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001 PREDICTING SEIZURE RECURRENCE WITH AND WITHOUT ANTIEPILEPTIC DRUG TREATMENT FOLLOWING SINGLE SEIZURES AND FOR EARLY EPILEPSY: A PREDICTIVE MODEL FROM A MULTICENTRE RANDOMIZED CONTROLLED TRIAL
A. G. Marson, L. Kim, A. L. Johnson, A. Jacoby, D. W. Chadwick on behalf of the MESS collaborators. Department of Neurological Science University of Liverpool, Department of Primary Care University of Liverpool, MRC Biostatistics Unit University of Cambridge
Rationale and Methods: The multicentre study of early epilepsy and single seizures (MESS) represents the largest epilepsy RCT so far. 1443 patients were recruited following a single seizure or with early epilepsy. Patients were randomized to either immediate or deferred treatment with an antiepileptic drug (AED). In order to predict seizure recurrence risk for individual patients associated with these treatment policies, data for time to a first seizure after randomization have been used to generate a predictive model.
Results: Results below are all hazard ratios (HR) with 95% CIs. Overall, there were significantly fewer seizure recurrences for patients allocated to immediate treatment, hazard ratio 1.4 (1.2 to 1.7). Regression models found the following clinical factors to be significantly associated with outcome, 2 or more seizures prior to randomization 1.6 (1.3 to 2.0), 3 or more seizures prior to randomization 2.6 (1.6 to 4.1), 10 or more seizures prior to randomization 1.3 (1.0 to 1.7), ‘brain pathology’ (learning difficulty, delayed development, neurological signs) 1.4 (1.1 to 1.8)), abnormal EEG 1.6 (1.3, 1.9). A predictive model using these factors is well calibrated within the MESS dataset.
Conclusions: MESS provides a simple prognostic model which will inform clinical decision making. The model is reliable within the MESS dataset and should be tested in other datasets and in clinical practice.
002 MEDICALLY REFRACTORY EPILEPSY ASSOCIATED WITH HYPOTHALAMIC HAMARTOMAS CAN BE SIGNIFICANTLY AMELIORATED USING STEREOTACTIC NEUROSURGICAL TECHNIQUES
C. Watts, C. Polkey, N. Mullatti, R. Selway. Depts Neurosurgery and Clinical Neurophysiology, Kings College Hospital, London
Objective: To determine the feasibility of a stereotactic approach to the surgical management of medically refractory epilepsy in patients with hypothalamic hamartoma.
Methods: Three adult male patients underwent detailed evaluation (MRI imaging, EEG, video telemetry, depth electrode recording and neuropsychological assessment). Following depth electrode confirmation of the origin of seizures patients 1 and 2 were subjected to thermocoagulation of the hamartoma and patient 3 received a deep brain stimulator implanted into the hamartoma.
Results: Patients 1 and 2 had over 75% seizure reduction with negligible epileptiform activity on post-operative EEG at 2 year follow-up. No adverse neurological, autonomic or psychological sequelae were detected in either patient. Pre-operatively patient 3 suffered sub-clinical seizures associated with prolonged bursts of polyspikes lasting 4–10 seconds whilst awake and increasing during sleep. Seven months after surgery epileptiform activity was strikingly reduced in the awake state and in sleep the discharges had reduced to 1–3 seconds. He and his family reported improvement in communication and social interaction.
Discussion: A stereotactic neurosurgical approach to the management of seizures associated with hypothalamic hamartomas offers a viable alternative to standard techniques with minimal morbidity compared to open surgery. The potential role of deep brain stimulation awaits further evaluation.
003 THE RISK OF ACTIVATION PROCEDURES DURING STANDARD ELECTROENCEPHALOGRAPHY (EEG). A STUDY OF 1000 RECORDS
H. Angus-Leppan. Royal Free and King College Hospitals, London
Adverse events during standard scalp EEG in 1000 random records out of a total of 3391 records during 2002 at Kings College Hospital were noted. Seizures and epileptiform activity were compared in the EEG during the resting, photic stimulation, hyperventilation and sleep phases.
Adverse events occurred in 131 of 1000 records. Seizures occurred in 60 records (45 electro-clinical and 15 non-epileptic seizures). Overall, the incidence of electro-clinical seizures was not statistically different during the resting (2.8%), sleep (2%), hyperventilation (2.1%) and photic stimulation (1.4%) EEGs. There was a higher frequency of electro-clinical seizures during hyperventilation and sleep in those with idiopathic generalised epilepsy (31.5%) and during photic stimulation in photosensitive patients (31%). The incidence of electro-clinical seizures was significantly less during activation procedures in partial epilepsies (2.6%).
This study has implications for informing patients about the risks of EEG. Seizure generation is the only serious common adverse event. Warning those without a prior diagnosis, particularly about photic stimulation, is not supported by these findings, because the risk of electro-clinical seizures was the same during both resting and activation EEG. In those with a prior diagnosis of generalised epilepsy or photosensitivity, activation procedures have a higher rate of seizure induction.
004 FUNCTIONAL MRI OF GENERALISED SPIKE WAVE ACTIVITY
K. Hamandi, A. Salek-Haddadi, L. Lemieux, A. Liston, M. Koutroumanidis, J. S. Duncan, D. R. Fish. Institute of Neurology, Queen Square and National Society for Epilepsy, Chalfont St Peter
Aim: To determine the haemodynamic correlates of generalised spike wave (GSW) using EEG correlated functional-MRI (EEG/fMRI).
Methods: Twelve patients with idiopathic generalised epilepsy (IGE) and two patients with cryptogenic generalised epilepsy were studied with EEG/fMRI. At 1.5 Tesla, 700 Blood Oxygen Level Dependent (BOLD) sensitive MRI scans were acquired over 35 minutes with simultaneous continuous EEG. fMRI time series were analysed using the Statistical Parametric Mapping (SPM2) software. Runs of generalised spike wave (GSW) were modelled as box-cars convolved with a canonical haemodynamic response function, and assessed at each MRI voxel to obtain statistical parametric maps.
Results: In the IGE group 4 patients had significant BOLD activation in the frontal lobe, correlated with GSW. 3 had no GSW during scanning, 5 had no significant BOLD change. Of the cryptogenic generalised cases, one had BOLD signal decrease in the caudate nuclei, posterior cingulate gyri and bi-parietal cortex and frontal activation; and the other bi-parietal deactivation and thalamic activation.
Discussion: These different haemodynamic correlates of spike-wave activity are likely to reflect different underlying pathophysiological mechanisms, in the different syndromes. Further studies are ongoing in well defined epilepsy cohorts to confirm this and sensitivity will be enhanced by using a 3T MRI scanner.
005 THE FIRST CLINICAL TRIAL OF ANTISENSE THERAPEUTICS IN MYASTHENIA GRAVIS: FINAL RESULTS AND ANALYSIS
D. H. McKee, S. Agus, H. Soreq, O. B. Joseph, S. Brawer, J. Sussman, Z. Argov. Greater Manchester Centre for Clinical Neurosciences; Hadassah University Hospital, Jerusalem; Ester Neurosciences
Objectives: An open label trial of EN101 in patients with myasthenia gravis. EN101 is an antisense oligodeoxynucleotide with a sequence designed to bind to acetylcholinesterase mRNA, preventing its translation into protein.
Methods: 16 patients with generalised myasthenia gravis were recruited. All were taking at least 180 mg of pyridostigmine daily, discontinued following admission to hospital. EN101 was administered orally in escalating doses up to 500 micrograms/kg, then given as a single daily dose for the next three days. Following an EN101 washout period pyridostigmine was restarted. Patients were assessed using the Quantitative Myasthenia Gravis Score (QMG).
Results: A treatment response to EN101 was observed in 14/16 patients, with significant improvements in QMG scores throughout the treatment period. Average QMG scores improved from 13.2 at baseline down to 6.0 following the final dose of EN101 (p = <0.001), with mean percentage improvements in QMG of up to 53.4% (p = <0.05). Muscle groups becoming significantly weaker following discontinuation of pyridostigmine were most likely to respond to EN101. Cholinergic side effects were conspicuous by their absence.
Conclusions: In an open label trial EN101 appears to be effective in reversing symptoms of myasthenia gravis. The results justify further study in a randomised controlled trial.
006 IN VIVO STUDY OF CEREBRAL MICROGLIAL ACTIVATION IN MND USING [11C]-PK11195 PET
M. R. Turner, A. Cagnin, F. E. Turkheimer, C. C. J. Miller, C. E. Shaw, D. J. Brooks, R. B. Banati, P. N. Leigh. Institute of Psychiatry, London; University of Padova, Italy; Imperial College, London; Guy’s, King’s & St Thomas’ Medical Schools, London
There is increasing evidence that microglia are involved in the pathogenesis of MND. Microglial activation is a relatively early phenomenon in the transgenic superoxide dismutase (SOD1) mouse, and drugs aimed at inflammatory pathways, including minocycline and celecoxib, are effective at prolonging survival in this model. It is not known whether microglial activation is an early feature of the human disease process. We therefore used the PET ligand [11C]-PK11195, selective for the peripheral benzodiazepine receptor expressed by activated microglia, for the in vivo study of cerebral microglial activation in MND. Ten “probable” or “definite” MND patients underwent [11C]-PK11195 PET. The mean duration of symptoms was 25 months. Results were compared with fourteen healthy controls of similar age. Binding of [11C]-PK11195 was calculated for seven regions of interest. Significantly increased binding, and so microglial activation, was found in motor regions (pre-central gyrus and pons), and non-motor regions (dorsolateral prefrontal region and thalamus) in the MND patients. Binding within the motor cortex correlated closely with the degree of upper motor neurone involvement clinically. We conclude that microglial activation occurs relatively early in the evolution of the MND. [11C]-PK11195 PET may be useful in monitoring the response to drugs that modify microglial activation.
007 NEUROPHYSIOLOGICAL MEASUREMENT OF DISEASE PROGRESSION IN AMYOTROPHIC LATERAL SCLEROSIS: A PROSPECTIVE STUDY
M. de Carvalho, M. Scotto, A. Lopes, M. Swash. Dept of Neurology, Santa Maria Hospital, University of Lisbon, Portugal, Department of Mathematics, University of Alveiro, Portugal, and Dept of Neurology, Royal London Hospital, Queen Mary School of Medicine, University of London
In order to evaluate the potential value of neurophysiological measurements in assessing progression in amyotrophic lateral sclerosis we studied 96 patients with El Escorial probable or definite amyotrophic lateral sclerosis (ALS). We used the Amyotrophic Lateral Sclerosis Functional Rating Scale, the forced vital capacity and a composite score of muscle strength using the MRC scale in 32 limb muscles, as clinical measures. All the neurophysiological measurements were made in the ulnar nerve-abductor digiti minimi (ADM) nerve-muscle system. Normal values were established in studies of 92 healthy patients matched for age and sex. In half of the hands in which the ADM muscle was of normal strength MUNE revealed a reduced number of functioning motor units. 28 ALS patients were studied in a test-retest design at an interval of one month to establish reproducibility of the neurophysiological and clinical measures. This study showed that MUNE and NI were reliable in repeated measurements in patients with ALS. The NI showed a lower mean difference percentage than MUNE in the two sets of data. 39 patients were followed for six months, and 30 of these were followed for 12 months in serial clinical and neurophysiological observations. MUNE, NI and MVIC of the ADM muscle proved to be the most sensitive parameters. In a group of 11 patients with slow progression, evaluated for an 18-month period there was more variability in the data, reflecting the variable course of these patients. There was a trend for MUNE to be the most sensitive measure in this group. In a small group of 9 patients with rapid progression, who could be followed for only six months, all parameters were sensitive to change. These data demonstrate the potential utility of these neurophysiological measures in following groups of patients with ALS in clinical trials.
Supported by a grant from The Motor Neurone Disease Association.
008 THYMECTOMY IN MYASTHENIA GRAVIS: COMPARISON OF OUTCOME IN SANTIAGO, CUBA AND NOTTINGHAM
N. Shahrizaila, O. A. Pacheco, D. G. Vidal, F. R. Miyares, A. J. Wills. Queens Medical Centre, Nottingham; Hospital Saturnino Lora, Santiago de Cuba
Objective: We compared the outcome of thymectomy for myasthenia gravis (MG) in two healthcare systems. In Nottingham, thymectomy is performed for thymic enlargement and considered in antiacetylcholine receptor (AchR) antibody positive patients. In Santiago, thymectomy is considered in all generalised MG patients irrespective of their radiological findings or AchR antibodies.
Method: 22 MG patients in Nottingham and 75 in Santiago who had a thymectomy were identified and their notes reviewed. We compared the median age, stage of disease, thymic histology and clinical outcome at two years post-thymectomy.
Results: The median ages for the Cuban and Nottingham patients were 25 and 35 respectively. The median stage of disease was IIa by Osserman’s classification in both. In Nottingham, 59% (13/22) showed an improvement compared to 88% (66/75) in Santiago (p<0.01). There were significantly more cases of thymoma in Nottingham whereas thymic hyperplasia and atrophy were a more frequent finding in Cuban patients. The majority of cases who improved post-thymectomy had thymic hyperplasia on histology in both Nottingham (46%) and Cuban (61%) patients.
Conclusion: Selecting MG patients based on thymic enlargement alone or AchR antibody positivity may be inadequate and thymectomy should perhaps be considered in all patients with generalised myasthenia.
009 THE MULTIPLE SCLEROSIS MONITORING STUDY: PROGRESS TO DATE
C. Cooper, J. Palace, M. Pickin, M. Boggild, J. Nichol on behalf of the Monitoring Study Consortium. Universities of Sheffield, Oxford and Liverpool
The ‘Risk-Sharing’ scheme for the prescribing of Interferon and Glatiramer was proposed by the Department of Health (DOH) in response to negative NICE guidance in February 2002. The DOH directed that the four licenced agents be made available within the NHS according to ABN guidelines, conditional on the development of a long-term monitoring study. The study aims to collect outcome data on 5–7000 patients treated over a period of 10 years. Outcome data will be compared with clinical trial and natural history data to assess cost-effectiveness of these agents. If necessary, further price adjustments will be made to ensure the price paid by the NHS for each treatment falls within a pre-specified cost per QALY limit.
Despite slow early recruitment, resulting from widespread funding and infrastructure issues, since May 2002 over 3000 patients have gone on to treatment, the majority of whom have been entered into the monitoring study. Patients are being recruited from 61centres and we anticipate completing recruitment of the cohort by Summer 2004.
By Spring 2004 baseline clinical and demographic data on 2500 patients will be available. Difficulties encountered in implementation and steps being taken to address acknowledged weaknesses in the study design will be discussed.
010 AXONAL PROTECTION IN A MODEL OF MS: COMPARISON OF EFFICACY OF DIFFERENT ANTICONVULSANTS
D. A. Bechtold, M. Davies, R. Kapoor, K. J. Smith Neuroinflammation Research Group. King’s College, London
Axonal degeneration is a major cause of permanent neurological deficit in multiple sclerosis (MS), but there is no effective therapy for axonal protection. We have previously shown that flecainide, a sodium channel-blocking agent, provides significant protection of axons in an animal model of MS, chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE). We have now examined the efficacy of carbamazepine, lamotrigine and phenytoin for axonal protection in CR-EAE.
CR-EAE was induced in rats (n = 100, DA, male, 200–250 g) randomly assigned to receive carbamazepine (200 mg/kg/day), lamotrigine (15 mg/kg/day), phenytoin (60 mg/kg/day) or vehicle p.o. from 7 days post-inoculation. The extent of dorsal column axonal loss was assessed histologically 27–28 days later.
