 15/214 (7.0%), RVH: 13/214 (6.1%), RBBB and I° heart block: 10/214 (4.7%) each. External ECG monitoring advised: 23/214 (10.8%), possible: 2/23 (52.2%). Echocardiogram advised: 68/214 (31.8%), possible: 25/68 (36.8%). Findings: normal: 15/25 (60%), old MI: 3/25 (12.0%), LVH 2/25 (8%), HOCM, ASD, MR and constrictive pericarditis: 1/25 (4%) each.

Conclusion One of the first studies to prospectively and systematically evaluate epilepsy patients for cardiac abnormalities. Majority (60.3%) interictal ECG’s abnormal. Minority had cardiac morbidity.

Email: sanjiv.petkar@googlemail.com

THE RISK OF TONIC–CLONIC SEIZURES FOLLOWING MINOR SEIZURES; FURTHER ANALYSIS OF THE MESS STUDY

A. G. Marson, J. Rogers, K. Hemming, J. Hutton, D. W. Chadwick. University of Liverpool, Liverpool, UK, University of Warwick, Coventry, UK

Background The MESS study showed that early antiepileptic drug treatment reduces the recurrence risk but has no effect on long term outcome. Here we investigate the risk of a tonic–clonic seizure, with or without treatment, for patients with differing seizure types.

Methods MESS recruited 1442 patients with a first seizure or early epilepsy who were randomly allocated to immediate or deferred treatment. Regression modelling was undertaken to assess the risk of a tonic–clonic seizure, with or without treatment.

Results Patients with simple/complex partial seizure only had a low risk of tonic–clonic seizures. The tonic–clonic seizure risk was higher and similar for patients with a tonic–clonic seizure only, tonic–clonic seizure with partial seizures, tonic–clonic seizure with other generalised seizures, absence and or myoclonus only. Antiepileptic drug treatment had no influence on the risk of a tonic–clonic seizure in those presenting with simple/complex partial seizures.

Conclusions Patients presenting with simple/complex partial seizures are at low risk of a tonic–clonic seizure. Patients presenting with minor generalised seizure types have a higher tonic–clonic seizure risk which is similar to patients presenting with a tonic–clonic seizure.

Email: a.g.marson@liv.ac.uk

ADVERSE EFFECT OF PHENYTOIN IN SEVERE BRAIN INJURY

C. Pinder. The Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Anticonvulsants are often used for the prevention or treatment of seizures in the acute stages of brain injury. Phenytoin is often used as it can be given intravenously. It is often continued for many months or even years. A case of a brain-injured patient will be presented, who was severely cognitively impaired 1 year following her injury. Despite previously therapeutic levels of phenytoin, on withdrawal of the phenytoin she started to improve and subsequently made a very good recovery. Similar but less dramatic effects have been noted in similar cases. Previous literature (as will be discussed) has documented cognitive side effects of phenytoin. This has significant implications for the use of phenytoin in the rehabilitation phase following brain injury, as demonstrated by this case. We conclude that patients with severe cognitive impairment following brain injury, who are taking phenytoin should have this changed to one of the newer anticonvulsants that have less cognitive side effects.

Email: colin.pinder@thewaltoncentre.nhs.uk

PHENOTYPIC DIVERSITY ASSOCIATED WITH THE MITOCHONDRIAL M.8313G>A POINT MUTATION

K. O’Rourke, M. Buddles, M. Farrell, R. Howley, S. Sukuraman, S. Connolly, D. Turnbull, M. Hutchinson, R. Taylor. St. Vincent’s University Hospital, Dublin, Ireland, Mitochondrial Research Group, Institute of Ageing and Health, The Medical School, Newcastle University

We report the clinical, histochemical and molecular genetic findings in a patient with progressive mitochondrial cytopathy due to the m.8313G>A point mutation in the mitochondrial tRNALys (MTTK) gene. The clinical features in this case are severe, including short stature, myopathy, peripheral neuropathy and osteoporosis, while extensive analysis of maternal relatives would indicate that the mutation has arisen de novo and not been maternally-inherited. This report of a second case, together with single muscle fibre mutation analysis demonstrating a clear segregation of mutation load with cytochrome c oxidase deficiency, confirm the mutation is pathologic.

Email: killian.orourke@gmail.com

MERLIN’S TUMOURS: FROM BENCH TO BEDSIDE

C. O. Hanemann, S. Ammoun. Peninsula Medical School, Plymouth, UK

Schwannomas are common, are a paradigm for tumours caused by the same gene defect (loss of merlin) which are 50–60% of all meningiomas and 20–30% of all ependymomas and all tumours as part of Neurofibromatosis 2 (NF2). Schwannomas are also the hallmark of NF2 patients, which have a great medical need because of multiple tumours. Current treatment options for schwannomas are surgery and radiosurgery frequently leaving the patient with considerable morbidity and mortality especially in case of NF2. Thus, it is highly relevant to find a drug therapy of these tumours (Hanemann, 2008). Using a human in vitro model, we have established relevant read outs like abnormal proliferation and Schwann cell adhesion and deciphered the underlying biochemistry. This allowed us to validate a variety of molecular targets, esp. growth factor receptors and signalling molecules. Due to this and additional work we were then able to choose Sorafenib as a promising agent for the treatment of these tumours. We show that Sorafenib is efficient in reducing schwannoma growth. Based on these data we are currently planning a multi-centre clinical trial in the UK.

Email: Oliver.Hanemann@pms.ac.uk

THE NEUROLOGICAL MANIFESTATIONS OF THE CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME

¹J. Kitley, ²L. Ginsberg, ¹A. Pinto, ²H. Lachmann. ¹Southampton General Hospital, Southampton, UK, ²Royal Free Hospital, London, UK

Introduction The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited auto-inflammatory condition. CAPS is characterised by periodic urticarial-like rash, conjunctivitis, and fever. It may be complicated by sensorineural deafness, destructive arthropathy and chronic polymorphonuclear meningitis. 30% develop amyloidosis with consequent renal failure and death. Recently it has been shown that anti-interleukin-1 treatment leads to complete resolution of symptoms within 24 h and prevents development of amyloidosis.

Methods We report a case of CAPS with myalgia, papilloedema, headache, sensorineural deafness and chronic aseptic meningitis and review the neurological involvement in 12 other cases. Each patient was formally assessed by a consultant neurologist and ophthalmologist, and the diagnosis confirmed by demonstrating a NLRP3 mutation on genetic testing.

Results 12 patients (92%) had headache, of which 7 (54%) had features of migraine and 4 (31%) had features of raised intracranial pressure. Six patients (46%) had sensorineural deafness, 3 (23%) had papilloedema, 2 (15%) had optic disc pallor and 9 (69%) complained of myalgia.

Conclusion CAPS is a rare but treatable condition that may present to neurologists for a number of reasons. Early recognition and treatment leads to resolution of symptoms and prevents morbidity and mortality.

Email: jokitley@doctors.org.uk

HAEMATOPOIETIC STEM CELL TRANSPLANTATION FOR MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOPATHY

S. R. Hammans, M. Stroud, K. Orchard. Wessex Neurological Centre, Southampton, UK

Mitochondrial neurogastrointestinal encephalopathy (MNGIE ) is caused by recessive mutations in the gene encoding thymidine phosphorylase (TP) causing disruption of the nucleotide pool and defects of mitochondrial DNA. Clinically MNGIE is a mitochondrial encephalopmyopathy with characteristic features: ophthalmoplegia, gastrointestinal dysmotility, cachexia, demyelinating peripheral neuropathy and an asymptomatic leucoencephalopathy.

It is uniformly fatal, usually in early adult life.

Our patient is female, 41, unable to walk and dependent on parenteral nutrition with a predicted prognosis of less than 2 years. We identified a sister with normal TP function, and identical HLA type.

After full discussion we proceeded with a haematopoietic stem cell transplant (HSCT) with careful selection of conditioning schedule. 100% chimaerism and restoration of normal TP function and nucleotide levels were achieved. Complications were transient. At 16 months post transplant there is no neurological improvement, but recent improvement in weight and appetite has been observed.

An international consortium has recorded 9 such transplants, with 4 deaths. Only 2 successful transplants were performed prior to our patient, with clinical improvement between 1–2 years post transplant.

We conclude that HSCT is a novel, promising but potentially dangerous treatment. We strongly recommend that further transplants should be performed on a collaborative basis.

Email: simon.hammans@suht.swest.nhs.uk

A NOVEL GTP CYCLOHYDROLASE 1 MUTATION IDENTIFIED IN A BRITISH KINDRED WITH VARIABLE PHENOTYPES RANGING FROM PARKINSON’S DISEASE TO DOPA-RESPONSIVE DYSTONIA

A. J. Lewthwaite, T. D. Lambert, E. J. Simons, V. Bonifati, K. E. Morrison, D. J. Nicholl. University of Birmingham, Birmingham, UK, Erasmus MC Rotterdam, Rotterdam, The Netherlands

Background As part of our on-going study of familial Parkinson’s disease (PD) we investigated a unique British kindred in which clinical diagnosis of movement disorders has proved challenging for over 20 years.

