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ABN MEDAL AWARD 2002
Lord Walton of Detchant
Lord Walton of Detchant has made outstanding contributions in neurology, medical education, and scientific research. He is arguably the most renowned British neurologist of his generation. He was born in the north east of England and trained at King’s College in the University of Durham, now the University of Newcastle on Tyne, where he graduated in 1945 with First Class Honours and Distinctions in Medicine, Surgery, and Midwifery. During National Service he served in the Western Approaches and the Middle East, later joining the TA and gaining the TD. He demonstrated his potential for research and writing during his MD thesis on subarachnoid haemorrhage, on which he was examined by Professor Natrass and Sir Charles Symonds, and which he later turned into an outstanding book in 1956. He was persuaded by Natrass and Henry Miller to forego an initial interest in paediatrics and, after a research fellowship, part of which was at the National Hospital, he spent time in Boston with Raymond Adams before writing his second book, a comprehensive text on polymyositis, the start of his lifelong interest in muscle disease. He founded the Muscular Dystrophy Laboratories at NGH and his phenotypic classification of muscle disease laid the foundation for subsequent studies in molecular genetics. In 1961 he wrote the book that became a standard text for medical students, Essentials of Neurology. In 1964 he edited the first edition of Disorders of Voluntary Muscle and in 1969, shortly after his appointment as Professor, he was invited to follow Lord Brain as author of Diseases of the Nervous System. In 1971 he succeeded Henry Miller as Dean of Medicine, a post which he held for a decade and during which he was knighted in 1979. Towards the end of his time in Newcastle he became successively President of the BMA, President of the GMC, then President of the RSM, he moved to Oxford as Warden of Green College in 1983. His writing continued and there followed Skeletal Muscle Pathology, Introduction to Clinical Neurosciences, and The Oxford Companion to Medicine. In 1989 he left Green College, became President of the WFN, and was appointed to a Life Peerage. During his stewardship the WFN increased in strength and importance and his tenure culminated in the successful British bid for the World Congress in 2001. His work in the House of Lords continues, his is a respected opinion whenever matters medical, scientific, or educational are discussed, and he has served as member and chairman of several important committees and reports. What Lord Walton has given to neurology, medicine, and research is evident to all, but to those who have worked for him and with him his interest in the individual, willingness to spend time with juniors, kindness, and generosity are equally apparent and more important. Colleagues around the world will applaud this Association for its recognition of his work and this award of the ABN Medal for 2002. Lord Walton, we look forward to your talk on “Fifty Years in Neurology”.
4 October 2002
THE CLINICAL AND BEHAVIOURAL CORRELATES OF RIGHT TEMPORAL LOBE ATROPHY
Chan D, Anderson V, Sampson EL, Scahill RI, Whitwell JL, Stevens JM, Fox NC, Rossor MNInstitute of Neurology, London; National Hospital for Neurology and Neurosurgery, London, UK
Background: The present syndromic variants of frontotemporal lobar degeneration (FTLD)—frontotemporal dementia, progressive non-fluent aphasia, semantic dementia—reflect focal pathological damage to the frontal lobes or to the left temporal lobe. This study aims to identify the clinical correlates arising from focal degeneration of the right temporal lobe.
Methods: Ten patients with focal right temporal lobe atrophy (RTLA) were identified on the basis of the MRI appearances. The associated clinical, neuropsychological, and behavioural features are documented. Volumetric MRI analysis of the whole temporal lobe, hippocampus, and amygdala are compared with data obtained on patients with focal left temporal lobe atrophy (LTLA) who present with semantic dementia (SD) and with controls.
Results: The most frequently identified symptoms associated with RTLA patients were: impairment of episodic memory (90%), impairment of face recognition (60%), getting lost (70%), disinhibition (70%), and change in dietary preference (50%). By contrast, patients with LTLA typically exhibited preservation of episodic memory until later in the disease and did not get lost. Other symptoms observed in RTLA patients were: depression (30%), aggressive behaviour (30%), hyperreligiosity (20%), somatisation disorders (20%), and visual hallucinations (20%).
In RTLA patients the mean whole right temporal lobe volume was 62% of the control value. A similar reduction was observed in the volume of the right hippocampus (mean volume 61% of normal) but there was more severe atrophy of the right amygdala (55%). Lesser atrophy of the left hippocampus (90% of normal) and left amygdala (72%) were also observed. This pattern in RTLA patients of asymmetric, predominantly right sided, temporal lobe atrophy with disproportionately severe amygdala involvement represented the mirror image of the pattern of temporal lobe atrophy observed in SD patients.
Discussion: Patients with right temporal lobe atrophy exhibit clinical features that differ from those that characterise the current syndromic variants of FTLD. The disproportionate severity of right amygdala atrophy may underpin some of the behavioural features associated with RTLA atrophy. These findings will help to define a “right temporal” variant of FTLD.
DIAGNOSIS OF DEMENTING DISEASES USING MAGNETIC RESONANCE IMAGING: IMPACT OF VENTRICULAR AND EXTRAVENTRICULAR CSF MEASUREMENTS
Beeston C, Thacker N, Jackson A, Varma A, Taylor C, Neary DUniversity of Manchester, Manchester; Hope Hospital, Salford, UK
Background: Previous work used CSF volume as a marker for brain atrophy in dementing diseases, and showed that simple measures of CSF volume in 12 regions within the skull could provide diagnostic information. Here we hypothesise that separating cortical from ventricular CSF will increase the diagnostic capability of these measurements, since we assume that increases in cortical and ventricular CSF arise from different disease processes.
Methods: A combination of ventricle location using an active appearance model, and intensity based segmentation is used to segment the lateral ventricles automatically, from MR scans of patients with Alzheimer’s disease (AD; n=26), Frontotemporal dementia (FTD; n=18), and vascular dementia (VaD; n=8), and age matched normal volunteers (n=34). Regional CSF volumes are combined to form five measures of the relative degrees of atrophy in different regions of the brain, for both ventricular and cortical CSF. These measures were chosen based on known differences in regional atrophy in different types of dementia.
Results: The measurements were found to have clear diagnostic value, allowing AD to be distinguished from FTD with sensitivity of 84% and specificity 88%. The measurements providing most diagnostic information reflected the known regional atrophy patterns in these two diseases. Measurement of regional atrophy was unhelpful in diagnosing VaD.
Discussion: Separating ventricular from cortical CSF enhances the diagnostic capability of simple measurements of CSF volume, used as a marker for atrophy in the brain. The measurements can be made automatically, and so could form the basis of software to be used in peripheral clinics, helping to decide which patients should be referred to a specialist centre for further neuropsychological testing.
THE ACCURACY OF THE PULVINAR SIGN ON MRI IN THE DIAGNOSIS OF VARIANT CREUTZFELDT-JAKOB DISEASE
Collie DA, Summers DM, Will RG, Knight RSG, Sellar RJNational CJD Surveillance Unit ; Western General Hospital, Edinburgh, UK
Background : Variant Creutzfeldt-Jakob disease (vCJD) is a rare but important fatal cause of dementia linked to bovine spongiform encephalopathy in cattle. The diagnosis of definite vCJD can be made only by histopathological assessment of CNS tissue, either by brain biopsy or at postmortem. A non-invasive accurate test for the disease is highly desirable. Tests used in the diagnosis of sporadic CJD (ie EEG abnormalities, CSF 14–3–3 protein levels) are less useful in vCJD. Characteristic MRI changes have been described in vCJD, specifically hyperintensity of the posterior thalamus relative to the anterior putamen (the “pulvinar sign”).
Methods: The available MRI examinations of the first 100 cases of vCJD referred to the UK national CJD surveillance unit in Edinburgh were reviewed independently by two neuroradiologists. Each examination was scored for the adequacy of greyscale/windowing and contrast, and movement artefact. For each relevant sequence of each examination, the signal intensity of the grey matter of the cortex and deep nuclei were scored using a semi-quantitative scale. In cases of disagreement between observers, a consensus opinion was obtained. Each sequence was then scored as positive or negative for the presence of the pulvinar sign. Unit records and scans of patients referred through the unit over the 5 years during which the vCJD scans were collected were reviewed to identify any other cases with a positive pulvinar sign.
Results: 92 patients had imaging available for review. Two patients had no imaging performed, and in six cases imaging currently remains unobtainable. 117 scans were available; 70 patients had one scan, 20 had two scans, one had three scans, and one four scans. 70.7% (80/113) of T2 weighted images, 79.4% (50/63) of proton-density weighted images and 97.2% (35/36) of FLAIR images were positive for the pulvinar sign. Diffusion weighted imaging was positive in three of the five cases where it was available. 100 of 117 examinations (85.5%) were considered positive on one or more sequences at consensus review. The percentage of positive scans increased annually as scan quality improved. Of the 22 patients with two or more scans, the first scan was positive in 17, and in three all the scans were considered negative. In one case the first scan was negative and the second positive, and in one case the first scan was positive and the second negative. No scans of patients with a final diagnosis other than vCJD and a positive pulvinar sign (ie false positive) has been identified on scans reviewed prospectively through the UK CJD Surveillance Unit in Edinburgh during the 5 year period of this study.
Discussion: The MRI scans assessed in this study were a highly heterogeneous group, having been acquired as clinical investigations in over 20 imaging centres across the UK. The image quality was variable, due to movement artefact and variations in scan protocols. Despite this the pulvinar sign was positive in the majority of cases. With the increasing availability of FLAIR imaging, the sensitivity of this sign for vCJD has increased to over 95%. The presence of the pulvinar sign on MRI scanning is currently the most accurate non-invasive diagnostic test for vCJD, and may avoid the need for more invasive tests. Further monitoring of MRI in vCJD and assessment of newer MRI sequences is required to establish whether this accuracy can be further improved.
THE FIRST HUNDRED CASES OF VARIANT CREUTZFELDT-JAKOB DISEASE: EARLY PSYCHIATRIC AND NEUROLOGICAL FEATURES AND RETROSPECTIVE DIAGNOSTIC EVALUATION
Spencer MD, Knight RSG, Will RGNational CJD Surveillance Unit; Western General Hospital, Edinburgh, UK
Background : Difficulties in the early diagnosis of variant Creutzfeldt-Jakob disease (vCJD) arise in part because of the predominantly psychiatric presentation. Studies have failed to identify specific features to differentiate the syndrome at the time of presentation from psychiatric disorders. The presence of psychiatric features may lead to a psychiatric diagnosis, treatment with psychotropic medication and a delay in subsequent neurological assessment and diagnosis. The aim of this study was to assess in detail the early psychiatric and neurological features of vCJD to determine whether there are features that may allow earlier diagnosis.
Methods: Retrospective case note analysis was conducted for the first 100 cases of vCJD. Hospital and general practitioner notes, correspondence and questionnaires were searched for demographic data, referral data, initial ex tempore diagnoses, psychotropic interventions, investigations requested by psychiatrists, and the timings of psychiatric and neurological features. Retrospective ICD-10 (International Classification of Diseases, 10th Revision) diagnoses were generated by the application of the OPCRIT (Operational Criteria) checklist.
Results: Psychiatric features dominate the early stages of vCJD. Eighty five per cent of cases display psychiatric features at clinical onset and 63% were seen by a psychiatrist during the clinical course. In the early stages dysphoria, withdrawal, anxiety, insomnia, and loss of interest are common and neurological features are rare. Neurological features suggestive of vCJD are common but occur relatively late in the clinical course. Sixty two per cent of patients received an initial psychiatric diagnosis and 72% received psychotropic therapy. A retrospective ICD-10 psychiatric diagnosis could be generated for 50% of patients.
Discussion: Although the diagnosis of vCJD may be impossible in the early stages of the illness, there are combinations of psychiatric and neurological features that may allow early diagnosis in a significant proportion of cases.
NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS
Joseph F, Scolding NInstitute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK
Background : Systemic lupus erythematosus (SLE) is a chronic multisystem disease of uncertain aetiology. Neuropsychiatric involvement (NPSLE) occurs in about 50% of patients and carries a poor prognosis.
Methods: A retrospective case records analysis of patients diagnosed as having SLE between1990 to 2001 in four major centres in the south west and south Wales generated 250–300 cases, 30 satisfying the criteria for NPSLE. These were studied.
Results: There were 28 females and two males. The mean time from SLE diagnosis to NPSLE was 6 years. The most frequent neurological features were headaches (16/30), seizures 16/30 (nine generalised, seven partial), ocular involvement (8/11) strokes and transient ischaemic episodes (4/11). Personality change (29%), confusion (26%), psychosis (16%), and depression (16%) were the principal psychiatric features. Six patients presented with NPSLE as the first feature of SLE; surprisingly, four had movement disorders (Parkinsonism in two, chorea in one and myoclonus in one). Brain MRI and EEG were frequently but non-specifically abnormal. 19/25 were ANA positive, 14/19 Anti-DNA positive, 7/18 APA positive, 2/7 LA positive. CSF was analysed in 16; one showed lymphocyte pleocytosis, three mildly raised protein and 2/9 had positive oligoclonal bands. The long term outcomes were: four asymptomatic, 12 mild disability, 12 moderate disability, one severe disability, and one death.
Discussion: Movement disorders were more common first presentations of SLE than anticipated, and often responded well to treatment with immunosuppressants. EEG appears to be a sensitive but non-specific indicator of NPSLE; CSF examination is often unhelpful.
