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A COMPARISON OF NEUROPSYCHOLOGICAL ASSESSMENT AND MRI IMAGING SCORES IN THE EARLY DIAGNOSIS OF ALZHEIMER'S DISEASE
CJ Galton, R Swainson, R Vessy, BJ Sahakian, JR Hodges Addenbrookes Hospital, Cambridge, UK
The aim of this study is to address whether neuropsychological measures or imaging scores best predict which patients with questionable dementia progress to fulfil criteria for Alzheimer's disease (AD). MRI images of 50 subjects (18 with early AD, mean MMSE 21.4, and 32 with memory complaints, mean MMSE 27.3) were examined using the temporal lobe rating scale. Subjects underwent a standard battery of neuropsychological tests at baseline, and were clinically followed up for a mean of 19 months. Patients who converted to AD (converters n=11), relative to non-converters, were impaired at baseline assessment on general cognitive tests (Addenbrookes cognitive examination (ACE) and ADAS cog), measures of episodic memory, category fluency, and the graded naming test. The mean scores of the temporal lobe rating scale demonstrated that converters had more hippocampal and parahippocampal atrophy than non-converters. Discriminant analysis demonstrated that the best test for distinguishing the converters from the questionable group, was the ACE score. In combination, the medial temporal lobe rating and graded naming test were also contributory.
MRI imaging measures may be valuable if used in conjunction with neuropsychology, but progression to dementia is best predicted by performance on neuropsychological tests.
EARLY COGNITIVE DECLINE IN CREUTZFELDT-JAKOB DISEASE OCCURRING IN RECIPIENTS OF PITUITARY-DERIVED HUMAN GROWTH HORMONE
RJ Cordery, M Hall, L Cipolotti, L Davidson, P Adlard, MN Rossor National hospital for Neurology and Neurosurgery, London, UK
Most cases of Creutzfeldt-Jakob disease (CJD) in recipients of human cadaveric growth hormone, present with a cerebellar syndrome. Dementia is thought to occur late and as a minor feature of the illness. However, neuropsychology data published on these cases is largely qualitative and anecdotal. The first published case, of a 22 year old woman, does include neuropsychology performed 7 months after the onset of a cerebellar syndrome. This showed evidence of intellectual decline, with a verbal IQ of 80. Subsequent reports hint at the possibility that cognitive problems may be present in the initial stages of the illness.
In order to assess early cognition, we report detailed assessment at referral (mean 4.5 months from the onset of symptoms, range 4–6 months) in five patients with histologically proved human growth hormone derived CJD. All presented with a cerebellar syndrome and only one had noticed mild memory problems. On formal testing however, four had demonstrable, mild intellectual decline, as measured on the WAIS-R. One case showed selective visual memory impairment and frontal executive dysfunction.
These findings suggest that, although not the presenting feature, mild cognitive decline may be evident in the early stages of CJD associated with human cadaveric growth hormone treatment.
LATERALITY OF UNEXPLAINED MOTOR AND SENSORY SYMPTOMS: A SYSTEMATIC REVIEW 1965–2000
J Stone, A Carson, R Goldbeck, S Lewis, B Thomas, CP Warlow, M Sharpe University of Edinburgh, UK
Background: Unilateral unexplained motor and sensory symptoms present commonly to neurologists. The literature has suggested that left sided symptoms are far more common than right.
Methods: A systematic review of the literature since 1965 to test this hypothesis. All studies describing one or more patients with unexplained, hysterical, psychogenic, or non-organic sensory or motor symptoms (excluding pain, visual, and auditory symptoms) were included.
Results: 124 studies with 1045 patients were analysed. The overall proportion of left sided weakness and sensory symptoms was 57% (CI 53%–60%). This figure was accentuated in studies which specifically set out to study this question (64% on the left). However, when laterality was reported incidentally there was no significant effect (51% on the left). Unexplained movement disorders were left sided in 38% (CI 31–38%). Female sex was related to left sided symptoms. Handedness and date of study did not influence laterality.
Interpretation: The data do not provide strong evidence for lateralisation of unexplained motor and sensory symptoms except for right sided movement disorder and possibly left sided symptoms in women. Retrospective studies specifically looking at lateralisation may have produced misleading positve results through bias. Consideration of the biology of these phenomena should not place undue weight on laterality.
HAEMOGLOBIN CONCENTRATION AND STROKE RISK IN 13 000 PATIENTS WITH ESTABLISHED CEREBROVASCULAR DISEASE
SC Howard, DA Power, PM Rothwell on behalf of Cerebrovascular Cohort Studies Collaboration Radcliffe Infirmary, Oxford, UK
Small studies and case reports have suggested that polycythaemia may increase the risk of ischaemic stroke. There is physiological evidence to support this, but there have been no adequately powered cohort studies. We therefore pooled detailed individual patient data from cohort studies and clinical trials in which patients presenting with a TIA or non-disabling ischaemic stroke had haemoglobin measured at baseline and had been followed up.
Using data on 13 009 patients with 60 000 patient-years of follow up from eight independent studies, the relation between haemoglobin and risk of stroke was assessed by Cox regression adjusting for age, sex, other baseline factors associated with haemoglobin, and stratifying by study population.
Stroke risk had a “U” shaped relation across eight predefined categories of haemoglobin concentration (p=0.03). This was most marked for fatal ischaemic stroke (p=0.001), haemorrhagic stroke (p=0.02), and recurrent ischaemic stroke in patients presenting with a lacunar event (p=0.005). The respective hazard ratios for haemoglobin above the normal range were 3.57 (95% CI=1.87–6.84), 2.97 (95% CI=1.07–8.20), and 1.49 (95% CI=0.79–2.81).
Haemoglobin concentration is an independent predictor of ischaemic and haemorrhagic stroke in patients with established cerebrovascular disease. Correction of mild polycythaemia or anaemia may reduce the risk of stroke.
A COMPARISON OF CT VERSUS DIFFUSION WEIGHTED IMAGING IN HYPERACUTE STROKE USING A SYSTEMATIC QUANTITATIVE SCORE (ASPECTS)
PA Barber, MD Hill, AM Demchuk, JH Warwick Pexman, ME Hudon, A Tomanek, RR Frayne, AM Buchan for the ASPECTS Study Group Foothills Medical Centre, Calgary, Canada
Background: Tissue plasminogen activator (TPA) when administered <3 hours of symptom onset for acute ischaemic stroke produces improved functional and neurological outcome. Recent advances in neuroimaging with magnetic resonance (MR) diffusion weighted imaging (DWI) have raised hopes regarding the accurate identification of ischaemic tissue with improved safe administration of the treatment. CT is considered less sensitive and reliable than DWI for the detection of ischaemic change in hyperacute stroke. We hypothesised that CT is as good as DWI when the scans are read by experienced observers.
Methods: All patients had a CT scan (within 6 hours of stroke onset) prior to MRI (<7 hours of onset). Non-contrast enhanced CT scans were performed on fourth generation scanners with 5 mm slice thickness parallel to the infraorbital meatal line, and appropriate window width (80 HU) and centre level review settings (40 HU). MR imaging was performed on a 3Tesla machine and included DWI (single shot EPI TR=7000 m2s−1, TE=99 ms, b=1000 mm s−1, 19 5 mm slices/3 mm gap). A quantitative scoring system (ASPECTS) was applied to CT and DWI at baseline and follow up (<36 hours) by five independent observers (three stroke neurologists and two neuroradiologists) with only knowledge of the stroke side. The reliability of each modality was assessed for each observer with intraclass correlation coefficients. Bland Altman plots were used to measure the agreement between CT and DWI using ASPECTS.
Results: 80 patients (65% male; mean age 68.4±13.2) had CT and DWI at baseline. The median NIHSS was 9. The mean onset to CT (136 minutes) compared with onset to MRI (240 minutes) (p<0.001). The median baseline CT and DWI ASPECTS values were equal at 8. Intraclass correlation coefficients confirmed excellent reliability between observers for CT (0.81 (95% CI 0.76–0.86)) and DWI (0.78 (95% CI 0.72–0.84)) at baseline. CT ASPECTS predicted DWI ASPECTS (linear regression p<0.001) at baseline. The difference of means between DWI and CT at baseline was −0.3 ASPECTS, allowing for the mean difference in time for the scans.
Conclusions: CT appears comparable with DWI for assessing patients with hyperacute stroke when viewed by experienced observers using ASPECTS, and when sound CT imaging quality is achieved. The CT scan remains the imaging modality of choice in hyperacute stroke, while the challenge for MRI is to reliably identify salvageable brain tissue.
HISTORY OF STROKE IN FIRST DEGREE RELATIVES OF PATIENTS WITH TIA AND ISCHAEMIC STROKE IN RELATION TO CLINICAL SUBTYPE AND INTERMEDIATE PHENOTYPES
UGR Schulz, CP Warlow, PM Rothwell
Radcliffe Infirmary, Oxford; Western General Hospital, Edinburgh, UK
Some rare mendelian stroke syndromes have been characterised, but the genetic epidemiology of the common forms of ischaemic stroke and TIA remains uncertain. Previous studies have not considered specific clinical and aetiological subtypes or assessed whether familial susceptibility is related to intermediate phenotypes.