Aims and Methods To present clinical features and molecular genetic data in a dominant kindred with phenotypes ranging from PD to dopa-responsive dystonia (DRD). Family members had dopamine transporter scans (DaTSCANs) performed and were screened for mutations and copy number variation in: Parkin, DJ-1, PINK1 and LRRK2 and in the GTP cyclohyrolase 1 gene (GCH1), the most common cause of DRD.

Results 2 individuals have clinical features consistent with slowly progressive PD, 1 with benign parkinsonism and 2 with DRD. The median age of disease onset is 50 with a median duration of 20 years. No mutations were found in the PD genes, but a novel heterozygous missense mutation (c.A5G) in GCH1 was detected in 4 out of 5 affected family members.

Conclusions We suggest that variable expression of this novel GCH1 mutation provides an explanation for the diverse clinical presentations observed. The association of a GCH1 mutation with a wide range of phenotypes furthers our understanding of late onset DRD, and suggests a potential role for this gene in PD.

Email: alewthwaite@hotmail.com

B-CELL LYMPHOMA OF THE CAVERNOUS SINUS MASQUERADING AS TOLOSA–HUNT SYNDROME

A. Sadnicka, O. Malik, C. McGuigan. Department of Neurology, Imperial College Health Care Trust, Charing Cross Hospital, Fulham Place Road, London W6 8RF, UK

Case History We report the case of a previously fit and well 76-year-old woman who presented with unilateral retro-orbital pain and ipsilateral left sixth nerve palsy. An MRI brain did not reveal any abnormality. Over the following 2 weeks, she required hospital admission with uncontrollable retro-orbital pain. On examination the sixth nerve palsy persisted and there was also involvement of the left third and fourth nerves. A painful ophthalmoplegia secondary to cavernous sinus pathology was suspected and a rapid resolution of pain with prednisolone 50 mg once daily was noted, suggesting a diagnosis of Tolosa Hunt Syndrome, as defined by IHS criteria. Attempts to reduce the dose of steroid led to recrudescence of pain. Subsequently numbness developed in the distribution of the ophthalmic division of the trigeminal nerve. A third MRI revealed a left cavernous sinus mass. Systemic investigations were performed and a thoracic paravertebral mass identified. Non-Hodgkin (B-cell) Lymphoma was diagnosed histologically. Unfortunately the patient succumbed to overwhelming sepsis.

Conclusion This case documents a rare presentation of Non-Hodgkin Lymphoma mimicking Tolosa–Hunt syndrome and highlights the need for meticulous follow up of painful ophthalmoplegia. We suggest, despite recent literature, that Tolosa–Hunt Syndrome should remain a diagnosis of exclusion.

Email: asadnicka@doctors.org.uk

CHARACTERISTICS AND EXAMINATION OUTCOMES AMONG CANDIDATES ATTENDING AN MRCP PACES CLINICAL NEUROLOGY REVISION COURSE

C. Deed, H. C. A. Emsley. Royal Preston Hospital, Preston, UK, University of Liverpool, Liverpool, UK

Background and Methods Anecdotally, the MRCP Practical Assessment of Clinical Examination Skills (PACES) neurology station causes particular concern among candidates. A survey was undertaken of candidates attending the Walton Centre MRCP PACES Clinical Neurology course between February 2006 and October 2008.

Results 143 (55%) candidates returned a completed questionnaire. Overall 96% provided self-defined ethnicity data, the majority being White (31%) or Asian (57%). There were 60 (42%) UK/EU, and 83 (58%) overseas graduates. Comparing UK and overseas graduates, 98% UK (15% overseas) specified English as a first language, 92% UK (63% overseas) had worked in a UK teaching hospital, 10% UK (6% overseas) in a UK neurology post. A greater proportion of UK than overseas graduates cited inadequate neurology exposure or teaching or its perceived difficulty as the reason for attending the course. Overseas graduates made more PACES attempts than UK graduates. Overall 34 (65%) UK and 34 (41%) overseas graduates passed PACES, 32 (62%) UK and 30 (36%) overseas graduates at their first attempt.

Conclusions There appears to be a lower pass rate among overseas by comparison with UK graduates, the greatest difference identified in this survey being the proportion specifying English as a first language. This merits further study.

Email: h.emsley@liv.ac.uk

AN AUDIT OF REFERRALS WITH POSSIBLE PARKINSON’S DISEASE TO THE MOVEMENT DISORDERS CLINIC AT UNIVERSITY HOSPITAL COVENTRY AND WARWICKSHIRE

R. Dobson, D. Bindman, A. Lindahl. University Hospital Coventry and Warwickshire, Coventry, UK

Background NICE guidelines for Parkinson’s Disease (PD) were published in 2006. Suspected PD should be seen untreated within 6 weeks by a specialist in the differential diagnosis of PD. The diagnosis should be made clinically using UK Brain Bank criteria.

Methods All new patients in the Movement Disorders clinic referred with possible PD between October 2007 and October 2008 were audited. 96 patients were identified and 84 case notes reviewed.

Results 76% referrals were from GPs. 26% had previously diagnosed PD. 77% previously undiagnosed were referred untreated. 59% were seen within 6 weeks. 48% were diagnosed with PD, 11% vascular parkinsonism, and 4% drug-induced parkinsonism. Four per cent were diagnosed with dementia with Lewy Bodies, 2% with Multiple System Atrophy and 1% with Progressive Supranuclear Palsy. Other diagnoses made included essential tremor (11%) and dystonic tremor (7%).

Conclusions NICE guidelines have implications for service planning and delivery. The delay in seeing 41% patients, especially internal referrals, encourages non-specialists to treat. Fewer than 50% referrals were diagnosed with PD, with a wide range of diagnoses made in the remainder, highlighting the importance of reviewing patients untreated.

Email: ruthdobson@doctors.org.uk

USE OF RITUXIMAB IN NEUROLOGICAL PRACTICE – THE WALTON CENTRE EXPERIENCE

A. Krishnan, R. Menon, A. Selvan, M. Doran. The Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Monoclonal antibodies target specific antigenic cells and have established roles in oncology and rheumatology practice. Rituximab is a chimeric monoclonal antibody that targets CD20 antigen on B lymphocytes. B cell expression and proliferation is implicated in the pathogenesis of various neurological conditions. Reports of the use of rituximab in multiple sclerosis and antibody mediated diseases like demyelinating neuropathies and myasthenia are on the rise. We present our experience with rituximab in the following neurological conditions.

Case 1 – A 27-year-old female with anti-Musk antibody positive refractory myasthenia gravis who failed to respond to repeated course of immunoglobulins, plasma exchange and corticosteroid therapy.

• Case 2 – A 66-year-old male with progressive painful sensory neuropathy associated with cryoglobulinemia.

• Case 3 – A case of resistant paraproteinemic Anti MAG associated neuropathy.

• Case 4 – A 38-year-old female with fulminant Susac’s disease despite corticosteroids and cyclophosphamide.

Rituximab should be considered in patients with immune mediated neurological diseases who fail to respond to standard treatment. We suggest that it may be feasible to include monoclonal antibodies in future clinical studies with clinical and antibody levels as outcome measures.

Email: anita.krishnan@thewaltoncentre.nhs.uk

BRAIN MICROBLEEDS AS A RISK FACTOR FOR COGNITIVE DECLINE IN STROKE CLINIC PATIENTS: 6-YEAR FOLLOW-UP STUDY

S. Gregoire, K. Smith, N. Sokolovsky, L. Cipolotti, M. Brown, H. Jager, D. Werring. Stroke Research Group, UCL Institute of Neurology, Department of Brain Repair and Rehabilitation, Queen Square, London, UK

Introduction Cerebral microbleeds (MB) on gradient-recalled echo (GRE) T2* MRI are a potential predictor of the risk of intracerebral haemorrhage and cognitive impairment. We compared the progression of cognitive function in stroke patients with and without MBs, after a 6-year interval.

Methods 24 patients with MBs and 31 matched MB-free patients with baseline cognitive data were reassessed with similar cognitive tests and the results compared.

Results The mean time between baseline and follow-up (FU) was 5.96 years. Fourteen of the original cohort had died and 3 were lost to FU. Of the remaining 31 patients, 26 (84%) agreed to be reassessed. At FU, the prevalence of executive dysfunction was significantly greater in patients with MBs compared to MB-free patients (78% vs 27%, p = 0.021). MB patients had a higher prevalence of impairments in executive and speed and attention (SA) functions at FU compared to baseline (frontal executive: 78% vs 4%, p = 0.044; SA: 89% vs 38%, p = 0.002); the increase in the proportions of patients impaired in these domains was less marked in MB-free patients.