COGNITIVE AND BEHAVIOURAL PROFILE OF ATYPICAL PARKINSONIAN SYNDROMES (PSP, CBD, MSA, DLB)
Bak TH, Donald LM, Hodges JRMRC CBU, Cambridge, UK
Background : Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and dementia with lewy bodies (DLB) are often described as “Parkinson plus syndromes”. While their clinical picture has been characterised in detail over the last decade and diagnostic criteria have been established more recently, much less is known about their cognitive and behavioural profiles. The frequency and severity of cognitive impairment in these diseases has often been underestimated, particularly when only Mini Mental State Examination (MMSE) was used to assess the cognitive function.
Methods: We have examined 12 CBD and DLB, 18 MSA, and 30 PSP patients with three different cognitive tests: MMSE, DRS (Dementia Rating Scale) and ACE (Addenbrooke’s Cognitive Examination). In addition we have obtained an independent assessment of their behavioural changes from their carers, using CBI (Cambridge Behavioural Inventory).
Results: MMSE failed to detect cognitive impairment in the majority of patients, even when a higher cut off score was employed. The detection rates of ACE and DRS were comparable. The cognitive function was most affected in CBD and DLB and least in MSA. All four diseases demonstrated, however, a characteristic profile of impairment. PSP had the greatest impact on verbal fluency, DLB on orientation and CBD on language. Also CBI showed a different pattern of impairment for each disease—eg, PSP was characterised by most profound apathy but other psychiatric symptoms were more frequent in CBD and DLB.
Discussion: Our study demonstrated that cognitive and behavioural changes are frequent in “Parkinson plus syndromes”, most pronounced in DLB and CBD and least detectable in MSA. Each disease is characterised by a specific pattern of cognitive and behavioural impairment. Moreover, these patterns can be detected using a short and easy to administer test like ACE. The neuropsychological profile can contribute, therefore, to the differential diagnosis of parkinsonian syndromes.
A YORKSHIRE KINDRED WITH YOUNG ONSET ATYPICAL PSP AND CENTRAL HYPOVENTILATION DUE TO A NOVEL HOMOZYGOUS S352L TAU MUTATION
Nicholl DJ, Greenstone MA, Rizzu P, Clarke CE, Crooks D, Heutink PQueen Elizabeth Hospital, Birmingham; Hull Royal Infirmary, Hull, UK; Erasmus University, Rotterdam, The Netherlands
Background : Since 1998, >20 different heterozygous mutations have been described in the tau gene which result in frontotemporal dementia with parkinsonism. We describe a family with a novel mutation in the tau gene, which results in a young onset, rapidly progressive neurodegenerative disorder with central hypoventilation.
Methods: All available family members, who originate from Yorkshire, UK were examined neurologically and the two affected members examined at autopsy. The coding regions of the tau gene were sequenced in all family members.
Results: Case 1: A 30 year old male presented with type 2 respiratory failure and bilateral vocal cord paralysis that required tracheostomy. Over the subsequent 2 years, he had progressive respiratory failure and apnoeic episodes, until he developed mild extrapyramidal signs (with normal range of eye movements), dying 4 years after onset. Case 2 (sister of case 1). Aged 29 years, she was admitted in acute respiratory failure after brief illness with a GCS coma scale 3/15, but no focal signs. All investigations were negative and she died within one month of onset. The two affected members’ parents were first cousins. At autopsy, there were widespread neurofibrillary tangles with tau immunoreactivity particularly in brain stem nuclei- the pathological appearances resembled that of progressive supranuclear palsy. Both cases carried a homozygous S352L tau mutation. Six unaffected members (including both parents) were examined, and no evidence of a neurodegenerative disorder was noted, and all were heterozygous, apart from a single individual who was homozygous wild type. This S352L mutation was not found in 102 unrelated United Kingdom control subjects.
Discussion: This is the first report of a kindred with an autopsy proven tauopathy with a homozygous tau mutation. The history of consanguinity, presence of a homozygous coding mutation, and absence of any clinical signs in the parents all suggest a recessive mode of inheritance. The phenotypic features (central hypoventilation, aggressive disease course, and early age of onset) differ greatly from those reported with other mutations. Work is in progress to establish the functional effect of this mutation on tau expression and microtubule binding.
THE EFFECTIVENESS OF NATALIZUMAB ON MRI OUTCOME MEASURED IN PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS
Dalton C, Barker G, MacManus D, Miszkiel K, Bates D, Blumhardt L, Hawkins C, Palace J, Sharief M, Swingler R, Young C, Miller D and the International Natalizumab MS Trial GroupInstitute of Neurology, London; Royal Victoria Infirmary, Newcastle; Queens Medical Centre, Nottingham, North Staffs Royal Infirmary, Stoke on Trent; Radcliffe Infirmary, Oxford; Guy’s Hospital, London; Ninewells Hospital, Dundee; The Walton Centre, Liverpool, UK
Background : Natalizumab, a humanised monoclonal antibody specific for α4 integrins, is an α4 integrin antagonist of the emerging class of therapeutics known as selective adhesion molecule inhibitors (SAMIs) which reduced the occurrence of new brain lesions in experimental models of MS and in early clinical studies of MS.
Methods: 213 MS patients from 17 sites in the United States, seven in the United Kingdom and three in Canada were randomly assigned to monthly infusions of 3 or 6 mg/kg Natalizumab or placebo for 6 months and were followed for a further 6 months in a phase II clinical study.
Results: During the 6 month treatment period, a total of 35 relapses were reported in 26/71 placebo patients; 18 relapses occurred in 13/68 patients receiving 3 mg/kg Natalizumab, and 15 occurred in 14/74 patients 6 mg/kg (p=0.019). Applying more stringent objective relapse criteria, there were 18 relapses in 15/71 placebo patients; three relapses in 3/68 patients receiving 3 mg/kg Natalizumab and eight relapses in 8/74 patients receiving 6 mg/kg Natalizumab (p=0.004). There was one anaphylactoid reaction in the 3 mg/kg group which rapidly responded to steroids and three reports of serum sickness, one in each group including placebo.
Discussion: During the 6 month follow up period there was no significant difference in the number of active scans and reported relapses between the placebo and treated arms. Natalizumab significantly reduced clinical relapses and MRI lesion activity over a 6 month period. Further studies are under way to investigate longer term safety and efficacy including the effect on disability.
CORTICAL MULTIPLE SCLEROSIS
Zarei M, Chandran S, Compston DAS, Hodges JRDepartment of Neurology, Addenbrooke’s Hospital Cambridge, UK
Background : Neuropsychiatric complications of MS are well recognised, however the presentation of MS with neuropsychiatric or cognitive symptoms has generally been considered a rare occurrence. We describe six patients presenting with severe depression and progressive cortical dementia whose extensive investigation lead to the subsequent diagnosis of MS.
Methods: Six cases (five female, one male; aged 38–60) with neuropsychiatric symptoms were referred to the Memory and Cognitive Disorders Clinic at Addenbrooke’s Hospital, Cambridge between 1996–2001 and were assessed by JRH and DASC independently. Patients underwent neuropsychological assessment and were followed up for 2–5 years.
Results: Our cases presented with depression (n=3) and amnesia (n=4). Neuropsychological profile of progressive amnesic syndrome in these patients revealed severe amnesia not improving with cues, a characteristic of cortical dementia. One case had distinct pure cortical dysphasia, dysgraphia and dyslexia in a context of an amnesic syndrome. All patients became demented on follow up. MRI brain imaging of all six cases revealed changes ranging from cerebral atrophy to white matter high signal abnormalities. Paraclinical investigations also included VER (delayed in four cases) and CSF examination (OCB+ in four cases). All six cases fulfilled the MacDonald and colleagues diagnostic critera for MS. Natural history of the disease varied from relapsing remitting to primary progressive. Review of previous case reports of MS presenting with neuropsychiatric symptoms showed that depression and amnesia are the most common presenting symptoms.
Discussion: Dementia complicating MS is well recognised, however MS presenting with dementia is rare. Our series represents the largest reported single series of such cases. We suggest that cognitive/neuropsychiatric presentation of multiple may represent a subgroup with predominate cortical involvement. Neuropsychological profile of these patients in particularly severe amnesia and pure cortical symptoms support this hypothesis. In addition critical review of 17 previously reported cases of MS presenting with neuropsychiatric symptoms show a pattern of symptomatology which can be explained by a syndrome of cortical pathology. We suggest cortical variant of MS is underdiagnosed and that further studies involving detailed structural and functional imaging along with neuropsychological assessment should be undertaken examining the frequency and clinical outcome of cortical presentation of MS.
GENETIC ANALYSIS OF MULTIPLE SCLEROSIS IN EUROPEANS (GAMES)
Compston DAS, Sawcer SJ, and the GAMES consortiumUniversity of Cambridge, Cambridge, UK
GAMES set out to identify genetic factors conferring susceptibility to multiple sclerosis by screening the genome indirectly for linkage and association using markers for susceptibility genes evenly distributed at a density of 0.5 -10 centiMorgans. We argued that independent identification of the same chromosomal regions, using different genetic tactics, would increase confidence in their candidature as susceptibility loci. GAMES has coordinated genetic studies in 19 European populations. Results are available on a dedicated web site (http://www.mrc-bsu.cam.ac.uk/MSgenetics). Linkage analyses included in the GAMES project provide whole genome screening (using a subset of 400 microsatellite markers) in 521 multiplex families from the United Kingdom, Italy, Sardinia, Scandinavia, Turkey and Australia. Associations have been screened by comparing 5893 cases and 5903 controls from the 19 populations (23 cohorts) using a standard set of 6000 microsatellite markers spaced to provide a 0.5cM map of the genome typed in samples of pooled DNA. Provisional analysis (due to be finalised by June 8th 2002) has identified linked and associated regions on chromosomes 6p (MHC), 6q, 10p, 11p, 17q, 19q, and 22p. Because cases were not typed individually, GAMES is concerned only with genes conferring disease susceptibility and not those influencing disease progression or the clinical course.
CORTICOSTEROIDS DO NOT PREVENT OPTIC NERVE ATROPHY FOLLOWING OPTIC NEURITIS
Hickman SJ, Kapoor R, Jones SJ, Altmann D, Plant GT, Miller DHInstitute of Neurology, London; Moorfields Eye Hospital; the National Hospital for Neurology and Neurosurgery, London, UK
Background : Optic nerve atrophy has been shown to develop following optic neuritis. There has been recent interest in the use of corticosteroids as neuroprotective agents. Pulsed corticosteroid treatment has been shown to reduce the development of cerebral atrophy in multiple sclerosis. This study assesses whether corticosteroids prevent the development of optic nerve atrophy following optic neuritis.
Methods: Optic nerve short tau inversion recovery images from a recent randomised placebo controlled trial of intravenous methylprednisolone in acute optic neuritis were evaluated. Imaging was performed before randomisation and 6 months later. Mean optic nerve area was measured by an observer blinded to image identity and acquisition order from two consecutive orbital slices using a semiautomated contouring technique.
Results: At baseline optic nerve mean area was 18.4 mm2 in affected optic nerves and 17.8 mm2 in unaffected optic nerves (n=45, p=0.3). After 6 months optic nerve mean area was 16.4 mm2 in affected optic nerves and 17.4 mm2 in unaffected optic nerves (n=59, p=0.019). The mean area of affected optic nerves in the corticosteroid group was 15.9 mm2 (n=30) compared with 16.9 mm2 (n=29) in the placebo group (p=0.29). The mean measurement coefficient of variation was 3.8%.
Discussion: This technique was able to demonstrate optic nerve atrophy following optic neuritis. There is no evidence from these data that intravenous methylprednisolone prevents the short term development of optic nerve atrophy following optic neuritis.
THE 12 YEAR PROGNOSIS OF UNILATERAL FUNCTIONAL WEAKNESS AND SENSORY DISTURBANCE
Stone J, Rothwell PM, Warlow CP, Sharpe MWestern General Hospital, Edinburgh; The Radcliffe Infirmary, Oxford; Royal Edinburgh Hospital, Edinburgh, UK
Background: Although patients with unilateral “medically unexplained” or “functional” weakness and sensory disturbance present commonly to neurologists we know little about their long-term prognosis.
Methods: We studied a previously assembled cohort of 60 patients who had been seen by consultant neurologists in Edinburgh between 1985 and 1992 and received a diagnosis of unilateral functional weakness or sensory disturbance. Current symptoms and health status were assessed by contacting the patient and their family doctor.
Results: Follow up data relating to misdiagnosis was obtained in 49 patients (82%) and patient questionnaire data in 42 patients (70%). The mean duration of follow up was 12.5 years. 83% of patients still reported weakness or sensory symptoms. Self reported limitation of physical function, distress, and multiple symptomatology were common. Patients with sensory symptoms alone had a better functional outcome than those with weakness. Twenty nine per cent had taken medical retirement. Only one patient had developed a neurological disorder which, in hindsight, explained the original presentation. One patient had died of unrelated causes.
Discussion: Patients with unilateral functional weakness and sensory symptoms often remain symptomatic, distressed and disabled 12 years after diagnosis. These symptoms very rarely become explained by a recognisable neurological disorder in the long term
THE RELATIONSHIP BETWEEN TREATMENT WITH VALPROATE, LAMOTRIGINE, AND TOPIRAMATE AND THE PROGNOSIS OF THE IDIOPATHIC GENERALISED EPILEPSIES
Nicolson A, Smith D, Appleton R, Chadwick DThe Walton Centre for Neurology and Neurosurgery ;Alder Hey Children’s Hospital, Liverpool, UK
Background : We aim to analyse a large population with IGE to determine their general characteristics, whether the newer AEDs lamotrigine (LTG) and topiramate (TPM) offer any advantages over valproate (VPS) or are as effective, and whether there are specific prognostic factors in patients with IGE.