We studied family history of stroke in 545 ischaemic strokes (Oxfordshire Community Stroke Project) and 469 TIAs (hospital based series). We related history of stroke in first degree relatives (FDRs) to baseline clinical characteristics, subtype of stroke, and risk of recurrence.
Information on family history was available in 537 strokes and 467 TIAs.
Stroke had occurred in at least one FDR in 101 (18.9%, 95%CI=16–22) strokes and in 98 (21%, 95%CI=17–25) TIAs. In both cohorts, a history of hypertension was strongly associated with family history (p<0.01) and became more frequent with increasing numbers of affected FDRs (p<0.01). However, there was no relation between family history and hyperlipidaemia, diabetes, stroke subtype, or risk of recurrence.
We found no evidence of a major independent genetic component in TIA and ischaemic stroke. However, the strong link between family history of stroke and hypertension suggests that genetic susceptibility to hypertension may explain a substantial proportion of the familial clustering of cerebral ischaemic events.
A LATERALITY SHIFT OF BROCA'S AREA IN THE RECOVERY OF SPEECH PRODUCTION AFTER STROKE
SC Blank, RJS Wise Hammersmith Hospital, London, UK
The production of both propositional speech (PrSp) and non-propositional speech (NPrSp) in normal subjects activates the left frontal operculum (Broca's area). We used PET to investigate speech production in five aphasic stroke patients with lesions that included the left frontal operculum.
All patients initially presented with severe non-fluent aphasia. Patients were scanned 16 months—10 years after stroke (median 4 years), when recovery of aphasia was deemed to be maximal. All subjects could count aloud fluently, but the extent of recovery of PrSp varied considerably, from occasional single word output to sentences.
Subjects were scanned under three experimental conditions; counting aloud (NPrSp), PrSp in response to autobiographical questions, and a non-speech state (XSp) when they attended to occasional environmental sounds. In normal subjects, PrSp and NPrSp contrasted with XSp revealed activation within Broca's area and the left anterior insula. In patients, activation was seen in the right frontal operculum. Thus, in patients with extensive damage to left premotor areas for articulation, homologous regions within the right hemisphere are recruited for the motor act of speech. This is direct evidence of plasticity within the neural systems engaged in speech production, and confirms Mohr's hypothesis about laterality shift of function in the frontal operculum.
CLINICAL FEATURES AND DISEASE COURSE OF PSP IN THE UNITED KINGDOM
U Nath, Y Ben-Shlomo, RG Thomson, N Wood, AJ Lees, DJ Burn Royal Victoria Infirmary, Newcastle upon Tyne, UK
Objective: To conduct a clinical survey of PSP and also to estimate its crude mortality rate in the United Kingdom.
Methods: 187 cases of PSP were identified in the context of a United Kingdom based prevalence study. Record-based confirmation of diagnosis according to the NINDS-SPSP criteria were performed in all cases and structural clinical assessment was also performed in a third of these cases. Information relating to subsequent death of patients was compared with national death certificate data collected all patients recorded as having PSP according to the ninth version of the International Classification of Diseases (ICD9).
Results: The median age of the clinical cohort was 72 years (n=187). Non-specific visual problems such as diplopia and eyelid apraxia occurred in 39% and 17% of all patients but data on these items was not routinely recorded. Information from those patients undergoing standardised assessment (n=49) revealed frequencies of 61% and 43% for these features respectively. Tremor was present in 21% of all cases and information from clinically examined cases suggested that this was usually postural. Early onset of diplopia and cases without tremor appeared to be associated with a shorter disease survival. PSP was mentioned in 57% of death certificates of cases identified by record review.
Conclusion: PSP is frequently misdiagnosed. Visual symptoms are prominent and often disabling. Clinical factors such as early onset of diplopia are significantly associated with poorer survival. Mortality rate for PSP is significantly underestimated.
PROGRESSION OF NIGROSTRIATAL DYSFUNCTION IN A PARKIN KINDRED: AN 18F-DOPA PET AND CLINICAL STUDY
NL Khan, DJ Brooks, N Pavese, NW Wood, AJ Lees, P Piccini Institute of Neurology, Queen Square, London; Imperial College School of Medicine, Hammersmith Hospital, London; Royal Free Hospital and University College Medical School, London, UK
We have used 18F-dopa PET to serially study a family with young onset parkinsonism with mutations in the parkin gene whose clinical picture is characterised by the presence of severe resting leg tremor. Four patients have been studied twice, 10 years apart, to assess disease progression. Additionally, we have studied five asymptomatic family members; four of whom carry a single parkin mutation and one individual with a normal genotype. Two of the carriers and the individual with the normal genotype had a repeat 18F-dopa scan. In the parkin patients the rate of loss of 18F-dopa uptake was similar in caudate and in putamen (1.3% and 1.2% per annum respectively) indicating that disease progression is slower than that in idiopathic PD. The group of asymptomatic carriers also showed significant dopaminergic dysfunction in striatum bilaterally and in ventral midbrain and three of them developed subtle extrapyramidal signs. However in the two carriers scanned twice, 18F-dopa dysfunction did not progress with time, at least over a 7 year period.
The slow rate of disease progression in parkin patients may explain the near normal longevity of some young onset PD patients. The development of mild signs of basal ganglia dysfunction in three carriers with abnormal striatal 18F-dopa uptake suggests that these individuals are “manifesting heterozygotes” and may eventually develop parkin disease.
UNILATERAL TRANSPLANTATION OF HUMAN PRIMARY FETAL TISSUE IN FOUR PATIENTS WITH HUNTINGTON'S DISEASE: NEST-UK SAFETY REPORT
AE Rosser on behalf of the NEST-UK consortium Universities of Cardiff, Cambridge, Aberdeen, Belfast, London, and Manchester, UK
Huntington's disease (HD) is an inherited CAG repeat disorder typically manifesting in mid-life and leading to death within approximately 20 years. The principle pathology is focal degeneration of the major projection neurons of the striatum, making cell replacement by neural transplantation a potential treatment strategy. There is substantial experimental evidence that neural transplants can yield functional recovery in animal models of HD and several clinical trials have commenced. To date, only a few HD patients have received operations and the approach remains experimental. We report here the first phase of a Medical Research Council (MRC) supported clinical safety trial of neural transplantation in four patients with mild-moderate HD who have received unilateral grafts of human fetal striatal tissue. This is a multicentre UK-based trial affiliated to the organisation NECTAR (European Network for CNS transplantation and repair). At the time of writing all significant adverse events relate to the immunotherapy. There were no acute surgical events; no evidence of tissue contamination or overgrowth; and no evidence that the procedure has produced acceleration of the clinical course. Neural transplants would be expected to take at least 12 months to establish and to start to ameliorate function, thus the efficacy of these procedures will be reported at a later date.
FAST MICROGRAPHIA AND PALLIDAL PATHOLOGY
NP Quinn Institute of Neurology, Queen Square, London, UK
Micrographia is well recognised in Parkinson's disease (PD). Typically, the initial size and speed of the patient's handwriting is good, but rapidly becomes progressively smaller and slower, and may ultimately grind to a halt.
There exists another, quite distinct, form of micrographia which I call “fast micrographia”, in which handwriting is microscopic from the outset, does not (indeed cannot) become progressively smaller, is accomplished at (astonishingly) normal speed, and does not fatigue. However, this micrographia can be so marked as to resemble a straight line, so that even the patients are often unable to read what they have written. In contrast with the micrographia of PD, many patients with fast micrographia have completely normal alternating finger movements.
Fast micrographia is most often observed in patients with progressive supranuclear palsy, who sometimes volunteer “microscopic” writing as their presenting complaint. However, it can also be seen in patients with acquired bilateral lesions of the globus pallidus. Illustrative videotapes will be shown.
Fast micrographia should be considered a clinical feature suggestive of underlying pallidal pathology.
PROSPECTIVE STUDY OF DEVELOPMENT OF INFANTS BORN TO MOTHERS WITH EPILEPSY
FH James, S Fairgrieve, SA Lynch, MJ Jackson University of Newcastle upon Tyne, Newcastle, UK
Objective: to establish if infants born to mothers with epilepsy are at increased risk of developmental delay.
Methods: Our prospective study of pregnant women with epilepsy identified 292 babies whose mothers gave consent to follow up with developmental assessment using Bayley's scales.
Results: We have examined 149 babies at 2–3 years to date: 59 were exposed to valproate, 61 to carbamazepine (50 in each group were on monotherapy). 31 children (21%) have delayed development and 13 (8.7%) have severe delay when the population prevalence of severe delay =1.5% (OR 6.27, 95%CI 3.2–11.1). Developmental delay was associated with exposure to valproate (OR 4.42, 95%CI 1.77–11.5). However, mothers of children with epilepsy had low educational achievement; only 47% achieved five GCSEs (grade A–G) compared with 85% of the population. Only 26% of mothers of delayed children obtained five GCSEs.