Conclusion The presence of MBs is associated with subsequent cognitive decline, particularly affecting frontal executive and SA functions. MBs may contribute to cognitive impairment in multiple domains.

Email: s.gregoire@ion.ucl.ac.uk

ENHANCED EX VIVO INHIBITION OF PLATELET FUNCTION AFTER ADDITION OF DIPYRIDAMOLE TO ASPIRIN IN ISCHAEMIC CEREBROVASCULAR DISEASE – INTERIM RESULTS FROM THE TRINITY ANTIPLATELET RESPONSIVENESS STUDY

W. O. Tobin, J. A. Kinsella, D. R. Collins, T. Coughlan, D. O’Neill, T. M. Feeley, S. F. Tierney, R. P. M. Murphy, D. J. H. McCabe. Departments of Neurology, Age Related Heath Care, and Vascular Surgery, The Adelaide and Meath Hospital, Dublin, incorporating the National Children’s Hospital, Trinity College Dublin, Dublin, Ireland

Vascular events following stroke may reflect “resistance” to antiplatelet agents, but platelet function monitoring is not routinely performed.

Transient ischaemic attack (TIA) and ischaemic stroke patients were assessed in our ongoing longitudinal study (a) at baseline on aspirin, and subsequently (b) at 14 days and (c) ⩾90 days after adding dipyridamole. Platelet function was assessed with the PFA-100® which activates platelets by exposure to high shear stress and biochemical stimulation with either collagen and ADP (C-ADP) or collagen and epinephrine (C-EPI). “Dipyridamole responsiveness” was defined as prolongation of PFA-100 closure times during follow-up by more than twice the coefficient of variation of the assay (prolongation of C-ADP by >14%, or C-EPI by >15%).

To date, 42 patients have been followed up at 14 days, and 35 at 90 days. Median C-ADP increased from 89 s at baseline to 105 s at 14 days (p = 0.026) and 100 s at 90 days (p = 0.008). 23/42 patients (55%) at 14 days, and 15/34 (44%) at 90 days were “dipyridamole non-responders”. C-EPI was not prolonged by dipyridamole (p⩽0.8).

The addition of dipyridamole to aspirin inhibits collagen-ADP-induced platelet adhesion/aggregation following ischaemic stroke. Further studies are needed to determine whether “dipyridamole non-responders” are at higher risk of recurrent vascular events than “dipyridamole responders”.

Email: dominick.mccabe@amnch.ie

IS THE OUTCOME OF CERVICAL ARTERY DISSECTION REALLY BENIGN?

R. K. Menon, H. S. Markus, J. W. Norris. St George’s University of London, London, UK

Introduction Cervical artery dissection (CAD) is an important cause of stroke in persons aged <50 yrs. estimated at about 2.5/100 000. Data from published retrospective series indicate a low annual rate of subsequent events (stroke, TIAs or death) of about 5%/year.

Method We analysed data, retrospective and prospective, on patients with CAD admitted to St George’s Hospital, London, January 1995–August 2007. Study entry points were transient ischemic attack (TIA), stroke, and Horner’s syndrome.

Results Of the total 101 patients, 58 were men, and 43 women (mean age 48+/−10) with 111 dissection. Seventy five had carotid, 36 vertebral and 9 multiple vessel dissections. 22 patients presented TIA, with 67 stroke, and 7 with purely Horner’s syndrome. At follow up (11+/−3 months) there were 21 clinical events −15 strokes (5 died) and 6 TIAs.

Discussion Our data indicate a much higher rate of events after CAD than most published series, but are clearly subject to referral bias. The ongoing prospective UK multicentre feasibility study (CADISS) will hopefully clarify this.

Email: drranjuygc@yahoo.co.uk

MRI DYNAMICS OF MICROBLEED ACCUMULATION IN STROKE PATIENTS: 5-YEAR FOLLOW-UP STUDY

S. Gregoire, M. Brown, R. Jager, D. Werring. Stroke Research Group, UCL Institute of Neurology, Department of Brain Repair and Rehabilitation, Queen Square, London, UK

Introduction Cerebral microbleeds (MBs) on gradient-recalled Echo (GRE) T2*-weighted MRI may be a biomarker with prognostic relevance for stroke recurrence and cognitive decline. Little is known about their dynamics over time. We assessed the development of new MBs in a cohort of stroke patients screened for microbleeds at baseline.

Methods 48 patients with ischaemic stroke (IS) or transient ischemic attack (TIA; 21 with MBs; 27 matched MB-free) were followed up after 5 years with GRE T2*-weighted MRI. Two trained observers recorded the presence of new MBs on baseline and follow-up (FU) scans.

Results The mean interval between MRIs was 5.5 years. Twelve patients (25%) of the original cohort had died and 3 (6%) were lost to FU. Of the remaining 33 patients, 21 (64%) agreed to have a repeat MRI. Among patients with MBs at baseline, 50% had new MBs at FU compared to 8% of controls (p = 0.047). The presence of MBs at baseline was a significant predictor of new MBs at FU (p = 0.048).

Conclusion Ischaemic stroke patients with MBs are at high risk of developing new MBs over a 5-year period. The presence of MBs at baseline predicted the development of new MBs. Larger studies are needed to confirm these findings.

Email: s.gregoire@ion.ucl.ac.uk

INHIBITION OF POST INJURY CNS CELL APOPTOSIS VIA SPECIFIC SIRNA

M. R. Douglas, Z. Ahmed, N. Prasad, M. Berry, H. Kalinski, H. Ashush, E. Alpert, E. Fenstein, A. Logan. Molecular Neuroscience Group, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK, Quark Pharmaceuticals, 6501 Dumbarton Circle, Fremont, CA 94555, USA

The failure of CNS axon regeneration following injury is attributed to limited neurotrophic factor stimulation coupled with the activity of myelin and other glial scar derived axon growth inhibitors in the neuropil. This results in early and prominent cellular apoptosis, as seen in the optic nerve crush (ONC) model of CNS injury. Following optic nerve transection, retinal ganglion cells (RGC) rapidly die, through a range of apoptotic processes. Inhibition of these processes is likely to be important in the design of successful therapeutic strategies to promote CNS regeneration.

We demonstrate that caspase-2 has key functions in promoting post ONC RGC apoptosis. Other caspases, such as caspase-3, are primarily located in the horizontal and bipolar cells of the inner nuclear layer. In contrast, caspase-2 was predominantly expressed and activated in RGC. Following the intravitreal injection of proprietary modified siRNA targeting caspase-2 at the time of ONC, we observed prominently enhanced RGC survival, with 50% and 10% at 7 and 30 days post ONC, respectively, as detected by quantification of Fluoro-Gold back- filled RGC in retinal wholemounts. These results demonstrate that siRNA targeting caspase-2 promotes RGC cell survival following injury. This may form an important therapeutic approach towards the promotion of CNS repair.

Email: m.r.douglas@blueyonder.co.uk

NOVEL 7-TESLA MORPHOLOGICAL FEATURE DISTINGUISHES BETWEEN DEMYELINATING AND ISCHEMIC WHITE MATTER BRAIN LESIONS

N. Evangelou, E. C. Tallantyre, J. E. Dixon, A. Al-Radaideh, M. J. Brookes, P. S. Morgan, P. G. Morris. University of Nottingham, Nottingham, UK

Introduction It is possible to diagnose multiple sclerosis (MS) following a single clinical event based on MRI evidence of dissemination in time and space. However, the finding of white matter brain lesions is not specific to MS. Using 7-Tesla MRI we have recently demonstrated that demyelinating lesions are usually centred on small veins. Here we test whether this morphological feature distinguishes between MS lesions and small non-specific white matter lesions on 7-T MRI.

Methods We scanned 21 MS patients and 8 controls (subjects with asymptomatic small vessel ischemia on MRI). Using 7-T FLAIR and T2*-weighted acquisitions we identified white matter brain lesions and determined the presence or absence of a central vein.

Results We identified 689 lesions in MS patients and 218 lesions in controls. Lesions seen in the brains of MS patients were significantly more likely to be centred on a vein than lesions seen in controls (80% vs 17%, p<0.001). Using this MR feature we could reliably classify the clinical status of all individuals.

Conclusions These results suggest a new approach to the diagnosis of MS which could minimise uncertainties in prognosis. Our 7-T technique could be modified for application on lower field clinical MR scanners.

Email: nikos.evangelou@nuh.nhs.uk

HIGH FIELD MRI REVEALS MULTIPLE SCLEROSIS CORTICAL GREY MATTER LESIONS AND ALLOWS QUANTITATIVE ASSESSMENT OF NEURONS AND AXONS

Klaus Schmierer. UCL Institute of Neurology, London, UK

Introduction Pathological change in the cortical grey matter (CGM) is an important feature of multiple sclerosis (MS). However, CGM lesions (CGML) are massively underreported on conventional MRI. We used MRI at 9.4 T to (i) try and detect CGML and (ii) test association of T1, T2, and magnetisation transfer ratio (MTR) with quantitative histology.