Methods: 854 children and adults with IGE were identified, and data were collected on seizure and syndrome types, previous febrile convulsions, family history, EEG/ imaging, AED details and seizure outcome. Kaplan-Meier analysis was carried out to calculate retention curves for each AED, and multivariate analysis performed to identify prognostic factors.
Results: Remission rate was highest with VPS monotherapy (45%), although when used as first-line produced remission in 50% compared with 34% when used later. Remission with combination therapy was most likely with VPS/LTG (16%). There was no significant difference between the retention curves for each of the AEDs.
Discussion: This confirms the efficacy of VPS in IGE, and of LTG and TPM as useful treatment options. The high remission rate with VPS/LTG provides further evidence for this combination’s efficacy. Appropriate treatment is possibly more likely to be effective when given early, and with further patient details we will analyse factors that may independently influence outcome.
LONGER TERM OUTCOME IN CHILDREN BORN TO MOTHERS WITH EPILEPSY
Adab N, Vinten J, Kini U on behalf of the Liverpool and Manchester Neurodevelopment GroupThe Walton Centre, Liverpool; St Mary’s Hospital, Manchester, UK
Background : The longer term outcome of antiepileptic drug exposure in utero on cognitive delay and its possible association with dysmorphic features (DF) remains unclear, particularly with reference to specific drugs.
Methods: We recruited children of mothers with epilepsy, attending regional epilepsy clinics in Liverpool and Manchester. Structured interviews, hospital records, clinical examination, blind assessment of photographs and psychometric tests (Weschler) were used to assess exposure, DF and intelligence quotient (IQ).
Results: Of the 249 children born to 158 mothers, 41 were exposed to sodium valproate (VPA), 52 to carbamazepine (CBZ), 21 to phenytoin (PHT), 49 to polytherapy, and 80 were unexposed.
Mean verbal IQ was significantly lower in the VPA group (83.61, CI 78.26–88.86) compared to non-exposed (90.90, CI 87.29–94.5) and other monotherapy groups (CBZ 94.08, CI 89.61–98.54; PHT 98.48, CI 90.56–106.39).
Although those with marked or moderate features of fetal anticonvulsant syndrome more commonly had low average full scale IQ, 20 ( 43.5%) of the 46 children with IQ < 79 were considered to have normal faces
Discussion: The retrospective nature of our results must be interpreted with caution, nonetheless the results suggest that VPA exposure in particular may carry increased risk for neurodevelopment in children exposed in utero.
A STUDY OF DÉJÀ VU IN PATIENTS WITH TEMPORAL LOBE EPILEPSY, STUDENTS, AND NEUROLOGY OUTPATIENTS
Warren-Gash C, Zeman AUniversity of Edinburgh, Edinburgh, UK
Objectives: (1) To examine quantitative and qualitative features of déjà vu in epilepsy patients, neurology outpatients and students. (2) To investigate the relationship between déjà vu, anxiety and depression and dissociative symptoms. (3) To establish whether EEG or imaging findings are consistently lateralised in patients with déjà vu.
Methods: A retrospective questionnaire based on Sno’s Inventory for “Déjà vu Experiences Assessment” and incorporating the HAD scale, was completed by three sample groups. Subjects were 50 epilepsy patients experiencing ictal déjà vu, 50 neurology outpatients attending Edinburgh hospital clinics, and 50 medical students. EEG and imaging findings were examined for epilepsy patients.
Results: Déjà vu prevalence was 88% in students and 74% in neurology outpatients. In epilepsy patients, déjà vu occurred significantly more often, lasted longer, and was associated with more physical features (headache, blackout), emotions (fear, distress) and dissociation (derealisation/ depersonalisation) than in controls. Déjà vu frequency increased with anxiety and depression across the three groups. There was no evidence for an association between laterality of pathology and déjà vu.
Conclusions: Déjà vu is common in the general population but can occur as an aura of TLE. While qualitatively similar to non-epileptic déjà vu, in epilepsy déjà vu has some distinctive associated features.
PREDICTING PROLONGED DYSPHAGIA FOLLOWING ACUTE STROKE
Broadley S, Salonikis S, Croser D, Cheek A, Cottrell J, Creevy M, Taylor J, Thompson PDepartment of Medicine University of Adelaide and Depts Neurology, Radiology and Speech Pathology, Royal Adelaide Hospital, S Australia
Background : Dysphagia is common after acute stroke. Being able to predict those patients who go on to have prolonged dysphagia would facilitate clinical trials of different feeding methods.
Methods: All consecutive patients admitted to the Royal Adelaide Hospital with acute stroke were assessed for stroke type and severity (Barthel index), evidence of dysphagia and abnormalities on neuroimaging. Dysphagia was assessed using the water swallow test and the Parramatta Hospitals dysphagia assessment. In the first phase (n=149) all data were collected. In the second predictive phase (n=104) only those factors found to be of importance in the first phase were collated. Lesion analysis from CT/MRI in all patients was performed.
Results: The water swallow test was found to be predictive of aspiration pneumonia with high sensitivity. Stroke severity (Barthel index <20), dysphagia score (Parramatta Hospitals dysphagia assessment <80), dysphasia and involvement of frontal/insular cortex on neuro-imaging were all found to be independently predictive of prolonged dysphagia (>10 days). Identifying those patients with three out of four of these factors predicted prolonged dysphagia with sensitivity of 74% and specificity of 92%.
Discussion: Patients failing a water swallow test should be referred for more formal assessment by speech and language therapists. It is possible to predict prolonged dysphagia following acute stroke with high specificity with relatively few clinical parameters. This should facilitate further research on this vulnerable group.
HOMOCYSTEINE AND CEREBRAL SMALL VESSEL DISEASE: A POTENTIAL DISEASE MECHANISM THROUGH ENDOTHELIAL DYSFUNTION
Hassan A, O’Sullivan M, de Souza R, Bamford J, Briley D, Brown M, Thomas D, Markus HDepartments of Clinical Neurosciences and Clinical Biochemistry, SGHMS, London; St James’s University Hospital, Leeds; Stoke Mandeville Hospital, Aylesbury; National Hospital for Neurology and Neurosurgery, London; Thames Valley Nuffield Hospital, Slough, UK
Background : Homocysteine is believed to be toxic to endothelium. Detrimental effects on cerebral autoregulation and blood-brain barrier function could be potential mechanisms leading to symptomatic cerebral small vessel disease (SVD). The aim of this study was to determine whether homocysteine is a potential modifiable risk factor for lacunar stroke and if homocysteine levels were associated with significant endothelial dysfunction.
Methods: 172 white lacunar stroke patients and 172 asymptomatic community controls of similar age, sex and geographical residence were tested. Patients were in a stable state, at least 2 months after their last clinical event. Serum homocysteine levels were measured using a high performance liquid chromatography method. Endothelial dysfunction was assessed in a subgroup of 110 lacunar strokes and 50 controls using the soluble markers thrombomodulin (TM), intracellular adhesion molecule (ICAM 1), tissue factor (TF) and tissue factor pathway Inhibitor (TFPI). The extent of leukoaraiosis and number of lacunar infarcts was graded in pateints in whom MRI was performed (n=141; 82%).
Results: Mean homocysteine levels were higher in patients with lacunar stroke 14.55 μmol/l (13.85–15.34) v controls 12.02 (11.43–12.64), p<0.0005. The odds ratio for lacunar stroke increased with increasing quartiles of homocysteine. There was a significant independent association between homocysteine and large lacunar infarct grade (p=0.007) and leukoaraiosis grade (p=0.02), but not small lacunar infarcts (p=0.8). Homocysteine levels were associated with TM (r=0.37, p<0.0005), ICAM1 (r=0.18, p=0.02) and TFPI levels (r=0.28, p<0.0005).
Discussion: Mild to moderate hyperhomocysteinaemia is a risk factor for lacunar stroke, with homocysteine levels associated with the presence and radiological extent of SVD (lacunar infarcts and leukoaraiosis). In this population homocysteine correlated with measures of endothelial activation and damage, suggesting that increased risk could be mediated by endothelial dysfunction.
CAN OUTPATIENT NEUROLOGY SERVICES EVER PROVIDE SUFFICIENTLY RAPID ASSESSMENT OF TIA AND MINOR STROKE?
Flossmann E, Cifelli A, Coull A, Silver L, Rothwell PM for the Oxford Vascular Study (OXVASC)The Radcliffe Infirmary, Oxford, UK
Background : The risk of major stroke in patients presenting with TIA or minor stroke (mS) is very high in the days immediately following the initial event. To be effective, investigation and appropriate prevention must be instigated as soon as possible. However, some elements of the delay to specialist assessment, such as delays in patients presenting to medical attention and delays in referral to secondary care, are beyond the immediate control of neurology services. We therefore determined the causes and extent of delays that remains even with a daily “emergency” TIA/mS clinic.
Methods: We compared time to clinic assessment, and causes of delay, in 100 consecutive patients referred to a weekly TIA/mS clinic by GPs and 100 consecutive patients referred by GPs to a daily (except weekends) “emergency” TIA/mS clinic in OXVASC.
Results: The median time from TIA/mS to clinic assessment was 25 days (IQR=12–41) in the weekly clinic and 5 days (3–6) for the daily clinic. Median time from TIA/mS to date of clinic referral was 7 days (2–16) for the weekly clinic and 2 days (1–5) for the daily clinic. The subsequent median delay between date of referral and clinic assessment was 13 days (7–23) for the weekly clinic and 2 days (0–3) for the daily clinic.
Discussion: The introduction of a daily “emergency” TIA/mS clinic significantly reduced the overall delay to assessment, and also encouraged faster referral by GPs. However, the residual delay of 5 days still seriously undermines the potential effectiveness of stroke prevention. Optimal prevention will require public education to encourage patients to seek medical attention immediately, and may only be possible if patients are assessed by “on call” services.
AMBULATORY TRANSCRANIAL DOPPLER MONITORING FOR CIRCULATING ASYMPTOMATIC CEREBRAL EMBOLI
Mackinnon AD, Aaslid R, Markus HSSt George’s Hospital Medical School, London, UK; Hemodynamics AG, Berne, Switzerland
Background : Transcranial Doppler (TCD) detection of circulating asymptomatic emboli is currently limited to short recordings by equipment size. Embolisation shows marked temporal variability. Prolonged recordings may improve sensitivity, akin to 24 hour blood pressure and electrocardiographic (ECG) recordings. We have developed and evaluated the first portable TCD machine for continuous ambulatory recording of the middle cerebral artery (MCA) Doppler signal and subsequent embolic signal detection.
Methods: The system consists of an 18×11.5×3.2 cm battery powered Doppler unit and a 13 mm servo controlled 2 mHz transducer probe mounted on spectacles (or fixed with a headband). First conventional TCD is used to find the MCA Doppler signal via the transtemporal window. Fixation of the ambulatory probe is either with glasses or headband, the Doppler unit is carried in the pocket of a lightweight sleeveless jacket. The MCA waveform is displayed on a laptop and the transducer position optimised using dedicated software. The laptop is disconnected once the MCA is located. An autosearch algorithm restores the vessel insonation during recording if signal quality falls. The quadrature raw audio signal is stored on flashdisk and Digital Audio Tape for later analysis. Recordings (2–4 hours) were made on normal volunteers (n=3) and ambulatory acute stroke patients (n=7) to optimise transducer fixation. consecutive ambulatory acute stroke patients (n=24) were recruited until 20 ambulatory recordings (10 with glasses, 10 with headband) were performed. Patients’ assessment of the device was determined with a standard questionnaire.
Results: Of the 24 patients recruited, three did not have transtemporal windows and it was not technically possible to maintain ambulatory probe fixation in one. Of those suitable (n=20) 11 were male, median age 66 (range 38–91). In 16 patients set up time was in the range 15–30 minutes. Median ambulatory time was 5 hours 40 min (range 325–385 min). Of the data recorded onto a flash disk, the median time an MCA Doppler signal was achieved was 5 hours 4 min (range 190–326 min) equating to 96% of available file recording time.
Discussion: Ambulatory TCD is possible and patients tolerated recordings of 5–6 hours well (based on questionnaire). The technique is likely to improve the sensitivity of recording for asymptomatic cerebral emboli.
THE ROLE OF ENDOTHELIAL DYSFUNCTION IN LACUNAR INFARCTION AND ISCHAEMIC LEUKOARAIOSIS
Hassan A, Hunt B, O’Sullivan M, Parmar K, Bamford J, Briley D, Brown M, Thomas D, Markus HDepartment of Clinical Neurosciences, SGHMS, London; St Thomas’ Hospital London, St James’s University Hospital Leeds, Stoke Mandeville Hospital, Aylesbury, National Hospital for Neurology and Neurosurgery, London; Thames Valley Nuffield Hospital, Slough, UK
Background : Patients with cerebal small vessel disease (SVD) can present with focal lacunar infarcts in isolation or with diffuse white matter changes, referred to radiologically as leukoaraiosis. Leukoaraiosis can also be caused by non-vascular pathology; the term ischaemic leukoaraiosis has been used to define a group with a vasular pathology and is defined as clinical lacunar stroke with radiological leukoaraiosis. Endothelial dysfunction which can lead to breakdown of the blood-brain barrier, impaired cerebral autoregulation and prothrombotic changes is believed to be important in mediating disease. Circulating levels of intracellular adhesion molecule 1(ICAM1), thrombomodulin (TM), tissue factor (TF), and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage. We measured these markers in a prospective series of patients with SVD to determine the pattern of endothelial activation and whether there are differences in pateints with isolated lacunar infarction and ischaemic leukoaraiosis.