Conclusion: Children born to mothers with epilepsy in this study have increased risk of developmental delay at 2–3 years. The risk is increased with exposure to valproate and with maternal educational underachievement. Examination of the rest of the cohort followed by multivariate analysis will be undertaken in an attempt to identify the cause of developmental delay in these infants.
QUANTITATIVE MRI ABNORMALITIES WITH HISTOPATHOLOGICAL CORRELATION IN REFRACTORY EPILEPSY: A TOOL TO PREDICT SURGICAL OUTCOME?
TN Mitchell, SL Free, M Thorn, SM Sisodiya, SD Shorvon Institute of Neurology, Queen Square, London, UK
Focal cortical dysplasia (FCD) is the commonest neurodevelopmental lesion causing refractory epilepsy. 50% of FCD patients have poor outcome after surgery, continuing seizures despite complete lesion resection, suggesting the presence, undetected on preoperative MRI, of additional epileptogenic abnormalities. Some forms of FCD may represent a forme fruste of tuberous sclerosis (TSC).
30 subjects with FCD, one with TSC, and 100 age matched controls had volumetric MRI scans. Quantitative analysis gave measures of regional distribution of grey and white matter and cortical thickness.
The TSC and 10 (33%) FCD patients had additional extralesional abnormalities in areas that seemed normal on visual inspection of the MRI. The patient with TSC subsequently died. On postmortem, distinct pathological abnormalities (heterotopic grey matter, dysplastic giant neurons) were demonstrated in areas shown only by quantitative MRI analysis to be abnormal. The proportion with additional quantitative abnormalities, which could be additional subtle malformation, in our FCD group is comparable with that with a poor outcome after focal FCD resection.
Our technique could have potential application as a prognostic presurgical screening tool to prevent patients unlikely to achieve seizure freedom from being needlessly exposed to the risks of surgery.
A PROFILE OF EPILEPSY IN A UK POPULATION
NF Moran, K Poole, G Bell, J Solomon, S Kendall, M McCarthy, D McCormick, L Nashef, J Sander, SD Shorvon Institute of Neurology, Queen Square, London, UK
Objective: To describe the characteristics of epilepsy in a representative UK sample, including demographic features; onset age; duration; severity; antiepileptic drug (AED) use and the impact of epilepsy on life.
Methods: A large, geographically comprehensive survey using a postal questionnaire distributed by general practitioners to 3455 unselected patients receiving AEDs for epilepsy, in all UK regions.
Results: There were 1652 replies. The mean age was 44 years; 47% males. The mean onset age, 25 years, and the mean duration, 20 years, were comparable with epidemiological studies. In the preceding year, 52% of patients had no seizures; 8% a single seizure, 17% 2–9 seizures, and 23% >10 seizures; 64% had mild epilepsy and 32% severe. There was a marked and significant decrement of seizure frequency with increasing age. The most common AEDs were carbamazepine (37%), valproate (36%), phenytoin (29%). Monotherapy was used in 68% of patients. Patients taking multiple AEDs reported significantly higher adverse effects. The major impacts on life were work and school difficulties, driving, and psychological, with variation according to age and severity.
Conclusions: Seizures remain uncontrolled in half of people with epilepsy in the UK with significant psychosocial impact. Our findings help address the deficiency of information on the characteristics of epilepsy in the elderly, in whom the condition is an increasing health problem.
THE MANAGEMENT OF ADULTS WITH EPILEPSY
D Smith, I Crook, IR Williams on behalf of the North West Clinical Neuroscience Partnership Project Walton Centre for Neurology and Neurosurgery, Liverpool, UK
Suspected and established epilepsy are common reasons for referral to hospital clinics. Optimal management, ideally, involves cooperation between an epilepsy clinic and primary care. Because these facilities are not widely available these patients can be exposed to misdiagnosis, incomplete diagnosis and suboptimal therapy and inadequate counselling. There is a need for expansion or reorganisation of services and concise guidelines could facilitate the care of these patients.
The North West Clinical Neuroscience Partnership project has developed a framework for service provision for adults with possible or definite epilepsy. A multidisciplinary team made contributions, based on reviews of available evidence, to the guidelines document. This document contains recommendations on (a) a structure for service provision, (b) diagnosis of epilepsy, and (c) the management and follow up of newly diagnosed and refractory epilepsy and includes specific advice regarding choice of treatment and the management of epilepsy in women, people with learning disability and the elderly.
This framework could facilitate best practice/shared care in either established or evolving services. Specific aspects of care are easily amenable to prospective audit. Adherence to guidelines is a transparent method of demonstrating the accountability of a service assuring commissioners/patients that a system capable of delivering quality care is in existence.
CLINICAL FEATURES OF PARANEOPLASTIC NEUROLOGICAL DISORDERS: A RETROSPECTIVE STUDY
JH Rees, I Sutton, R Weil, M Barnett National Hospital for Neurology and Neurosurgery, London, UK
There is a paucity of information about paraneoplastic neurological disorders (PND), a heterogeneous group of immune mediated conditions associated with a variety of different tumours. We report the preliminary results of a retrospective observational study investigating the clinical features of 57 patients with PND, ascertained principally via the British Neurological Surveillance Unit. The average (SD) age of onset was 63 (11) years and there was a female preponderance (3:1). The most often reported syndromes were sensory neuro(no)pathy (33%) and cerebellar degeneration, either pure (21%) or in association with brainstem/limbic encephalitis/neuropathy (23%). SCLC was the most frequent underlying tumour type (28%), followed by breast (16%), ovarian (9%) and other lung (7%) carcinoma. No tumour was identified in 19%. Forty six per cent of patients received immunomodulatory therapy and 67% of patients had their tumour treated. Only a minority of patients responded to these treatments and often only briefly. Progressive deterioration was the rule and 40% of patients with adequate follow up were dead at 12 months. We conclude that the diagnosis of PND leads to the detection of a tumour in 80% of cases but treatments are poor. More research is needed to improve the prognosis of these difficult conditions.
AUDIT OF 2 WEEK URGENT REFERRALS FOR CNS/BRAIN TUMOURS
AJ Wills, DSNA Pengiran Tengah Queens Medical Centre, Nottingham; Derbyshire Royal Infirmary, Derby, UK
Objective: To audit patients referred from general practitioners (GPs) via the 2 week wait system and contrast with neurological cancer patients identified independently of this system.
Methods: GP referral letters were reviewed and compared with Department of Health (DoH) guidelines. Patient case notes were examined to determine the actual neurological diagnosis. A list of patients with cancer that were not identified by the system was compiled separately.
Results: Forty five patients were referred during a 9 month period, with 41 sets of case notes available. 13 referrals did not follow the DoH guidelines. Only four patients actually had CNS tumours (two astrocytomas, two cerebral metastases). The remainder were diagnosed with chronic daily headache (10), epilepsy (five), migraine (three), ?demyelination (two), essential tremor (two), other (16). At least 69 neurological cancers were identified during this period who were not referred via the 2 week system.
Conclusion: CNS cancers present in a diverse manner. Eliciting a neurological history and interpreting neurological signs can be challenging and many GPs have little neurological training. These guidelines, even when followed stringently, do not seem to increase diagnostic precision. Inappropriate referrals have extended already lengthy waiting times for neurology outpatient clinics and may have inadvertently delayed other patients with urgent neurological problems being seen. We suggest that the use of these guidelines in neurological practice is re-considered at the earliest opportunity. Perhaps a system of closer communication between primary and secondary care would be a more effective use of time and resources.
IRREVERSIBLE DAMAGE TO THE SPINAL CORD AFTER SPINAL ANAESTHESIA
K Hamandi, J Mottershead, T Lewis, IEC Ormerod, IT Ferguson Frenchay Hospital, Bristol, UK
Neurological features are a recognised rare complication of spinal and epidural anaesthesia. A number of mechanisms of injury to the spinal cord have been suggested. We report five cases of damage to the distal spinal cord after spinal anaesthesia. All patients were female undergoing orthopaedic (three patients) or obstetric (two patients) surgery. They had significant unilateral leg weakness and sensory disturbance after anaesthesia, which persisted at 2 year follow up. Three patients experienced pain on injection, the other two were under general anaesthetic at the time of spinal injection. Two patients were overweight and two had significant lumbar lordosis. MRI of the lumbosacral spine showed similar findings, in all cases, of high signal within the conus medullaris consistent with the clinical findings. Direct trauma was the most likely mechanism of injury. This is the first series to report detailed neuroimaging and long term follow up in all cases which shows that permanent neurological deficit has occurred. The use of spinal and epidural anaesthesia is becoming more widespread. Neurologists are likely to be involved in the management of complications and should be aware of this rare but serious complication.
A DOUBLE BIND PLACEBO CONTROLLED STUDY OF INTRANASAL SUMATRIPTAN IN ACUTE CLUSTER HEADACHE
PJ Goadsby, JA van Vliet, A Bahra, V Martin, SK Aurora, NT Mathew, MD Ferrari Leiden University Medical Centre, Leiden, The Netherlands; Cincinnati Headache Center, Cincinnati, USA; Headache Center, Seattle, USA; Houston Headache Clinic, Houston, USA; Institute of Neurology, Queen Square, London, UK
Cluster headache attacks reach a peak of pain intensity quickly, and are short lasting; therefore acute treatments must be rapidly acting. This study sought to determine if intranasal sumatriptan is an effective treatment of acute cluster headache.