There was no difference in neurological deficit between the groups. Axonal degeneration was substantial in control animals (40.1±43.9% loss), but lamotrigine provided significant axonal protection (9.8±11%; p<0.01). Phenytoin showed a modest protective effect (24.2±21.2%), but carbamazepine was not effective.
Lamotrigine provides significant protection from axonal degeneration in an animal model of MS, and so may be an effective therapy in this and other inflammatory demyelinating disorders of the CNS.
011 CANNABINOIDS IN MS – LONG-TERM RESULTS FROM THE CAMS STUDY
L. Teare, J. Vickery, P. Fox, D. Wright, H. Sanders, A. Thompson, J. Zajicek on behalf of the UK MS Research Group. Peninsula Medical School, Plymouth; University of Plymouth; National Hospital for Neurology & Neurosurgery, London
The Cannabinoids in MS (CAMS study) was a 3-arm multicentre randomised controlled trial, which evaluated the effects of oral whole cannabis extract, the major active component of cannabis (tetrahydrocannabinol, THC) with placebo. The main part of the study lasted for 15 weeks and results failed to demonstrate any efficacy of cannabinoids on spasticity, as measured by the Ashworth scale, although patient symptoms of spasticity, pain, muscle spasms and sleep quality were improved, as was patient walking time. We also found an unexpected reduction in relapse rate in the active treatment groups.
Here we present the results from the follow-up study, where patients remained masked to treatment allocation, which continued for up to 52 weeks. Of the 657 patients originally treated, end of trial data were available in 182/211 in the cannabis extract arm, 166/206 in the THC arm and 188/213 in the placebo arm. 320/657 patients continued medication throughout the study (120 cannabis extract, 99 THC and 101 placebo). 85% of patients completed 52 weeks on the study. We will present the long-term results on all patients, with particular emphasis on safety and efficacy data.
012 CEREBROSPINAL FLUID NEUROFILAMENT HEAVY CHAIN LEVELS IN ACUTE OPTIC NEURITIS AND MULTIPLE SCLEROSIS PATIENTS TREATED WITH ORAL HIGH-DOSE METHYLPREDINOLONE
E. T. Lim, F. Sellebjerg, T. L. Sorensen, D. Grant, D. Altmann, G. Keir, E. J. Thompson, G. Giovannoni. Department of Neuroinflammation, Institute of Neurology, University College London
This study looked at the cerebrospinal fluid (CSF) neurofilament heavy chain levels in subjects who participated in two controlled clinical trials that supported the use of high-dose oral methylprednisolone therapy for attacks of optic neuritis (ON) and multiple sclerosis (MS). The objective was to determine whether CSF neurofilament heavy chain levels (NfHSMI34 and NfHSMI35) were associated with measures of disease activity. Eighteen patients were included in the ON trial (8 received treatment) and 32 subjects were included in the MS attack trial (15 received treatment). Levels of CSF NfHSMI34 and NfHSMI35 were measured at baseline and a week after treatment using ELISA method. Baseline CSF NfHSMI34 and NfHSMI35 correlated with baseline enhancing lesion volume (ELV) (r = 0.50, p = 0.005 and r = 0.53, p = 0.002 respectively). CSF NfHSMI35 at week 3 also significantly correlated with baseline gadolinium-enhanced MRI (r = 0.65, p = 0.0001), whereas there was borderline evidence between CSF NfHSMI34 measured at week 3 and baseline gadolinium-enhanced MRI (p = 0.33, p = 0.06). In conclusion CSF neurofilament heavy chain levels, thought to be a marker of axonal pathology, correlated with gadolinium enhancing lesion volume in subjects with ON and MS. This study supports the view that acute inflammation in ON and MS results in axonal pathology.
013 CLINICAL TRIALS IN MULTIPLE SCLEROSIS – THE IMPORTANCE OF THE OUTCOME MEASURE
J. Zajicek, A. Thompson, J. Hobart. Peninsula Medical School, and Derriford Hospital, Plymouth; National Hospital for Neurology & Neurosurgery, London
Clinical trials in MS have been hampered by the lack of appropriate clinical outcome measures. Using the EDSS as an outcome measure, trials require large numbers of patients followed up for prolonged periods in order to demonstrate effects. Such studies are expensive and prone to high dropout rates, typically 10% per annum, making interpretation of results difficult.
In order to develop clinical trials for progressive disease, reduce dropout and assess the long-term impact of treatments in MS we have been comparing outcome measures. We tested the properties of various outcome measures for MS trials by evaluating their responsiveness, intercorrelations and statistical significance of change scores in 77 consecutive patients receiving steroids for MS relapse. We demonstrate that, in order to obtain the same significant clinical effect using the different scales, sample sizes vary substantially. If 100 patients are required for the patient-orientated MSIS-29, the numbers for the other scales are: MSFC = 219; SF-36 = 381; EDSS = 891; UKNDS LL = 1371. Standardised response means varied from 0.33–1.22 and significance of change scores varied from p<0.001 (MSIS 29 and MSFC) to p>0.05 (UKNDS LL). These findings have important implications for the cost, length and feasibility of clinical trials in MS.
014 PUNDING IN PARKINSON’S DISEASE: ITS RELATION TO THE DOPAMINE DYSREGULATION SYNDROME
A. H. Evans, R. Katzenschlager, D. Paviour, S. Appel, A. D. Lawrence, A. J. Lees. Reta Lila Weston Institute of Neurological Studies & National Hospital for Neurology and Neurosurgery, London; MRC Cognition and Brain Sciences Unit, Cambridge
Punding is a term that was coined originally to describe complex prolonged, purposeless and stereotyped behaviour in chronic amphetamine users. 50 patients with higher dopamine replacement therapy (DRT) requirements (>800LEU/day) from 123 unselected patients with Parkinson’s disease from a Parkinson’s disease clinic were interviewed. Punding was defined as a repetitive stereotypical behaviour that was recognised by the patient as disruptive (i.e. preventing sleep, eating, timing of medication doses or everyday social interactions) but associated with feelings of calmness / relief. 17 (14%) patients of the 50 were identified to pund. Punding was acknowledged as disruptive and unproductive by the patients themselves, but forcible attempts by family to interrupt the behaviour led to irritability and dysphoria. Punders were of a similar age, disease duration and disability to nonpunders but used significantly higher doses of DRT (1707 LEU/day versus 1130, p<0.001), and more rescue doses (3/day versus 0.2, p<0.001). Punding was frequently associated with a pattern of compulsive DRT use characteristic of dopamine dysregulation syndrome (10/17 versus 0/33, p<0.001). We believe that this is an under-reported, socially disabling phenomenon which is commonly associated with the syndrome of dopamine dysregulation and is phenomenologically distinct from both obsessive-compulsive disorder and mania.
015 ALTERED AMPA RECEPTOR TRAFFICKING UNDERLIES LEVODOPA-INDUCED DYSKINESIA
M. A. Silverdale, P. Hallett, A. R. Crossman, J. M. Brotchie. Department of Neurology, Hope Hospital, Manchester; Manchester Movement Disorders Laboratory, Manchester
Levodopa-induced dyskinesia is a disabling problem in patients with Parkinson’s disease. We and others have proposed that overactivity of striatal AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole-propionate) receptor transmission may underlie dyskinesia. In this series of studies, we provide evidence for this hypothesis by demonstrating that the AMPA receptor antagonist, GYKI 52466, has a marked anti-dyskinetic action in the MPTP-lesioned marmoset, a non-human primate model of Parkinson’s disease.
Having demonstrated that AMPA receptor transmission is overactive during levodopa-induced dyskinesia, we next used Western blot and tissue fractionation analysis from striatal tissue prepared from dyskinetic versus non-dyskinetic non-human primates with MPTP-induced parkinsonism, to explore mechanisms underlying this overactivity. No change in total striatal AMPA receptor levels or phosphorylation state was demonstrated in the dyskinetic tissue. However, an increase in the trafficking of striatal AMPA receptors from the synaptic vesicles, into the post synaptic membrane, was found in the dyskinetic versus non-dyskinetic tissue.
The increased movement of striatal AMPA receptors from the cytoplasm into the post-synaptic membrane during dyskinesia may cause the hypersensitivity of AMPA receptors and provide a biochemical mechanism for levodopa-induced dyskinesia. This concept may enable the development of improved treatments for this common problem.
016 ANTI-BASAL GANGLIA ANTIBODIES IN PATIENTS WITH ATYPICAL DYSTONIA AND TICS: A PROSPECTIVE STUDY
M. J. Edwards, E. Trikouli, D. Martino, M. Bozi, R. C. Dake, A. J. Church, A. Schrag, A. J. Lees, N. P. Quinn, G. Giovannoni, K. P. Bhatia. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London; Neuroimmunology Unit, Department of Neuroinflammation, Institute of Neurology, London; Neurosciences Unit, Institute of Child Health, London; Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, London
Anti-basal ganglia antibodies (ABGA) have been associated with Sydenham’s chorea, PANDAS and Tourette’s syndrome. It is unknown whether they also play a role in adult onset movement disorders.
We prospectively assessed the incidence of ABGA in 65 adult patients with atypical movement disorders. For comparison, we also assessed the incidence of ABGA in 50 healthy adults, 50 adults with mixed neurological disorders, and 57 adults with typical idiopathic primary dystonia.
The majority of patients with atypical movement disorders were female, and presented with dystonia of a distribution unusual for the age of onset (adult onset generalised/focal leg dystonia) or of an unusual phenomenology (e.g. fixed dystonia). Precipitating factors and psychiatric co-morbidity were commonly observed. We found ABGA to be positive in 65% of this group. In contrast, ABGA were rare in healthy adults (2%, p<0.0001), adults with mixed neurological diseases (0%, p<0.0001), and patients with idiopathic primary dystonia (6%, p<0.0001).
Individuals with atypical movement disorders are significantly more likely to harbour ABGA than are healthy control subjects, neurological controls, and patients with idiopathic primary dystonia. Our results suggest a possible autoimmune basis for a proportion of cases of atypical movement disorders, which may be of importance in their diagnosis and management.
017 DIFFUSION TENSOR IMAGING DEMONSTRATES DIFFERENTIAL INVOLVEMENT OF BRAIN STRUCTURES IN MSA AND PSP
C. R. V. Blain, G. J. Barker, J. M. Jarosz, V. C. Williams, S. C. R. Williams, P. N. Leigh. Institute of Psychiatry, Kings College London
Diffusion Tensor Imaging (DTI) provides a quantitative approach to understanding the evolution of microstructural change in vivo. We studied five patients with Multiple System Atrophy (MSA) and five with Progressive Supranuclear Palsy (PSP) selected by consensus diagnostic criteria and five healthy age-matched controls. Each subject underwent DTI in a 1.5 Tesla system. Regions of interest within the brain stem (superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP) and pons) were selected from the T2 weighted (b = 0) images and transposed onto inherently co-registered Mean Diffusivity (MD) and Fractional Anisotropy (FA) maps. The Mann-Whitney U test was used to compare the mean MD and FA at each level for each group. In MSA, FA was significantly reduced in the MCP compared to PSP patients (p = 0.009) and controls (p = 0.008), whereas in PSP, FA was markedly reduced in the SCP compared to MSA patients (p = 0.009) and controls (p = 0.009). Within the pons, FA was significantly increased in patients with MSA, but not those with PSP, at the level of both the SCP and MCP, compared to the control group (p = 0.009). Hence DTI is a sensitive technique able to detect changes in the brain stem in MSA and PSP.
CB is supported by the Wellcome Trust.
018 INTRADETRUSOR INJECTIONS OF BOTULINUM A TOXIN TO TREAT SEVERE DETRUSOR OVERACTIVITY
C. J. Fowler, R. Popat, A. Apostolidis, T. Yap, P. Dasgupta, P. Anand. Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery, London; Peripheral Neuropathy Unit, The Hammersmith Hospital, Imperial College London; Department of Urology, Guy’s and St Thomas’ Hospitals, London
We describe the results of a new outpatient technique for injecting botulinum A toxin into the detrusor muscle of patients with severe detrusor overactivity (DO). We also report results of research into the mechanism of action of this treatment.
45 patients (18 multiple sclerosis; 9 other neurogenic; 18 idiopathic DO) were assessed by voiding diary, questionnaire and cystometry pre and at 4 and 16 weeks post treatment. Using an ultrafine injection needle, 200–300 units of Botox® diluted in 20–30 mls of saline were injected through a flexible cystoscope into 20–30 bladder muscle sites. The procedure took 20 minutes and was well tolerated (mean discomfort score 3.20±1.98 on a scale of 0–10).
No patients experienced significant side effects. All patients showed a significant improvement in their bladder capacity (P<0.0001), mean number of voiding episodes / 24 hours (P<0.0001), mean number of incontinence episodes / 24 hours (P<0.0001) and mean number of urgency episodes / 24 hours (P = 0.0004) which lasted for 7–9 months.
Our immunohistochemical studies on minute bladder biopsies taken pre and post treatment showed that treatment with botulinum A toxin is associated with a significant decrease of receptors expressed by sensory nerve fibres in the bladder suburothelium.
019 A PET STUDY IN SPONTANEOUS MIGRAINE
S. K. Afridi, N. Giffin, N. Ward, H. Kaube, R. S. J. Frackowiak, P. J. Goadsby. Institute of Neurology, London
Introduction: Since the seminal observation of brainstem activation in migraine there has only been a single case substantiating this finding. This study aimed to test the hypothesis that brainstem activation could be detected in migraine and to refine the anatomical localisation with higher resolution positron emission tomography (PET) than previously used.
Methods: We used H215O PET to scan five migraineurs during spontaneous unmedicated migraine attacks. Three had migraine without aura and two had migraine with aura. The patients were, in addition, scanned in the inter-ictal period. None were taking preventive medications during either phase of the study.
Results: Comparing the migraine state to the pain-free state a significant area of activation was seen in the dorsal pons. Activation was also identified in areas known to be involved in pain processing: anterior cingulate, cerebellum, thalamus, insula and prefrontal cortex.
Interpretation: For the first time we have shown pontine activation in spontaneous migraine with aura as well as replicating previous findings of brainstem activation in migraine without aura. These findings provide further evidence for the role of the brainstem in migraine, and suggest no important difference between patients with and without aura with regard to brainstem activation.
020 SOMATIC MOSAICISM IN SPORADIC EARLY-ONSET ALZHEIMER’S DISEASE
S. J. Tabrizi, J. A. Beck, M. Poulter, T. Campbell, J. B. Uphill, G. Adamson, J. F. Geddes, T. Revesz, M. Davis, N. Wood, J. Collinge. Department of Neurodegenerative Disease/MRC Prion Unit, Department of Molecular Neuroscience, Institute of Neurology, London; Department of Histopathology and Morbid Anatomy, Royal London Hospital, London
Alzheimer’s disease (AD) is the commonest neurodegenerative disease worldwide. Rare familial cases may be caused by mutations in one of three genes – amyloid precursor protein, presenilin 1 and presenilin 2; however the molecular basis of more than 99% of all AD cases is unknown. Somatic mutation has been considered a mechanism that may account for a proportion of sporadic cases of AD, but to date there has been no evidence for this. We now report a sporadic early onset case of AD, and show that this individual is a somatic mosaic for a mutation in the presenilin-1 gene, suggesting a novel molecular mechanism for AD. Quantification of the mosaicism using novel methodology demonstrated the degree of mosaicism at 8% in peripheral lymphocytes and 14% in cerebral cortex in the index case. Characterisation of this case has important implications for the aetiology of sporadic AD, and for other apparently sporadic neurodegenerative diseases such as Parkinson’s disease, motor neurone disease, and Creutzfeldt-Jakob disease.