Methods Post mortem brain of 21 subjects with MS was used. Fixed tissue blocks were placed in a 9.4-T MR system. MR experiments consisted of spin echo acquisitions for T1 and T2 and gradient-echo acquisitions for MTR. In-plane image resolution was 117 mm². After scanning tissue blocks were processed for embedding in paraffin and sections stained for myelin-basic protein (MBP), SMI31 and cresyl violet (CV). Student’s paired t-tests and regression were applied.

Results 28 CGML were detected on MRI; excellent correspondence was achieved with histology. Healthy looking cortex and CGML differed in T2, MTR, myelin content, neuronal and axonal density. Correlation was detected between myelin content and MTR (r = 0.76; p = 0.03), and between neuronal density and (i) T2 (r = −0.6; p = 0.01) and (ii) T1 (r = −0.5; p = 0.02).

Conclusion High-resolution T2 weighted MRI at 9.4 T allows detection of all types of CGML. T2 and T1 are predictors of neuronal density, and MTR of myelin.

Email: k.schmierer@ion.ucl.ac.uk

AXONAL DAMAGE IN CLINICALLY ISOLATED SYNDROMES: AN OPTICAL COHERENCE TOMOGRAPHY STUDY

C. Oreja-Guevara, S. Noval, P. Bermejo, L. Gabaldón, B. Manzano, E. Diez Tejedor. University Hospital La Paz, Madrid, Spain

Objective The aim of the study was to examine retinal nerve fibre layer (RNFL) measured by optical coherence tomography (OCT) in patients with clinically isolated syndromes (CIS) and to investigate whether RNFL thickness is useful for determining the prognosis of patients with CIS.

Methods Patients with CIS underwent a neurological and ophthalmological examination (visual acuity and OCT). High field brain MRI was performed within 3 months of the first attack.

Results 24 patients with CIS were recruited: 8 patients with optic neuritis (ON), 6 with spinal cord syndrome, 5 with brainstem symptoms and 5 with sensory and other syndromes. Seven patients fulfilled at least three out of four Barkhof criteria in MRI. 54.2% of all patients and 56.3% of the patients without ON showed the presence of at least one quadrant of an optic nerve with a decreased RNFL thickness. The presence of at least one quadrant of an optic nerve with a RNFL thickness at a p<5% cut-off value had a sensitivity of 71% and a specificity of 59% for predicting positive MRI (dissemination in space).

Conclusion Patients with CIS but without ON showed affected RNFL thickness. OCT may be useful for predicting conversion in multiple sclerosis and useful a surrogate biomarker.

Email: orejacbn@gmail.com

NEUROLOGY 1961

M. Swash. Royal London Hospital, London, UK

A televised Grand Round from the Albert Einstein College of Medicine, broadcast in the USA (as a sponsored program supported by the Upjohn Company), featured Dr Joseph M Foley, Dr AB Baker, Dr Michael DeBakey, Dr Wilder Penfield, Dr Donald McCrae, and Dr MacDonald Critchley. The subject was the management of stroke. An edited digitised video, in the black and white TV format of the day, of this telecast will be shown. There are startling insights in relation to current views on stroke investigation and management, and the personalities of the protagonists, all of whom were colourful and highly influential and innovative neurologists. The video has been rescued from obscurity by Dr Robert Daroff and colleagues from Cleveland, Ohio and deposited in the Allen Memorial Library of Case Western Reserve University Health Sciences School.

Email: mswash@btinternet.com

LIFE AND DEATH DIAGNOSES

D. Chadwick. Walton Centre, Liverpool, UK

While case reports with extreme outcomes may not necessarily form a wholly reliable basis for clinical practice, two cases will be presented that highlight the need for an accurate diagnosis of epilepsy.

A 19-year-old university student woke her boy-friend with an apparent brief convulsive episode arising from sleep but with little post-ictal confusion. Neurological assessment including EEG and MR scan was normal. The student and her family were told that she may have had a single tonic–clonic seizure, but that no further steps were necessary in view of the normal investigations. Her father phoned 18 months later. She had had no further symptoms until found dead in bed one morning.

A young woman, with mild to moderate learning difficulties developed episodes of loss of consciousness in her early teens. For many years, she was treated as having epilepsy, though her clinicians remained concerned that she might have psychogenic non-epileptic attacks. She had attacks recorded on a number of occasions which were non-epileptic. On this basis, she was advised to phase out antiepileptic medications. Over the next 18 months, her attacks became more frequent and more in keeping with tonic–clonic seizures. She died 40 minutes into a witnessed convulsion.

Email: d.w.chadwick@liv.ac.uk

THE NEUROLOGICAL CONDITION OF CARLOS II, KING OF SPAIN

M. C. Lawden. Leicester General Hospital, Leicester, UK

The reign of King Carlos II (1665–1700), last of the Spanish branch of the Hapsburg dynasty was disastrous for Spain. As the only surviving son of King Phillip IV he succeeded to the throne of a worldwide empire, but his physical and mental disabilities prevented him from ruling except in name. Despite two marriages he was unable to father an heir and with his death Spain and Europe were plunged into the War of the Spanish Succession. It has long been believed that Carlos’s disabilities arose because of multiple consanguinity within the House of Habsburg. Yet Carlos’s appearance and his neurodevelopmental problems are consistent with an alternative diagnosis unrelated to inbreeding, that of Fragile X syndrome.

Email: mark.lawden@uhl-tr.nhs.uk

TOO MUCH OF A GOOD THING: THE UNRELIABILITY OF RELIABILITY STATISTICS

A. A. Pace, J. P. Zajicek, J. C. Hobart. Clinical Neurology Research Group, Peninsula College of Medicine and Dentistry, Plymouth, UK

Background A mantra in scale development and evaluation is that rating scales should be reliable. There are minimum accepted values that reliability indices should satisfied (eg reliability ⩾0.80). However, while high reliability is a good thing, excessively high reliability is detrimental to measurement.

Aim To illustrate, using two studies, how and why reliability can be too high.

Methods We examined the reliability of two scales: MRC summed strength scores from the Methotrexate in CIDP study, and summed Ashworth spasticity scores from the Cannabinoids in Multiple Sclerosis study.

Results The reliability of both scales was very high (0.89; 0.88). However, in-depth analysis indicated redundancy in both scales. Essentially, duplicated information from similar items marginalised total scores, increasing total score variance and hence reliability. When this was accounted for, the reliability of both scales dropped profoundly (0.70; 0.60).

Conclusion Inclusion of excessively similar items in a rating scale over-inflates its reliability. Although this implies the scale’s measurement ability is strengthened, in fact it is weakened. Scale developers and evaluators should acquaint themselves with this well described but often unknown flaw in measurement theory (called the attenuation paradox), and familiarise themselves with methods for testing its presence and impact on scale performance.

Email: adrian.pace@pms.ac.uk

INFORMED CONSENT – WHO IS IN THE KNOW?

A. L. Cox, A. J. Coles. Addenbrooke’s Hospital, Cambridge, UK

The consent procedure attempts to ensure that participants clearly understand the trial’s aims, risks and benefits prior to participation. We audited patient satisfaction with this procedure, and their understanding of the trial, using an anonymous postal questionnaire. 110 participants, enrolled in 7 different trials, were contacted and 55 responded. While between 98 and 100% of individuals said they understood the aims, benefits and risks of their trial, only 35% identified these; 17% recalled none of this information. This did not correlate with the elapsed time since consent (range 1 to 76 months). 100% received written information and 96% felt this was the right amount, but 10/55 (19%) said they received this less than an hour before signing. Despite this, all individuals felt they had adequate time to consider the information, and all but one felt they had enough opportunity to ask questions. In conclusion, patients are satisfied with the consent procedure; however, many participants lack a good understanding of the aims, risks and benefits of taking part. We would recommend that investigators routinely test their participant’s understanding, prior to allowing them to sign the consent form, thus ensuring that informed consent is being given.

Email: alc1000@googlemail.com

PREDICTING SHORT-TERM PROGNOSIS IN MULTIPLE SCLEROSIS FROM PRESENTING FEATURES USING A CLINICAL DECISION TREE

M. D. Cossburn, G. I. Ingram, C. L. Hirst, T. P. Pickersgill, N. P. Robertson. Cardiff University, Cardiff, UK, Cardiff and Vale NHS Trust, Cardiff, UK

Five years after disease onset 40% of patients with MS have developed significant disability (EDSS>4). Prediction of outcome in early disease is problematic but increasingly important with the development of more effective interventions with higher risks and limited window of therapeutic opportunity. A tool which predicts early phase disability would be a valuable addition to clinical assessment.

Employing detailed longitudinal data from an incident cohort, we have developed a Bayesian classification tree model to predict 5 year disability. Data from 341 patients (252 female) with relapsing remitting MS followed for more than 5 years was used to construct the predictive model and a further 68 patients (42 Female) used for validation.