Patients with episodic and chronic cluster headache, by International Headache Society criteria, were recruited and after explanation and obtaining informed consent, were randomised to a double blind placebo controlled two period crossover study. Patients were instructed to treat two acute cluster headaches of at least moderate pain severity, with at least a 12 hour break, using intranasal sumatriptan 20 mg or matching placebo. Patients recorded the time of onset of the attack, time of treatment, headache severity on a five point scale (0-nil, 1-mild, 2-moderate, 3-severe, 4-very severe) at 5, 10, 15, 20 and 30 minutes after treatment. The primary end point was the headache response defined as: very severe, severe or moderate pain becomes mild or nil, at 30 minutes. Secondary measures included pain free rates, treatment of associated symptoms and adverse events. The primary end point was analysed using a multilevel analysis approach with MLwiN (www.ioe.ac.uk/multilevel) with p<0.05 as the level of significance for testing.
In total, 118 patients were recruited; 97 males and 21 females. Of these 86 provided efficacy data on attack one and 80 on attack two. Twenty five provided no efficacy data because their bout ended, seven were lost to follow up. Six cycled out of a cluster period between attack one and attack two. Modelling the treatment outcome as a binomial where response was determined by treatment, using the patient as the level 2 variable, and considering period effect, sex, site and cluster headache type as other variables of interest, the effect of intranasal sumatriptan 20 mg was superior to placebo at 30 minutes on the headache response end point (p=0.01). For the first attack the placebo response rate was 11/37 (30%) and the sumatriptan 20 mg rate 29/50 (58%); for the second attack the rates were 15/45 (33%) and 18/36 (50%), respectively. There were no serious adverse events.
It can be concluded that intranasal sumatriptan 20 mg is effective in the acute treatment of cluster headache when compared with placebo. For cluster headache patients these data add a further evidence based treatment to the management portfolio of this disabling primary headache.
EFFECT OF THE ADENOSINE (A1) RECEPTOR AGONIST GR79236 ON TRIGEMINAL NOCICEPTION WITH BLINK REFLEX RECORDINGS IN HEALTHY HUMAN SUBJECTS
NJ Giffin, F Kowacs, V Libri, P Williams, PJ Goadsby, H Kaube Institute of Neurology, Queen Square, London, UK
There are no good migraine models in humans, but development of a low current intensity trigeminally mediated blink reflex (BR) has allowed the study of nociceptive transmission in the trigeminal nucleus caudalis. Adenosine is antinociceptive in humans and animals. GR79236 is a highly potent and selective adenosine A1 receptor agonist. We investigated the effect of GR79236 on the nociceptive BR using 12 female healthy volunteers randomised in a placebo controlled double blind crossover study. BRs were elicited by supraorbital nerve stimulation with standard or nociception-specific electrodes at random intervals of 12–18s. BR responses were recorded bilaterally from infraorbital muscles. Each measurement was based on 25 sweeps. Areas under the curve (AUCs) of the R2 component of the BR were calculated from the rectified EMG, before and 30 minutes after drug (GR79236 (10 mg/kg)) or placebo. Primary end point: median AUC at 30 minutes, modelled using analysis of covariance.
There was a non-significant reduction of the ipsilateral nociceptive R2 after GR79236 vs placebo of 17%. However, there was a significant reduction of the contralateral nociceptive R2 (p<0.05) of 20%. There were no significant adverse events.
The results suggest that GR79236 may inhibit trigeminal nociceptive pathways. The nociception specific electrode directly depolarises cutaneous fibres and GR79236 may therefore act at second order trigeminal neurons in the nucleus caudalis, or more rostrally, crossing the blood-brain barrier. This suggests that it may be effective in primary headache disorders.
A STUDY OF THE ACQUIRED NEUROMYOTONIA PHENOTYPE OF PERIPHERAL NERVE HYPEREXCITABILITY
P Maddison, I Hart, K Mills, A Vincent, J Newsom-Davis Radcliffe Infirmary, Oxford; University of Liverpool, Liverpool; The Walton Centre for Neurology and Neurosurgery, Liverpool; King's College Hospital, London, UK
Acquired neuromyotonia (NMT) and cramp fasciculation syndrome (CFS) represent the severe and mild manifestations of generalised peripheral nerve hyperexcitability (PNH) respectively. Anti-voltage gated potassium channel (VGKC) antibodies have been implicated in autoimmune PNH disease pathogenesis. We studied 44 consecutive patients with NMT seen in two centres to determine the significant clinical, immunological, and electrophysiological features of this phenotype.
The mean age at symptomatic onset was 47 years (range 9–74): over half (64%) were male. Associated autoimmune diseases and other autoantibodies were found in 22 (50%): an immunoprecipitation assay detected raised titres of anti-VGKC antibodies in 16 out of 40 (40%) patients.
All patients had at least two of the three principal symptoms of muscle twitching, cramps, and muscle stiffness. Other often observed features were increased sweating in 25 (57%) muscle weakness in 16 (34%), and pseudomyotonia in 16 (34%).
Spontaneous, abnormal activity detected electromyographically comprised characteristic doublet, triplet, and multiplet motor unit (or partial motor unit) discharges, in addition to fasciculations and fibrillations. The most common abnormality on EMG, in all but three patients, were doublet discharges, with intraburst frequencies often exceeding 100 Hz (mean 168 Hz, range 40–280 Hz). Multiplets (runs of >3 discharges) were found in the remainder.
NMT is a phenotype of autoimmune PNH that seems to be distinct from CFS only in terms of the severity of symptoms, signs and EMG features observed, with both sharing immunological associations.
HETEROPLASMIC MITOCHONDRIAL DNA MUTATIONS: DETERMINING THE MECHANISM OF INHERITANCE
PF Chinnery, DC Samuels, DT Brown, DM Turnbull University of Newcastle upon Tyne, UK
Mitochondrial DNA (mtDNA) mutations cause progressive disabling neurological disease in at least 1 in 8000 of the UK population. Many mtDNA mutations are heteroplasmic, with a mixture of mutant and wild type mtDNA present within the same individual. A higher percentage level of mutant mtDNA (mutation load) is associated with more severe disease. Females harbouring heteroplasmic mtDNA point mutations transmit a variable amount of mutant mtDNA to their offspring, making it extremely difficult to predict the outcome of pregnancy. In mice, the variation in mutation load between offspring is determined by random genetic drift and a restriction in the number of mtDNA molecules early in embryogensis (the mitochondrial “genetic bottleneck”). It remains to be established whether the same mechanism operates in humans. We studied the mechanism of inheritance of the most common transmitted heteroplasmic mtDNA defect: the A3243G (“MELAS”) mutation. By measuring mutation load in 82 individual human primary oocytes we show that random drift is the principal mechanism behind the transmission of heteroplasmy in human pedigrees with mtDNA disease. We also provide the first direct evidence of a mitochondrial genetic bottleneck in humans, ennabling the first direct measurement of bottleneck size. These findings will have important implications for genetic counselling.
RESULTS OF A UNITED KINGDOM-WIDE CLINICAL AND MOLECULAR GENETIC STUDY OF MYOTONIA CONGENITA
NP Davies, LH Eunson, MG Hanna Institute of Neurology, Queen Square, London, UK
Myotonia congenita is the commonest skeletal muscle channelopathy and is caused by mutations in the skeletal muscle chloride channel gene (CLCN1) on chromosome 7q35. The aims of the study were to analyse the clinical and genetic features of myotonia congenita in the UK, to look at genotype-phenotype correlation in this group, and to develop a DNA based diagnostic service
In collaboration with the British Neurological Surveillance Unit we identified over 100 families with inherited myotonia. We initially performed SSCP analysis of all 23 exons of the CLCN1 gene in index cases from 42 families. In order to check that no mutations had been missed with this technique we subsequently analysed all the exons by direct DNA sequencing.
Using SSCP analysis mutations were identified in 50% of cases. This figure rose to 65% with DNA sequencing. In this mutation positive group the age at onset varied from 1–16 years (mean 5.6), muscle pain was reported in 20% and 50% reported exacerbation of muscle stiffness in a cold environment. Twelve novel mutations have been identified. In particular the finding of a severe myotonic phenotype in association with compound heterozygosity and a mild phenotype with a new homozygous nonsense mutation (C242X) will be highlighted.
DNA based diagnosis is a realistic option in myotonia congenita. Although the mutations identified are spread across the gene it seems that exon 8 is a hot spot in this population. Genetic counselling in this disorder is complex and should include consideration of both genetic and functional expression data if available.
A CYSTEINE RESIDUE CLOSE TO THE C-TERMINUS OF THE E SUBUNIT IS ESSENTIAL FOR SURFACE ACETYLCHOLINE RECEPTOR (ACHR) EXPRESSION: IMPLICATIONS FOR ACHR DEFICIENCY SYNDROME
J Ealing, S Brownlow, M Al-Murani, M Brydson, A Vincent, D Vaux, D Beeson John Radcliffe Hospital, Oxford; University of Oxford, Oxford, UK
AChR deficiency is a recessively inherited form of congenital myasthenia in which adult AChR (α2βδε) are severely reduced or absent at the neuromuscular junction. We have identified two new mutations at the extreme C terminus of theε subunit in AChR deficiency patients and have investigated the mechanism by which such distal mutations may affect expression.