021 THE CLINICAL RELEVANCE OF NEUROIMAGING IN OUT-PATIENT NEUROLOGY
U. C. Wieshmann. Walton Centre for Neurology and Neurosurgery, Liverpool
Aim: Modern cross sectional neuroimaging with CT and MRI provides fascinating images of the nervous system and has greatly enhanced our understanding of neurological disorders. The aim of this study was to assess the role of neuroimaging in an out-patient neurological setting.
Methods: 2720 patients attending out-patient neurology clinics were reviewed. 863 patients with 20 different clinical neurological syndromes had CT or MRI scanning. The results of the scans were reviewed and compared with the clinical diagnosis. A judgment regarding the clinical relevance based on relevance to diagnosis, prognosis and therapeutic implication was made for each abnormal scan result.
Results: Overall 316 scans (37%) were abnormal. The range was 0% (motor neuron disease) to 93% (MS). Only 13% of all scans were considered clinically relevant using the above criteria. In 11 of 20 conditions not a single clinically relevant abnormality was identified. These included chronic headaches without signs, migraine, generalised epilepsy, non organic disorders, transient sensory disturbances without signs and extrapyramidal disorders. MS, stroke and myelopathy were the conditions with the highest proportion of clinically relevant abnormal scans.
Conclusion: While neuroimaging is highly relevant for certain neurological conditions, for the majority of conditions neuroimaging has at best a contributory role.
022 THE EVOLUTION OF DEMENTIA IN PARKINSON’S DISEASE
E. M. Dunn, R. H. S. Mindham, E. G. S. Spokes. Department of Neurology, The General Infirmary at Leeds; Academic Unit of Psychiatry and Behavioural Sciences, University of Leeds
Background: Estimates of the frequency of dementia in Parkinson’s disease vary widely. The most satisfactory approach is longitudinal follow-up of a cohort of patients.
Methods: The Leeds study of Dementia in Parkinson’s disease recruited 89 idiopathic Parkinson’s disease patients, and 50 control subjects matched for age, gender and level of education, between 1985 and 1990. Eighteen rounds of assessment have occurred, including detailed tests of cognition, mood, disability and the severity of neurological signs.
Results: At entry to the study mean age was 64 years with a mean of 7.4 years elapsed from the onset of motor symptoms. Most patients were assessed to be in Hoehn and Yahr stage I, II or III (69 of 89). At entry just one patient was demented by the criteria of the Diagnostic and Statistical Manual of Mental Disorders, revised third edition (DSM III-R). Twenty-four further patients went on to become demented over the course of the study. There was a mean of 15.1 years between motor onset and assessment as demented. Just three control subjects were assessed as demented.
Conclusion: Dementia occurs in Parkinson’s disease much more frequently than in control subjects. However, prolonged follow-up shows this to be a relatively late manifestation.
023 SHOULD WE TREAT TIA AS A MEDICAL EMERGENCY?
S. J. Allder, M. Stevenson, C. Doyle, A. Pandor, P. Rothwell, G. Venables, S. M. Thomas. Clinical Neurology, Royal Hallamshire Hospital; John Radcliffe Hospital; SchARR Institute; Sheffield Vascular Institute; Northern General Hospital
Introduction: Emerging data relating to the risk of stroke following a transient ischaemic attack (TIA) has led to calls for patients with TIA to be treated as a medical emergency. There are currently little health economic data to support or refute such a major change in clinical practice.
Methods: We have used modelling techniques to evaluate the likely clinical and economic impact of four different clinical pathways for patients with TIA. Our conventional pathway was via a routine outpatient process. The three alternative pathways were fast track clinics that delivered either streamlined medical or surgical treatment alone or an integrated clinic, which delivered both. Sensitivity analyses were performed around timings to treatment, effectiveness of medical treatment and costs of delivering the service.
Results: A modelled fast track clinic that delivered medical therapy alone by day 14 was highly cost-effective. Delivering streamlined treatment for surgery alone appeared considerably less cost-effective, however the integrated service was remained highly cost-effective. Additionally, the increment of moving from therapy at day 14 to treatment for patients on the same day as their TIA, i.e. on day 1, was also highly cost-effective, even using conservative estimates for the impact of medical therapy.
Discussion: Setting up services that optimise medical treatment for patients with TIA on the day of their event are likely to be highly cost-effective.
024 CEREBRAL MICROBLEEDS ON T2*-WEIGHTED GRADIENT ECHO MRI: A NEW VASCULAR CAUSE OF COGNITIVE DYSFUNCTION?
D. J. Werring, D. W. Frazer, L. J. Coward, N. A. Losseff, H. Watt, L. Cipolotti, H. R. Jager, M. M. Brown. Institute of Neurology, University College London and The National Hospital for Neurology and Neurosurgery, Queen Square, London
Gradient-echo T2*-weighted magnetic resonance imaging sensitively detects cerebral microbleeds, which appear as small dot-like hypointensities. Microbleeds have generated interest as a marker for a bleeding-prone microangiopathy, but are considered clinically silent. Since microbleeds are located throughout the brain and cause tissue damage, we hypothesized that they would cause cognitive dysfunction. We studied patients with microbleeds (n = 25) and controls (n = 30) matched for age, gender, IQ, co-existing ischaemic small vessel disease (SVD) and presence/location of cortical infarction, using a comprehensive neuropsychological battery. Microbleeds were found throughout the brain, most commonly in the basal ganglia. Frontal-executive dysfunction was present in 60% of microbleed patients compared with 30% of controls (p = 0.03). Microbleed count (but not ischaemic SVD severity) was an independent predictor of frontal-executive dysfunction (odds ratio = 1.34, p = 0.03); furthermore, patients with impaired frontal-executive functions had more microbleeds in frontal and basal ganglia regions (p = 0.002 and p = 0.048 respectively). There was a correlation between microbleed count and number of cognitive domains impaired (r = 0.44, p = 0.03). We conclude that microbleeds are independently associated with cognitive dysfunction; the striking impact on frontal-executive functions is likely to result from microbleed-associated tissue damage in frontal-subcortical systems. These findings have important implications for the diagnosis of stroke patients with cognitive impairment.
025 ENDOVASCULAR TREATMENT FOR CAROTID ARTERY STENOSIS: A COCHRANE SYSTEMATIC REVIEW OF THE RANDOMISED EVIDENCE
L. J. Coward, R. L. Featherstone, M. M. Brown. Institute of Neurology, University College London
Reliable data from trials of endovascular treatment versus surgery for carotid artery stenosis are necessary to inform patients and target treatment appropriately. We performed a systematic review of all randomised trials comparing endovascular treatment with carotid endarterectomy. Five small to medium sized trials were included. Comparing the safety of the two treatments over all trials at 30 days post procedure, there was no significant difference in the risk of death or any stroke (odds ratio [OR] 1.26, 95% confidence interval [CI] 0.82–1.94), the risk of death or disabling stroke (OR 1.22, CI 0.61–2.41) or the risk of death, any stroke or myocardial infarction (OR 0.99, CI 0.66–1.48). Endovascular treatment significantly reduced the rate of cranial neuropathy (OR 0.12, CI 0.06–0.25). Both treatments appeared equally effective at preventing stroke or death at one year post procedure (OR 1.36, CI 0.87–2.13). Data from completed randomised trials suggest that endovascular intervention is at least as safe as surgery. However, other trials have been stopped prematurely because of concerns over the safety of stenting. Current evidence does not support a change in practice away from recommending endarterectomy for suitable carotid artery stenosis. Large randomised trials of carotid stenting are required.
026 RECOVERY FROM APHASIA: THE ROLE OF THE BASAL LANGUAGE AREA
D. J. Sharp, S. K. Scott, J. Crinion, R. J. S. Wise. Imperial College, London
Although aphasia is associated with left MCA territory infarction, neurosurgical studies have demonstrated profound aphasic disturbances after electrical stimulation of the inferotemporal (IT) cortex. This region lies between posterior and middle cerebral artery territories, and is rarely involved in stroke disease. It is involved in semantic dementia and herpes simplex encephalitis, diseases associated with loss of language comprehension. Primate IT cortex, comprising highest order unimodal visual cortex, and adjacent heteromodal perirhinal cortex (PRC), form associations within and between visual and other sensory modalities. The human primate is unusually skilled at being able to associate arbitrary auditory percepts (words) with the multimodal sensory properties of objects. We have performed a meta-analysis on four of our published functional neuroimaging studies, two involving automatic speech comprehension (‘passive’ listening to imageable speech) and two requiring controlled access to the meaning of object nouns. Although activity in prefrontal cortex distinguished controlled from automatic speech processing, there was common activation within left IT cortex. Activity within this region is modulated by the presence of left superior temporal cortical infarction, which disrupts projections to IT cortex. We propose that recovery of imageable speech comprehension after MCA territory aphasic stroke is dependent on intact IT cortex.
027 RECURRENT STROKE RISK AND CERVICAL ARTERIAL DISSECTION: IMPLICATIONS FOR A THERAPEUTIC TRIAL
J. Norris, H. Markus.St Georges Hospital Medical School, University of London
Although anticoagulants (AC) and antiplatelet agents are traditional therapeutic drugs for cervical arterial dissection, no evidence based data exist to justify their use. Also the annual recurrence rates of clinical events documented in retrospective studies is low, only 1–2%, necessitating unwieldy numbers for a therapeutic trial.
However, recent prospective data published by the Canadian Stroke Consortium indicate an annual post dissection rate of stroke, TIAs and death of 15% (17 of 116 patients) mostly in the weeks immediately following the dissection. In 105 patients who completed follow up, event rates on AC vs antiplatelets were 8.3% vs 12.4% (ns). We calculate that for a 2 arm trial with 80% power and 5% significance, 913 patients are needed in each group, a figure very similar to the recent Cochrane analysis. Most large metropolitan hospitals admit 10–12 patients/yr, so a 5 year trial involving 50 centres enrolling 2000 patients, assuming a 20% default in enrolment, would answer the question.
A feasibility study of 10 centres over 2 years is suggested initially. Potential strategies would include ximelagatran instead of warfarin to facilitate ‘blinding’, combination antiplatelet agents, and a short initial period of AC (3 months?) in view of the later low event rate.
028 PLASMA HOMOCYSTEINE, AND ISCHAEMIC STROKE: “MENDELIAN RANDOMIZATION” PROVIDES FURTHER EVIDENCE OF CAUSAL LINK
J. P. Casas, L. E. Bautista, A. D. Hingorani, P. Sharma. Centre for Clinical Pharmacology, BHF laboratories at UCL; Population Health Sciences, University of Wisconsin Medical School, USA.; Hammersmith Hospitals Acute Stroke Unit & Imperial College, University of London
Background: High homocysteine levels have been associated with an increased risk of ischaemic stroke, but whether this association is causal remains controversial. Carriers of the MTHFR/C677T polymorphism have a higher level of homocysteine. We evaluated whether the odds ratio (OR) of stroke derived from the difference in homocysteine levels conferred by the MTHFR polymorphism is consistent with the OR estimated from a genetic meta-analysis, using the principle of ‘Mendelian randomization’.
Methods: All electronic databases were searched for studies that evaluated association between homocysteine levels and MTHFR polymorphism, and for studies that evaluated MTHFR polymorphism and risk of stroke. Pooled OR and 95%CI were calculated using random and fixed effect models.
Findings: 106 studies met the selection criteria. Among 11 350 subjects without cardiovascular disease, the weighted mean difference in homocysteine levels between homozygous for the T allele compared with carriers of the C allele was 1.65 mmol/L (95%CI: 1.20–2.10). The OR for stroke corresponding to this difference in homocysteine was 1.19 (1.14–1.25). In our genetic meta-analysis (n = 10 702 patients) the observed OR for stroke was 1.24 (1.10–1.40) for TT-genotype subjects compared with carriers of the C allele.
Interpretation: These data are consistent with a causal relationship between homocysteine levels and stroke.
029 CLINICAL HETEROGENEITY OF MOVEMENT DISORDERS ASSOCIATED WITH ANTIPHOSPHOLIPID SYNDROME
D. Martino, N. K. Chew, P. Mir, A. Cifelli, N. Bajaj, M. J. Edwards, K. P. Bhatia. Sobell Department of Motor Neuroscience and Movement Disorders, Neurosciences Directorate, Department of Neurology, Queen’s Medical Centre, Nottingham
Movement disorders have only rarely been reported in association with antiphospholipid syndrome (APS). In such cases, chorea has been most frequently observed, with hemidystonia, parkinsonism and hemiballismus also reported. Tics and myoclonus have never been described in association with APS.
We describe six cases of APS (1 male, five females, mean age: 42; Range: 16–80) presenting with combinations of chorea, dystonia, tics, myoclonus and a corticobasal degeneration-like syndrome. Orofacial dyskinesias were prominent in three patients, and one patient presented with self mutilatory movements with tongue and lip biting. Psychiatric disturbance was prominent in three patients, and two patients had previously received a diagnosis of somatization disorder. Two patients had a dramatic improvement in their symptoms in response to treatment with oral anticoagulation.
Movement disorders in APS are clinically heterogeneous, and can include tics and myoclonus. Chorea, when it occurs, often affects the mouth, and can cause lip and tongue biting. Correct diagnosis of the condition can be difficult as patients with APS associated movement disorders can present with psychiatric disturbance and multiple unusual physical symptoms so that a diagnosis of somatization disorder can be contemplated. Oral anticoagulation should be considered in the treatment of movement disorders associated with APS.
030 LIAISON NEUROLOGY FOR ACUTE MEDICAL ADMISSIONS
R. B. Forbes, J. J. Craig, M. E. Callender, V. H. Patterson. Departments of Medicine and Neurology, Royal Victoria Hospital, Belfast
Objectives: To evaluate a liaison neurology service to an acute medical admissions unit.
Design: Cohort study before and after the introduction of a liaison neurology service.
Subjects: 176 people (96 usual care, 80 liaison service available) with neurological symptoms admitted acutely to the Royal Victoria Hospital Belfast.
Results: Before the introduction of a liaison neurology service, 10% were seen by neurologist, 72% had diagnosis at discharge and median length of stay was 6 days. When a liaison service was made available, 54% were seen by a neurologist, 92% left hospital with a diagnosis (odds ratio 3.0 95%CI 1.4–7.1), and median length of stay reduced to 3 days (p = 0.03, log rank test). Significant changes in diagnosis were made in 34% of cases assessed by a neurologist.
Conclusions: The introduction of a liaison neurology service was associated with more diagnoses being made and with a shorter length of hospital stay. Liaison neurology is an effective model for the delivery of care to an acute medical admissions unit.
031 RECENT OUTBREAK OF TETANUS IN INTRAVENOUS DRUG USERS
K. M. Gormley, N. J. Gutowski. Royal Devon & Exeter Hospital
Tetanus is an acute, often fatal infection caused by an exotoxin produced by Clostridium tetani. It is characterised by generalized rigidity and spasms of voluntary muscle with death usually by respiratory paralysis. Tetanus is rare with only 175 cases reported to the Communicable Disease Surveillance Centre (CDSC) between 1984 and 2000. One at-risk group is intravenous drug users (IDUs), who may contract tetanus using contaminated needles, drug paraphernalia or heroin. However, only 2 of the 175 cases were in IDUs during 1984–2000. By comparison, in the United States (US) IDUs comprise 15–18% of cases. Since July 2003 seven cases of tetanus in IDUs have been reported in the UK with one death. There is a wide geographical distribution to the cases reported, raising the possibility of more in the near future. In this recent outbreak a 30 year old female IDU with tetanus was admitted to Exeter. The clinical management of this patient is described, as is diagnostic testing and prophylaxis of tetanus. In conclusion, it is noted that there are currently no nationally agreed treatment guidelines in the UK, which if an increased incidence is anticipated is a matter therefore needs urgent addressing.