Methods: One hundred and ten white patients with previous lacunar stroke and 50 community controls were studied. All stroke patients were in a stable state at least 2 months after their last clinical event. Markers of endothelial function were measured on venous blood samples. Brain scans were used to classify patients into isolated lacunar infarction (n=47) and ischaemic leukoaraiosis (n=63). The number of lacunes and severity of leukoaraiosis was also scored on MRI.
Results: ICAM1, TM, and TFPI were elevated in the patients compared with the controls (p≤ 0.006). The ischaemic leukoaraiosis group had a different marker profile with lower levels of TFPI (p=0.01) and a higher TF/TFPI ratio (p=0.01) compared with the isolated lacunar infarction group. TM levels were associated with the number of large lacunes (p=0.008) and the leukoaraiosis score, but TF levels and the TF/TFPI ratio were associated only with the extent of leukoaraiosis (p≤0.02)
Discussion: There is evidence of chronic endothelial dysfunction in lacunar stroke and endothelial prothrombotic changes may be important in mediating the ischaemic leukoaraiosis phenotype. Therapies which help to stabilise endothelium may have a role in patients at risk of clinical lacunar events.
A STUDY OF IMPAIRED AWARENESS DUE TO STROKE
Louis-Auguste J, Zeman AWestern General Hospital, University of Edinburgh, Edinburgh, UK
Background : Stroke presenting with impaired awareness opens a window on the anatomical basis of arousal; conversly, the presence of impaired awareness after stroke may raise the likelihood of certain types and locations of pathology. We report a preliminary survey of the relationship between conscious level, assessed by the Glasgow Coma Scale (GCS) and by a binary judgement of drowsiness, and the clinical and radiological features of stroke, in a large hospital series.
Methods: We examined clinical and radiological data recorded prospectively in the Lothian Stroke Register between 1993 and 1998.
Results: 820 (75.4%) patients were admitted with a Glasgow Coma Score (GCS) of 15, 268 (24.6%) with a GCS <15. Reduction of the GCS was associated with dysphasia, gaze palsy, hemianopia; the presence of stroke lesions, haemorrhage, and mass effect on CT. A significant excess of patients with left hemisphere lesions, among those with reduced GCS, was attributable to dysphasia. However, drowsiness and reduction of the eye score were associated with right hemisphere lesions.
Discussion: These findings underline the limitations of the GCS in the assessment of conscious level after stroke: reduction of the GCS often reflects dysphasia, whereas the CGS often fails to capture the presence of drowsiness. The association between right hemisphere lesions, drowsiness, and reduction of the eye score may suggest a privileged role for the right hemisphere in arousal.
HIGH EARLY RISK OF STROKE AFTER A FIRST TRANSIENT ISCHAEMIC ATTACK
Lovett JK, Dennis MS, Sandercock PAG, Bamford J, Warlow CP, Rothwell PMThe Radcliffe Infirmary, Oxford; Western General Hospital, Edinburgh; St James’s Hospital, Leeds
Background : The commonly quoted risk of stroke after a TIA of 1–2% at 7 days is likely to be an underestimate due to delayed inclusion of patients in previous studies. The real risk is unknown and guidelines vary on how urgently patients should be seen. We have used data from the Oxfordshire Community Stroke Project (OCSP), and a recent audit in Oxford, to estimate the early risk of stroke after a TIA and the effects of delays in presentation and referral for specialist assessment.
Methods: The early stroke risk was estimated in all OCSP patients who had a definite first ever TIA (n=209). Analyses were performed from onset of TIA, referral to the TIA service, and from clinic assessment.
Results: The stroke risk from the date of TIA was 8.6% (95%CI 4.8–12.4%) at seven days and 12.0% (7.6–16.4) at 30 days. These risks from referral date were 2.4% (0.3–4.5) and 4.9% (1.9–7.8) respectively, and 1.9% (0.1–3.8) and 4.4% (1.6–7.2) respectively from clinic assessment.
Discussion: The early risk of stroke after TIA is higher than commonly quoted. However, these data, taken with the results of our recent audit, suggest that even a daily TIA clinic is unlikely to have a significant impact on stroke risk without public education about the symptoms of TIA and the need to seek medical attention urgently.
A SPATIAL MEMORY DEFICIT EXACERBATES VISUAL NEGLECT FOLLOWING STROKE
Malhotra P, Parton A, Driver J, Husain MImperial College of Science, Technology, and Medicine, London; Charing Cross Hospital, London, UK
Background : Right hemisphere stroke patients with unilateral neglect are often unaware of left-sided stimuli, reflecting their bias to direct attention towards the right. Previously we showed that many neglect patients also refixate stimuli to the right, forgetting where they have looked before.
Methods: To test directly whether neglect patients have impaired spatial working memory, we devised a new task specifically to measure `spatial span’ (analogous to `digit span’) in these patients. Our task avoids any confounding effect of impaired perception of leftward spatial locations by using only a vertical array presented centrally.
Results: On this vertical spatial memory task, neglect patients (n=10) were impaired at remembering spatial locations compared to stroke patients without neglect (n=10) and healthy age-matched controls (n=10). Furthermore, the degree of neglect correlated with the failure to retain spatial locations, suggesting that impaired spatial working memory exacerbates neglect. All patients accurately located single stimuli, showing that performance was not related to defective spatial localisation. Neglect patients were also impaired on a second vertical spatial memory task which did not require memory for sequence order.
Discussion: We conclude that a deficit in transsaccadic spatial working memory is an important component of the neglect syndrome and is a potential target for pharmacological intervention.
DIFFUSION TENSOR MRI PROVIDES INDEPENDENT MARKERS OF COGNITIVE DYSFUNCTION IN ISCHAEMIC LEUKOARAIOSIS
O’Sullivan M, Morris RG, Huckstep B, Jones DK, Williams SCR, Markus HSSt George’s Hospital Medical School, London; Institute of Psychiatry, London, UK
Background : Cerebral small vessel disease is an important cause of cognitive impairment and vascular dementia. T2 weighted MRI typically reveals focal lacunar infarcts and diffuse hyperintensity, described as leukoaraiosis, but the correlation between these abnormalities and cognitive impairment is weak. One possible reason is that abnormalities on T2 weighted images are relatively non-specific, and fail to distinguish pathological changes that disrupt white matter projections from those that do not. Abnormalities in normal appearing white matter could also play a part. Diffusion tensor MRI (DTI) is a technique which may provide more quantitative information about damage to white matter tracts.
Methods: 36 patients with ischaemic leukoaraiosis, defined as radiological leukoaraiosis and a clinical lacunar stroke, and 19 matched control subjects with normal MRI scans, underwent DTI, conventional MRI and neuropsychological assessment. Mean diffusivity and fractional anisotropy (FA), within and outside visible lesions, were measured along with brain, ventricle and lesion volumes.
Results: Mean diffusivity was increased, and FA reduced, in normal-appearing white matter of patients. In patients, mean diffusivity in normal-appearing white matter correlated with IQ (r=−0.46, p<0.01) and executive dysfunction (Wisconsin Card Sorting Test total errors r=0.41, p<0.05). Similar correlations were not found with FA or changes within lesions. In multivariate analysis, including brain, ventricle and lesion volumes, significant independent correlations were found for mean diffusivity of normal appearing white matter only (IQ Beta=-0.504, p=0.008).
Discussion: Mean diffusivity of normal appearing white matter correlates more strongly with cognitive measures than lesion load on T2 weighted MRI and is a new independent marker of cognitive dysfunction in ischaemic leukoaraiosis.
DIAGNOSIS OF SPORADIC CREUTZFELDT-JAKOB DISEASE USING THE PUTAMEN INTENSITY GRADIENT
Colchester ACF, Hojjat SA, Will RG, Collie DAUniversity of Kent at Canterbury; Western General Hospital, Edinburgh, UK
Hyperintensity in the basal ganglia and cortex has been reported in sporadic Creutzfeldt-Jakob disease (sCJD), with good sensitivity and specificity for diagnosis. However, it is unclear how visual analysis by radiologists compensates for the wide variation in absolute intensities between MR scans, and control groups have been absent or poorly defined.
We carried out quantitative analysis of 28 digital dual echo (PD and T2) MR scans from 20 patients (10 sCJD, 10 non-CJD dementia). MR scans came from many different hospitals, with widely varying acquisition settings. We measured average intensities in the caudate head, putamen, thalamus (divided into posterior, medial and lateral parts) and frontal white matter. For normalisation, intensities were expressed as ratios of one structure to another. Results were analysed by means of ROC curves. There were no significant differences, between sCJD and controls, in absolute values of these structures nor in any of the ratios.
We then analysed the intensities within the putamen, where there is a gradual reduction of intensity from front to back. We found that the T2 intensity gradient was significantly greater in sCJD than controls, with sensitivity and specificity of 0.89, which is comparable to any available non-invasive test for sporadic CJD.
COGNITIVE DYSFUNCTION AFTER ISOLATED BRAIN STEM INSULT: AN UNDERDIAGNOSED CAUSE OF LONG TERM MORBIDITY
Garrard P, Bradshaw D, Jager HR, Thompson AJ, Losseff N, Playford DTNational Hospital for Neurology and Neurosurgery, London, UK
Objective: Although the importance of cognitive impairment to functional recovery after brain injury is well recognised, it is commonly assumed that cognition will be spared following an isolated infratentorial insult. Rehabilitation of such cases tends to focus on motor recovery, yet in the course of rehabilitation they frequently encounter profound problems which may persist long after discharge. Our experience of this group is that they too exhibit cognitive dysfunction which significantly impact on function.
Methods: We describe seven patients with isolated brain stem lesions demonstrated on magnetic resonance imaging, admitted to the Neurological Rehabilitation Unit between December 1999 and March 2001. All underwent detailed neuropsychological assessment using standardised tests.
Results: All patients demonstrated impaired attention, and all but one significant executive dysfunction. The two most severely impaired showed additional naming deficits. Memory disturbance was seen in one case. Posterior cortical dysfunction was not seen. The severity of functional impairment was unrelated to lesion size.
Discussion: These deficits imply disruption of distributed systems involving brain stem and frontal areas. Functional imaging may provide further insights into the anatomy and mechanisms of such brain stem-hemisphere interactions. This preliminary survey suggests, however, that deficits underpinned by such mechanisms may be more widespread than has previously been recognised.
PROBABALISTIC DIAGNOSTIC CLASSIFICATION OF DEMENTING DISEASE USING AN AUTOMATED ANALYSIS OF THE DISTRIBUTION AND SEVERITY OF CEREBRAL ATROPHY
Jackson A, Thacker NA, Varma A, Bathgate D, Snowden JS, Neary DUniversity of Manchester, Manchester; Hope Hospital, Salford, UK
Background : One major discriminator of dementing diseases is the pattern and severity of cerebral atrophy. We present a novel system which allows reliable use of atrophy data for clinical diagnosis.
Methods: The study was performed on 18 patients with frontotemporal dementia (FTD), 19 with Alzheimer’s disease (AD), 11 with vascular dementia (VAD), and nine normals. The analysis software automatically segments the CSF space from MRI data and rotates it into a standard coordinate system based on the orientation and dimensions of the CSF space itself. The coordinate space is arbitrarily divided into 12 equal spaces and the proportion of CSF in each of these volumes is used as the basis for a Parzen classifier.
Results: The technique identified AD patients from a mixed population of AD and normal age matched controls with a sensitivity of 95% and specificity of 93%. This performance was improved by applying a Bayessian probability threshold of 80% to produce sensitivity and specificities of 97%. FTD patients were identified from a population of AD and FTD with a sensitivity of 79% and specificity of 72% rising to 82% and 92% respectively after application of an 80% probability threshold
Discussion: The technique presented here supports automation of atrophy measurements producing probabilistic disease classification for use in diagnostic decisions.
DO RATES OF CEREBRAL ATROPHY IN ALZHEIMER’S DISEASE ACCELERATE?
Janssen JC, Chan DC, Jenkins R, Whitwell J, Watt H, Frost C, Fox NC, Rossor MNInstitute of Neurology, London, UK
Aims: To determine the progression of cerebral atrophy in patients with early onset Alzheimer’s disease (EOAD) using serial volumetric MR brain scans.
Methods: Twelve EOAD patients were recruited into a longitudinal study and underwent a minimum of three scans over several years. Two independent techniques were used to determine rates of brain atrophy: (1) The brain boundary shift integral (BBSI); and (2) sequential measurements of total brain volume (TBV). To evaluate changes in atrophy rates with disease severity, atrophy rates were plotted relative to the time when the Mini Mental State Examination (MMSE) was 23/30.
Results: Progressive atrophy was observed in all patients with variation between subjects. The mean rate of atrophy at MMSE 23 was 2.29% (95% CI 1.95–2.63%) per year. Rates of atrophy increased with time by 0.28% (95% CI 0.16–0.39%) per year. However, over periods of one to two years the progression of atrophy could be approximated to a linear relationship. The results obtained using BBSI and TBV were highly concordant.