Naturally occurring and artificial mutations were introduced into the ε subunit cDNA by in vitro mutagenesis. Wild type or mutant ε subunit cDNAs were transfected into HEK 293 cells with cDNAs for the α, β, and δ AChR subunits. Surface expression of AChR was quantified by radioimmunoprecipitation of 125I-α-bungarotoxin labelled receptor using an ε specific antisera. To determine the subcellular location of ε subunits, fluorescently labelled ε subunits were visualised using confocal microscopy. Lack of a cysteine residue (Cys 470), four amino acids from the C terminus of the ε subunit, effectively abolished surface expression of the intact receptor in HEK 293 cells. Preliminary confocal data suggests that the mutant ε subunits accumulate in the endoplasmic reticulum.
These novel results reveal a previously unidentified signal sequence involved in the assembly and/or transport of AChR. Additionally, these results provide a mechanism by which frameshift or non-sense mutations in the C terminus region of the e subunit lead to AChR deficiency.
SERUM AUTOANTIBODIES TO OLIGODENDROCYTE AND NEURONAL CELL SURFACE ANTIGENS IN MULTIPLE SCLEROSIS PATIENTS
O Lily, J Palace, A Vincent Radcliffe Infirmary, Oxford, UK
Recent evidence suggests that autoantibodies may be important in the pathogenesis of multiple sclerosis (MS), but the antigens to which they bind remain unknown. We incubated cultured human CNS cell lines with sera from MS patients and other inflammatory neurological disease controls (OIND). Surface binding was measured using flow cytometry and considered positive if greater than the mean +2 standard deviations of 12 healthy controls.
Antibody binding to two control cell lines was similar using MS or non-MS sera. By contrast, 70% (16/23) of secondary progressive (SP) MS sera demonstrated positive binding to SK-N-SH neuroblastoma cells compared with 29% (10/35) of relapsing remitting (RR) patients (p<0.001) and 0/16 OIND controls. Also, 40% of MS sera showed positive binding to HOG oligodendroglioma cells with no significant difference between RR and SP patients. Differentiation of the oligodendroglial cells resulted in the loss of positive antibody binding seen using MS sera, suggesting that the relevant antigens are present on oligodendrocyte precursor cells rather than mature oligodendrocytes. Sera with antineuronal antibodies generally also had anti-oligodendroglial antibodies, although antibodies against one cell line could not be absorbed by the other. These results support reports of heterogeneity in MS pathology, with autoantibody mediated processes important in a subgroup of patients.
NON-INVASIVE VENTILATION IN MOTOR NEURON DISEASE: CURRENT UK PRACTICE
SC Bourke, PJ Shaw, T Williams, GJ Gibson University of Newcastle; University of Sheffield; Royal Victoria Infirmary, Newcastle, UK
Background: The clinical application of non-invasive ventilation (NIV) in motor neuron disease (MND) has not been reported in the UK.
Methods: A questionnaire assessing clinical practice over the previous 12 months was sent to all UK consultant neurologists, with a second mailing to non-responders after 6 weeks.
Results: The response rate was 75.9%. 1719 new patients were diagnosed, and 2280 patients were under review. 234 patients were referred for NIV and 126 were currently receiving NIV. Most responders (172/265) did not refer any patients for NIV, however three neurologists made 30% of all referrals. The referral rate correlated with the number of new patients seen (r=0.40, p<0.00001).
Referral for NIV was based mainly on symptoms rather than physiological impairment. 73% of responders measured vital capacity, and less than 50% checked blood gases or serum bicarbonate. Referral was influenced by level of dependence, rate of progression, and bulbar involvement.
Conclusion: In the UK only a small proportion of MND patients are referred for NIV, with marked heterogeneity of practice. This may reflect concerns that NIV may prolong suffering, and emphasises the need for a controlled trial assessing its impact on quality of life.
AN MRI STUDY OF COMPLICATED EARLY CHILDHOOD CONVULSION
RA Grünewald, T Farrow, CDC Rittey, P Vaughan, J Mundy Royal Hallamshire Hospital; Ryegate Children's Centre, Sheffield, UK
Objectives: About half of adults with hippocampal sclerosis have a history of complicated early childhood convulsion (cECC). The objective of the study was to assess the extent of structural brain abnormality present soon after a first cECC.
Methods: Children under the age of 5 years underwent brain MRI within 14 days of their first complicated febrile or non-febrile ECC. None had previously experienced an epileptic seizure. Hippocampal volumes and T2 relaxation times were measured. The control group consisted of children undergoing brain MRI for reasons other than epilepsy.
Results: Nine of the 17 experimental subjects had significant hippocampal volume asymmetry (3 standard deviations from the mean of the control group), although in only three of these was the asymmetry apparent on visual inspection of the MRI. Three experimental subjects had extrahippocampal neuropathology. None of the 10 control subjects had significant hippocampal volume asymmetry (p<0.001). T2 relaxometry did not suggest that oedema contributed to the asymmetry.
Conclusions: There is a high prevalence of structural brain abnormalities and hippocampal asymmetry in children within 2 weeks of the first complicated early childhood convulsion, unrelated to oedema. This suggests that in some cases the complicated EEC is the result of pre-existing brain abnormalities.
A DOUBLE BLIND SINGLE DOSE CROSS OVER STUDY OF THE EFFECTS OF PRAMIPEXOLE, PERGOLIDE, AND PLACEBO ON TREMOR AND UPDRS (III) IN PARKINSON'S DISEASE
P Navan, LJ Findley, R Pearce, J Jeffs, PG Bain Imperial College School of Medicine, London; Havering Hospital NHS Trust, Essex; Hammersmith Hospital, London UK
Design: 10 tremulous PD patients were pretreated with domperidone and taken off anti-parkinsonian medication. Each patient received single doses of 0.5 mg pramipexole, 0.5 mg pergolide, and placebo, but in random order. Rest tremor and UPDRS (part III) were measured at baseline and 30 minute intervals for 4 hours. The results were examined using ANOVA by area under the curve (AUC) and peak effect (Bonferroni corrected; significance: 5% level).
Results: (1) AUC analysis showed a significant difference between the three treatments on rest tremor (p=0.045) (pramipexole differed from placebo at 10% level) but not UPDRS (III). (2) Peak effect analysis demonstrated a difference in treatment effects on UPDRS (III) (p=0.04) (pergolide better than placebo, p=0.048) and rest tremor (p=0.005) (no significant difference between active drugs, both significantly better than placebo). Pergolide caused a significantly greater incidence of nausea (p=0.005) and vomiting (p=0.014) than pramipexole. No significant differences between the 3 treatments on incidence of drowsiness or sleep (McNemar's test).
Conclusion: 0.5 mg pramipexole or pergolide can improve UPDRS (III) and rest tremor in PD. Pergolide had the strongest effect on peak UPDRS (III), whereas pramipexole had the greatest effect on rest tremor (AUC). Pramipexole is significantly better tolerated than pergolide.
PALLIDAL STIMULATION FOR UNUSUAL MOVEMENT DISORDERS: 1 YEAR OUTCOME OF FOUR PATIENTS
SG Parkin, RP Gregory, TZ Aziz The Radcliffe Infirmary, Oxford, UK
Pallidal stimulation has become an established mode of treatment in Parkinson's disease when medical therapy has failed. There is historical evidence to suggest that surgery to the basal ganglia can benefit a wide range of movement disorders. The relative safety of deep brain stimulation has allowed us to re-explore its benefit to other, less common conditions. We report the outcome of pallidal stimulation in a consecutive series of patients with idiopathic generalised dystonia, familial myoclonic dystonia, idiopathic progressive chorea, and tardive dyskinesia with captocormia. All had failed an exhaustive trial of medical therapy. Highly significant benefits were seen in various movement disorder rating scales and quality of life measures. These were maintained at 1 year. The obvious clinical benefits, rarity and heterogeneity of conditions of this type, precludes the use of randomised clinical trials. Detailed follow up of individual patients is important to provide evidence for the application of pallidal DBS in such conditions.
CRITERIA FOR INITIATING NON-INVASIVE VENTILATION IN MOTOR NEURON DISEASE
SC Bourke, PJ Shaw, R Bullock, GJ Gibson University of Newcastle, Newcastle; University of Sheffield, Sheffield; Newcastle General Hospital, Newcastle, UK
Objective: We studied the criteria which best predict benefit from quality of life (QOL) and compliance with non-invasive ventilation (NIV) in motor neuron disease (MND).
Methods: 23 subjects were recruited. QOL (SF-36, chronic respiratory disease questionnaire, sleep apnoea quality of life index (SAQLI), vital capacity, and maximum respiratory pressures were assessed two monthly and polysomnography four monthly. Subjects were offered a trial of NIV with any of: (1) orthopnoea, (2) unrefreshing sleep or daytime sleepiness, (3) Daytime PaCO2 >45 mm Hg, (4) SaO2 <90% for ≥5% of the night, (5) apnoea hypopnoea index >10.