032 THE CLINICAL USE OF SERIAL MEASUREMENTS OF APPARENT DIFFUSION COEFFICIENT (ADC) IN UNTREATED ADULT SUPRATENTORIAL LOW-GRADE GLIOMAS
J. H. Rees, R. B. Ramachandran, C. Benton, A. Waldman, H. Watt, P. Tofts, H. R. Jäger. National Hospital for Neurology and Neurosurgery, Institute of Neurology, UCL, London
Introduction: Low-grade gliomas are slow growing primary intrinsic tumours that have the propensity for malignant transformation. Conventional MRI scan sequences cannot detect the earliest changes of malignant transformation.
Aim: To determine whether quantitative measurement of the apparent diffusion coefficient (ADC) of low-grade gliomas can be used to distinguish transforming from non-transforming tumours.
Methods: Longitudinal MRI diffusion weighted images were obtained at baseline and follow-up of four biopsy proven transformers and five non-transformers. Tumour boundaries were copied onto ADC maps and ADC histograms were normalised to a total tumour volume of 100%. We calculated tumour growth and tumour volume percentage with ADC values <1000×10−6 mm2/s (TUV<1000).
Results: Tumour volume increased on average by 30% in transformers (mean follow-up 18 months) and by 16% in non-transformers (mean follow-up 23 months). All transformers showed a left-shift of the peak location (Fig.1) on follow-up indicating a decrease in ADC values compared to a small right-shift in non-transformers (Fig.2). The TUV<1000 between baseline and follow-up increased by 9.2% (range 6–14.5%) in the transformers and decreased by 4% (range 0.7–10.6%) in non-transformers.
Conclusion: ADC histogram analysis can differentiate between transforming and non-transforming tumours and may be useful in the serial monitoring of untreated low-grade gliomas.
033 FOOD ANTIBODIES IN NEUROLOGICAL POPULATIONS
A. J. Wills, D. S. N. A. Tengah, R. J. Lock, D. J. Unsworth. QMC, Nottingham Department of Immunology Southmead Hospital Bristol
Objective: It has been claimed that a significant proportion of patients with cryptogenic neurological disorders are “gluten sensitive”. This claim is predominantly based on the presence of anti-gliadin antibodies (AGA) particularly of IgG type.
Methods: We identified 27 patients with cryptogenic ataxia, 32 with neuropathy, 49 with multiple sclerosis (MS) and 30 controls. We assayed the prevalence of common food antibodies (Ig G and Ig A) in these groups including AGA, bovine serum albumin (BSA), lactoglobulin and ovalbumin. HLA tatus was also ascertained as well as the presence of anti-tissue transglutaminase (TTG).
Results: We found a higher frequency of food antibodies (particularly of IgG type) in all the patient groups but this did not reach statistical significance. We found no particular association with HLA DQw2 in the ataxia patients in contrast to previously published data. TTG positivity was seen in one patient with MS suggesting occult celiac disease.
Conclusions: Our results raise a number of issues with regard to the nosological status of “gluten ataxia”. The presence of IgG food antibodies in neurological populations may reflect a generalised heightened response of the immune system or be secondary to altered gut permeability. These results suggest that gluten restriction is unlikely to benefit patients with cryptogenic neurological disorders.
034 NEUROLOGY TRAINING IN THE UK: A DIAGNOSTIC SURVEY OF 5200 PATIENTS
P. Maddison. Queen’s Medical Centre, Nottingham
A diagnostic survey was undertaken of all patients seen during a 4-year training programme. The patients were categorised by type of assessment, namely: ward referral, new out-patient, follow-up out patient, and ward in-patient.
Over 5200 patients were assessed over this 4-year period, and yearly reviews of records and results were undertaken in all patients in whom a diagnosis had not been established. The most common diagnoses were: epilepsy (17%), headaches (14%: migraine 5%, others 9%), cerebrovascular disease (11%), multiple sclerosis (9%) and movement disorders (9%). Most patients were seen in clinics (new patients 22%, follow-ups 45%).
A consistent incidence figure of between 4% and 5% was seen throughout the training period for diagnoses of unknown neurological disease, non-organic medically unexplained symptoms, and miscellaneous, rare conditions. Patients with unknown neurological disease were seen more frequently as ward in-patients, and patients with medically unexplained symptoms were seen more frequently as ward referrals than the rest of the patients (chi squared, trend, P<0.001). Cerebrovascular disease was the most commonly encountered diagnosis amongst all ward referrals; headaches other than migraine amongst new out-patients; epilepsy amongst out-patient follow-ups; and multiple sclerosis amongst ward in-patients. The range and frequency of common neurological conditions encountered in teaching hospitals were no different to that seen in the district general hospital (chi squared, trend, P = 0.2).
035 SATIVEX® IN THE TREATMENT OF PATIENTS WITH CHRONIC REFRACTORY PAIN DUE TO MS OR OTHER DEFECTS OF NEUROLOGICAL FUNCTION
M. K. Sharief, W. G. Notcutt, I. Mutiboko, C. Hawkes, J. Bolt, R. L. Potts, E. J. Smith. Guy’s, King’s and St Thomas’ School of Medicine, London and GW Pharmaceuticals, Ely, Cambridgeshire (on behalf of the Trial Investigators)
Evidence suggests cannabinoids may be effective in treating neuropathic pain. We conducted a 4 week (1 week run-in and 3 weeks treatment), randomised, double-blind, placebo controlled, parallel group trial in patients with chronic neuropathic pain of a whole plant extract oromucosal spray containing delta-9-Tetrahydrocannabinol (THC):Cannabidiol (CBD); (GW-1000-02, Sativex®), as adjunctive analgesic treatment. Each spray delivered 2.7 mg THC:2.5 mg CBD.
Results: 70 patients were randomised; 36 received GW-1000-02, 34 received placebo. Treatment difference in pain Box Scale-11 scores during week 3 of treatment was 0.39 boxes in favour of GW-1000-02 (p = 0.332; 95%CI: -1.18, 0.40). The median percentage of days on which patients took escape medication was 5% (GW-1000-02) and 45% (placebo); median treatment difference was 18% of days in favour of GW-1000-02 (p = 0.006; 95%CI: -47.62, 0.00). Mean treatment difference in a 5-point scale of sleep disturbance was 0.34 boxes in favour of GW-1000-02 (p = 0.052; 95%CI: -0.68, 0.00). Treatment was generally well tolerated; withdrawals were similar in both groups.
Conclusion: GW-1000-02 is efficacious in the treatment of chronic refractory pain of neuropathic origin, demonstrated by the statistically significant decrease in escape medication requirement in the treated group. This was accompanied by a decrease in sleep disturbance in the treated group.
036 POSTER SCORING AT SCIENTIFIC MEETINGS: FIRST IMPRESSIONS COUNT
P. E. M. Smith, G. N. Fuller, F. D. Dunstan. Department of Neurology and Department of Medical Statistics, University Hospital of Wales College of Medicine, Cardiff; Department of Neurology, Gloucester Royal Hospital, Great Western Road, Gloucester
There are no agreed methods to assess scientific posters. At a recent ABN meeting we attempted to inform poster-scoring guidelines.
31 posters were randomised into 2 groups, and each group randomly assigned to 14 neurologists. They “quick scored” (from 50) their posters, viewing each for 10–15 seconds, and “detailed scored” the others, awarding 0–1 each for 12 presentation characteristics; 0–8 each for correct facts, originality, and scientific merit; and 0–7 each for quickly understandable message, and “star-quality” (total 50). 11 non-neurologists “quick scored” all posters.
Neurologists’ quick scores (ranked) correlated well (r = 0.75) with other neurologists’ ranked detailed scores, especially for presentation (r = 0.65), message (r = 0.65), and star-quality (r = 0.64), but not for facts (r = 0.09), originality (r = 0.15), or science (r = 0.02). Four of 6 posters top-ranked on quick scoring were in the 6 top-ranked on detailed scoring, and vice versa. Non-neurologists’ scores correlated (r = 0.49) with neurologists’ detailed scores, but did not identify the highest-ranked posters.
Thus neurologists’ (but not non-neurologists’) “quick scores” generally could identify posters ranked highest on detailed scoring by other neurologists.
Our suggested guidelines for scientific poster assessment are:
Advise presenters that both presentational and scientific qualities will be scored.
5–10 specialists “quick score” all posters.
Specialists then “detailed score” the top-ranked 6–10 posters, assessing presentation, facts, originality, science, quickly understandable message, and star-quality.
037 CONFUSION IN A FISHERMAN
T. Solomon. Walton Centre for Neurology & Neurosurgery, Liverpool
A 46 year old man with chronic renal failure, and a cadaveric renal transplant two months earlier, presented with a week’s history of fatigue, then 2 days of fever, rigors and lethargy. He had been freshwater fishing 10 days, earlier, but had no recent foreign travel. On examination he was pyrexial with rigors, and lethargic; the general medical and neurological examinations were otherwise unremarkable. A full blood count was consistent with chronic anaemia, and CSF examination showed a neutrophil pleocytosis (35 cells/mL), moderately elevated protein (54 mg/dL) with a normal glucose ratio and no organisms. All other diagnostic investigation were negative. He was transfused with two units of blood and 2 days later became obtunded with nystagmus in the primary position and all directions, bruxism, and generalized rigidity, with brisk deep tendon reflexes but flexor plantars. An initial MRI was normal, but a 2nd MRI on day 10 of admission showed high signal intensities in the periaqueductal grey matter, right caudate, and both thalami (on T2-weighted and FLAIR images). Despite treatment with steroids he developed flaccid areflexic weakness of all limbs, became ventilator dependent and died. One other investigation came back as positive. The differential diagnosis and final diagnosis of this condition, that all ABN members need to be aware of, will be discussed.
038 IDENTIFICATION OF PINK1 (PARK6), THE FIRST MITOCHONDRIAL GENE CAUSING PARKINSON’S DISEASE
N. Wood, M. Muqit. Institute of Neurology, London
Objective: To identify a novel gene responsible for PARK6 linked Parkinson’s disease (PD).
Background: PD is a frequent neurodegenerative disease with prevalence close to 20% after age 60. Most cases are sporadic, but a subset of patients has positive family history. The pathogenetic mechanism leading to degeneration of the dopaminergic neurons in the substantia nigra remains poorly understood however much progress has been made by elucidating genes involved in Mendelian forms of PD.
Methods: We previously mapped the PARK6 locus to a 12.5 cM region on chromosome 1p36 in a large consanguineous family from Sicily with early onset PD. Linkage analysis identified two additional families which allowed refining the candidate interval to 2.8 Mb, containing approximately 40 genes.
Results: We have identified two distinct homozygous mutations in the affected individuals from the three families in a putative protein kinase PINK1. The two Italian families, which shared a common haplotype around the gene, harboured the same stop mutation, while a distinct missense mutation was found in the third family. The nonsense mutation was predicted to dramatically alter the protein structure. To confirm the pathogenic role of the missense mutation, the wild-type and mutant protein were transiently expressed in dopaminergic cell lines. Preliminary data showed that PINK1 localises to the mitochondria and the mutant protein disrupts the mitochondrial activity in response to cellular stress.
Conclusions: PINK1 represents the first mitochondrial gene directly involved in PD pathogenesis. Moreover it also implicates the role of a protein kinase and its pathway in neurodegeneration. This opens a new field of PD research.
039 CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME: A VERY UNUSUAL PRESENTATION WITH STATUS EPILEPTICUS
L. J. Coward, N. P. Hirsch, D. M. Kullmann, S. B. Lucas, R. S. Howard. Institute of Neurology, University College London, The National Hospital for Neurology and Neurosurgery, London; St Thomas’s Hospital, London
Catastrophic antiphospholipid syndrome (CAPS) is a rare but devastating syndrome. The clinical presentation of CAPS is complex involving multiple organs concurrently over a short period of time; typically, patients develop a widespread thrombotic vasculopathy with severe thrombocytopaenia.
A previously healthy 30 year old Indian woman was admitted to hospital 4 weeks post partum following a short illness of headache and lethargy followed by sudden onset of frequent generalised tonic-clonic seizures refractory to treatment. She was treated for presumed viral encephalitis but her condition suddenly deteriorated and she developed renal, respiratory and cardiac failure necessitating inotropic support and haemofiltration. Despite aggressive treatment for presumed septic shock, she died following a cardiac arrest. Thrombophilia screen indicated the presence of the lupus anticoagulant. Post mortem examination showed micro thrombosis throughout the brain and small vessel thrombosis or haemorrhage in the lungs, myocardium, kidneys, liver and adrenal glands.
Catastrophic APS may present as critical illness due to unexplained multi-organ failure. The condition should also be considered in the differential diagnosis of patients with post-partum encephalopathy, status epilepticus or presumed viral encephalitis associated with seizures.
040 ANTI-ALZHEIMER DRUGS IN ADULTS WITH DOWN’S SYNDROME WHO ARE CLINICALLY DEMENTING
S. W. Brown, W. Mathurin, J. McBrien, S. Whitwham, S. Masters. Developmental Disability Research & Education Group, Peninsula Medical School, Universities of Plymouth and Exeter, UK
Several medications are now licensed for treatment of dementia of Alzheimer type (DAT). The usual assessment tools for monitoring outcome, such as the mini-mental state exam, are unsuitable for people with intellectual disability (ID). People with Down’s syndrome (DS) are prone to develop DAT 30–40 years earlier than the general population. We have established a network of specialist memory clinics for people with ID in southwest England. Our assessment and follow-up protocol includes, inter alia, use of the Dementia Scale for Mental Retardation (DMR). More than 200 people with DS have been screened, and >50 are under treatment, using cholinesterase inhibitors. Mean age at diagnosis is 54 years, with no gender difference. Detailed analysis of a subset where serial DMR scores were obtained showed that in the last 2 assessments before treatment there was a significant deterioration in total scores (p = 0.0078) whereas treatment seemed to stabilise scores with the social subscale showing an improvement (p = 0.034). Mean time between assessments was 10.8 and 7.4 months respectively. Choice of medication did not affect cognitive or social outcome. There are advantages and limitations to the use of the DMR, and appropriate use of assessment tools for people with ID will be discussed.
041 MR INTENSITY ANALYSIS TO DISCRIMINATE VARIANT, SPORADIC CJD, AND NON-CJD DEMENTIA PATIENTS
A. C. F. Colchester, S. A. Hojjat, I. Zerr, D. A. Collie. Kent Institute of Medicine and Health Sciences, University of Kent at Canterbury, Canterbury; University Hospital, Gottingen, Germany; Western General Hospital, Edinburgh
We have previously presented preliminary data from computer analysis of MRI scans to validate the diagnosis of vCJD using posterior thalamus hyperintensity. For sCJD, we established a new quantitative approach involving measurement of the gradient of intensity change within the putamen, which produced excellent discrimination of sCJD from non-CJD dementia (NCD) controls. However, in our earlier work we derived sensitivities and specificities in the same group of patients from whom the optimum intensity thresholds were derived.
In the present paper we present results on processing of T2 and PD MRI from a larger group consisting of 19 vCJD scans, 38 sCJD (including 22 sCJD scans from Germany), and 22 NCD scans. We evaluate the performance of the algorithm, in the discrimination of all three groups, on a separate set of patients from those used to define the quantitative criteria.