Discussion: These results provide structural support for the clinical impression that there is considerable variability in rate of progression between EOAD patients. However for an individual patient their rate of change remains relatively constant with a gradual acceleration over time.
DOES MRI/MRS PERMIT ANTEMORTEM DIAGNOSIS OF PROGRESSIVE SUBCORTICAL GLIOSIS OF NEUMANN?
Larner AJ, Smith ETS, Doran MThe Walton Centre for Neurology and Neurosurgery, Liverpool, UK
Background : Progressive subcortical gliosis of Neumann (PSG) is an unusual dementing disorder of variable clinical phenotype. Diagnosis depends on the pathological demonstration of gliosis in superficial and deep cerebral cortical layers and subcortical white matter, sometimes extending to basal ganglia, thalamus, and brain stem. We report on a patient with magnetic resonance imaging and spectroscopy (MRI/MRS) findings suggestive of a diagnosis of PSG.
Results: A 62 year old woman presented with a neurobehavioural syndrome suggestive of frontotemporal dementia, with impairments in personal and interpersonal conduct, emotional blunting, and loss of insight. MRI showed symmetrical frontotemporal atrophy and, on T2 weighted and FLAIR images, confluent and symmetrical high signal intensity changes in frontal subcortical white matter. MRS of this region showed a huge myoinositol peak, increased myoinositol:creatine ratio, and reduced N-acetyl aspartate. The MRI/MRS changes were interpreted as consistent with extensive gliotic change in frontal subcortical white matter, suggesting a diagnosis of PSG.
Discussion: Prior reports of MR imaging in PSG are very few. The striking MRI appearances in our patient were almost identical to those in one previous biopsy proved case. We suggest that MRI/MRS may be helpful in establishing the diagnosis of PSG antemortem without recourse to cerebral biopsy
PRESENTING FEATURES IN FRONTOTEMPORAL DEMENTIA: DISTINCT COGNITIVE AND BEHAVIOURAL PROFILES IN THE LEFT AND RIGHT TEMPORAL LOBE VARIANTS
Thompson SA, Hodges JRCambridge University, Cambridge; MRC Cognition and Brain Sciences Unit, Cambridge, UK
Background : Frontotemporal dementia (FTD) is a progressive dementia syndrome characterised by both cognitive and behavioural symptoms. The objectives of this study were to describe the presenting and early symptom clusters, cognitive deficits and behavioural changes in a large series of patients with temporal variant FTD (tvFTD), and to characterise the distinct profiles of patients with predominantly left (LTLV) and predominantly right (RTLV) temporal lobe atrophy.
Methods: The presenting features in 45 patients with tvFTD were examined retrospectively from hospital casenotes. Patients were classified as LTLV (n=36) or RTLV (n=9) on the basis of neuroimaging performed within 6 months of presentation. Cognitive and behavioural symptoms were recorded and compared across the two groups, and the results of both clinic-based cognitive testing (n=25), detailed neuropsychometry at presentation (n=44), and structured carer questionnaires (n=17) were analysed where available.
Results: Patients with LTLV and RTLV presented with distinct cognitive and behavioural profiles. Word-finding difficulty was the most frequent early complaint of LTLV patients, although depression, irritability and behavioural changes of rigidity, disinhibition, change in food preference and preoccupation with puzzles, also occurred in greater than 25% of cases. The RTLV patients presented with a combination of difficulty with person recognition (from face and voice) and increased levels of irritability, sleep disturbance and social withdrawal. Increased apathy and loss of empathy were other early features. These profiles were reflected in the clinic based cognitive testing with the LTLV patients showing greater levels of anomia (LTLV=0.28; RTLV=0.92), poor verbal recall (LTLV=0.21; RTLV=0.46) and poor category fluency (LTLV=0.24; RTLV=0.43). Similar results emerged from neuropsychometry.
Discussion: Patients with LTLV and RTLV presented with distinct cognitive and behavioural profiles, suggesting a degree of lateralisation of function of the anterior temporal regions, both behaviourally and cognitively. Clinically, the characterisation of these early syndromes may be of value in the diagnosis and management of these patients.
PATTERNS OF NEUROPSYCHOLOGICAL DEFICITS IN VASCULAR, aLZHEIMER’S, AND FRONTOTEMPORAL DEMENTIAS
Varma AR, Doubleday E, Gibbons Z, Snowden JS, Neary DHope Hospital, Manchester, UK
Background : Patterns of neuropsychological deficits are poorly characterised in vascular dementia (VaD). The diagnostic value of neuropsychological deficits in the differentiation of VaD, Alzheimer’s disease (AD), and frontotemporal dementia (FTD) is also unknown
Methods: We studied consecutive patients with VaD (n=19), AD (n=24), and FTD (n=20). All patients underwent standardised neuropsychological evaluation (qualitative and quantitative) aimed at tapping the following domains: memory, orientation, language, span, perception, praxis, spatial, executive function, personality and insight.
Results: Patients with AD were the most amnesic (p=0.002) and lost information over time (p=0.004). This memory deficit (unlike the VaD and FTD groups) was not improved with cues. Memory impairment across VaD and FTD groups was not significantly different.
The incidence of primary spatial impairment (p=0.000) and losing track (p=0.000) was more frequent in AD than VaD and FTD groups. Primary language deficits were significantly more frequent and severe in AD (p=0.002) and FTD (p=0.03) patients in comparison to VaD. Loss of insight and gross personality change differentiated FTD from AD and VaD groups. Although executive dysfunctions (frontal deficits) including perseveration were observed in VaD, they were most severe in FTD (p=0.001).
Discussion: The absence of cortical (primary language, spatial or perceptual) deficits and a milder memory impairment differentiates VaD from AD. Preservation of personality and insight and a milder executive dysfunction distinguishes VaD from FTD. A qualitative analysis of patterns of neuropsychological deficits can be helpful in the distinction of VaD, AD, and FTD.
VARIANT CREUTZFELDT-JAKOB DISEASE: AN EPIDEMIOLOGICAL UPDATE IN RELATION TO GEOGRAPHICALLY ASSOCIATED CASES AND HISTORY OF VACCINATION
Ward HJT, Everington D, Cousens S, Gill N, Smith PG, Will RNational CJD Surveillance Unit, Edinburgh; London School of Hygiene and Tropical Medicine, London; PHLS Communicable Disease Surveillance Centre, London, UK
Although the exact route(s) by which humans became infected with BSE is unknown, consumption of foods containing mechanically recovered meat seems one of the most plausible routes. However, the investigation of the Leicestershire cluster of variant Creutzfeldt-Jakob disease (vCJD) cases raised the possibility of cross contamination of meat in butchers’ shops.
Epidemiological investigation of geographically associated cases of vCJD in six areas has not replicated the Leicestershire findings. A survey of vCJD cases and controls revealed that only two cases and four controls purchased beef only from local butchers. It seems unlikely that the “Leicestershire hypothesis” can explain the majority of vCJD cases.
The young age distribution of vCJD has focused attention on routes of exposure specific to young people. Some vaccine production involved bovine-derived materials. Although risk assessments have concluded that transmission of BSE by this route is most unlikely, the possibility cannot be excluded and continued epidemiological surveillance is required.
Investigation revealed two pairs of vCJD cases and five pairs of community controls who shared vaccines from the same batch. The probability of observing two pairs of cases who have been vaccinated from the same batch is high (45%). Vaccines seem unlikely to be the principal transmission route of BSE to humans.
VARIANT cREUTZFELDT-JAKOB DISEASE: DEVELOPMENT OF A NATIONAL COORDINATED CARE PROGRAMME
Weller B, Will R, McLean GNational CJD Surveillance Unit, Edinburgh, UK
Background : Variant Creutzfeldt-Jakob disease (vCJD) is a devastating illness described in 1996 with 122 cases to 31 May in the United Kingdom. The Douglas report (1999) highlighted major inadequacies in the care provided to vCJD sufferers and as a result a national CJD care unit has been formed. National care coordinators visit all cases of vCJD, to provide information to relatives and health professionals, to advise on coordination of necessary services and on symptom management. A care fund is administered by the care coordinators to overcome deficiencies in services which cannot be provided local authorities.
Methods: Case record audit of the first 22 patients referred to the National CJD Care Unit
Results: The mean age was 26 with a mean disease duration following referral of 5.2 months. All patients had significant functional disability at referral. All had gait disturbance with ataxia (five bed or chair bound 10 walking with assistance, eight independent) and cognitive disabilty (mmse 19/30 n=11) and the majority required assistance with ADLS. Sixteen of the 22 patients were cared for at home. All patients became totally dependent with loss of mobility, swallowing and continence and all developed behavioural changes most commonly aggression or anxiety. Other symptoms and medications used are described along with the most often required equipment and services. Uses of the national care fund are also documented.
Conclusion: This study illustrates the rapidly progressive nature of this illness, particularly after diagnosis and shows that severe disability and troublesome symptoms are already present in all patients at diagnosis.
For patients to return home, input from a wide range of health professionals must be coordinated rapidly with provision of appropriate equipment and house adaptations. Accumulation of data relating to the course of this illness after diagnosis will enable prediction of the care requirements of vCJD patients and their more timely provision and enable a more systematic use of medication for symptom relief.
USE OF SHORT TERM VIDEO EEG IN THE DIAGNOSIS OF ATTACK DISORDERS
McGonigal A, Russell AJC, Malik A, Oto M, Duncan RSouthern General Hospital, Glasgow, UK
Background : Distinguishing epileptic seizures from other attack disorders, particularly psychogenic non-epileptic seizures (NES) may require video-EEG recording. Inpatient video-EEG resources are limited in the United Kingdom, potentially delaying diagnosis. Short term video-EEG has been shown to be a reliable method of recording habitual NES in selected patients, avoiding the need for additional inpatient recording in some; its role in wider clinical practice requires evaluation.
Methods: We collected information in a database on 170 short term video-EEG recordings performed for investigation of attack disorder over an 18 month period.
Results: Age range was 14–86 years; 54 male, 116 female. An attack was recorded in 99/170 (58%); in 66/99 (66.7%) this was a habitual NES, in seven (7.1%) an epileptic phenomenon, in 14 another type of attack (eg movement disorder), and in 12 an inconclusive event. A further 11/170 had no attack recorded, but diagnostic history and/or EEG. Video-EEG performed within 2 days of referral (31/170) was associated with a high yield of recorded attacks (28/33, 90.3%); 19 of these were habitual NES.
Discussion: Short term video-EEG is an inexpensive and reliable diagnostic tool, which can facilitate early diagnosis in some. It complements existing investigative methods and has implications for current use of video-EEG resources.
PERCUTANEOUS STEREOTACTIC THERMOCOAGULATION OF HYPOTHALAMIC HAMARTOMAS: EFFICACY AND SAFETY
Mullatti N, Selway R, Elwes R, Polkey CKing’s College Hospital, London, UK
Background : Hypothalamic hamartomas may present with medically intractable epilepsy, typically with a complex seizure disorder including gelastic seizures, behavioral disturbance and precocious puberty. Open surgery is difficult and its risks may be unacceptable to patients. We present a minimally invasive method of treatment for hypothalamic hamartomas
Methods: Two cooperative adult patients who suffered with a severe seizure disorder and MRI evidence of a hypothalamic hamartoma, underwent stereotactic placement of depth electrodes into the hamartoma and areas that appeared semiologically or electrically to be involved in their seizures. Direct recording from the lesions confirmed them to be the site of seizure onset. Electrical stimulation of the lesions reproduced their habitual seizures at low threshold. Using local anaesthetic, the electrode in the hamartoma was replaced with a thermocoagulation electrode. Gradually increased thermal lesions were created within the hamartomas up to 80 Celsius.
Results: The procedure was well tolerated by both patients. The procedure was halted in one patient when dizziness occurred and in the other when reversible unilateral pupillary dilatation occurred. Post-peratively there were no complications. One patient gained immediate benefit in terms of seizure frequency although at 6 months continues to have about 30% of baseline frequency. The other had little immediate change but a progressive reduction over 6 months also to 30% of baseline.
Discussion: Stereotactic thermocoagulation is an effective, minimally invasive technique for the treatment of hypothalamic hamartomas
PROSPECTIVE ANALYSIS OF THE OUTCOME OF LEVETIRACETAM TREATMENT
Smith D, Nicolson AThe Walton Centre for Neurology and Neurosurgery, Liverpool, UK
Background : By prospectively analysing all patients treated with levetiracetam (LEV) since licensing in the UK, we aim to provide information to guide the rational prescribing of this new AED.
Methods: All patients treated with LEV were identified and data collected on the age of onset, diagnosis, previous medical and AED history, initial dosing regime, efficacy, adverse events, whether or not the patient remains on LEV and, if not, the reason for withdrawal. Kaplan-Meier survival analysis was used to estimate the overall retention rate and multivariate analysis to determine factors affecting retention.
Results: Follow up data were available in 210 of 255 patients to have received LEV. 146 (70%) remain on treatment, with seizure control improving in 105 (50%) and 14 (7%) were seizure free. The commonest adverse events requiring withdrawal were sedation and psychiatric symptoms. Factors most predictive of retention were a low starting dose and slow titration, and an absence of a psychiatric history.
Discussion: This study shows LEV to be well tolerated and efficacious. A significant proportion of patients have had a worthwhile improvement in seizure control, with a remission rate of 7% in this refractory population. Low initial dose with a cautious titration reduces the chances of drug withdrawal.
HOW ACCURATE ARE SEIZURE DESCRIPTIONS?