Results: The improvement in the SAQLI symptoms domain (most responsive index) after 1 month NIV (effect size: mean difference/SD), and compliance are shown. Results for subjects in whom only one criterion for NIV was met are in brackets.
10/16 subjects starting NIV elected to continue. Among these, orthopnoea was the commonest indication (9/10). Moderate/severe bulbar weakness was associated with lower compliance (4.22 v 8.47 h/day) and less improvement in QOL (effect size: 1.85 v 3.28).
Conclusions—Orthopnoea was the best predictor of compliance with and benefit from NIV in MND. Moderate/severe bulbar involvement was associated with poorer (although still clinically useful) compliance and response.
RESPONSIVENESS OF QUALITY OF LIFE INSTRUMENTS AND DOMAINS TO NON-INVASIVE VENTILATION IN MOTOR NEURON DISEASE
SC Bourke, PJ Shaw, R Bullock, GJ Gibson University of Newcastle, Newcastle; University of Sheffield, Sheffield; Newcastle General Hospital, Newcastle, UK
Background: As a prelude to a randomised controlled trial of non-invasive ventilation (NIV) in motor neuron disease (MND), we studied which quality of life (QOL) instruments are most responsive. We report the results of an efficacy analysis of the impact of NIV on QOL in 10 subjects with MND.
Methods: QOL and functional status were assessed at 0, 1, and 3 months after initiation of NIV, then 2 monthly intervals using SF-36, general wellbeing schedule (GWbS), chronic respiratory disease questionnaire (CRDQ), sleep apnoea quality of life index (SAQLI), Epworth sleepiness scale (ESS), and ALS functional rating scale (ALSFRS). The maximum improvement in each index was assessed by effect size (mean difference/SD).
Results: Effect sizes for all responsive instruments are shown.
The GWbS and SF-36 energy vitality and health change showed non-significant improvements. The largest improvements were in domains assessing sleep related symptoms, which were maintained for a mean ≥320 days (Kaplan-Meier). As expected the SF-36 physical function domain and ALSFRS declined with disease progression.
Conclusion: NIVimproves QOL in selected patients with MND. QOL domains assessing sleep related symptoms were most responsive, and the improvement was maintained at or above baseline for ≥320 days despite disease progression.
THE EFFECT OF CANNABIS BASED MEDICINAL EXTRACT ON LOWER URINARY TRACT DYSFUNCTION IN ADVANCED MULTIPLE SCLEROSIS: PRELIMINARY RESULTS
CM Brady, R DasGupta, OJ Wiseman, CM Dalton, KJ Berkley, CJ Fowler National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Aims: The primary aim of this open label pilot study is to evaluate the safety, tolerability, and efficacy of two preparations of sublingual cannabis based medicinal extract (CBME) in patients with advanced multiple sclerosis (MS) and refractory lower urinary tract symptoms (LUTS).
Methods: Patients with advanced MS (Kurtzke score ≥6.5) and refractory LUTS (detrusor hyperreflexia demonstrated by cystometry) are eligible for recruitment into this ongoing study. Frequency-volume incontinence charts and pad testing are completed during the run in (3 weeks) and treatment (16 weeks) periods. For the first 8 weeks of treatment, patients receive CBME containing equal amounts of cannabidiol (CBD) and tetrahydrocannibinol (THC) whereas a THC only preparation is prescribed for weeks 9–16. Patients self titrate the CBME until urinary symptoms are relieved or unacceptable side effects occur. To assess the acute effects of CBME, cystometry is performed and cannabinoid concentrations are taken before and after maximum tolerated dose of CBME at 4, 8, and 16 weeks on treatment.
Results: We report results of the first eight patients (2M:6F, age 31–64). A paired t test was used.
The average cystometric capacity increased from 265 ml at baseline to 439 ml at 8 weeks, and to 353 ml at 16 weeks after dosing with CBME in the department.
Conclusions: These preliminary results indicate that CBME may prove to be an effective additional treatment for refractory urinary symptoms in a selected group of patients with advanced MS.
INTRONIC AND MISSENSE MUTATIONS WITHIN THE LAMP-2 GENE IN DANON DISEASE (X LINKED VACUOLAR CARDIOMYOPATHY AND MYOPATHY)
NP Davies, C Beesley, PM Elliott, J Holton, B Lake, DN Landon, P Lee, H Mundy, B Winchester, MG Hanna Institute of Neurology, Queen Square, London; Institute of Child Health, London, UK
Danon disease is an X linked disorder characterised by cardiomyopathy, vacuolar myopathy, and variable mental retardation. It is now known to be due to mutations within a gene encoding the lysosomal associated membrane protein LAMP-2 on Xq24.
We report three families with Danon disease. Affected males in each family presented with profound cardiac symptoms but had mild proximal myopathy. Mental retardation was apparent in only three out of five affected males. Proximal myopathy and mental retardation were not apparent in affected females. Age at death was 15–24 years for men and 29–40 years for women. Muscle biopsies revealed the characteristic vacuolar myopathy. We also showed intense deposition of the complement membrane attack complex (MAC) on vacuolated fibres. This immunoreactivity has been previously reported to be specific for another vacuolar myopathy (X linked myopathy with excess autophagy, XMEA). Genetic analysis revealed three new mutations in the LAMP-2 gene. We report the first missense mutation in LAMP-2 (W321R). In addition, two new intronic mutations were detected.
In summary, we confirm the clinical and pathological characteristics of Danon disease and suggest that deposition of MAC on vacuolated fibres may be a feature. We identified three previously unreported mutations in the LAMP-2 gene. The W321R mutation represents a new mutational mechanism, as all other mutations disrupt splicing or lead to premature truncation of the protein. In view of the sparse skeletal muscle signs in this disorder, we would recommend a skeletal muscle biopsy in any young patient with an apparently isolated cardiomyopathy.
GLUTEN ATAXIA AND GLUTEN NEUROPATHY: THE EFFECT OF A GLUTEN-FREE DIET
M Hadjivassiliou, RA Grünewald, AK Chattopadhyay, RH Kandler, JA Jarratt, GAB Davies-Jones The Royal Hallamshire Hospital, Sheffield, UK
We studied the effect of gluten free diet on patients with ataxia and/or peripheral neuropathy associated with gluten sensitivity.
Sixteen patients with gluten ataxia (sporadic ataxia with circulating antigliadin antibodies) were assessed before and after 12 months treatment with a gluten free diet. Subjective assessment of clinical state by visual analogue scale improved from mean score (SD) at baseline 0.49 (0.17) to 0.7 (0.26). When compared with a heterogenous control group of eight ataxic patients without gluten sensitivity or who declined treatment with a gluten free diet, the improvement was significant (repeated measures ANOVA p=0.002). Improvement was also seen in time standing with feet together without corrective movement (baseline 19.1seconds (22.7), 12 months 31.2 seconds (26.4), p=0.05 Student's t test). There was a trend towards improvement in computerised measures of latency and accuracy of arm coordination.
Sural sensory action potentials were measured in a group of 13 patients with gluten neuropathy before and 12 months after starting a gluten free diet. Baseline and 12 month repeat measurements were also made in a control group of five subjects with gluten neuropathy who declined the diet. There was some increase in amplitudes in the group treated with diet: 1.4 μV (1.3) v 2.3 μV(2.1) but none in the control group : 1.6 μV v 1.1 μV(1.2). The change in amplitude between the two groups was not significant (p=0.067 Mann-Whitney).
These preliminary data suggest that a gluten free diet may be of benefit in some patients with neurological manifestations of gluten sensitivity.
HUMAN COMPLICATION OF THE FOOT AND MOUTH CRISIS
KAC Harkness, TG Staunton Norfolk and Norwich Hospital, Norwich, UK
We report an unusual complication of the foot and mouth crisis. After our patient, a marksman, had examined a culled bull for signs of life, the animal's head moved, trapping his feet and causing him to lose balance. He fell backwards onto the horn of another dead animal, sustaining a penetrating injury to the occiput. He did not lose consciousness but complained of loss of vision in the right hemifield, 30 minutes after the initial injury. In the neurosurgical unit CT demonstrated a left comminuted depressed occipital skull fracture with some impingement of the left occipital-parietal lobe. The patient was managed conservatively with intravenous antibiotics and discharged 1 week later.
Two weeks later the patient developed occipitofrontal headache with photophobia and presented to our neurology unit. He was afebrile, no meningism, no papilloedema, a resolving right field defect was noted. MRI and MRA images were performed. The vertebral arteries were normal. A left occipital skull fracture with an organising extradural haematoma indentating the left occipital lobe was demonstrated. Abnormal high signal was seen within the sagittal sinus. MRV demonstrated venous thrombosis occluding the posterior two thirds of the sagittal sinus. The patient was anticoagulated and symptoms resolved in a few days.