The results show that our methods can be generalised to a new set of patients and allow discrimination between all three groups with high reliability (figures are for equal sensitivity and specificity): (1) sCJD v NCD using the putamen gradient, 86%; (2) vCJD v NCD, 87%, and vCJD v sCJD, 85%, both using the posterior thalamus-to-frontal white matter ratio.
042 REGIONAL RETROSPECTIVE AUDIT OF PRION DISEASE (1990–2001)
M. Doran, A. J. Larner. Walton Centre for Neurology and Neurosurgery, Liverpool
Objective: To audit referrals from the catchment area of a regional neuroscience centre, the Walton Centre for Neurology and Neurosurgery in Liverpool, to the Creutzfeldt-Jakob Disease Surveillance Unit (CJDSU), Edinburgh, between 1990 and 2001.
Method: Case note review to ascertain diagnostic accuracy, and management of terminal phase of disease (location of care, hydration, do not resuscitate orders).
Results: Of 82 patients referred to CJDSU over the 12 year period, 43 (52%) had pathologically confirmed prion disease (33 sporadic CJD, 8 vCJD, 2 iatrogenic disease). Three cases had never been seen by a neurologist. Of non-prion cases having postmortem (8), the commonest diagnoses were Alzheimer’s disease and dementia with Lewy bodies. All patients were cared for, and died, in hospital. One went temporarily to a nursing home. No patient went to a hospice. 32/43 patients (75%) received subcutaneous, nasogastric, or intravenous fluids when oral fluid intake proved inadequate. Only two patients had a PEG tube inserted. In only 9/43 cases (21%) could discussion about resuscitation policy be found in the notes.
Conclusions: Implementation of guidelines on the nursing care of prion disease, published by the CJD Support Network in 2002, may reduce the heterogeneity of case management observed in this retrospective audit.
043 NASU-HAKOLA DISEASE: CLINICAL MANIFESTATIONS OF A NOVEL MUTATION OF TREM2 GENE
B. H. Ridha, J. Paloneva, R. W. Keen, L. Peltonen, J. Wherrett, M. N. Rossor. Dementia Research Group, National Hospital for Neurology and Neurosurgery, London; Department of Molecular Medicine, National Public Health Institute, University of Helsinki, Finland; The Royal National Orthopaedic Hospital, Stanmore; University of Toronto, Ontario, Canada
Background: Nasu-Hakola disease (NHD), or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, is a rare autosomal recessive condition causing a combination of skeletal and neuropsychiatric symptoms. Mutations in two genes encoding different subunits of the same receptor signalling complex have been shown to result in the same phenotype. Mutations in the TYROBP gene on chromosome 19q13.1 are responsible for 79% of NHD cases, while mutations in TREM2 gene on chromosome 6p21.2 are responsible for 21% of cases. Here we present detailed clinical features of a case of NHD with a novel mutation in the TREM2 gene.
Case report: A Sri Lankan man developed gait disturbance, recurrent falls and fractures of wrists and ankles associated with osteoporosis in his mid 30s. He then developed progressive cognitive decline with predominantly frontal executive dysfunction and behavioural change in his late 30s. Neuroimaging revealed generalised brain atrophy, diffuse white matter disease and basal ganglia calcification. Genetic analysis revealed a novel homozygous point mutation in the TREM2 gene.
Discussion: The patient developed the typical features of NHD with recurrent bony fractures and progressive frontal dementia. NHD should be considered in young-onset dementia with a history of recurrent fractures and osteoporosis.
044 PHYSIOLOGICAL IMAGING OF LANGUAGE-INDUCED SEIZURES USING SIMULTANEOUS EEG, EMG & FUNCTIONAL MRI
A. Salek-Haddadi, K. Hamandi, M. P. Richardson, M. J. Koepp. Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square. London; MRI Unit, National Society for Epilepsy, Chalfont St. Peter, Bucks
Aim: To map language-induced seizures using functional MRI, in relation to language and motor areas.
Methods: Seven patient with primary reading epilepsy were studied at 1.5 Tesla (GE Horizon) using whole-brain EPI (TE/TR 40/3000, 64×64 matrix) for 35 minutes. A difficult text was presented word-at-a-time to be read either silently or aloud. Simultaneously and using an MR-compatible system (1) Ten channels of scalp EEG, (2) Submental EMG, (3) left-handed button press, and (4) online audio, were recorded as necessary to detect events of interest. Language and motor (hand/mouth) mapping was performed using a simple block-design. All data were analysed using SPM2.
Results: No abnormalities were found on motor/language activation. In 6 patients symptoms were only elicitable on reading aloud so events were self-indicated (3) but we were unable to identify consistent activation. In one patient however, abundant jaw jerking occurred on silent reading alone and in association with left-frontal spikes. Strong activation was observed within left SMA and pre-motor areas, most pronounced within the ipsilateral thalamus and caudate nucleus. There were an intimate relationship to language and face representation with excellent reproducibility.
Conclusion: Our results demonstrate the feasibility of studying induced seizure activity and a role for subcortical structures in ictogenesis.
045 COUNSELLING OF WOMEN WITH EPILEPSY ON ANTI-EPILEPTIC DRUGS: VALUE OF NURSE-LED CLINIC
D. F. Smith, S. Lewis. Neurology Department, Wrexham Maelor Hospital
Objective: To determine whether nurse-led clinic could improve documentation of counselling about gender-specific issues.
Methods: The case-notes of 100 women of child-bearing age, including pubertal adolescents, attending epilepsy and teenager clinics were examined. Data collection included documentation of counselling about contraception, pregnancy, including risks of epilepsy and teratogenic potential of drugs, and the genetic risk of epilepsy. The audit was repeated after commencement of a nurse-led clinic for women.
Results: 78 were receiving monotherapy. 23/45 of those on enzyme-inducing AEDs had been informed about risk of pill failure. Only 5/71 were told that pregnancy was usually uncomplicated. 92 were not told that tonic-clonic seizures carry risks to mother, pregnancy and fetus. 39 women were told about risk of spina bifida but only 6 warned about other malformations. 11/31 receiving valproate were told about fetal valproate syndrome. Only 9 were informed about genetic risk of epilepsy in offspring. After the intervention there was a dramatic improvement in quality of documented counselling (figures will be available).
Conclusion: Within a specialist clinic the quality of documented counselling was grossly inadequate but the use of specific nurse-led clinic rectified the problem. This approach is recommended to all those who care for women with epilepsy.
046 EXECUTIVE DYSFUNCTION IN TEMPORAL LOBE EPILEPSY: EVIDENCE OF PREFRONTAL ATROPHY USING VOXEL-BASED MORPHOMETRY
U. C. Wieshmann, S. Keller, G. Baker, C. Denby, N. Roberts. The Walton Centre for Neurology and Neurosurgery, Liverpool; The Magnetic Resonance and Image Analysis Research Centre (MARIARC), University of Liverpool
Aim: We used voxel-based morphometry (VBM) on three-dimensional Magnetic Resonance (MR) images to investigate grey matter volumetric correlates of executive dysfunction (ED) in patients with temporal lobe epilepsy (TLE).
Methods: Forty-five patients with TLE and 30 controls were included. Fifteen patients had ED based on Stroop and verbal fluency tasks. Thirty patients had no ED. We used SPM99 for VBM analyses of T1-weighted structural MR images. Comparisons were made between 1) TLE patients with and without ED, 2) TLE patients with ED and controls, and 3) TLE patients without ED and controls. Results are reported at a statistical threshold of p<0.05 (corrected for multiple comparisons).
Results: Patients with ED had reduced grey matter volume in prefrontal cortical regions compared with controls and patients without ED. This included bilateral medial PFC and lateral orbitofrontal cortex. Additional reduction of grey matter volume was apparent in right temporal neocortex, left putamen, and left temporo-parieto-occipital junction in patients with ED relative with patients without ED. No prefrontal grey matter reduction was apparent in patients without ED relative to controls.
Conclusion: These results suggest that atrophy of extrahippocampal neocortex including the PFC may be an underlying cause of ED in patients with TLE.
047 MORPHOLOGICAL DIFFERENCES OF SUCCESSFUL AND UNSUCCESSFUL EPILEPSY SURGERY
U. C. Wieshmann, S. Keller, C. Denby, N. Roberts. The Walton Centre for Neurology and Neurosurgery, Liverpool; The Magnetic Resonance and Image Analysis Research Centre (MARIARC), University of Liverpool
Aim: In a previous pilot voxel-based morphometry (VBM) study, we reported that patients who continue to have seizures after epilepsy surgery have reduced grey matter volume (GMV) in the ipsilateral temporal lobe posterior to the resection line (ABN Oxford 2002). The aim of this study was to repeat the study with improved VBM on a larger cohort of left temporal lobe epilepsy (TLE) patients.
Methods: Twenty-two patients with left TLE and left hippocampal sclerosis were included. Ten patients became seizure free, 12 continued to have seizures after epilepsy surgery. We used SPM99 for VBM analyses of T1-weighted structural MR images. Results were reported at a statistical threshold of p<0.05 (corrected for multiple comparisons).
Results: The largest effects were observed in the left temporal lobe. GMV reductions of left hippocampal head, body and tail, posterior parahippocampal and fusiform gyrus but also amygdala and entorhinal cortex were observed in surgical failures relative to successes. A GMV reduction of the contralateral right hippocampal body was also observed.
Conclusion: The main morphological differences between successfully operated patients and patients who continued to have seizures were in the temporal lobe ipsilateral to the seizure focus and extended posteriorly beyond the surgical resection line.
048 AN [11C] DIPRENORPHINE PET STUDY OF ENDOGENOUS OPIOID RELEASE FOLLOWING SPONTANEOUS SEIZURE
A. Hammers, M-CAsselin, R. Hinz, D. J. Brooks, J. S. Duncan, M. J. Koepp. MRC-CSC, Cyclotron Building, Imperial College London, Hammersmith Hospital, London; National Society for Epilepsy and DCEE, Institute of Neurology, Queen Square, London; Hammersmith Imanet, London
Objective: To investigate changes in opioid receptor availability following spontaneous complex partial seizures (CPS) in temporal lobe epilepsy (TLE).
Methods: Four patients with TLE had paired PET scans using the non-specific opioid receptor ligand [11C]-diprenorphine (DPN). Two had normal MRI and ictal left frontotemporal EEG changes, and 2 had right hippocampal sclerosis with concordant ictal EEG changes in 1 but contralateral changes in the other. The first scan was performed 1.5–15 h postictally; the second (baseline) scan after 7–20 seizure-free days. Test-retest variation was established in 13 controls. All subjects had quantitative [11C]-DPN PET. Spectral analysis and metabolite-corrected arterial plasma input functions yielded parametric images of DPN volume-of-distribution (Vd). Images were spatially normalised to our DPN template in stereotaxic space using SPM99 software, and difference images calculated.
Results: Global DPN-Vd test-retest variation in controls was 0.3±9.5%, and hippocampal DPN Vd variation –1.9±10.6%. All 4 patients showed a postictal decrease in DPN-Vd, concordant with the side of ictal EEG changes. Quantification in the presumed epileptogenic hippocampi showed a 2–10% decrease.
Conclusions: We found evidence for the release of endogenous opioids following spontaneous CPS in TLE, suggesting they have a role in terminating seizures. These findings may be useful for presurgical localisation.
049 CARDIAC AUTONOMIC MODULATION IN PATIENTS WITH EPILEPSY
M. G. Tighe, M. J. Hennessy, C. D. Binnie, L. Nashef, R. S. Delamont. Departments of Neurology & Clinical Neurophysiology, King’s College Hospital, London; Department of Neurology, University College Hospital, Galway, Ireland
Objective: To investigate cardiac autonomic modulation (CAM) in patients with epilepsy.
Background: The mechanism of Sudden Unexpected Death in Epilepsy (SUDEP) is unknown. Case control studies implicate antiepileptic drug (AED) polytherapy and frequent AED changes as risk factors. Techniques to noninvasively explore autonomic modulation of the heart have been developed. The current study used Heart Rate Variability techniques (HRV) in the time domain to evaluate CAM in a group of patients with epilepsy.
Methods: 39 consecutive subjects were evaluated in the long term epilepsy monitoring unit of King’s College Hospital. 19/39 underwent CBZ withdrawal to precipitate seizures. ECG samples were selected on day 1 prior to drug manipulation and on day 4 in the CBZ withdrawal subset when blood serum levels had fallen by 80% of admission level. Time domain analysis was carried out on 24 hour ECG samples from all subjects.
Results/Conclusion: 45% of subjects had Triangular Index of 30 or less indicating markedly reduced HRV (n = 150 –200). Time domain parameters thought to represent parasympathetic activity were significantly increased following CBZ withdrawal (SDNN, RMSSD, SNN50, Wilcoxen Signed Ranks Test).
Conclusion: Measures of overall HRV were markedly reduced. Measures thought to indicate parasympathetic modulation were significantly increased following CBZ withdrawal.
050 URINARY RETENTION IN WOMEN: CAUSES AND TREATMENT
C. J. Fowler, R. B. C. Kavia, R. DasGupta, S. Elneil. National Hospital of Neurology and Neurosurgery, London
In the last 3 years, 145 women (mean 34.8 years, range 12–81) with complete urinary retention have been referred from neurologists or urologists UK wide. No definite diagnosis could be made in 32. In 3 severe urethral pain prevented voiding, 1 developed multiple system atrophy, in 4 a high intake of opiates was thought to be contributory and in 8, urinary retention was associated with Chronic Idiopathic Pseudo-Obstruction. However in the majority (97) urethral pressure profile, sphincter volume measurement and EMG indicated an underlying primary disorder of striated sphincter relaxation which has been hypothesized to be due to a hormonally sensitive channelopathy.
The only treatment found to be effective in restoring micturition is neuromodulation, whereby a temporary stimulating electrode is inserted through S3 foramen and continuous stimulation applied to the pre-sacral neural plexus. 25 women underwent this procedure and those in whom it restores voiding become eligible for implant of a permanent stimulator. 3 have had this done and 15 are awaiting an implant. The mechanism of this successful intervention is uncertain: it does not appear to alter abnormal sphincter activity but may enable voiding by “re-informing” brainstem micturition centres. Functional brain imaging is being used to explore this further.
051 ACUTE NEUROLOGY IN A DGH: THE RUH EXPERIENCE
D. E. Bateman, J. Nixon, K. Dawson, P. Lyons. Dept Neurology N Cumbria, Neurology Dept University Hospital Wales, Neurology Dept RUH
The ABN launched its Acute Neurology document with a great flourish of publicity in 2002. We report our experience with the intention of helping colleagues set up similar services elsewhere.
Audit prior to setting up the service showed that neurology admissions comprised 12% of the general medical take. Based on this data we estimated that an acute neurology service run by neurologists would save the hospital 3.4 beds and 10 CT scans per month.
The service was set up with the following staff: 3 P/T Consultants, one SpR, 4/5 of 2 SHOs. Criteria for admission via neurology were drawn up as follows: CVA, Men/Enceph, Neg acute confusion, SAH, Cord compression, Epilepsy, Head Injury after 5 days
CVA was responsible for 40% of neurology admissions, epilepsy 10% headache 10% meningitis 7% and tumours 7%. 4 patients were admitted each weekday resulting in 36 in patients.
Running the service required 6 sessions of consultant time per week. The difficulties of running the service and the minimum essential requirements for the service will be discussed.
With these provisos it is possible and a big step forward in the management of acute neurology with better outcomes and better use of resources.