The model correctly estimated the level of 5-year disability in 52/68 cases (weighted Kappa: 0.523 p<0.001). Receiver operating characteristics AUC was 0.76 (CI: 0.641 to 0.879, p<0.001). Sensitivity and specificity for prediction of disability classification was 81.1% and 79%, respectively.

This model, based on extensive clinical data collected from disease onset, is moderately effective in predicting 5 year patient specific disability. Outcome models in MS using classification trees may provide a useful adjunct to guide clinical management and levels of early therapeutic intervention. Incorporating additional laboratory and imaging data may further improve utility.

Email: cossburnmd@hotmil.com

MITOCHONDRIAL DEFECTS IN MULTIPLE SCLEROSIS: IMPLICATIONS FOR REMYELINATION

D. Mahad, I. Ziabreva, J. Rist, G. Campbell, R. J. M. Franklin, D. M. Turnbull, Abstract.

In multiple sclerosis (MS), the lack of remyelination is regarded as an important cause of chronic axonal degeneration, the pathological substrate of disease progression. The failure of remyelination in MS is partly due to a block in differentiation of oligodendrocyte progenitor cells (OPCs). Defects of mitochondria, the most efficient producers of energy, have been implicated in the pathogenesis of MS. The mitochondrial respiratory chain consists of four complexes and ATP synthase. Complex IV, where over 90 percent of oxygen is consumed, is particularly susceptible to reactive oxygen species mediated damage. Complex IV defects are present within oligodendrocytes and demyelinated axons in acute and chronic MS lesions.

We investigated the role of complex IV in the survival of oligodendrocyte lineage cells and the capacity of OPCs to differentiate, in vitro. Mature oligodendrocytes are more susceptible to complex IV defects than OPCs, with apoptosis being the predominant mode of their demise. Partial inhibition of complex IV leads to a significant reduction in the capacity of OPCs to generate mature oligodendrocytes, either because of an impairment of differentiation or differentiation into a more susceptible phenotype. Mitochondrial defects are important contributors to primary oligodendrocyte dysfunction as well as remyelination failure in MS.

Email: mahadd@doctors.org.uk

SEX RATIO IN AN OXFORD BASED STUDY OF MULTIPLE SCLEROSIS PATIENTS

L. Matthews, L. Kent, A. Weir, A. Nairne, J. Palace. Multiple Sclerosis Group, John Radcliffe Hospital, Oxford, UK

Introduction Recent epidemiological studies suggest a longitudinal increase in the female:male sex ratio of multiple sclerosis (MS). This may provide insight into the role of environmental factors in its aetiology. The Oxford MS database of 2030 patients was interrogated to investigate a hypothesised rise in female:male sex ratio in association with increasingly recent birth year.

Methods The cohort of 2030 MS patients was collected over a 15-year period. Numbers of women and men were averaged over 5-year blocks according to year of birth. Female:male ratio was calculated for each group.

Results In this Oxford-based dataset, female:male sex ratio by year of birth increases in a progressive trend over a 50-year period from 0.79:1 (1931–1935) to 3.42:1 (1976–1980). A possible seasonal effect on MS births was also noted during data analysis with a relative spring peak and autumn nadir seen in female patients born in the last 45 years.

Discussion Although incidence rates cannot be obtained, a higher female:male sex ratio in younger MS patients has been observed in this English population-based cohort. This can add strength to corresponding findings in other populations. The longitudinal trend observed implicates changing environmental factors as a possible cause.

Email: lucymatthews@doctors.org.uk

DO BRITISH NEUROLOGISTS THINK ABOUT NEUTRALISING ANTIBODIES TO INTERFERON BETA?

R. A. Farrell, G. Giovannoni. Institute of Neurology, UCL & ICMS, Barts, UK, London School of Medicine and Dentistry, London, UK

MS is a common disease and disease-modifying therapies carry a significant economic burden. Interferon beta became widely available in the UK via the Department of Health’s Risk Sharing Scheme (RSS 2002) with strict prescribing guidelines. Neutralising antibodies (NAbs) to IFN-beta develop in ∼25% of patients. Their impact on relapse and disease progression rates is controversial. ABN, European and American prescribing guidelines have incorporated (albeit cautiously) NAbs. As NAb testing and alternative, effective therapies are available, we have a duty to provide the best available, cost-effective treatment for patients.

Objectives To evaluate current opinion and awareness regarding NAbs/testing among UK Neurologists.

Methods An anonymous, online survey (www.surveyonnet.co.uk) was distributed in the ABN newsletter and via email, posing questions regarding NAbs, data was collected online.

Results All respondents (n = 91) treated MS subjects, regularly prescribed Interferons and were aware of NAbs, 93% were Consultants and 78% were aware that testing is available funded by the NHS. Commencing IFN-beta 67% of those surveyed counselled patients about NAbs, 57% believing they abrogate treatment efficacy (42% do not know). However, only 27% said it influenced product choice, 20% routinely screening for NAbs (30% never, 38% only following relapses). Following a positive test; 43% retested in 3 months, 38% discussed alternative treatments and 30% did nothing unless patient actively relapsing.

Discussion This study confirms that despite awareness of NAbs many remain unsure of their significance and unaware that testing is available. A need remains for independent studies, such as the RSS to address these questions and to improve national guidelines.

Email: r.farrell@ion.ucl.ac.uk

LESIONS IN PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS SHOW GREATER AXONAL LOSS COMPARED WITH LESIONS IN SECONDARY PROGRESSIVE DISEASE

E. C. Tallantyre, L. Bo, O. Al-Rawashdeh, T. Owens, C. H. Polman, J. Lowe, N. Evangelou. University of Nottingham, Nottingham, UK, University of Bergen, Bergen, UK, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands

Introduction The pathological substrate of progressive disability in MS is hypothesised to be axonal loss. It remains unclear whether patients with primary progressive (PP) and with secondary progressive (SP) MS represent separate clinical entities.

Methods Human post-mortem cervical spinal cord from 54 patients (17 PP, 30 SP and 7 controls) was examined to determine the number of surviving corticospinal-tract axons, the degree of demyelination and inflammation. Associated clinical data was used to calculate motor disability for each patient preceding death.

Results Motor disability in PP and SP groups was similar preceding death. Corticospinal axonal counts were equally low in PP and SPMS groups vs controls. However, SPMS patients showed a significantly higher degree of demyelination within both the white and grey matter of the cervical spinal cord. MS patients with greater motor disability before death showed more extensive axonal loss. Axonal density was significantly reduced within demyelinated white matter, particularly in PPMS.

Conclusions These findings support axonal loss as the pathological substrate of progressive disability in both PP and SPMS with a common plaque-centred mechanism. More extensive axonal loss within areas of demyelination in PPMS could explain high levels of axonal loss observed in these patients despite low levels of demyelination.

Email: emma.tallantyre@nottingham.ac.uk

WHAT IS THE CASELOAD FOR MULTIPLE SCLEROSIS MULTIDISCIPLINARY SERVICES? AUDIT DATA FROM A SUPRAREGIONAL NEUROSCIENCES CENTRE

M. Calabresi, R. Thomson Glover, A. Nandhra, D. Toothill, C. A. Young. The Walton Centre for Neurology and Neurosurgery, University of Liverpool, Liverpool, UK, University of Barcelona, Barcelona, Spain

In 2003 the UK National Institute for Clinical Excellence published guidelines for the management of multiple sclerosis (MS) which advocated provision of specialised services as a key priority. However, the guidelines acknowledge that there is little information on the extent of need for the different team members.

We studied a systematic sample of outpatients attending the Walton Centre for Neurology and Neurosurgery, which serves over 3 m people and has run a multidisciplinary MS clinic for 15 years. The audit sample was all traceable records of patients who attended one neurologist’s multidisciplinary MS clinic at least once in 12 months from January 2007 (N = 362). Patients saw the different disciplines based on different team members’ analysis of their need, GP referral and/or patient choice.

We reviewed the records of 2098 visits. Less than 1% of patients did not see a physician. Other services with high attendance included specialist nurse (64%), physiotherapist (48%), occupational therapist (35%) and orthoptist (27%). The study of service use according to the patients’ disease course and disability status revealed differences in the patterns of attendance. Finally we show that MS care requires a multidisciplinary team and that the number of attendances with this model can be kept low.

Email: carolyn.young@thewaltoncentre.nhs.uk

PATHOGENIC MECHANISMS UNDERLYING MYASTHENIA GRAVIS ASSOCIATED WITH MUSK ANTIBODIES

S. Viegas, J. Cossins, L. Jacobson, P. Waters, R. Webster, M. I. Leite, A. Vincent. Department of Clinical Neurology, University of Oxford, Oxford, UK

Antibodies against muscle specific kinase (MuSK) are detected in a proportion of myasthenia (MG) patients without acetylcholine receptor (AChR) antibodies, who often have prominent ocular, bulbar and facial muscle involvement. Purified IgG from patients causes dispersal of AChR clusters on cultured myotubes, but how they act in vivo is unclear. We aimed to establish whether these antibodies are pathogenic, how they cause disease and why certain muscles are preferentially involved.