Wieshmann UC, Mannan JThe Walton Centre for Neurology and Neurosurgery, Liverpool, UK
Background : The aim of the study was to assess the accuracy of seizure descriptions.
Methods: Twenty subjects (10 medical students, four neurological senior house officers and six non-medical students) viewed a video of a partial, secondary generalised seizure with left sided onset and documented their observations. The seizure had eight key features. Subjects scored one point for each described key feature (“positive score”). One point was subtracted for each false observation (“negative score”).
Results: The mean positive score was 3.45 (range 1 to 6). Unresponsiveness and lateralising features were often missed. The mean negative score was 0.75 (range 0 to 3). Erroneously described features included “patient rolled over”. Left and right were sometimes confused. The mean total score was 2.7 (range −2 to 6). A non-medical and a medical student achieved the highest scores. Senior house officers and students who had received epilepsy teaching did not score consistently higher than non-medical students.
Discussion: Seizure descriptions by witnesses are usually incomplete and often incorrect. Previous epilepsy teaching or working on a neurology ward did not consistently improve the accuracy. The limited ability of witnesses to describe seizures accurately needs to be taken into account when seizures are classified.
CHARLES KARSNER MILLS (1845–1931) AND HIS SYNDROME
Carroll C, Gardner-Thorpe CDerriford Hospital, Plymouth; Royal Devon and Exeter Hospital, Exeter, UK
Charles Mills, a well known physician in Philadelphia, was responsible for the development of much of the neurological service in that City. A keen writer, he is best known for his descriptions of hemiparesis without structural explanation. Mills’ syndrome is long forgotten in many circles but cases do arise from time to time and the condition is not yet explained fully even with the more sophisticated investigations available to neuroscientists of the 21st century.
Two cases are presented to illustrate the Mills’ original description of a progressive, ascending or descending hemiplegia without significant sensory involvement and without obvious structural cause on imaging.
Rare case reports suggest the syndrome represent a hemiplegic form of primary lateral sclerosis. Postmortem studies of Mills’ original cases revealed non-specific, staged, irregular lesions of the pyramidal tracts predominating on one side at the level of the spinal cord and in the brain stem. The motor cortex and Betz cells were normal.
However a similar clinical picture has been described in the context of a focal cortical degeneration (primary progressive hemiparesis) with loss of Betz cells confirmed on postmortem examination. A relationship with corticobasal degeneration and with motor neuron disease is possible.
HYPOCRETIN (OREXIN IN NEUROLOGICAL, SLEEP AND PSYCHIATRIC DISORDERS: A PROSPECTIVE STUDY OF CSF HYPOCRETIN
Ebrahim IO, Howard RS, Williams AJ, de Lacy S, Semra Y, Kopelman MD, Sharief MKSt Thomas’ Hospital, London, UK
Background : The hypocretins (orexins) are recently described hypothalamic neuropeptides thought to play a significant role in the regulation of sleep, arousal and activation. It has been suggested that disruption of hypocretin neurotransmission causes narcolepsy-cataplexy (NC). Previous studies in patients with neurological illness have found that CSF hcrt-1 did not differ significantly between patients and normal controls. There have been no published reports on CSF hcrt levels in patients with psychiatric disorders. There is a paucity of literature on CSF hcrt levels in patients with other disorders of excessive daytime somnolence (EDS). The role of CSF hypocretin-2 (hcrt-2) levels in these sleep disorders is unclear. We report here a study measuring, in the first instance, CSF hcrt-1 levels in a variety of neurological and psychiatric conditions. Secondly, we report findings on CSF hcrt-1 and hcrt-2 from a prospective study in patients with NC, monosymptomatic narcolepsy (MN), and primary hypersomnia (PH).
CSF hcrt-1 in neurological and psychiatric disorders: CSF samples from 194 patients with a variety of neurological and psychiatric diagnoses were analysed for hcrt-1 levels.
CSF hcrt-1 and hcrt-2 in NC, MN and PH: In addition to CSF hcrt-1 and hcrt-2 levels, patient assessments included the following: Epworth Sleepiness Score (ESS); clinical evaluation; and HLA typing; conventional nocturnal polysomnography (NPSG); multiple sleep latency testing (MSLT).
CSF hcrt-1 in neurological and psychiatric disorders: Hcrt-1 was detectable in all the specimens tested. The mean Hcrt-1 for the entire sample was 176 ± 53 pg/ml.
CSF hcrt-1 and hcrt-2 in NC, MN and PH: CSF hcrt-1 was undetectable in all the patients with NC (n=14) with a mean CSF hcrt-2 level of 4.32 pg/ml. Very low levels of CSF hcrt-1 were found in patients with MN (n=4; mean = 48 pg/ml) and the mean CSF hcrt-2 level was 2.86 pg/ml. The mean CSF hcrt-1 was 67.9 pg/ml and the mean CSF hcrt-2 level was 7.1 pg/ml in patients with PH.
Discussion: CSF Hcrt levels in patients with neurological and psychiatric disorders were within the control range. The finding that low levels of CSF hcrt-1 are present in some patients in all of the sub-groups analysed suggests that low hcrt-1 levels may reflect hypothalamic dysfunction and/or damage. This provides further evidence that undetectable levels hcrt-1 in CSF is highly specific for narcolepsy. Our findings for CSF hcrt-1 levels in NC confirms this. We have not replicated the finding that there may be a variant of narcolepsy with normal or high levels of CSF hcrt-1. We report, for the first time, very low levels (<100 pg/ml) of CSF hcrt-1 levels in MN and PH in this small sample and a generalised deficiency of hcrt-2 in all these patients with EDS.
NOICICEPTIN/ORPHANIN FQ, AN ORL-1(NOP1) AGONIST INHIBITS TRIGEMINOVASCULAR ACTIVATION IN THE RAT
Goadsby PJ, Akerman S, Bartsch TInstitute of Neurology, London, UK
Background : The recently discovered heptadecapeptide nociceptin (NCE)/orphanin FQ has been identified as the endogenous ligand for the ORL-1 (NOP1) receptor, but does not bind to opioidergic μ, δ, or κ receptors nor are the effects of nociceptin antagonised by naloxone.
Methods: We studied the effects of the ORL-1 (NOP1) receptor ligand nociceptin (NCE) and the nociceptin antagonists [Nphe1]nociceptin(1–13)NH2 and nocistatin (NST) on neurogenic dural vasodilatation (NDV) in the rat dura mater evoked by electrical stimulation of a closed cranial window. The middle meningeal artery was visualised using intravital microscopy, and the vessel diameter analysed using a video dimension analyser.
Results: NCE (1, 10, 100 nmol kg−1 iv, n=10) significantly and dose-dependently suppressed neurogenic dural vasodilatation maximally by 65 % (p<0.01). Neither [Nphe1]nociceptin(1–13)NH2 (100 nmol kg−1; n=5) or nocistatin (NST, 100 nmol kg−1; n=4) alone had an effect on NDV (p>0.05). Baseline vessel diameter was not significantly affected by application of NCE, NST, or [Nphe1]nociceptin(1–13)NH2. Application of the selective NCE antagonist [Nphe1]nociceptin(1–13)NH2 (10, 100 nmol kg 1 iv, n =8) dose-dependently and significantly (p< 0.01) reversed the inhibition of NDV induced by application of NCE (10 nmol kg−1). NST (10, 100 nmol kg−1, n=7) failed to reverse the effects elicited by NCE. Application of NCE elicited a dose dependent transient decrease in arterial blood pressure (p<0.01). [Nphe1]nociceptin(1–13)NH2 dose dependently reversed the cardiovascular effects induced by application of NCE (10 nmol kg−1) (p<0.01), whereas NST did not alter the blood pressure reaction elicited by NCE.
Discussion: The results show that nociceptin inhibits neurogenic dural vasodilatation, an effect which is antagonised by [Nphe 1 ]nociceptin(1–13)NH 2 , but not by nocistatin. ORL-1 (NOP 1 ) receptors located on trigeminal sensory fibres may be involved in the regulation of dural vessel diameter and hence may play a part in migraine pathophysiology.
SCREENING OF THE SPASTIN GENE IN AUTOSOMAL DOMINANT HEREDITARY SPASTIC DOMINANT HEREDITARY SPASTIC PARAPLEGIA REVEALS SEVEN NOVEL MUTATIONS
Proukakis C, Crosby AH, Auer-Grumbach M, Wagner K, Reid E, Patton MA, Warner TTSt George’s Hospital Medical School, London; Royal Free and UC Medical School, London; Karl-Franzens University, Graz, Austria; University of Cambridge, Cambridge, UK
Background : Hereditary spastic paraplegia (HSP) is a heterogeneous condition characterised in its pure form by progressive lower limb spasticity. Mutations in the SPG4 (spastin) gene are responsible for up to 40% of autosomal dominant (AD) cases.
Methods: A cohort of 41 mostly pure HSP patients from Britain and Austria, 30 of whom displayed AD inheritance, was screened for mutations in SPG4 by single strand conformation polymorphism (SSCP) analysis followed by sequencing of samples with mobility shifts. Where relevant, sequences were confirmed by subcloning and control chromosomes were screened.
Results: We identified eight SPG4 mutations, all in AD patients. All but one of these were novel: four frameshift mutations (190–208dup19, 1259–1260delGT, 1702–1705delGAAG, 1845delG), two splice site mutations (1130–1g>t, 1853+2t>a) and one missense mutation within the AAA cassette (1633G>T). We also detected a silent change (1004G>A), previously reported as a mutation, which was also present in controls.
Discussion: The frequency of SPG4 mutations detected in AD HSP was 26.7%. If only pure AD HSP is considered, this rises to 33.3%. SSCP is a valuable screening tool for SPG4 mutations in AD HSP. Most patients will have unique mutations. Screening of SPG4 in apparently isolated cases of HSP may be of less value.
VOLUMETRIC REGISTRATION OF LOW GRADE GLIOMAS: A QUANTITATIVE APPROACH TO MEASURING TUMOR
Rees JH, Benton C, Fox N, Waldman A, Moore EA, Jager R, Stevens J, Tofts PInstitute of Neurology, London; National Hospital for Neurology and Neurosurgery, London; Charing Cross Hospital, London, UK
Background : Low grade gliomas (LGG) are primary brain tumours that have a propensity to transform into malignant gliomas. This is an unpredictable event in their natural history and may be preceded by a phase of increasing tumour growth. We hypothesise that techniques incorporating volumetric measurements with serial registration may be more sensitive than conventional MRI techniques in detecting the earliest stages of malignant transformation
Methods: Patients with low grade gliomas were scanned on a 1.5 T system (LX/MRi, GE Medical Systems) using a range of imaging sequences. For volumetric analysis, coronal 3D IR-prepped SPGR scans were acquired before Gd contrast administration. The data were analysed using in house software, MIDAS (Medical Information Display and Analysis System) and DispImage. Once registered, scans were displayed showing differences in normalised intensity overlaid on the base images. Signal differences greater than ±20% were shown with a colour overlay. Scans were analysed qualitatively for changes in mass effect, tumour volume, and tumour signal intensity for each scan pair. In addition quantitative volumes were determined using a combination of automatic contouring and manual editing of FLAIR images using DispImage.
Results: Of 41 patients scanned to date, seven have transformed, five have left the study and one has died. All scans have been successfully registered. Tumour growth has been assessed qualitatively and quantitatively and is present in all patients when standard sequences are reported as showing no change. There is a large range (6–25%) of volume changes in each 6 month period.
Discussion: It is now possible to apply accurate computerised registration and lesion volume measurements to the study of untreated low grade gliomas. This is the first study to quantitate tumour growth by analysis of FLAIR images which provide the greatest sensitivity in relation to signal contrast between tumour and normal tissue. It is anticipated that these techniques will enhance our ability to monitor the natural history of low grade gliomas.
[11C]-WAY100635 PET: A SURROGATE MARKER FOR MND?
Turner MR, Rabiner EA, Doder M, Shaw CE, Grasby PM, Brooks DJ, Leigh PNKing’s College London; Hammersmith Hospital, London, Institute of Neurology, London, UK
Background : There is an urgent need for a reliable in vivo marker of disease in MND, for monitoring in clinical trials and to reduce diagnostic delay. WAY100635 is a selective ligand for the serotonin 5-HT1A receptor, known to be expressed by cortical pyramidal neurons.
Methods: Seven MND patients, and one presymptomatic patient with a family history, underwent [11C]-WAY100635 PET. None were taking any serotonergic medication and the presence of significant depression was excluded. Data were compared to 11 healthy, age matched, volunteers.
Results: Global cerebral postsynaptic binding of [11C]-WAY100635 was on average 32% less in the MND patients (SD 6, p<0.0001). Autoreceptor (raphe) binding was 35% less (SD 6, p<0.0001). Values for the presymptomatic patient were 33% and 20% reduction respectively. In this pilot study no regional cortical variation was seen.
Discussion: The marked reduction in cerebral binding of [11C]-WAY100635 is greater than that reported for any other degenerative or affective disease state. This may represent a down regulation of receptors, or physical loss of neurons bearing them. Serotonergic systems may be involved in the control of motor neuronal excitability, cognitive pathways, and possibly have a neurotrophic role. [11C]-WAY100635 PET has potential as a sensitive in vivo surrogate marker in MND, and as a presymptomatic diagnostic tool.