052 FATAL FULMINANT ACUTE DISSEMINATED ENCEPHALOMYELITIS PRESENTING WITHOUT BRAIN MRI WHITE MATTER LESIONS
N. W. S. Davies, K. Cikurel, M. K. Sharief, R. S. Howard. GKT School of Medicine, King’s College London, King’s College Hospital, London, The National Hospital for Neurology and Neurosurgery, London
Acute encephalitis is caused either by microbial invasion or autoimmune attack of the brain. Whilst the histopathologies of these syndromes are distinct, distinguishing between them clinically is more difficult. Such distinction however is critical, as the syndromes require very different treatments. MR imaging of the brain is of particular value in identifying the diffuse enhancing white matter lesions typical of acute disseminated encephalomyelitis (ADEM).
We describe the cases of two women who presented with acute onset encephalopathies preceded by short prodromal illnesses. In both cases their rapid deterioration in levels of consciousness necessitated admission to intensive care units for control of rising intracranial pressure. Both cases died as a result of coning 5 and 25 days respectively after the onset of their illnesses. In neither case did repeat MR imaging of the brain reveal findings typical of ADEM. Post mortem examinations were performed in both cases, which revealed the diagnoses to be ADEM.
The diagnosis of ADEM should be considered in all cases of fulminant encephalitis, even where the MR imaging is not typical. Inclusion criteria for studies of the natural history of ADEM should not exclude cases that lack typical imaging changes on MRI.
053 VARIATIONS IN COGNITIVE FUNCTION ARE DEMONSTRABLE IN VGKC ANTIBODY POSITIVE LIMBIC ENCEPHALITIS: ANOTHER CHANNELOPATHY?
T. P. Harrower, L. D. Kartsounis, A. Vincent, R. N. de Silva. Essex Centre for Neurological Sciences, Oldchurch Hospital, Romford, Essex; Neurosciences Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford
A 66 year-old male presented with a 12 month history of gradual onset and variable memory loss. Physical and neurological examinations were normal. Neuropsychological testing confirmed isolated and significantly variable deficiencies. Orientation was poor and variable during an observation period of 5 weeks. Similarly, face recognition, recall of daily headlines and recent personal events were poor and variable. Correct word recognition varied between 20/25 and 44/50, whilst recognition of non-verbal material varied between 16/30 and 25/30. Autobiographical recall of events and facts was poor, and demonstrated retrograde memory impairment. MRI head revealed bilateral increase in signal in the medial temporal lobes. Serum electrophoresis showed the presence of a monoclonal gammopathy without immune paresis. CSF showed a monoclonal band, resembling that in the serum. Anti-voltage gated potassium channel (VGKC) antibodies were detected at 557pM (normal <100pM) in the serum and in the CSF (17pM, normal <2pM). The variable nature of the memory impairment, in this case, contrasts with the more severe and persistent impairments in VGKC antibody-associated encephalopathies described recently (Vincent et al Brain in press) and raises the possibility that ion channel antibodies can cause episodic disorders similar to those associated with ion channel mutations.
054 RECURRENT PARANEOPLASTIC LIMBIC ENCEPHALITIS
G. Mazibrada, N. Davies, A. Vincent, D. Nicholl. The Queen Elizabeth Hospital, Birmingham; John Radcliffe Hospital, Oxford
Paraneoplastic limbic encephalitis (PLE) is a rare disorder associated with an underlying malignancy and characterized clinically by personality change, confusion, cognitive dysfunction, short term memory loss and seizures. It is frequently associated with antineuronal antibodies and temporal lobe abnormalities on MRI.
Here we present a case of a 42 year old female who presented clinically and radiologically with recurrent Paraneoplastic limbic encephalitis associated initially with malignant thymoma and subsequently, after seven years, with breast cancer. On both occasions she was found to have characteristic MRI changes and antineuronal anti Hu antibodies. Each time her symptoms started after removal of the tumour and radiotherapy/chemotherapy treatment. On each occasion she was treated with plasmapheresis and responded well to the treatment, especially during the initial presentation.
To our knowledge there is no case report describing recurrent PLE associated with thymoma and breast cancer. Furthermore, Anti Hu antibodies are not known to be associated with malignant thymoma, to our knowledge this is the first described case. Our patient developed symptoms after removal of the tumour and completion of radiotherapy/chemotherapy treatment suggesting delayed immunological process developing after the removal of the presumed cancer antigen.
055 (NON-) AVAILABILITY OF BASIC NEUROLOGICAL EXAMINATION EQUIPMENT ON DISTRICT GENERAL HOSPITAL WARDS – RESULTS OF AN AUDIT
G. T. A. Warner, A. M. Wing. St Georges Hospital & Royal Surrey County Hospital
An audit standard for basic neurological clinical tools has been proposed.1 A simple tick-box questionnaire was sent to every ward “manager” asking if the 4 items in the basic neurological examination “kit” were available in full working order.
There was a good response with replies from 15/23 wards (8/9 medical & 7/14 non-medical). Ophthalmoscopes were available on 8/15 wards (5/8 & 3/7 respectively), tendon hammers on 11/15 (6/8 & 5/7) and 128 Hz tuning forks on 5/15 (3/8 & 2/7). No wards had neurological pins (“Neurotips®). 13/15 had incomplete “kits” (7/8 & 6/7).
The survey was considered valid by virtue of accompanying comments stating that items had “gone missing” or were “in pieces”.
Irrespective of the portability of such items away from the ward (which could be overcome with relative ease), concern arises that basic examination equipment vital for neurological assessment is unavailable to ward-based doctors. The cost of such “kit” totals only £200–250 and compares favourably with other essential items such as resuscitation equipment.
A request for funding has been made with a view to undertaking a second audit cycle.
056 DOWNPATRICK REVISED: ACUTE NEUROLOGY IN A 21ST CENTURY DISTRICT GENERAL HOSPITAL
M. W. Weatherall. Department of Neurology, Royal Preston Hospital
The current gold standard survey of acute neurological admissions to a district general hospital is that undertaken at Downpatrick Hospital in Northern Ireland in the early 1980s, but neurological practice has changed significantly since that time. Contemporary information is needed on the numbers of patients presenting to hospital acutely with neurological problems, and the subsequent utilisation of neurological, neurosurgical, neuroradiological and neurophysiological services.
This prospective study presents information on 1197 admissions to the medical directorate of the Royal Preston Hospital, a large district general hospital in the North West of England with an embedded sub-regional neurosciences centre. Patients were admitted under general physicians or directly to neurology over 42 days in two periods between July and October 2003. 183 patients (15.2%) presented with neurological problems, of whom 13 were admitted directly to neurology. 32 patients were referred by the general physicians for a neurological opinion; of these 9 were admitted under neurology and 13 were given outpatient appointments. The neurosurgeons admitted 4 of 7 patients referred to them. 109 patients (9.1%) underwent cranial CT scanning, 68 within 48 hours of admission. 10 patients (<1%) had an EEG during their admission; only 1 patient had an EMG.
057 PROPRANOLOL MODULATES TRIGEMINOVASCULAR NOCICEPTION IN THE VENTROPOSTEROMEDIAL NUCLEUS OF THE THALAMUS: A POSSIBLE SITE OF ACTION IN MIGRAINE
K. G. Shields, P. J. Goadsby. Institute of Neurology, London
The ventroposteriomedial (VPM) nucleus of the thalamus relays trigeminal sensory input to the somatosensory cortex. In vivo electrophysiological recordings were made from the cell bodies of thalamocortical relay neurones in rats (n = 76). We investigated whether microiontophoretic ejection of ‚ antagonists could inhibit activity following superior saggital sinus (SSS) stimulation and specifically “post-synaptic” actions of these drugs through their modulatory actions on L-glutamate evoked third order neuronal firing.
Propranolol inhibited the response to SSS stimulation (P<0.001) and also L-glutamate ejection (P<0.001). This reflected antagonism of ‚ receptors as it could be blocked by co-ejection of isoproterenol (SSS: P = 0.02; L-glutamate: P = 0.006). 5HT receptor antagonism did not contribute to propranolol’s action as neither (S)-WAY 100135 (P = 0.2), nor GR127935 (P = 0.6) ejection produced inhibition of L-glutamate evoked neuronal firing.
Atenolol inhibited both responses (SSS: P = 0.003, L-glutamate: P<0.001). Neither the ‚2 antagonist ICI 118,551 (SSS: P = 0.9, L-glutamate: P = 0.4), nor the ‚3 antagonist SR 59230A produced any significant inhibition (SSS: P = 0.7, L-glutamate: P = 0.2). Beta blockers may exert some of their therapeutic effects in migraine through ‚1 adrenoceptor antagonism in the thalamus.
058 THE CERVICAL DYSTONIA IMPACT PROFILE (CDIP-58): A NEW PATIENT-BASED RATING SCALE
S. J. Cano, T. T. Warner, R. Fitzpatrick, K. Bhatia, A. J. Thompson, J. C. Hobart. Department of Clinical Neurosciences, Royal Free & University College Medical School, London; Department of Clinical Neurosciences, Peninsula Medical School, Derriford Hospital, Plymouth; Neurological Outcome Measures Unit, Institute of Neurology, London; Department of Public Health and Primary Care, University of Oxford, Oxford; Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London
Cervical dystonia (CD) is the most prevalent form of focal dystonia. The range of treatments (e.g. botulinum toxin injections through to surgery) which requires a rigorous outcome measure. This study developed a rating scale suitable for clinical trials and practice, and comparisons of current treatments.
Stage 1 generated a pool of items from patient interviews, expert opinion and literature review. Stage 2 selected the best items to form a rating scale of health impact of CD, by analysing responses to items in a postal survey of CD patients using Rasch technology methods. Stage 3 evaluated the measurement properties of the new rating scale, by analysing responses to items in an independent postal survey.
Stage 1 and Stage 2 resulted in a 58-item rating scale named the CD Impact Profile, CDIP-58. In Stage 3, analyses supported the measurement properties of the CDIP-58 as defined by Rasch technology: mean square infit (0.57–1.52), item calibration range (33.0–68.5), patient separation (2.52–3.38), and differential item functioning across independent samples.
The CDIP-58 is a new rating scale for CD, developed according to recommended scientific guidelines that will enable evaluation of current and new treatments. It represents patients’ perceptions and satisfies criteria for rigorous measurement as defined by Rasch technology and traditional psychometric criteria. Studies to assess its ability to detect treatment change are underway.
060 AN INVESTIGATION INTO THE ROLE OF MITOCHONDRIA IN THE AXONAL RESPONSE TO DEMYELINATION USING A MYELIN BASIC PROTEIN MUTANT (SHIVERER) MOUSE MODEL
H. E. Andrews, M. J. Barron, J. Edgar, D. M. Turnbull, D. Bates, I. R. Griffiths, P. Nichols. Department of Neurology, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne; Applied Neurobiology Group, Department of Veterinary Surgery and Reproduction, University of Glasgow Veterinary School
Axonal pathology in Multiple Sclerosis (MS) has been described in the historical medical literature for over a century but new insights into the consequences of axonal loss and its relationship to progressive neurological disability in MS have stimulated renewed interest in this area.
MR spectroscopy studies have shown evidence of impaired axonal mitochondrial function in MS lesions and oxidative damage to mitochondrial DNA and impaired mitochondrial enzyme activity has been demonstrated in chronic MS plaques.
The aim of this study was to investigate changes in mitochondrial enzyme activity in the axons of the Shiverer mouse which carries a mutation in the Myelin Basic Protein gene and shows progressive dys-myelination from birth. We found an increased density of mitochondrial enzyme activity (cytochrome c oxidase) in the demyelinated areas in Shiverer brain tissue. Preliminary studies in human MS post-mortem brain tissue have confirmed a similar increase in mitochondrial activity in chronic MS plaques.
Our findings suggest that in demyelinated axons the adaptive changes necessary to maintain conduction produce an increased energy requirement. If mitochondrial function becomes compromised or energy demands exceed capacity then axon viability may become compromised resulting in the progressive axonal loss which is so characteristic of secondary progressive MS.
061 UVEITIS AND MULTIPLE SCLEROSIS
C. Constantinescu, L. Edwards. Clinical Neurology, University Hospital, Nottingham
Multiple sclerosis is a common debilitating neurological disease thought to be due, at least in part, to disordered autoimmunity. Uveitis can cause significant visual morbidity and is frequently seen in association with systemic disease.
We studied 658 patients consecutively recruited from our multiple sclerosis management clinic between June 2002 and June 2003. All had been diagnosed with multiple sclerosis. The notes were reviewed to find those who had been given diagnoses of uveitis by an ophthalmologist and further characteristics of these patients and their conditions were studied.
16 patients (2.43%) had diagnoses of uveitis, compared to a normal population prevalence of 0.02% (odds ratio 127; 95% confidence intervals 75–215). Anterior uveitis was the most prevalent type. The diagnosis of multiple sclerosis was slightly more likely to precede that of uveitis. Visual acuity was variably affected.
Interesting presentations of Fuch’s heterochromic cyclitis, sarcoid uveitis and granulomatous-type uveitis in the absence of granulomatous diseases (in accordance with previous reports and thought to be due to disordered autoimmunity) were also noted.
062 EVIDENCE THAT NORMAL APPEARING GREY AND WHITE MATTER MTR ABNORMALITIES PREDATE SYMPTOM ONSET IN RELAPSING-REMITTING MS
G. R. Davies, D. R. Altmann, A. Hadjiprocopis, W. Rashid, D. T. Chard, C. M. B. Griffin, R. Kapoor, A. J. Thompson, D. H. Miller. NMR Research Unit, Institute of Neurology, Queen Square, London
In MS, the magnetisation transfer ratio (MTR) is abnormal in normal-appearing grey and white matter (NAGM and NAWM). However, it is unclear whether this MTR abnormality begins prior to or following symptom onset. NAGM and NAWM MTR were serially measured in a cohort of early relapsing-remitting MS (RRMS) patients and a hierarchical regression model was used to assess rates of change.
Twenty three RRMS patients (mean disease duration 1.9 years, EDSS<3.0) and 19 healthy controls were imaged yearly for two years (mean follow-up was 24 months for the patients and 18 months for controls).
At baseline, NAGM and NAWM MTR were significantly lower in MS patients than in controls. In patients, there was a significant reduction in NAGM and NAWM MTR with time whereas there was no significant change in controls. The rate of decline of NAGM MTR was significantly greater than the rate of NAWM MTR decline. Assuming that the rates of change are linear, backwards extrapolation suggests NAGM and NAWM MTR abnormalities respectively began 2.1 years before (95%CI: 0.6, 6.1) and 3.2 years before (95%CI: 0.9, 13.0) symptom onset.
In RRMS, NAWM and NAGM abnormalities appear likely to precede clinical symptoms.
063 A PROSPECTIVE STUDY OF DISEASES ASSOCIATED WITH MULTIPLE SCLEROSIS IN A COHORT OF 658 CONSECUTIVELY RECRUITED PATIENTS
L. J. Edwards, C. Constantinescu. Queen’s Medical Centre, Nottingham
The cause of multiple sclerosis remains unknown. It is largely regarded as being an inflammatory autoimmune disease and has been reported in association with other inflammatory or autoimmune diseases. We performed a prospective study in 658 consecutive patients diagnosed with MS attending our outpatient MS management clinic between June 2002 and June 2003. Prevalence of associated conditions in these patients was calculated and compared with values from population studies using chi-square tests, odds ratios and confidence intervals. The MS population had significantly increased rates of asthma, inflammatory bowel disease, type I diabetes mellitus, pernicious anaemia, autoimmune thyroid disease, uveitis, bipolar disorder and melanoma compared to the general population. There were also interesting associations seen with paraproteinaemia, polyglandular autoimmune syndrome and rare single case associations.