Mice were immunised with recombinant human MuSK and developed antibody titres comparable with patients. They showed swallowing impairment, weight loss and 5/10 developed marked weakness. Ex-vivo electrophysiology revealed both pre- and post-synaptic abnormalities. Their endplates were fragmented with loss of AChR but no complement deposition was identified, in contrast to AChR immunised mice. Similar electrophysiological abnormalities were identified in mice following passive transfer with purified IgG. Expression of MuSK was not changed in these models but facial muscles had higher MuSK expression than limb muscles.

These results confirm that MuSK antibodies are pathogenic with a mechanism of action subtly distinct from AChR antibodies and not involving complement. The combination of pre- and post-synaptic abnormalities may explain the more severe phenotype associated with this form of myasthenia gravis.

Email: angela.vincent@imm.ox.ac.uk

UNDERGRADUATE PRIZE FACILITATING PLASTICITY: THE NEUROCHEMICAL EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION

J. Best. FMRIB Centre, Oxford, UK

Transcranial direct current stimulation (tDCS) is a non-invasive technique used to modulate cortical excitability. Anodal stimulation increases excitability, while cathodal stimulation decreases it. Based on observations of abnormal patterns of excitability in chronic stroke patients, tDCS has been investigated for use in stroke rehabilitation. Early trials have shown encouraging results, but the mechanisms underlying these effects are poorly understood. In the work reported here, undertaken in collaboration with Dr. Charlotte Stagg at the FMRIB Centre, Oxford, in vivo magnetic resonance spectroscopy is used to demonstrate rapid, polarity-specific changes in GABA and glutamate/glutamine levels associated with anodal and cathodal stimulation, respectively. We further report modulation of myo-inositol concentration in the stimulated cortex. In doing so, we provide the first direct observations on the neural mechanisms underlying tDCS, and, since there is substantial evidence that GABA inhibits cortical reorganization, provide a rational basis for the investigation of anodal stimulation as an adjunct to physical rehabilitation in promoting neuroplasticity after stroke. As abnormal inositol metabolism is a feature of some neuropsychiatric conditions, our findings also suggest that tDCS could have wider clinical applications.

PATHOGENIC POTENTIAL OF COMPLEMENT-FIXING ANTIBODIES IN SERONEGATIVE MYASTHENIA AND THEIR NEUROPHYSIOLOGICAL CORRELATION

S. Jacob, S. D. Viegas, M. I. Leite, J. Cossins, D. Besson, B. P. Morgan, R. Kennett, A. Vincent. Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK

Seronegative myasthenia (SNMG) is clinically similar to acetylcholine receptor antibody positive myasthenia gravis (AChR-MG). We have recently shown that SNMG patients have antibodies that bind to AChRs clustered on a human embryonic kidney cell transfected with AChR and rapsyn cDNAs (cell-based assay, CBA); but it was not clear whether these “low affinity” AChR antibodies would be pathogenic.

The low affinity AChR antibodies are predominantly of the IgG1 subclass. Moreover, they activate complement in-vitro. Neurophysiological changes assessed by single fibre electromyography (EMG) examinations (performed simultaneous to the serum collections) correlated with antibody levels, with more marked neuromuscular transmission defects seen in patients with complement-fixing antibodies. Finally, purified IgG preparations from two SNMG patients were injected into mice for three or five days (50 mgs/day), and results compared with injection of antibodies from AChR-MG. Significant reductions in miniature end-plate potential amplitudes were demonstrated with complement deposition at the neuromuscular junctions.

These experiments indicate that antibodies in SNMG have the ability to fix complement, transfer disease to mice, and their presence correlates with the degree of neurophysiological abnormalities. The testing of these antibodies in SNMG patients would improve the diagnostic sensitivity and guide the clinician in commencing appropriate pharmacological therapies.

Email: saijujacob@hotmail.com

PROTEIN INTERACTORS OF EAAT2 AND THEIR ROLE IN MOTOR NEURONE DISEASE/AMYOTROPHIC LATERAL SCLEROSIS

Y. Y. Dong, E. F. Goodall, Z. Ahmed, P. M. Pettingill, S. Hill, M. R. Douglas, K. E. Morrison. School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

Glutamate excitotoxicity has been implicated in numerous neurodegenerative diseases, including motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS). The glutamate transporter EAAT2 is the primary regulator of extracellular glutamate concentrations in the mammalian CNS and specific reductions in its expression and transport function have been reported in MND patients and rodent models. In previous studies we found no abnormalities in the genomic DNA or mRNA of EAAT2 in MND patients. We now hypothesise that abnormalities in the protein interactors of EAAT2 may cause its dysfunction in MND. Using yeast 2-hybrid screening followed by mammalian co-localisation and co-immunoprecipitation experiments, we have identified 4 novel protein interactors of EAAT2. We have undertaken functional studies showing that interactions with one of these interactors lowers the maximal rate of EAAT2 specific glutamate transport without altering its plasma membrane localisation. Genomic DNA sequence analysis of the interactors is currently underway. We have identified several variants in MND patients and are currently assessing their specificity by sequence analysis of controls. Further studies on these novel interactors of EAAT2 may shed light on the role of glutamate excitotoxicity in MND and produce new targets for future treatments.

Email: k.morrison@bham.ac.uk

CHARACTERISATION OF SH3TC2, A PROTEIN ASSOCIATED WITH CHARCOT–MARIE–TOOTH DISEASE TYPE 4C

R. C. Roberts, F. Buss, J. Kendrick-Jones, M. M. Reilly, J. P. Luzio. Cambridge Institute for Medical Research, MRC Laboratory of Molecular Biology, MRC Centre for Neuromuscular Diseases, Cambridge, UK

The Charcot–Marie–Tooth (CMT) diseases encompass a large group of heterogeneous hereditary neuropathies. Although pathogenic mutations have been identified in many genes associated with CMT, the precise functions of these genes both in health and disease are not well understood. CMT type 4C is a severe childhood-onset sensorimotor neuropathy inherited in an autosomal recessive fashion, often associated with early-onset scoliosis. Genetic studies have confirmed that this form of CMT is associated with mutations in the previously uncharacterised transcript, SH3TC2. The SH3TC2 gene is predicted to encode a protein containing 1288 amino acids with a molecular weight of 144 kDa. Sequence analysis reveals two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, which are predicted to be involved in protein–protein interactions. To investigate the roles that SH3TC2 plays within cells, we have expressed fluorescently-labelled constructs of SH3TC2 in mammalian cells. Our data show that SH3TC2 targets to a distinct intracellular compartment, implicating a potential role in intracellular membrane traffic. To identify interacting proteins, we are also isolating SH3TC2-associated protein complexes from mammalian cells. By taking these approaches, we will improve our understanding of the intracellular functions of SH3TC2, which may enable us to identify potential therapeutic targets.

Email: rcr20@cam.ac.uk

CLINICAL FEATURES OF THE SLOW-CHANNEL CONGENITAL MYASTHENIC SYNDROME

D. Lashley, G. Burke, D. Beeson, S. Jayawant, J. Palace. University of Oxford, Oxford, UK

Slow-channel congenital myasthenic syndrome (SCCMS) is a dominantly inherited disorder of neuromuscular transmission that deteriorates with acetylcholinesterase inhibitors. We report the first case series of SCCMS which includes 20 UK patients from 7 kinships.

Median onset age was 3 years and motor milestones were delayed in only 30%.

Penetrance was variable even within kinships and phenotype mild, with a median Quantitative Myasthenia Gravis (QMG) severity score of 13/39. The QMG was inversely correlated with onset age.

Muscle weakness was most profound in the finger extensors and thumb abductors, though also targeted facial muscles plus elbow and wrist extensors. There was ptosis in 7/20, mild to moderate opthalmoplegia in 13/20 and wasting of the hand muscles in 14/20. Forced vital capacity was reduced in half and 20% had nocturnal hypoventilation requiring support.

Electromyography confirmed neuromuscular transmission deficit and muscle biopsies showed non-specific myopathy. Of patients requiring treatment, 4/6 responded to quinidine and 5/5 to fluoxetine.

We confirm SCCMS as typically later in onset, with a frequently mild but with a characteristic pattern of weakness and wasting. Later onset predicts a less severe phenotype, open-channel blockers are effective though an initial response to acetylcholinesterase inhibitors may mislead.