CAMPATH-1H IN THE TREATMENT OF PATIENTS WITH WORSENING MULTIPLE SCLEROSIS
Cox AL, Le Page E, Coles AJ, Miller D, Hale G, Waldman H, Compston DASAddenbrooke’s Hospital, Cambridge; Institute of Neurology, London; Therapeutic Antibody Centre, Oxford, UK
Background : Campath-1H suppresses radiological and clinical markers of inflammation in secondary progressive multiple sclerosis (SPMS), but not disease progression. We compared the efficacy of Campath-1H in early relapsing-remitting multiple sclerosis (RRMS) versus SPMS.
Methods: A retrospective study of all 49 patients treated with Campath-1H was performed (cohort I, 37 SPMS patients; cohort II, 12 RRMS patients).
Results: Cohort l: Campath 1H treatment succeeded disease onset and progression by 11.8 and 3.6 years (means) respectively. Disability increased within 18 months in most patients, 2–5 years in those initially stabilised.
Cohort II: Campath-1H succeeded disease onset by 2.5 years (mean). In the year preceding treatment, mean relapse rate was 3.16/year, EDSS increased by 2.4 points. Three patients relapsed once after treatment without altering EDSS, five had no evidence of activity (reducing annualised relapse rate from 3.4 to 0.36). Retrospectively, two patients in cohort II had entered the progressive phase prior to treatment. Of these, one continued to progress, the second remains unchanged after 4.5 months.
Discussion: This study strengthens evidence that Campath-1H has greater efficacy when given early in RRMS. This principle supports a randomised trial comparing Campath-1H with β-interferon in RRMS.
AGGREGATE CULTURES FROM ADULT HUMAN BRAIN ARE A SOURCE OF OLIGODENDROCYTE LINEAGE CELLS
Halfpenny CA, Scolding NJUniversity of Bristol; Frenchay Hospital, Bristol, UK
Background : Transplantation of oligodendrocyte progenitors holds promise as a strategy for promoting brain repair in multiple sclerosis. However human progenitors have been difficult to study, and differ in their biology from rodent cells. While these cells can be grown from adult human brain, numbers are limited, and attempts to expand them in vitro have been largely unsuccessful.
Methods: Specimens resected during the course of epilepsy surgery were used as a source of early glial progenitors. Tissue was enzymatically dissociated and triturated, and then grown on a non-adhesive substrate, in the presence of FGF-2 and EGF. Cells were then plated onto polylysine coverslips and identified using immunofluorescence.
Results: Cells grown in these conditions formed aggregates, and expanded further as spherical bodies. On plating onto polylysine the cells extended processes and spread out. Non-adherent clumps stained for nestin, a putative marker of neural stem cells, and some cells retained this staining after adhering. Cells expressing markers of neurons, astrocytes and oligodendroglial lineages were seen from individual aggregates, although we observed considerable heterogeneity between the aggregates as to their relative populations. The expression of more mature oligodendroglial markers at later time points suggests that this lineage is well represented in these cultures
Discussion: The presence of significant numbers of oligodendrocyte lineage cells in these cultures provides a useful source for further study. Understanding the neurobiology of oligodendrocyte progenitors is an essential step for remyelination strategies. Further progress may lead to substantial expansion of this cell population and a possible source for therapeutic remyelination.
GENETIC SUSCEPTIBILITY TO MULTIPLE SCLEROSIS: AN ANALYSIS OF FOUR CANDIDATE GENES
Hensiek A, Roxburgh R, Sawcer S, Meranian M, Seaman S, Yeo T, Compston AUniversity of Cambridge, Cambridge, UK
We screened the genes encoding angiotensin converting enzyme (ACE), myeloperoxidase (MPO), insulin, and osteopontin for an influence on disease susceptibility and/or clinical progression of multiple sclerosis (MS). The ACE and MPO genes are encoded in one of the best-supported regions in several linkage screens (17q21-q23). MPO has previously been associated with the disease and serum ACE levels have been suggested to be an indicator of disease activity. Type I diabetes mellitus is more common in MS, suggesting that individual genes may contribute to susceptibility of both diseases—the insulin gene, a confirmed type I diabetes susceptibility locus, may therefore also be relevant to MS. The transcription of the T-cell cytokine osteopontin is increased in nervous tissue of patients with MS and rats with EAE; in addition, expression correlates with disease severity in the latter. We did not find significant allelic differences of the screened polymorphisms of these four genes in a large cohort of MS cases compared with controls. Furthermore, there was no allelic association of the osteopontin gene with disease severity. This indicates that despite strong theoretical reasons to consider them as potential candidates, these genes are not susceptibility loci for either the development or clinical severity of MS.
INFLUENCE OF DEPRESSION ON SELF REPORTING OF THE PHYSICAL IMPACT OF MULTIPLE SCLEROSIS IN TWO COMMUNITY BASED POPULATIONS
McGuigan C, McCarthy A, Hutchinson MSt Vincent’s University Hospital, Dublin, Ireland
Background : Depression is a common symptom in patients with multiple sclerosis (MS). It has a lifetime prevalence of 50%. Mood is known to affect one’s perception of wellbeing and health status. In recent years there has been an increasing acceptance of patient reported outcome measures of health status in clinical trials and health surveys. The aim of our study is to determine whether or not depression in two community based populations with MS influenced the self reporting of the physical impact of MS.
Methods: During the course of an epidemiological study 73 patients with clinically probable or definite MS (Poser criteria) were identified in County Wexford, Ireland. A further 103 patients with definite/probable MS were recruited from County Donegal. All patients were individually assessed and a Kurtzke EDSS and multiple sclerosis functional composite (MSFC) scores applied. Participants were asked to complete a Beck’s depression inventory II (BDI-II), multiple sclerosis physical impact scale (MSIS-20) and a multiple sclerosis psychological impact scale (MSIS-9).
Results: The population characteristics were similar for both counties. The average age of participants was 47.5 years (19–78), duration of MS 15 years (1–56). Female to male ratio 2.2:1. Average Kurtzke EDSS 4.7 (0–9). In the Wexford sample (n=73) 21 patients scored between 20–63 on the BDI-II form, indicating moderate–severe depression, the remaining 52 had minimal to mild depression. In Donegal (n=03) 19 patients scored above 20 on the BDI-II.
In each county the population was divided into two groups depending on the BDI-II score: 0–19 (minimal mild depression) and 20–63 (moderate/severe depression). There was no statistical difference between these groups for age, duration of illness, marital or employment status, clinical course, or treatment regimes. Disability levels as assessed by the Kurtzke EDSS and MSFC scores were also not statistically different. As expected the MSIS-9 (psychological impact score) was scored statistically worse in the more depressed groups (p< 0.001). The MSIS-20 (physical impact score) was also significantly worse in the more depressed group (p=0.05).
Discussion: Depression, as measured by the BDI-II, significantly affects patients interpretation of the physical impact of MS, as measured by the MSIS-20, in two community populations. Observer rated measures do not show such a relationship. Further longitudinal analysis is requried of the relationship between mood and patient rated measures of disease impact before they can be widely accepted as outcome measures for clinical trials and health surveys.
THE EFFECT OF CORTICOSTEROID ON CONDUCTION IN THE VISUAL PATHWAYS: A SERIAL STUDY USING VISUAL PSYCHOPHYSICS
Pye EM, Weatherby SJM, Kesson D, Foster DH, Hawkins CPThe Keele MS Research Group, Stoke on Trent; UMIST, Manchester, UK
Background : Acute multiple sclerosis (MS) relapses are characterised by episodes of neurological dysfunction secondary to inflammation, oedema and demyelination. Intravenous corticosteroid promotes more rapid recovery. Visual psychophysics provides an established measure of sensory deficit, which may be selective for different functional pathways.
Methods: Five patients (10 eyes) experiencing an acute, non-visual MS relapse having a three-day course of intravenous corticosteroid had serial visual psychophysics performed. Contrast thresholds were measured at three spatial frequencies (0.25, 1.0 and 4.0 cycles/deg) with counter-phase (chromatic modulated) and in-phase (luminance modulated) red-green gratings.
Results: At low spatial frequency throughout the study, chromatic thresholds were significantly lower than corresponding achromatic thresholds (p< 0.0003). At low and medium spatial frequencies a non-significant improvement from baseline in both chromatic and achromatic thresholds was seen after the third dose and sustained 1 week later. At high spatial frequency
improvements were not seen until 1 week postcorticosteroid.
Discussion: MS patients have subtle, subclinical deficits in vision not significantly improved by a course of corticosteroid. These chronic visual deficits may result from permanent structural injury. A degree of acute inflammatory change may still be present as shown by the trend towards improvement in contrast thresholds that favoured neither chromatic nor achromatic pathways.
MULTIPLE SCLEROSIS AND OCCULT GLUTEN SENSITIVITY
Tengah DSNAP, Unsworth DJ, Lock RJ, Wills AJDerbyshire Royal Infirmary, Derby; Southmead Hospital, Bristol; Queen’s Medical Centre, Nottingham, UK
Background : Gluten sensitivity has been reported to be associated with neurological conditions, eg idiopathic cerebellar ataxia and epilepsy. Antigliadin antibody (AGA), an anti-wheat protein antibody, has been used by many researchers despite its inferior specificity compared to antiendomysial (AEA) and tissue transglutaminase antibodies (TTG) which are directed against tissue. Previous studies have failed to show a link between gluten sensitivity and multiple sclerosis (MS). We aimed to screen a cohort of MS patients for evidence of true gluten sensitivity as well as the prevalence of AGA and antibodies against common foodstuffs including milk and egg.
Methods: Patients with MS were recruited from general neurology and MS clinics. AGA, TTG and antibodies to other common foods were detected by enzyme linked immunosorbent assay (ELISA). EMA was detected by indirect immunofluorescence. Thirty blood donors were the control group for the food antibodies.
Results: Forty nine MS patients were recruited. Ten patients showed some degree of positivity for coeliac antibodies. One had unequivocally positive results but no gastrointestinal symptoms and declined small bowel biopsy. The others had isolated positive results (at low titre) of dubious significance. Antibodies to other common foods are found with similar incidences in the MS and control populations (eg, IgG antiovalbumin 7/49 and 7/30, respectively).
Discussion: MS patients have a high prevalence of non-specific food antibodies (14–20%) but no statistically significant increase in true gluten sensitivity when contrasted with the general population. Our results suggest that AGA are unreliable as true indicators of gluten sensitivity in neurological populations.
FALIURE TO IDENTIFY CHANGE IN THE CERVICAL DYSTONIA MUSCLE PATTERN IS THE MAIN CAUSE OF REDUCED RESPONSE TO BTXA
Cordivari C, Vincent A, Misra VP, Catania S, Murray NMF, Bhatia KP, Lees AJThe National Hospital for Neurology and Neurosurgery, London, UK
Objective: To investigate the reasons which lead to patients with cervical dytonia becoming secondarily non-responsive to botulinum toxin type A (BTXA).
Methods: Twenty poorly responsive patients with cervical dystonia were assessed with TWSTRS, clinical observation, Extensor digitorum brevis (EDB) test and Immunoprecipitation assay (IPA) before and 15 days after treatment with 500 mμ of BTXA (Dysport™) into the neck muscles using EMG guidance simultaneously assessing muscle activity.
Results: Following EMG guided injections 10 patients showed a >40% improvement in their clinical response. EDB amplitude decrement >63%. Eight of these were antibody negative and two showed a low antibody titre (<1277 pM).
Ten patients were clinically unchanged. Eight of them had elevated antibody titres (13404–1743 pM), EDB decrement of <23%. The remaining two were antibody negative and had a significant EDB decrement, but they improved in clinical response to subsequent EMG guided injections targetting different muscles.
Discussion: The main cause behind decreased response to BTXA seems related to a change in pattern of dystonia which can be overcome by carefully directed EMG guided injections. When clinical improvement is poor an EDB test should be performed. IPA antibody test is required in borderline EDB decrement to confirm BTXA resistance.
CLINICAL PHENOTYPES IN PD AND THE DEVELOPMENT OF DEMENTIA
Dunn EM, Read NL, Mindham RHS, Spokes EGSUniversity of Leeds; Leeds Teaching Hospitals NHS Trust, Leeds, UK
Background : The concept of clinical phenotypes in Parkinson’s disease (PD) is well established. Use of such classifications in clinical practice is likely to vary between PD specialists. Tremor predominance is widely held to be a phenotype of good prognosis, with a lesser rate of dementia development. We explore these issues in two studies.
Methods: Study 1. With the assistance of the Parkinson’s Disease Research Group of the United Kingdom (PDRGUK), a questionnaire concerning the use and implications of clinical phenotypes was sent to approximately 110 United Kingdom PD specialists (both neurologists and geriatricians).
Study 2. 83 non-demented PD patients were recruited between 1985–1987. In addition to cognitive testing at 9 month intervals (Weschsler Adult Intelligence Scale (WAIS), Weschsler Memory Scale (WMS), Graded Naming Test (GNT), patients were assessed in terms of mood, disability and severity of disease (Hoehn and Yahr and Webster Rating Scale). In 51 patients assessment occurred 5 years prior to dementia development (if demented) or 5 years prior to their last assessment (if not). Clinical phenotype was judged at both these times (Time 1 and, 5 years later, Time 2) by the relative proportion of the Tremor, Bradykinesia, and Rigidity Webster component sub-scores.