Multiple sclerosis is associated with several other conditions. This work does not give evidence for the hypothesis that MS and atopy, reflecting Th2 and Th2 polarisation, respectively, are mutually exclusive. Further work, ideally with a matched control population, is indicated.
064 EXPLORING THE RELATIONSHIP OF RELAPSING MYELITIS WITH NEUROMYELITIS OPTICA (DEVIC’S DISEASE) AND MULTIPLE SCLEROSIS
A. Jacob, R. Nicholas, K. Das, M. Boggild. The Walton Centre for Neurology and Neurosurgery, Liverpool
Background and Methods: Small series of patients with relapsing myelitis (RM) not meeting diagnostic criteria for Multiple Sclerosis (MS) or NMO have been described. We compare the features of 12 RM patients, with a cohort of 17 patients of NMO to explore this relationship.
Results: 58% of RM and 76% of NMO patients were female with similar ages and ages of onset. Patients with NMO seemed more disabled (87% versus 50%). Spinal MRI identified identical spindle shaped lesions in both groups. CSF OCB was positive in 55% of RM patients, and in 26% of those with NMO. The length of lesions in those with positive OCB was smaller. One patient with RM showed delayed VERs but had absent OCB. Good response to immunosuppressants was seen in both groups especially in those without OCB.
Discussion: The findings seem to suggest that RM is not a homogenous entity but probably 3 subgroups: (1) a spinal variant of MS with positive OCBs and smaller spinal cord lesion lengths; (2) a distinct disease, with normal VERs, absent OCBs and other autoantibodies; and (3) a ‘forme-fruste’ of NMO with sub-clinical or delayed visual tract involvement. Subclassification of RM into these subtypes may help optimize treatment.
065 THE MULTIPLE SCLEROSIS WALKING SCALE (MSWS-12) AND AMBULATORY ACTIVITY ANALYSIS
O. R. Pearson, M. E. Busse, R. van Deursen, C. M. Wiles. Department of Medicine (Section of Neurology) & Department of Physiotherapy Education, University of Wales College of Medicine, Cardiff
Introduction: Impaired mobility is a marker of disability and an important outcome measure in multiple sclerosis (MS). The MSWS-12 is a patient-orientated measure of mobility. Ambulatory activity monitoring allows objective measurement of actual performed activity in an individual’s own environment.
Methods: One sample of MS patients in a static phase underwent 2 assessments 1–4 weeks apart (reliability sample). A second sample undergoing relapse were assessed 6–8 weeks apart. Walking mobility was evaluated by 7 days of activity monitoring (mean stepcount/24 hrs): patient perception of mobility was measured by the MSWS-12. Other assessments included timed walk, mobility and disability scales.
Results: In the reliability sample (n = 40, 28 female, EDSS 2.0–6.5) the test re-test reliability of the MSWS-12 was good (Intraclass Correlation Co-efficient (ICC) = 0.82). Correlations (Spearman’s rho) between self-report measures were excellent and moderate with disability scales. There was less correlation with objective measures of capacity (gait speed r = –0.64 p = 0.000) and actual performance (mean stepcount/24hr r = –0.49 p = 0.001). Across relapse (n = 25, 14 female) all measures showed significant change (MSWS-12 effect size = 1.6). The relationship between change in the MSWS-12 and activity monitoring was poor (r = –0.35 p = 0.083).
Conclusion: The MSWS-12 has been demonstrated to be psychometrically sound and responsive to short-term change (relapse). However it correlates less well with physician orientated measures than other self-report measures, confirming that patients and doctors opinions differ. MSWS-12 appears to measure a different concept from actual performed activity. The explanation for why patient opinion does not reflect performance needs further investigation.
066 A COMPARISON OF THE RATE OF SWITCHED AND DISCONTINUED THERAPY BETWEEN INTERFERON-BETA 1A PREPARATIONS.
K. O’Rourke, M. Hutchinson. St.Vincent’s University Hospital, Dublin
Interferon 1a (IFNa) given as a 30 microgram weekly intramuscular injection became available for prescription in 1996 and a 22 or 44 microgram subcutaneous injection three times per week in 1997. A follow-up of all patients started on both treatments was carried out in order to ascertain the rates of treatment, substitution and discontinuation of the two preparations.
Of 57 patients commenced on interferon-beta-1a 30 micrograms per week,19 (33%) were no longer on the drug by July 2003; of this group of 19, 2 patients (3.5%) subsequently switched successfully to another IFNa preparation. 8 patients (14%) stopped interferon and the 9 remaining patients (15.7%) tried another interferon-beta-1a preparation before discontinuing therapy.
Of 89 patients who started interferon-beta-1a thrice weekly, 22 (24.7%) were no longer on treatment by July 2003; of this group of 22, 3 patients (3.3%) subsequently switched successfully to another IFNa preparation.10 patients (11.2%) stopped interferon and the 9 remaining patients (10.1%) tried another IFN1a preparation before discontinuing therapy.
Conclusion: Most patients who stopped one type of IFN1a therapy do not successfully switch to another DMT preparation.
067 EVIDENCE OF EVOLVING NORMAL APPEARING BRAIN TISSUE DIFFUSION TENSOR IMAGING ABNORMALITIES IN EARLY RELAPSING-REMITTING MULTIPLE SCLEROSIS
W. Rashid, A. Hadjiprocopis, C. M. Griffin, D. T. Chard, G. R. Davies, D. R. Altmann, C. Wheeler-Kingshott, A. J. Thompson, D. H. Miller. NMR Research Unit, Institute of Neurology, London
Introduction: Diffusion tensor MR imaging (DTI) parameters measure the magnitude (mean diffusivity (MD)) and directionality (fractional anisotropy (FA)) of water movement within a tissue. Studies investigating established multiple sclerosis (MS) show widespread abnormalities. The serial natural history of these parameters, however, remains unclear in early relapsing-remitting (RR) MS.
Methods: Sixteen RRMS patients (median disease duration 1.9 years; EDSS<3.0) and 11 age-matched controls had DTI yearly for two years. Whole normal appearing brain tissue (NABT) FA and MD histograms and models correcting for age, gender and brain volume were used.
Results: At baseline only FA mean (p = 0.010) and peak height (p = 0.003) were significantly different in patients in comparison to controls. Overall two year analysis revealed maintenance, but no increase, in the FA changes (mean (p = 0.015); peak height (p = 0.047)). Emergence of MD abnormalities were seen in peak height (p = 0.045) (over the course of two years); and in mean (p = 0.023) and peak location (p = 0.024) (at two years only) in MS patients.
Discussion: The baseline FA changes in RRMS may represent pathology disrupting neuronal fibre tracts with relatively little oedema, such as gliosis. The emergence of MD change, at two years, suggests the start of a measurable oedematous process within the NABT.
068 OPTIC NERVE MEAN AREA AND MAGNETIZATION TRANSFER RATIO AT TWO YEARS FOLLOWING ACUTE OPTIC NEURITIS
S. A. Trip, S. J. Hickman, A. T. Toosy, S. J. Jones, D. G. MacManus, G. J. Barker, G. T. Plant, A. J. Thompson, D. H. Miller. NMR Research Unit, Institute of Neurology, University College London; Department of Neuro-Ophthalmology, Moorfields Eye Hospital, London; Department of Clinical Neurophysiology, The National Hospital for Neurology and Neurosurgery, London; Institute of Psychiatry, Kings College London
Optic neuritis is an ideal model for the study of relapse in multiple sclerosis. There are reliable clinical measures of optic nerve function; conduction in the optic pathways can be measured using visual evoked potentials (VEP); and modern MRI techniques allow optic nerve structure to be analysed quantitatively. We present two year data from a prospective study of acute unilateral optic neuritis using these measures. 16 patients and 7 controls were available for follow up. Optic nerve atrophy and reduced magnetisation transfer ratio (MTR) persist at two years following an attack of optic neuritis and correlate with visual acuity, visual field mean deviation, and contrast sensitivity. Interestingly, analysis of this cohort at one year did not demonstrate any correlation of these MR parameters with visual function or VEP data. Optic nerve area, but not MTR, now correlates with both VEP amplitude and latency. A remarkably tight correlation with latency was found (r = −0.93, p<0.001) and could be explained biologically by a protective effect of remyelination (shorter VEP latency) on axonal integrity thereby slowing axonal loss and atrophy.
We plan to continue follow up at 3 years when a longitudinal analysis will be performed.
069 CANNABINOID RECEPTOR CB-2 EXPRESSION IN ACTIVATED MICROGLIA OF MULTIPLE SCLEROSIS AND AMYOTROPHIC LATERAL SCLEROSIS SPINAL CORD
Y. Yiangou, P. Facer, R. B. Banati, C. T. O’Shaughnessy, I. P. Chessell, P. Anand. Peripheral Neuropathy Unit and MRC Cyclotron Unit, Imperial College London, Hammersmith Hospital, London; Neurology and GastrointestinaI Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow
Cannabinoids ameliorate progression of clinical disease and pathology in animal models of multiple sclerosis (MS), but the mechanism is uncertain. Current dogma states that CB1 is expressed mainly in the CNS, and CB2 is restricted to the periphery, mainly inflammatory cells. We now report that CB2 is expressed by microglia in affected MS and amyotrophic lateral sclerosis (ALS) post-mortem spinal cord, and CB2 thus represents a novel therapeutic target for disease modification, without the side-effects of CB1 agonists. CB-2 immunostaining was found in control spinal cord in glial/macrophage like cells that were scattered throughout the tissue, similar to the microglial marker CD68. CB2 immunoreactive cells were more frequent in MS lesions, appearing as intense clusters; by image-analysis, control cord white matter, n = 8, % red, median and range, 0.225 (0.11–0.75), MS cord normal appearing white matter, n = 11, 0.19 (0.10–0.52), MS lesions, n = 8, 2.645 (0.51–6.46), P = 0.0003. In ALS cord CB2 immunoreactivity increased in degenerating corticospinal tract regions: control cord white matter, 0.159 (0.012–1.116) n = 8, ALS dorsolateral white matter 1.254 (0.154–5.75) n = 8, P = 0.01. Clinical trials are thus indicated in MS and ALS with novel CB-2 specific agonists, for disease progression and symptom management.
070 FSH DYSTROPHY MIMICKING MIYOSHI MYOPATHY
A. Barling, J. B. Winer, N. P. Davies. Birmingham Muscle and Nerve Centre, Queen Elizabeth Neuroscience Centre, Queen Elizabeth Hospital, Edgbaston, Birmingham
Background: Miyoshi myopathy is an autosomal recessive distal muscle disorder due to mutations in the gene encoding dysferlin. It characteristically presents with calf wasting and the CK level is markedly elevated. Here we present a family in whom affected members exhibited a Miyoshi myopathy phenotype but harboured the gene rearrangement typical of FSH dystrophy.
Patients: The 47 year old proband developed lower limb weakness at the age of 38. Specifically, he had noticed that he could not stand on his toes. When first examined he was found to have bilateral asymmetric calf wasting and pes cavus. His 44 year old brother presented at the age of 34 with an inability to stand on his toes and wasting of the calves. Mild scapular winging was identified at their most recent examination.
Results: Both patients had elevated CK between 400 and 500 IU/L. DNA analysis for the gene rearrangement causing FSH dystrophy (using double digest) was positive in both brothers.
Conclusion: FSH dystrophy demonstrates marked intra- and interfamilial phenotypic variation. In some pedigrees the condition appears to segregate in an autosomal recessive manner. We suggest that FSH dystrophy should be considered in patients presenting with a Miyoshi myopathy phenotype in whom CK levels are only moderately raised.
071 AN ENGLISH KINDRED WITH A DOMINANTLY INHERITED TUBULAR AGGREGATE MYOPATHY WITH MICROCORIA
D. J. Nicholl, H. S. Pall, M. R. Rose. Department of Neurology, Queen Elizabeth Hospital, Birmingham; Department of Neurology, Kings College Hospital, London
Tubular aggregates are inclusions found in a variety of neuromuscular disorders (OMIM 160565), and are rarely familial. Familial congenital microcoria (meiosis) has been described in 1 family linked to 13q31-32 (OMIM 156600) We provide the first description of a family with the occurrence of both a dominantly inherited tubular aggregate myopathy and pin-point pupils in affected members.
Methods: All available family members were examined neurologically and 2 affected members had muscle biopsies performed. Affectation status was based on family report (FR), photographs and personal examination (PE) including measurement of creatine kinase (CK).
Results: Four family members in 3 generations were identified with the co-occurrence of a proximal myopathy and microcoria. I:1 had a myopathy and microcoria for >40y and died aged 82y (FR). II:1 and II:2 developed a proximal myopathy aged 40y and 59y with CK of 534 and 600 respectively (PE). III:2 had microcoria and mild calf hypertrophy with otherwise normal examination, but had a CK of 1641 (PE). EMG showed no evidence of congenital myasthenia. Muscle biopsies revealed myopathy with tubular aggregates in type 2 fibres.
Another family member (IV:1) was identified as having dopa responsive dystonia, with no myopathic/ocular signs and a normal CK.
Conclusions: Although sporadic cases have been described, this is the first description of a kindred with a late onset dominantly inherited tubular aggregate myopathy with associated microcoria.
072 WHAT IS THE RISK OF CARDIO-PULMONARY FIBROSIS WITH CABERGOLINE USE IN PARKINSON’S DISEASE: AN OBSERVATIONAL STUDY OF 224 CASES
V. Dhawan, F. Stegie, P. Metcalf, P. Luce, G. Jackson, C. K. Ray.
Background: Recently there has been concern related to serosal fibrosis due to use of ergot dopamine agonists such as bromocriptine and pergolide for Parkinson’s disease (PD).
Objectives: Is there evidence of cardio-pulmonary fbrosis in patients on chronic cabergoline (a widely used ergot agonist) treatment?
Methods: 234 PD cases on Cabergoline (mean age 69.5 years (41–90 yrs), mean duration of disease 8.8 years, mean cabergoline dose = 3.7 mg (2–10 mg), mean duration of treatment 2.9 years, were analysed from 3 UK centres and those with complaints of shortness of breath identified.
Results: 17 (7.3%) cases were identified with a history of shortness of breath (SOB, mean age 71.4 years, mean dose of cabergoline 3.7 mg and mean duration of treatment = 3.3 years.) In 4, SOB was due to asthma, lung cancer, heart failure and parkinsonian rigidity respectively. Of the rest, transthoracic echocardiography and pulmonary function tests were within normal limits except one patient with mild mitral regurgitation and 3 other patients developed intractable cough with normal chest x-ray, in whom cough improved with reduction/stoppage of cabergoline.
Conclusion: Cabergoline therapy at conventional doses carry low risk of cardio-pulmonary fibrosis in non-susceptible individuals (1.7%) and routine lung function monitoring in asymptomatic subjects is unnecessary.