Email: daniel.lashley@clneuro.ox.ac.uk

EPHEDRINE TREATMENT RESULTS IN PROFOUND FUNCTIONAL IMPROVEMENTS IN DOK-7 CONGENITAL MYASTHENIA

D. Lashley, D. Beeson, S. Jayawant, J. Palace. University of Oxford, Oxford, UK

The Dok-7 synaptopathy is the most recently identified congenital myasthenic syndrome. Treatment is difficult as most fail to respond or deteriorate with acetylcholinesterase inhibitors and 3,4-diaminopyridine. We report our experience of ephedrine treatment in eight Dok7 patients.

The median Quantitative Myasthenia Gravis severity score was 15/39 prior to treatment. At 2 months follow up it was 11/39 and at 6–8 months 5/39. Little improvement was seen with the first dose. Percentage improvements at 2 and 6–8 months follow up were: in arms outstretched time 69% and 177%; leg raised time 72% and 94%; head lift time 38% and 113% and forced vital capacity 1% and 7%, thus demonstrating progressive improvement over the follow-up period. The responses in several patients were profound, eg a wheelchair-dependant adolescent was able to jog for two minutes, a young woman was able to wear high heels for the first time and a severely disabled child was able to jump.

Ephedrine may work through β2-adrenoreceptors to mediate recovery from the mutant-Dok-7-associated end-plate myopathy that occurs in this syndrome, though the mechanism by which this would occur is unclear.

Email: daniel.lashley@clneuro.ox.ac.uk

THE USE OF RITUXIMAB IN MYASTHENIA GRAVIS AND LAMBERT–EATON MYASTHENIC SYNDROME: UK EXPERIENCE

H. El-Naggar, P. Maddison. Nottingham University Hospitals NHS Trust, Nottingham, UK

Originally used to treat B-cell malignancies, the monoclonal anti-CD20 antibody rituximab has since been used successfully as a therapy for B cell-mediated autoimmune disorders such as rheumatoid arthritis. There is limited experience worldwide in the use of this treatment in other organ-specific autoimmune disorders such as myasthenia gravis. In an attempt to broaden our knowledge of the effects of rituximab in patients with autoimmune disorders of neuromuscular transmission, we collected data from members of the UK myasthenia interest group from all patients treated with rituximab. Over the last 3 years, 10 patients with generalised myasthenia gravis (acetylcholine receptor antibodies detected in seven, MuSK antibodies in three), and two with Lambert–Eaton myasthenic syndrome have been treated with rituximab in the UK. Almost all (11/12, 92%) were women, with a median age at disease onset of 21 years. All patients had previously been treated with prednisolone, second line oral immunosuppressants, and either intravenous immunoglobulin or plasma exchange. Rituximab treatment resulted in an excellent response (remission) in 3/12 (25%), with a good response seen in others (42%). Only one patient developed worsening of their myasthenia following treatment. There was no correlation between treatment success and pre-treatment disease duration, or antibody status.

Email: dr.hany@doctors.org.uk

A SYSTEMATIC REVIEW OF MYASTHENIA GRAVIS EPIDEMIOLOGY

A. S. Fitzpatrick, C. Cardwell, C. McCarron, J. McConville. Queens University Belfast, Belfast, UK, Department of Neurology, Royal Victoria Hospital Belfast, Belfast, UK, Department of Neurology, Ulster Hospital Dundonald, Belfast, UK

Our aim was to examine myasthenia gravis (MG) epidemiology to see if there is worldwide consensus in incidence rate (IR), prevalence rate (PR) and mortality rate (MR) of the disorder and, if not, to investigate the influence of environmental and technical factors on these statistics. 58 population-based studies were identified using multiple electronic databases, bibliography search and discussion with experts. Subgroup heterogeneity examination and regression analysis was used to assess the influence of study methodology, year and geographical area on observed rates. IR ranged from 1.7 to 21.3 per million person-years and PR from 15 to 179 per million reflecting the massive heterogeneity across studies: I2 = 96% (CI: 95% to 98%) and I2 = 98% (CI: 97% to 98%), respectively. This heterogeneity remained within studies of similar methodology and geographical area and from studies performed within decades. On multivariate analysis, only year was significantly associated with IR and PR (p = 0.01, p = 0.00) with a trend to increasing IR and PR with time (r = 0.57, r = 0.66). Case ascertainment and availability of diagnostic tests undoubtedly affect these observed frequencies and trends. However, the data also imply that as yet unidentified environmental factors influence symptom onset resulting in the observed variation in IR across geographically and genetically similar populations.

Email: aisling.fitzpatrick@belfasttrust.hscni.net

FACIAL ONSET SENSORY AND MOTOR NEURONOPATHY SYNDROME: AN EXPANDING PHENOTYPE

A. Chaouch, J. A. Knibb, P. Tidswell. Royal Preston Hospital, Preston, UK

Facial onset sensory and motor neuronopathy (FOSMN syndrome) is a recently described syndrome. Histopathologically, it is associated with dorsal root ganglia and anterior horn cell degeneration.

In this report, we describe a patient with the above described clinical features who, in addition, had pyramidal tract involvement.

A 62-year-old man presented with a 6-year history of sensory and motor disturbances in a left trigeminal nerve distribution, which subsequently progressed to involve the face, neck and limbs. Dysphagia occurred after 6 years.

Clinical assessment revealed atrophy and fasciculations of the temporalis, mentalis and masseter muscles bilaterally as well as the tongue and limbs. Mouth closure was weak. There was mild weakness of neck flexion. Power was preserved in all four limbs. Left corneal reflex was absent. Pinprick sensory impairment was noted over the left trigeminal nerve territory, scalp and neck as well as left arm and leg. Vibration sense was reduced below both knees. Proprioception was normal. Deep tendon reflexes were pathologically brisk. The right plantar was extensor.

The clinical features and extensive investigations supported a diagnosis of FOSMN syndrome. This report suggests that corticospinal tract involvement may also be present thus expanding the phenotype of this recently described clinical entity.

Email: aminachaouch@doctors.org.uk

BRACHIAL NEURITIS PRESENTING AS ISOLATED PHRENIC NERVE PALSY – TWO CASES

Nadeem Akhtar, Ali Al Memar. Kingston Hospital NHS Trust, Kingston upon Thames, Surrey, UK

Phrenic neuropathy associated with brachial neuritis has been well described in literature. It is rare to have an isolated phrenic neuropathy a presenting feature of brachial neuritis. We report two cases of isolated phrenic neuritis presented as acute onset of shoulder pain and dyspnoea. Both cases developed clinical symptoms within few weeks of invasive procedure, one case presented post prostatectomy and the other was post bone marrow donation. Both had dyspnoea pronounced particularly in supine position shoulder pain was also a prominent presenting feature typically waking up patient from sleep. The phrenic conduction studies showed mixed demyelination and axonal degeneration of the phrenic nerves. Sub-clinical evidence of brachial plexus involvement was present in our cases. Phrenic nerve paralysis should be considered as a differential diagnosis of acute onset dyspnoea, typically if it is also associated with shoulder pain and dyspnoea on supine positions. The prognosis for patients with unilateral phrenic neuropathy is more favourable than bilateral phrenic neuropathy. Our one case made a considerable recovery both clinically and electrophysiologically and the other one remained stable.

Email: drnadeemakhtar@hotmail.com

ALEMTUZUMAB IN THE TREATMENT OF IVIG-DEPENDENT CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

E. A. Marsh, J. G. Llewellyn, M. M. Reilly, A. Krishnan, M. Doran, A. M. Ryan, A. J. Coles, N. P. Robertson. University Hospital of Wales, Cardiff, UK, Institute of Neurology, University College London, London, UK, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK, Cork University Hospital, Cork, Ireland

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an idiopathic immune mediated neuropathy causing demyelination and conduction block generated by an aberrant autoimmune response, probably involving both T cells and antibodies. Diagnosis commonly prompts initial treatment with steroids, however 5–35% are unresponsive and become dependent on repeated courses of IVIg to maintain function. The role of further alternative immunosuppression remains unclear. Alemtuzumab is a humanised monoclonal antibody targeting the CD52 antigen on the surface of lymphocyte lineages. Single infusion results in rapid and profound lymphopoenia and offers clinical benefit in multiple sclerosis thought to occur as a result of modulation of regenerating T cell repertoires. We report clinical outcome in a series of patients with severe IVIg dependent CIDP treated with alemtuzumab. Seven patients with IVIg dependent CIDP were treated (dose range 60–150 mg). Two patients (1F, 1M) with mean age at diagnosis (AAD) of 19.5 years, had prolonged remissions (15–17 months). One male (AAD 51 yrs) had a partial response characterised by a halving of infusion frequency. No clear benefit was observed in 4 patients (2M, 2F) AAD 40.2 years. Two patients developed autoimmune disease. Alemtuzumab was well tolerated and effective in reducing IVIg dependence in 43% and may offer an alternative for a subset of early onset IVIg dependent CIDP patients failing more conventional immunosuppressive agents.