Results: Study 1. 51 replies were received. Of these 51, 89% felt that one could reliably classify patients into phenotype within the first 3 years after disease onset, although only 57% would routinely do so; 75% of respondents felt that tremor predominant PD has a better prognosis than other phenotypes. This was mostly (in 73% respondents) thought to be only the case if the clinical picture remained stable, with a change of phenotypic classification being made as soon as signs altered. In Study 2, no significant difference was found in the relative proportions of the Webster subscores at Time 1 between those who went on to develop dementia and those who did not. Demented patients, at Time 2, were more akinetic-rigid than non-demented patients.
Discussion: Clinical phenotypes are used in clinical practice by United Kingdom PD specialists to predict prognosis. If clinical signs change the prognosis is altered at once. Study 2 suggests that prediction of the risk of dementia development without adjustment of phenotypic classification in the interim period is not possible, supporting this approach.
THE NEURAL BASIS FOR COGNITIVE HETEROGENEITY IN PARKINSON’S DISEASE AS DETERMINED BY FMRI
Lewis S, Dove A, Robbins T, Barker R, Owen AUniversity of Cambridge, Cambridge, UK
Background : Cognitive impairment is a common feature of Parkinson’s disease and neuropsychological testing often reveals a pattern of deficit, which suggests that the underlying pathological substrate may lie in the frontostriatal circuitry of the basal ganglia of affected patients. To assess the neural basis of this pattern of impairment we have performed an event related functional MRI (fMRI) study using a working memory paradigm that allows aspects of maintenance, retrieval and manipulation to be tested.
Methods: Three subject groups underwent testing in this study. A group of 10 healthy, age matched controls, a sub-group of 10 PD patients with no discernible executive impairment (PDEU) and a sub-group of 11 patients who showed impaired performance on a `standard’, visuospatial test of executive function (The Tower of London Task TOL) but were well matched on all other demographic and cognitive measures tested (PDEI). Discrimination on the TOL was chosen as this task has been shown previously to be sensitive to deficits in the earliest stages of the disease
Results: The behavioural results on the working memory paradigm showed no significant differences between the three groups. On fMRI, a group analysis of all subjects showed activation of the familiar neural network associated with such tasks including the ventrolateral frontal cortex, striatum and posterior association areas in the parietal and occipital cortices. However, despite their similar behavioural performance, a region of interest comparison between the patient groups revealed that the PDEI subgroup significantly underactivated regions implicated in the frontostriatal circuitry (caudate, putamen, ventrolateral frontal cortex) but not posterior association cortical areas when compared to the patients in the PDEU sub-group. Furthermore, this impairment was most marked in those aspects of working memory that required the manipulation of information rather than its simple maintenance and retrieval.
Discussion: We believe that the present study is the first neuroimaging research to address cognitive heterogeneity in PD. The results clearly demonstrate that within PD there is a sub-group of patients who have a selective impairment in executive function, whilst being well matched on other disease features including other cognitive parameters and that this is related to a disturbance in the frontostriatal pathways. These results have obvious implications in the management of such patients given the correlation of cognitive impairment in PD with quality of life, depression and hallucinations.
STUDY OF MUTANT AND WILD TYPE TORSIN A IN HUMAN SH-SY5Y CELL LINES
Misbahuddin A, Placzek MR, Taanman J-W, Cooper JM, Warner TTRoyal Free and University College Medical School, London, UK
Background : TorsinA is the protein product of the DYT1 gene on chromosome 9q34 responsible for autosomal dominant early onset torsion dystonia. A single GAG deletion in this gene is responsible for almost all cases. TorsinA is widely expressed in the brain but its cellular function is unknown.
Methods: Constructs were created using the expression vector pcDNA3.1 and the cDNA from a patient with early onset torsion dystonia carrying the DYT1 GAG deletion, and a control. A haemagglutinin (HA) epitope tag was incorporated at the C terminus. The constructs were transfected into SH-SY5Y, a human neuroblastoma cell line. Successful stable transformants were selected by using neomycin. Presence and location of expressed protein was determined in clones by immunofluoresence using a monoclonal antibody to the HA tag. The size was determined by western blotting.
Results: Mutant and wild type protein demonstrated distinct subcellular localisation without overt effect on cellular morphology and survival. The wild type was expressed widely throughout the cytoplasm whilst the mutant protein appeared to form large perinuclear aggregates. Western blotting indicated a protein close to the predicted size of torsinA (38KDa) in all clones, which was not detected in the control cell lines. However, the mutant protein appeared to run at a smaller size in comparison to the wild type.
Conclusions: These results support the findings of differential localisation of mutant and wild type torsinA previously reported in mouse neural (CAD) and human embryonic kidney cell lines. We are now undertaking studies of subcellular localisation, protein interaction and function in the SH-SY5Y cell lines.
EARLY, LIMB ONSET DYSTONIA WITH LATE GENERALISATION IN AN IRISH FAMILY IN WHICH THE DYT1 (TOR1A) GAG DELETION HAS BEEN EXCLUDED
O’Riordan S, Lynch T, Bressman S, Hutchinson MSt Vincent’s University Hospital, Dublin; Mater Hospital, Dublin, Ireland; Beth Israel Hospital, New York, UK
Background : Primary torsion dystonia (PTD) is clinically and genetically heterogeneous. Most early, limb-onset PTD is due to a GAG deletion in the TOR1A (DYT1) gene. Affected members of the two large families in which the DYT6 and DYT13 loci were detected had “mixed” phenotypes with both childhood and adult onset and prominent cranial and cervical involvement.
Methods: Following identification of the proband who has early, limb onset dystonia, 16 consenting first and second degree relatives from three generations of the family were assessed. Assessment consisted of taking a detailed medical history from each individual and performing a standardised neurological examination, a segment of which was videotaped. The videotaped examinations were reviewed and rated by three neurologists. Individuals were rated as having definite, probable, possible, or no dystonia.
Results: The proband, a 66 year old woman, developed dystonia in her right leg at age 7 years. Within months her right arm became affected. She could write only with her left hand from age 12 years. Her dystonia remained stable until 10 years ago when she developed laryngeal dystonia. In the past 3 years she has developed left upper limb dystonia and prominent cervical dystonia. Investigations including cranial MRI, CSF and blood tests are normal. She does not carry the TOR1A GAG deletion. Recent treatment with levodopa, trihexphenidyl, and baclofen has resulted in minor improvement in her symptoms.
Her sister, aged 69 years, had onset of dystonia at age 5 years in her left leg. This remained stable and did not progress until about 20 years ago when she has developed dystonia of both upper limbs. More recently she has developed mild cervical dystonia.
Four other family members have definite dystonia. These are three children and one grandchild (aged 15 years) of the proband’s sister. The phenotype was one of generalised dystonia with prominent cranial involvement. The severity of dystonia was mild in all four of these individuals and indeed, three denied any symptoms. Five other individuals were rated as having probable dystonia and five others had possible dystonia. Significant postural upper limb tremor was noted in several individuals.
Discussion: We describe an Irish family with an unusual dystonia phenotype. Affected members have early limb onset dystonia with late generalisation and prominent craniofacial involvement. There is significant intrafamilial variation in dystonia severity. The DYT1 (TOR1A) locus has been excluded.
PICTURING THE ATROPHY PATTERNS OF PROGRESSIVE SUPRANUCLEAR PALSY AND MULTIPLE SYSTEM ATROPHY IN VIVO USING FLUID REGISTERED MRI
Schott JM, Paviour DC, Fox NC, Stevens JM, Lees AJ, Rossor MNInstitute of Neurology, London, UK
Background : Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are neurodegenerative disorders with phenotypic similarities but different pathologies. Little is known about the progression of atrophy in these conditions and how this correlates with histology.
Methods: Serial MRI scans were obtained from one patient with PSP and one with MSA, both of whom subsequently had their diagnoses confirmed at postmortem. Fluid registration of the serial scans was used to assess changes over time.
Results: We demonstrate differing patterns of regional distribution of atrophy between the two cases. In PSP there was diffuse atrophy throughout the brainstem. There was atrophy of the motor strip and precentral gyrus, with sparing of the sensory cortex, and only mild cerebellar atrophy. In MSA, there was extremely prominent pontine atrophy, with lesser atrophy of midbrain, medulla, and cerebellar white matter. Atrophy was also seen in the frontal lobes, the genu of the corpus callosum, and the anterior temporal lobes, with sparing of the hippocampi, and motor cortex. In both cases the atrophy patterns mirrored the clinical features and findings at postmortem.
Discussion: Fluid registration of serial MRI demonstrates specific patterns of in vivo regional atrophy in PSP and MSA. This technique may be a useful, non-invasive tool in differentiating focal neurodegenerative diseases during life, and elucidating the progression of pathology.
PREFERENTIAL EXPRESSION OF INSULIN-LIKE GROWTH FACTOR 1 (IGF-1) AND RECEPTOR (IGF-1R) IN SMALL DORSAL ROOT GANGLION NEURONS AND DOWN REGULATION WITHIN TWO MODELS OF NERVE INJURY
Craner MJ, Klein JP, Black JA, Waxman SGYale University School of Medicine, USA
Background : Neurotrophic factors are important for neuronal survival and can influence phenotypic expression in dorsal root ganglion (DRG) neurons. Perturbations in the levels of neurotrophic factors in response to nerve injury have been shown to modulate the expression of sodium channels in DRG neurons, which may contribute to neuronal hyperexcitability and the generation of neuropathic pain. IGF-I has been implicated in the pathogenesis of diabetic neuropathy and hyperalgesia.
Methods: In this study, we examined the distribution of IGF-1 and its receptor within DRG from two rodent models of nerve injury; sciatic nerve axotomy and streptozotocin-induced (STZ) painful diabetic neuropathy.
Results: We demonstrate that IGF-I and its receptor is preferentially expressed within a subpopulation of small DRG neurons in control rats, 79% positive in <25 μm vs 8.5% positive in >40 μm diameter neurons. There is a significant downregulation of both IGF factor and receptor in the DRG neurons of STZ rats by 44% and 70% respectively in <25 μm diameter neurons. A parallel reduction in expression is shown in axotomised DRG neurons for IGF-I (47%) but not for IGF-IR.
Discussion: These data suggest that IGF-I may play a part in sodium channel plasticity and contribute to the generation of neuropathic pain.
ABNORMAL OSCILLATORY DRIVE TO MOTOR NEURONS IN KALLMAN’S SYNDROME
Farmer SF, James L, Parekh A, Harrison LM, Mayston MJ, Stephens JASt Mary’s Hospital, London; National Hospital for Neurology and Neurosurgery, London; University College, London; Imperial College, London, UK
Background : X-linked Kallmans’s syndrome (XKS) subjects have misdirected fast conducting corticospinal tracts (CSTs). These subjects can be used to test hypotheses about normal motor control. Here we examine whether synchronous (∼20 Hz) EMG oscillations arise from activity in fast conducting CSTs.
Methods: We recorded simultaneous EEG (22–24 scalp electrode sites) and right and left first dorsal interosseous muscle (1DI) EMG in three subjects with XKS and seven controls. The coherence, phase, and cumulant were calculated between EEG and rectified EMG. In contrast to the controls, transcutaneous magnetic brain stumulation (TMS) in XKS subjects revealed strong ipsilateral as well as contralateral CST input to 1DI.
Results: Control coherence and cumulant mapping showed only contralateral ∼20 Hz oscillatory drive to 1DI. In the XKS subjects there was an abnormal ipsilateral contribution to ∼20 Hz oscillatory motoneuron drive. The ratio of ipsilateral/contralateral TMS responses in the XKS subjects determined the relative contibution of each motor cortex to ∼20 Hz oscillatory drive during unilateral 1DI activation.
Discussion: The results demonstrate abnormal oscillatory drive in XKS subjects, indicating in normal subjects that this drive is delivered by the fast conducting CST. XKS subjects achieve voluntary activation of hand muscles through ipsilateral, contralateral, or bilateral CST connections depending on their relative strength.
PERIPHERAL NERVE GRANULOMA IN A PATIENT WITH TUBERCLOSIS
Orrell RW, King R, Bowler JV, Ginsberg LRoyal Free and University College Medical School, London; Royal Free Hospital, London, UK
Background: The cause of peripheral neuropathy associated with tuberculosis is controversial. Possibilities include an immune mediated neuropathy, direct invasion of nerves, vasculitic neuropathy, compressive neuropathy, a meningitic reaction, and the toxic effects of antituberculous chemotherapy.
Methods: We present the clinical and pathological findings in a young man with painful motor and sensory neuropathy in the lower limbs. Biopsy of a cervical lymph node showed pathological and culture findings of Mycobacterium tuberculosis.
Results: Sural nerve biopsy (as illustrated) demonstrated many myelinated fibres undergoing acute axonal degeneration. Several non-caseating granulomata were present in the epineurium. There were no giant cells. There was marked immunocytochemical staining of CD4 lymphocytes in the epineurium, especially in relation to the granulomata, and blood vessels, and in patches in the endoneurium. There was less dense staining for CD8 lymphocytes in a similar distribution. Staining was negative for B lymphocytes in the endoneurium and epineurium. There was symptomatic improvement following antituberculous chemotherapy.
Discussion: Although granulomata within the nerve are well recognised in infection with Mycobacterium leprae, they have not been previously described in tuberculosis. Although the pathogenesis of neuropathy is uncertain, we suggest that the granulomata disrupted the endoneurial blood supply, producing the acute Wallerian-type degeneration observed.
It should not be assumed that neuropathy in patients with tuberculosis is the result of chemotherapy, and the possibility of a primary effect on the nerves should be considered.