A UNIQUE MODEL OF LISSENCEPHALY
L Kinton, KA Barth, C Howart, JS Duncan, M Gardiner, NW Wood, S Wilson Institute of Neurology, Queen Square, London; University College, London, UK
Disorders of neuronal migration are important causes of drug resistant epilepsy. Mutations in two genes LIS1 and DCX have been shown to cause one such condition, agyria/pachygyria/band heterotopia complex.
The zebrafish, Danio rerio, is used as a model organism for studying development of vertebrate systems including the CNS. Advantages of this model organism include rapid external development, transparency, and most recently morpholino antisense oligonucleotide technology for creating targeted gene knockdown. Conservation of genetic pathways across vertebrates make it a valid model organism.
The zebrafish orthologue of the LIS1 gene has been cloned and it shows a high degree of sequence conservation with human LIS1 (81% nucleotide, 93% amino acid identity). The expression pattern in the developing zebrafish is analagous to mammalian expression including high levels in the developing CNS.
The novel technique of morpholino antisense oligonucleotide injection has been performed against the lis1 gene. Graded reduction in lis1 protein translation and hence activity in the zebrafish embryo results (knockdown), providing an in vivo model of lissencephaly. These embryos show abnormalities in the developing brain, most notably the telencephalon and hindbrain. This is the first time this technique has been used to model a neurological disorder important in epilepsy pathogenesis.
USE OF INTERNET MEDICAL WEBSITES AND OF NHS DIRECT BY NEUROLOGY OUTPATIENTS BEFORE CONSULTATION
AJ Larner The Walton Centre for Neurology and Neurosurgery, Liverpool, UK
Objectives/methods: Two sources of medical information have recently become available to the general public: medical websites on the Internet, and the NHS Direct telephone helpline. This study measured the use of these resources before consultation by consecutive new referrals to general neurology outpatient clinics.
Setting: Two district general hospitals in north west England.
Results: Of 198 patients seen over 3 months, 66 (33%) had home access to the Internet. Of these 66, 15 (22%=7.6% of all patients) had accessed websites containing medical information; only one patient volunteered this information.
Of these 15, nine (60%) accessed information which was adjudged inappropriate in the light of the final diagnosis. This was due to: incorrect self diagnosis, based on self directed searches (5/9); incorrect diagnosis by another doctor (2/9); other, pre-existing (correct) diagnoses not relevant to current symptomatology (2/9).
Internet users accessing appropriate information found that searches were time consuming and generally provided nothing beyond what they already knew. Only one patient found website information “very helpful”, but this was inappropriate to the final diagnosis.
Only 4/198 patients (2%) had telephoned NHS Direct before consultation; none volunteered this information. In only one did the call relate to neurological symptoms.
Conclusions: In this study around a quarter of patients with home access to the Internet used medical websites before neurological consultation; use of NHS Direct was negligible. Information accessed from Internet sites was adjudged inappropriate in 60% of cases. Internet searches, although seldom volunteered, may influence patients' health beliefs and expectations, and hence the subsequent consultation. Such considerations may become increasingly relevant as personal Internet access expands.
AN IMPROVED METHOD OF QUANTIFYING ACTIVITY LEVELS IN NEUROLOGICAL PATIENTS
C Lawthom, RMW van Deurson, CM Wiles University Hospital Wales, UK
Current assessments of mobility rely on brief observations of walking and questionnaire based scales that are surrogate measures of everyday activity. Accelerometry techniques now allow unobtrusive activity measurement over many days. Activity levels in two patients and two matched healthy controls were measured using the Stepwatch Activity Monitor, a device worn on the ankle to record cadence over 3 to 8 days, both at home and in hospital. An interviewer administered diary, the Rivermead mobility index (RMI), and a digital camcorder recording of gait (with calculation of stride length and hence distance) were also used
Patient 1 (female; 74 years) recovering from Guillain-Barré syndrome, was independent (RMI: 8/15). The patient was active for on average 2.95 hours per day (h/d) ( range 1.3 to 4.1 h/d), and 18.43% of time awake: she walked an average of 1791 right steps covering a distance of 1593 m (range 857–2710 m) Activity levels rose after discharge from hospital with a change in activity pattern from directed activity to less vigorous, frequent independent activity. Patient 2 (female; 34 years) with improving inflammatory cervical myelopathy, was also independent (RMI: 8/15). This patient had very limited activity which coincided with physiotherapy, with little independent activity. As expected the two controls had far higher activity levels. Despite similar RMI scores, the patients showed very different activity levels: both showed reduced activity levels with walking, in one case virtually dependent on therapy. These data emphasise the wide range of normal activity levels in healthy and disabled people and the potential use of this technique in quantifying and monitoring mobility.
SPECIFYING THE EXECUTIVE DEFICIT IN PARKINSON'S DISEASE; A COMBINED BEHAVIOURAL AND EVENT RELATED FMRI STUDY
SJG Lewis, A Dove, R Cools, TW Robbins, RA Barker, A M Owen Cambridge Centre for Brain Repair, Cambridge, UK
Parkinson's disease (PD) is accompanied by a complex pattern of “frontal-like” impairments, which may include deficits in many aspects of working memory function. However, recent neuropsychological studies have questioned the psychological specificity of these “executive” deficits, while functional neuroimaging studies have been unable to identify the precise neural substrates responsible. In this study, two closely matched groups of patients with PD, differing only with respect to their performance on a standard test of executive dysfunction, were tested on a novel verbal working memory paradigm which allowed different aspects of performance to be assessed simultaneously, including maintenance, retrieval, and manipulation of the remembered information. The subgroup of patients with “executive” impairment were selectively impaired on the task, and specifically in those aspects of the test requiring the manipulation of information within working memory. These results suggest that it may be informative to functionally subdivide patients with PD according to whether their cognitive profile includes executive dysfunction or not; moreover, the specific nature of the impairment observed implicates the mid-dorsolateral region of the frontal cortex as a likely neural substrate. To test this hypothesis directly, event related fMRI was employed in similar groups of PD patients performing the same verbal working memory task.
GLUTEN ATAXIA IS IMMUNE MEDIATED
D Mahad, K Oates, C Williams, R Grünewald, SJL Howell, MN Woodroofe, M Hajivassiliou Royal Hallamshire Hospital, Sheffield, UK
Gluten sensitivity is a state of heightened immunological responsiveness triggered by the ingestion of gluten in genetically susceptible individuals. Organ specific manifestations include an enteropathy (coeliac disease) a dermatopathy (dermatitis herpetiformis) and CNS involvement (gluten ataxia). Gluten ataxia accounts for up to a third of idiopathic sporadic ataxias. It is defined by the presence of antigliadin antibodies in otherwise unexplained sporadic idiopathic ataxia. The mechanism of neurological damage remains obscure.
Postmortem brain tissue of two patients with gluten ataxia showed T cell infiltration and upregulation of chemokine expression. CSF from 10 patients with gluten ataxia showed upregulation of the chemokine IP-10 when compaired with controls. Serum from patients with gluten ataxia stained human cerebellar Purkinje cells at dilutions up to 1:800 with strong staining seen up to 1:400. At 1:400 staining was not seen in the control groups (five patients with other causes of ataxia, five normal controls, five patients with coeliac disease). Commercial antigliadin antibodies stained human Purkinje cells in a similar manner. Persistent staining after adsorption with crude gliadin was only observed when using sera from patients with gluten ataxia.
These data provide further support to our contention that gluten ataxia is immune mediated.
EVIDENCE FOR DEMENTIA IN SPAST-HEREDITARY SPASTIC PARAPARESIS
P McMonagle, P Byrne, S Webb, N Parfrey, M Hutchinson St Vincent's University Hospital, Dublin, Ireland
Objective: Cognitive impairment is recognised in SPAST-hereditary spastic paraparesis (HSP). It is unclear if this represents a dementia. Our aim was to examine SPAST-HSP pedigrees longitudinally for evidence of progressive cognitive decline.
Methods: Five families with SPAST-HSP were identified, 4 with detectable mutations and one based on linkage. Family members were tested for cognitive impairment at first visit and again after a minimum of 1 year. The Cambridge Cognitive Assessment (CAMCOG) has a maximum score of 107, scores <80/107 indicate cognitive impairment. Non-parametric tests of significance were used.
Results: 34 patients over age 20 from five families had paraparesis. Repeat CAMCOGs were available for 22. The age after 2.9 years follow up was 54.5 years. CAMCOG declined over that time from 86.6 to 82.4/107 (p=0.018). In those with cognitive impairment at baseline (n=9) CAMCOG declined further from 74 to 64.4/107 (p=0.012). The average age for this group was 66.4 years. CAMCOG for controls (age=65.9 years, n=9) showed little change (91.8 to 90.2/107, NS).
Conclusions: We have demonstrated longitudinal cognitive decline in those with SPAST-HSP and further decline in those with established cognitive impairment, suggesting that this is a dementing process.