Email: doctorellie@hotmail.com

EXECUTIVE AND FRONTAL DYSFUNCTION IN AN FMRI STUDY OF CEREBRAL SMALL VESSEL DISEASE

G. Lumley, J. Goodwin, L. M. Parkes, H. C. A. Emsley. Royal Preston Hospital, Preston, UK, University of Liverpool, Liverpool, UK, University of Manchester, Manchester, UK

Background Cerebral small vessel disease (cSVD) is an important but under-investigated cause of lacunar stroke, leukoaraiosis and vascular dementia. We are investigating novel imaging markers of cSVD and their correlation with cognitive dysfunction.

Methods Seven patients with cSVD (clinical lacunar stroke) and 20 age-matched controls underwent a battery of cognitive tests and a 3 T MRI protocol with structural and arterial spin labelling sequences, enabling collection of simultaneous blood oxygenation level dependent (BOLD) and cerebral blood flow signal during a Stroop task.

Results Structural scans showed changes attributable to cSVD. Patients showed executive dysfunction with significant (p<0.05, single tailed t-test) deficits on trail-making, digit span, verbal fluency and digit symbol tests, with the latter showing the most striking difference (patients 37±11, controls 59±11, p<0.0005). During the Stroop task, mean accuracy and mean response were reduced. Patients showed increased blood oxygen level dependent (BOLD) response to the Stroop task in frontal regions, and increased neurovascular coupling, attributable to reduced oxygen metabolism.

Conclusions These preliminary results suggest concordance with previous studies of structural changes in cSVD, though are limited by the small sample size. The promising results support this methodology to evaluate functional vs structural images and their correlation with cognitive dysfunction.

Email: h.emsley@liv.ac.uk

LATE ADULT ONSET TEMPORAL LOBE EPILEPSY WITH ANTIBODIES TO VOLTAGE GATED POTASSIUM CHANNELS

L. Matthews, A. Vincent, J. Palace. Oxford Radcliffe Hospitals NHS Trust, Oxford, UK, Department of Clinical Neurology, University of Oxford, Oxford, UK

Voltage gated potassium channel (VGKC) antibodies are generally associated with an autoimmune form of limbic encephalitis. We report two cases of late adult onset temporal lobe epilepsy (TLE) associated with raised VGKC antibody titres and no other symptoms of limbic encephalitis at presentation. The first case, a 57-year-old female, had high levels of VGKC antibody titres (1458 pM) 3 months after seizure onset. Magnetic resonance imaging (MRI) on 2 occasions was normal. A spontaneous fall in antibody titres to 134 pM (normal <100 pM) was observed over the following 6 months, ie 9 months from onset. The second patient was a 62-year-old female presenting with late onset TLE and abnormally high T2 and FLAIR signal on MRI in the right amygdala. VGKC antibody testing 6 months after seizure onset revealed a moderately raised titre (316 pM). Seizures in both patients were successfully controlled with anticonvulsant monotherapy. Previous VGKC autoimmunity is beginning to be recognised as a cause of late adult onset TLE and the diagnosis can be missed if serum is sent too late (ie after the antibody titres have normalised). Treatment implications will be discussed.

Email: lucymatthews@doctors.org.uk

INTER- AND INTRAFAMILIAL CLINICAL HETEROGENEITY IN FTDP-17 ASSOCIATED WITH MAPT 10+16 MUTATION

A. J. Larner, M. Doran. Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Mutations in the MAPT gene on chromosome 17 are usually associated with the phenotype of frontotemporal dementia and parkinsonism (FTDP-17), although other clinical phenotypes have occasionally been described. We report clinical findings in four families with the MAPT splice site 10+16 mutation seen in our clinic over a 12-year period. Two families showed a pattern suggestive of autosomal dominant disease transmission (at least 3 family members affected in at least two generations), the other two families showed familial disease (at least one first degree family relative affected). In three families, the probands presented with a phenotype suggestive of early-onset probable Alzheimer’s disease, namely amnesia evident on neuropsychological assessment. Correct diagnosis became apparent in one family only at post-mortem (tau pathology typical of other FTDP-17 families) and in the other two families because new clinical features developed over 3–4 years (behaviours typical of frontotemporal dementia, movement disorder typical of progressive supranuclear palsy). In the fourth family the proband presented with a parkinsonian movement disorder, with a family history of early onset dementia. The clinical heterogeneity observed both between and within families with the MAPT 10+16 mutation suggests the operation of other genetic and/or epigenetic factors in determining disease phenotype.

Email: a.larner@thewaltoncentre.nhs.uk

TRACTOGRAPHY AND THE DISTRIBUTED NETWORK DAMAGE UNDERLYING MEMORY IMPAIRMENT IN TEMPORAL LOBE EPILEPSY

M. Yogarajah, N. Focke, S. Bonelli, P. Thompson, M. Symms, M. Koepp, J. Duncan. Institute of Neurology, Buckinghamshire, UK

Refractory temporal lobe epilepsy (TLE) is associated with significant progressive memory impairment. We used diffusion tensor tractography in 25 left TLE patients and 30 controls to interrogate several white matter bundles thought to be critical to memory function. We hypothesised that the fornix would be critical to recall, rather than recognition memory, and the uncinate fasciculus (UF) would be critical to semantic memory. The cingulum was assessed as a control tract. Hippocampal volume, brain atrophy and language lateralisation indices were included as confounding factors in all correlation testing. All subjects underwent verbal and non-verbal memory recall tests derived from the AMIPB. Recognition memory was assessed using the Warrington recognition test, and semantic memory was assessed using the vocabulary subtest of the WAIS III. Tractography revealed significant bilateral damage to all tracts when compared to controls. Significant material specific correlations were present between the fornix and recall memory, and betweem the left UF volume and semantic memory scores. No correlations were present between the cingulum and memory function. This study demonstrates the widespread damage present in unilateral TLE, and suggests that tractography can provide unique information in understanding the structural basis of cognitive impairment in TLE.

Email: m.yogarajah@ion.ucl.ac.uk

SERUM ANTIBODIES IN EPILEPSY

T. Brenner, Y. Hart, S. J. Howell, J. Palace, G. J. Sills, M. J. Brodie, A. Vincent, B. Lang. Department of Clinical Neurology, University of Oxford, Oxford, UK, Royal Hallamshire Hospital, Sheffield, UK, Epilepsy Unit, Western Infirmary, Glasgow, UK, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK

In order to investigate whether autoimmune mechanisms against ion channels or receptors could be the pathogenic basis in some epilepsy patients, sera were collected from different patient groups: preexisting autoimmune disease or a suspected autoimmune basis (n = 120, immune cohort IC), consecutive newly-diagnosed patients (185, CEP), patients with temporal lobe epilepsy (95, TLE), and patients with drug-resistant epilepsy (72, DRE). All sera were screened for antibodies against voltage-gated potassium channels (VGKC), voltage-gated calcium channels (VGCC), glutamic acid decarboxylase (GAD), and N-methyl-d-aspartate receptor (NMDAR), and the results were compared to healthy and disease controls. Increased VGKC antibody titres were found in 15% of IC patients (half of which had acute or subacute onset), 6.5% of CEP patients, but only 1% in the DRE and TLE patient groups. VGCC and high titre GAD antibodies (>100 U/ml) were rare in all cohorts (<1% for VGCC and ⩽ 2% for GAD); NMDAR antibodies were present in all cohorts, but the prevalence varied from 0.5% (DRE) to 3% (IC). The results suggest an immune-mediated component in some forms of epilepsy, although further studies will be required to establish the pathogenicity of serum antibodies.

Email: tanja.brenner@clneuro.ox.ac.uk

ADVERSE EVENT REPORTING IN RANDOMISED CONTROLLED TRIALS

A. Shukralla, A. G. Marson. University of Liverpool, Liverpool, UK

Aim Randomised controlled trials are poor with regard to adverse events reporting. We aim to qualitatively and quantitatively review current dissemination of adverse events in clinical trials.

Methods Pub Med and Cochrane library searches between 2000 and 2008 using epilepsy, convulsions and seizure as key words. Search limits imposed: clinical trials, phase 1 to 4. Abstracts were qualitatively and quantitatively analysed using an Epi Info© database.

Results A total of 1806 abstracts were analysed, 1383 surgical, radiological, non AED related trials abstracts and observational studies were excluded. We analysed 121 trials. Efficacy and safety were analysed in 76% of trials, 12% examined efficacy only and 12% examined safety only. Discrete adverse events discussed in trials ranged from zero to 25 with a median value of eight. Majority of trials described adverse events in a symptom specific manner (68%) vs 17% used both system and symptom specific methods. Descriptive statistics were used in 48% of trials to compare adverse events, only 5% used only inferential statistics vs 34% used both methods. Thirty percent did not discuss adverse events in the conclusions.

Conclusions Current reporting of adverse events is poor determination of causality is variable. Collaboration between industry and clinicians would improve future reporting.

Email: arifshukralla@gmail.com