073 OXIDATIVE STRESS IN A NEURONAL MODEL OF ALPHA SYNUCLEIN OVEREXPRESSION
L. V. P. Korlipara, J. M. Cooper, A. H. V. Schapira. Department of Clinical Neurosciences, Royal Free and University College Medical School
A number of biochemical abnormalities, including mitochondrial complex I defects and evidence of increased oxidative stress, have been identified in the substantial nigra of Parkinson’s disease (PD) brain. In a small number of families with highly penetrant autosomal dominant PD, point mutations and genetic triplications in the gene encoding alpha synuclein have been described. Furthermore, alpha synuclein is the major constituent of Lewy bodies, indicating its importance in sporadic PD. Stable clones overexpressing wild type (WT-HA) and A53T mutant (A53T-HA) alpha synuclein with c-terminal haemaglutinin (HA) tags were generated and characterised in the human neuroblastoma cell line, SH-SY5Y. Immunocytochemical study revealed high levels of expression and partial colocalisation with the monoaminergic vesicles VMAT-1 and VMAT-2. Both WT-HA and A53T-HA overexpressing clones had significantly reduced activity of cellular aconitase, a sensitive marker of oxidative damage, and increased cell death following incubation with paraquat, when compared with empty vector control cells. Mitochondrial respiratory chain function in overexpressing clones was normal. These data suggest that alpha synuclein overexpression in SH-SY5Y results in conditions of increased oxidative stress which is not caused by a primary mitochondrial deficit. This may provide clues to understanding the pathophysiology of the bioenergetic deficits found in PD.
074 CAN PARKINSONIAN PHENOTYPE BE USED TO PREDICT LEVODOPA RESPONSE IN EXTRAPYRAMIDAL SYNDROMES WITH AND WITHOUT DEMENTIA?
S. Molloy, J. T. O’Brien, I. G. McKeith, D. J. Burn. Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne
Background: In Parkinson’s disease (PD) the extrapyramidal (EP) phenotype can be either tremor (TD) or postural (PIGD) predominant.
Aim: To assess if EP phenotype can predict levodopa (Ldopa) response in parkinsonian syndromes with and without dementia.
Methods: Patients with dementia with Lewy bodies (DLB), PD and PD with dementia (PDD) underwent an acute Ldopa challenge. Three parameters measured motor response – the unified PD rating scale part III (UPDRS III), finger tapping (FT) and walking time (WT) tests. An improvement of 20% or more in 2/3 parameters indicated response. Parkinsonian phenotype was calculated from components of the UPDRS II & III.
Results: 70.4% of patients with PDD (n = 27), 50% of patients with PD (n = 24) and 29% of patients with DLB (n = 14) demonstrated an Ldopa response (p = 0.034). PIGD phenotype was more common in PDD (89%) and DLB (71%) than in PD (46%) (p = 0.003). Parkinsonian phenotype and Ldopa response were statistically associated (p = 0.015) with significance maintained in the PDD group (p<0.001) alone.
Conclusion: The PIGD phenotype is predominant in both DLB and PDD. It is possible that PIGD phenotype predicts cognitive decline in PD but does not always predict Ldopa response, which is maintained in PDD but not DLB.
075 OLFACTORY TESTING DIFFERENTIATES IDIOPATHIC PARKINSON’S DISEASE FROM ESSENTIAL TREMOR
M. Shah, N. Muhammed, L. J. Findley, C. H. Hawkes. Essex Neuroscience Centre, Romford
Introduction: Olfactory dysfunction occurs in some tremor-dominant diseases particularly idiopathic Parkinson’s disease (IPD). Essential tremor (ET) may mimic IPD, the two may co-exist and occasionally ET may progress to IPD. Our previous work suggests that 80% of IPD patients have disordered olfaction while preliminary studies on ET patients indicate normal sense of smell.
Methods: 1) The 40-odorant University of Pennsylvania Smell Identification Test (UPSIT). 2) Olfactory Event Related Potentials (OERP) using a Burghart Olfactometer; stimulant H2S gas at 2ppm. Both tests were administered to: Controls: 70 subjects, aged 17–90y, ET: 51 patients 24–80y all conforming to the Bain criteria, and IPD: 54 patients aged 39–80y with predominant rest tremor fulfilling the criteria of the UK PD Research Group.
Results: Mean UPSIT-40 score: Controls 33; ET 32; IPD 18. Only the IPD group differed from controls. There was no significant difference of OERP latency/amplitude between control and ET patients. 40% IPD patients had no recordable tracing while the remaining 60% had significantly prolonged latency but normal amplitude.
Conclusion: There were marked differences between control/ET patients compared to the IPD group for both tests but no difference between control and ET for any measurement. A normosmic patient with tremor is more likely to have ET than IPD while someone with tremor and impaired olfaction may have IPD or related syndrome. Group overlap prevents complete separation on the basis of smell testing alone although hyposmia in suspected ET might require diagnostic review.
076 BASAL GANGLIA CHOLINERGIC AND DOPAMINERGIC FUNCTION IN PROGRESSIVE SUPRANUCLEAR PALSY
N. M. Warren, M. A. Piggott, E. Greally, M. Lake, L. Kilford, A. J. Lees, D. J. Burn. Medical Research Council; Newcastle General Hospital, Newcastle upon Tyne
Progressive supranuclear palsy (PSP) is a neurodegenerative syndrome characterised clinically by early postural instability, vertical saccadic dysfunction, variable akinetic/rigid symptoms and a subcortico-frontal dementia. In contrast to Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB), replacement therapies with dopaminergic and cholinergic agents has been disappointing in PSP. The neurochemical basis for this is unclear.
We measured autoradiographically dopaminergic (dopamine transporter, 125I PE21 and dopamine D2 receptors, 125I epidepride) and cholinergic (nicotinic receptors, 125I 5IA85380 and muscarinic M1 receptors, 3H pirenzepine) numbers in the striatum and pallidum of pathologically confirmed cases of PSP (n = 13) and compared results with DLB cases (n = 26) and normal controls (n = 26).
A marked loss of dopamine transporter in the striatum in PSP was detected, greater than in DLB, and consistent with loss of nigral projection neurones. Striatal nicotinic receptors were significantly reduced, reflecting loss of these nigrostriatal afferents. Notably, D2 and muscarinic M1 receptors were unchanged compared with controls, suggesting preservation of post synaptic striatal neurones while DLB patients had reduced M1 receptors.
These results do not account for the poor response to dopaminergic treatment in PSP, and are suggestive of relative preservation of striatal projection neurones bearing D2/M1 receptors.
077 INCREASED UROTHELIAL EXPRESSION OF CAPSAICIN RECEPTOR TRPV1 IN HUMAN URINARY BLADDER DISORDERS AND DECREASE AFTER INTRAVESICAL RESINIFERATOXIN (RTX) TREATMENT
A. Apostolidis, C. Brady, Y. Yiangou, P. Facer, J. B. Davis, C. J. Fowler, P. Anand. Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London; Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, UCL; Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow
We have previously reported increased capsaicin receptor TRPV1 nerve fibres in neurogenic detrusor overactivity (NDO), and their decrease with successful intravesical resiniferatoxin (RTX) treatment. However, the role of TRPV1 expressed by urothelial cells is not known in human disorders – in mice lacking the TRPV1 receptor, stretch-evoked ATP release from urothelial cells is diminished and reflex voiding reduced. We have studied TRPV1 in urothelium of bladder biopsies obtained from 14 patients with intractable NDO before and after treatment with intravesical RTX, 6 patients with painful bladder syndrome (PBS) and 8 controls. TRPV1-immunostaining was observed in basal and apical urothelial cells. Total urothelial, basal and apical cell TRPV1 expression was significantly increased in PBS by image-analysis compared to NDO (P = 0.0015, 0.002 and 0.023, respectively) and controls (P = 0.0007, 0.0013 and 0.04, respectively). Basal cell TRPV1 was increased in NDO compared to controls (P = 0.003). In the 5 patients that responded clinically to RTX, total urothelial and basal TRPV1 was significantly decreased after RTX (P = 0.016 and 0.032). Post-RTX changes of basal urothelium TRPV1 correlated well with the decrease of suburothelial TRPV1 nerve fibres. Our findings suggest a contributory role for urothelial TRPV1 in human bladder disorders and in the therapeutic effect of intravesical RTX.
078 INCREASE OF PURINERGIC RECEPTOR P2X7 IN INJURED HUMAN NERVES AND DORSAL ROOT GANGLIA
M. A. Casula, I. P. Chessell, C. Bountra, Y. Yiangou, R. Birch, P. Anand. Peripheral Neuropathy Unit, Imperial College, Hammersmith Hospital, London; Neurology and GastrointestinaI Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow; Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore
The purinergic receptor (P2X7) is a ligand-gated cation channel. We recently reported that in mice with a disrupted P2X7 gene, mechanical and thermal hyperalgesia were absent in both inflammatory and neuropathic pain models, whilst normal nociceptive processing was preserved. We have now studied its distribution in injured human dorsal root ganglia (DRG) and peripheral nerves by immunohistology and Western blotting. P2X7 was present in satellite and Schwann cells in DRG but not in neurons, and was increased in satellite cells after avulsion injury [controls n = 10, median (range) 0.38 (0.21–0.54); avulsed n = 12, 0.60 (0.17–0.76); P<0.05]. The ratio P2X7 : glial fibrillary acidic protein (GFAP) was increased in painful injured nerves [n = 11, 0.58 (0.26–1.78)] compared to control nerves [n = 13, 0.45 (0.06–0.58) P<0.05], and compared to injured nerves associated with no or low pain levels [n = 4, 0.22 (0.08–0.30); P<0.02]. Western blotting showed an elevated optical density of the 70 kDa band in injured nerve [n = 20, 36 (4.0–120)] compared to controls [n = 8, 11 (6.0–34.0); P<0.02]. We propose that P2X7 receptor activation leads to hypersensitivity via release of IL-beta and up-regulation of nerve growth factor, and that P2X7 is a therapeutic target for neuropathic and inflammatory pain.
079 INCREASED CYCLOOXYGENASE-2 (COX-2) EXPRESSION BY MACROPHAGES IN CHRONIC BUT NOT ACUTE NERVE INJURY IN HUMANS AND RODENTS
P. F. Durrenberger, P. Facer, R. A. Gray, I. P. Chessell, A. Naylor, C. Bountra, R. B. Banati, D. Elliot, P. Anand. Peripheral Neuropathy Unit, Imperial College, Hammersmith Hospital, London; Neurology CEDD, GlaxoSmithKline, Harlow; Department of Neuropathology, Imperial College, Charing Cross Hospital, London; Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore
Cyclooxygenases (Cox-1 and Cox-2) are responsible for prostanoid production, which may contribute to sensitisation of injured nerves and pain. We have investigated Cox-2 immunoreactivity (Cox-2-IR) and glial activation in injured human nerves (n = 12; 9 days to 12 years post-injury), uninjured control human nerves (n = 13), and in the chronic constriction injury (CCI) rat model, using immunohistological methods. Tissues were immunostained with specific antibodies to Cox-2, CD68 (human macrophage marker), or OX-42 (rat microglial marker), prior to image analysis. In human injured nerves, Cox-2-IR (in % area) was significantly increased overall (p<0.002) compared to controls, as was CD68-IR (p<0.0001). The time course of increased CD68-IR was rapid, within days of injury, but Cox-2 increases were apparent only from 2 to 3 weeks after injury, and persisted for years. Similar changes and time-course were found in the rat CCI model, both in the injured nerves and ipsilateral dorsal spinal cord. Thus, there appear to be different stages of invasion and activation of macrophages in the peripheral and central nervous system following peripheral nerve injury, with late expression of Cox-2, which may be pathogenic. Novel Cox-2 inhibitors may be indicated for chronic pain, and to prevent development of persistent pain.
080 ULCERO-MUTILATING NEUROPATHY: CLINICAL, PATHOLOGICAL AND MOLECULAR GENETIC STUDY OF A FAMILY WITH A NOVEL RAB7 MUTATION
H. Houlden, R. H. M. King, J. R. Muddle, T. T. Warner, M. M. Reilly, R. W. Orrell, L. Ginsberg. Department of Neurology, Royal Free Hospital, Pond Street, London; Centre for Neuromuscular Diseases, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London
The ulcero-mutilating neuropathies are characterised by prominent sensory loss with the development of ulcers, arthropathy, osteomyelitis and amputations. There are two known autosomal dominant genes for these syndromes: hereditary sensory neuropathy (HSN) type 1 caused by mutations in the SPTLC1 gene and Charcot-Marie-Tooth disease (CMT) type 2B caused by mutations in the small GTP-ase late endosomal protein RAB7. The range of clinical manifestations for both these genotypes is yet to be described fully.
We have identified an English family with ulcero-mutilating neuropathy inherited as an autosomal dominant trait over three generations. The age of onset was in the middle teens and the main clinical features were painful ulcers and amputations with sensory involvement in the feet. Investigation of the proband revealed cerebellar atrophy on imaging, small lower limb sensory action potentials and abnormal thermal thresholds. Nerve biopsy showed a chronic axonal neuropathy with sparing of the large fibres.
DNA analysis of the entire RAB7 gene revealed a novel heterozygous A to C mutation changing asparagine to threonine at codon 161. RAB7 is involved in late endosome degradation. The pathogenesis of the neuropathy is unknown but mutations may lead to glycolipid accumulation or inhibition of the nerve growth factor pathway.
081 “THE BREATHING ARM”: A CLINICAL MODEL OF CNS/PNS REGENERATION AND PLASTICITY
M. Htut, V. P. Misra, P. Anand, R. Birch, T. Carlstedt. Peripheral Neuropathy Unit, Imperial College London, Hammersmith Hospital, London; Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore
The “breathing arm” refers to spontaneous contractions of arm muscles in synchrony with respiration. This phenomenon may occur after brachial plexus injury, with or without any surgical repair. Synkinesis between respiration and arm muscles may be observed clinically, and / or by EMG examination (video will be shown). We have observed the breathing arm in 18 of 25 adult patients in whom this phenomenon was investigated, all with prior traumatic brachial plexus injuries. The breathing arm persisted up to 15 years after injury. EMG examination showed motor unit potentials firing in synchrony with inspiration during quiet breathing, and augmentation by forced inspiration. Co-contracting muscles on volitional limb movement did not always also co-contract with respiration. Transcranial magnetic stimulation showed smaller amplitude motor evoked potentials with longer latencies in the injured limb. These findings suggest that breathing arm muscles are innervated at least partly but not solely by motoneurones from the spinal cord C5 segment, which normally contributes some motor fibres via the phrenic nerve to the respiratory diaphragm. We conclude that patients in whom nerve grafts were implanted directly into the C5 spinal cord segment, the “breathing arm” indicates CNS to PNS regeneration, and in other cases primarily PNS regeneration.
083 ALTERATIONS IN CIRCULATING T CELL POPULATIONS IN ACUTE GUILLAIN-BARRÉ SYNDROME
J. Pritchard, A. C. Hayday, N. A. Gregson, R. A. C. Hughes. Guy’s, King’s & St Thomas’ School of Medicine, London
Guillain-Barré syndrome (GBS) is usually a monophasic disease and is considered autoimmune in origin. We studied circulating cells of the innate and adaptive immune systems by flow cytometry in 21 prospectively recruited, untreated GBS patients and 20 healthy controls. Of 13 markers used, the only abnormality found was a reduction of circulating CD4+CD25+ T cells, particularly those expressing MHC class II molecules, in the acute phase. The reduction tended to return towards normal after intravenous immunoglobulin.
This reduction in circulating CD4+CD25+ cells could be due to a true reduction in this population or could represent their migration from the peripheral circulation to sites of inflammation or lymphoid tissues.
This is the first description of a reduction in CD4+CD25+ cells in a monophasic autoimmune disease. CD4+CD25+ cells are recognised as having immunoregulatory properties but their precise cellular targets are not yet fully understood. In this GBS patient cohort reduced CD4+CD25+ cells were not associated with adaptive B cell immune responses against myelin proteins, but may have been associated with responses against gangliosides. Whether loss of regulatory T cells is important in the pathogenesis of GBS deserves further exploration.
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