TWO CLINICAL PRESENTATIONS OF ADULT ONSET RASMUSSEN'S SYNDROME SHARE COMMON IMMUNOLOGICAL AND PATHOLOGICAL FEATURES
RS Nicholas, AC Scott, IK Hart The Walton Centre for Neurology and Neurosurgery, Liverpool, UK
Childhood Rasmussen's syndrome (RS) is a focal cortical inflammation causing epilepsy and progressive neurological deficits. We studied six patients to define the clinical and pathological features of adult RS and performed comprehensive screens for anti-CNS and other autoantibodies. All patients presented with epilepsy (average age 29 years). There were two patterns of clinical onset and progression—rapid (neurological deficit ≤12 months after seizure onset; four patients) and slow (neurological deficit ≥42 months after seizure onset). The rapid form presented with focal increased signal on T2 MRI that later developed into ipsilateral hemisphere atrophy. Histology was similar to childhood RS. In the slow form, MRI brain showed focal cortical atrophy. On histology, there was moderate perivascular T cell infiltration, microgliosis, and reactive astrocytosis. In both forms, there was bilateral focal cortical hypoperfusion on SPECT scans. All patients had multiple serum and CSF immune abnormalities and had similar HLA haplotypes. We propose that adult RS has two clinical phenotypes—rapid and slow—that share similar brain, CSF, and serum autoimmune abnormalities. Our findings may help the early diagnosis of adult RS and identify candidates for immunomodulatory therapy before they develop extensive, irreversible neuron loss.
EPILEPSY SURGERY IN PATIENTS WITH ADDITIONAL PSYCHOGENIC SEIZURES
M Reuber, G Fernandez, M Kurthen, J Schramm, CE Elger University of Bonn, Bonn, Germany
Objective: To assess whether surgery to reduce or control epileptic seizures is safe and effective in patients known to have additional psychogenic seizures.
Methods: We reviewed our computerised database of 1342 patients evaluated for epilepsy surgery and identified 13 patients with both epileptic and psychogenic seizures on whom postoperative data were available. Outcome data were gathered from patient records and completed by telephone interviews. Mean postoperative follow up was 56 months.
Results: Epilepsy surgery led to relevant improvements in 11 of 13 patients. Seven patients became completely seizure free, two patients became free of epileptic seizures but continued to have infrequent psychogenic seizures, one patient reported an over 80% improvement of epileptic seizure frequency and an abolishment of psychogenic attacks, in one patient non-disabling epileptic seizures persisted at lower frequency but psychogenic seizures stopped. In two of 11 patients, epilepsy surgery failed to produce notable improvements. Although epileptic seizures improved, their psychogenic seizure disorder remained highly disabling. In both of these patients pathological illness behaviour had been noted preoperatively.
Conclusion: A diagnosis of additional psychogenic seizures should not be considered an absolute contraindication to epilepsy surgery although patients should undergo careful preoperative psychiatric evaluation.
EXPLORING THE CONNECTIVITY OF BAND HETEROTOPIA USING DIFFUSION TENSOR IMAGING
FJ Rugg-Gunn, M Guye, SH Eriksson, G Parker, GJ Barker, C Wheeler-Kingshott, JS Duncan University College London, London, UK
Introduction: Diffusion tensor imaging (DTI) is an MRI method that evaluates the diffusion of water molecules. DTI tractography allows mapping of white matter tracts. Band heterotopia (BHT) is a malformation of cortical development in which there are bands of ectopic grey matter in the subcortical white matter. Previous functional imaging has shown activations in BHT. We used tractography in five patients with BHT to determine whether connecting tracts could be identified in vivo.
Methods: Five patients with epilepsy and bilateral BHT were scanned with DTI. Anisotropy (diffusion directionality) maps were calculated and evaluated using fast marching tractography. This produced maps of the likelihood of connection which were used to determine the pathways of white matter tracts through the areas of BHT, and compared with control data.
Results: White matter tracts were identified passing from and through the BHT to the cortex in each patient.
Conclusions: Using tractography we have shown that white matter tracts traverse and connect BHT to overlying cortex. This shows the structural basis of the functional connectivity implied by activation studies and the absence of focal neurological deficit. This result demonstrates the potential of the method to indicate structural connectivity in vivo.
THE PROGNOSTIC VALUE OF INTRATHECAL IMMUNE RESPONSE AGAINST AXONAL COMPONENTS IN PATIENTS WITH MULTIPLE SCLEROSIS
OA Seidi, YK Semera, NA Gregson, MK Sharief Guy's Hospital, London, UK
Background: We have recently reported a significant correlation between clinical disability and intrathecal release of antibodies against axonal cytoskeleton in patients with primary and secondary-progressive MS.
Objectives: To determine the prognostic value of intrathecal antibodies to axonal proteins for future development of disability in MS patients.
Methods: In a prospective study, we measured intrathecal levels of antibodies against actin, tubulin and neurofilament light-subunit from 51 patients with relapsing-remitting, secondary, or primary-progressive MS. Patients were clinically monitored for 2 years after the lumbar puncture (LP). We included 52 patients with other neurological disorders and eight healthy subjects, as controls. We also measured antibodies against myelin basic protein (MBP) as a control antigen.
Results: Intrathecal levels of antibodies against all axonal proteins, but not anti-MBP, correlated with the expanded disability status scale (EDSS) score at the time of LP. Moreover, MS patients with high intrathecal levels of antibodies against axonal proteins accumulated more neurological disability at the end of the 2 year period compared with patients with low levels. By contrast, antibodies against MBP did not correlate with EDSS score at the end of the study.
Conclusion: The determination of intrathecal antibodies against axonal proteins may be clinically useful in MS patients.
MAPPING THE DISEASE LOCUS IN A LARGE KINDRED WITH GENERALISED EPILEPSY
A Siddiqui, M Davis, PH Dixon, M Johnson, M Koepp, SD Shorvon, JWA Sander, RM Gardiner, JS Duncan, NW Wood Institute of Neurology, Queen Square, London; University College London, UK
A large British family with epilepsy underwent careful clinical evaluation using a structured seizure questionnaire. There was similarity to the GEFS plus (generalised epilepsy and febrile seizures plus) phenotype in that affected individuals manifested a variety of childhood onset epilepsy phenotypes with or without preceding febrile seizures. A simulation analysis estimated a maximum lod score of 4.17 at theta=0 and 3.84 at theta=0.05. The known loci for GEFS plus on chromosome 19q and 2q and the febrile seizures loci on chromosome 8q, 19p, 2q, and 5q were investigated initially and excluded with lod scores ranging from −2.01 to −infinity.
Genome wide linkage analysis was undertaken using a medium density linkage mapping set. This contained 400 fluorescent dye labelled microsatellite markers that defined a 10 cM resolution index map.
This work identified two main regions of linkage on chromosome 2 and 5. These areas were investigated by genotyping further markers and constructing haplotypes. Two point lod scores are 3.01 at theta=0 and 2.41 at theta=0 respectively, and multipoint lod scores of 3.01 and 2.85 respectively. Searches are being carried out for candidate genes using the Draft Human Genome Browser.
MAGNETISATION TRANSFER RATION AND N-ACETYL ASPARATE AS INDEPENDENT MARKERS OF MYELIN AND AXONAL INTEGRITY IN DEMYELINATING LESIONS: A MAGNETIC RESONANCE IMAGING STUDY OF CENTRAL PONTINE MYELINOLYSIS
NC Silver, DG MacManus, CA Davie, DH Miller Institute of Neurology, University College London, UK
Magnetisation transfer ratio (MTR) measurement seems promising as a putative marker of demyelination in the CNS. Small MTR reductions may also occur as a result of axonal loss, oedema, or inflammation. The individual contribution of tissue components to MTR values in healthy tissue is unknown. Central pontine myelinolysis (CPM), a condition characterised by severe demyelination and occasional minimal axonal loss in the absence of inflammation or oedema, provides a useful in vivo model to assess the effect of myelin disruption on MTR.
Three patients with CPM were studied with magnetisation transfer imaging and proton magnetic resonance spectroscopy (MRS) on one or more occasions during their illness. Moderate to severe MTR reductions were observed in acute lesions and resolution of MTR parallelled clinical recovery. Marked MTR reductions were observed despite general preservation of N-acetyl aspartate (NAA; an in vivo MRS marker of axonal integrity).
These observations support the hypotheses that (a) myelin forms the predominant contribution to MTR values in healthy white matter, (b) demyelination itself can result in severe MTR reduction, (c) profound MTR reduction may be seen in the absence of significant neuronal damage, (d) MTR and NAA provide relatively independent markers of myelin and axonal pathology, and (e) MTR and NAA may provide useful diagnostic and prognostic information in CPM.
A PROSPECTIVE STUDY OF EPILEPSY SURGERY IN THE UK
JK Solomon, A McEvoy, SD Lhatoo, ND Kitchen, SD Shorvon Institute of Neurology, Queen Square, London, UK
The treatment of epilepsy has been revolutionised by improvements in epilepsy neurosurgery. We wished to determine the number of consultant neurosurgeons performing epilepsy surgery in the United Kingdom and to evaluate prospectively the total number of epilepsy procedures performed.
All practising consultant adult and paediatric neurosurgeons in the United Kingdom were sent a postal questionnaire asking if they had performed epilepsy surgery in the last year. Each identified surgeon was then asked to record the type and number of surgical procedures they had performed in a questionnaire mailed to them at the end of every month for 6 consecutive months commencing February 2000.
Thirty two consultant neurosurgeons in current practice who performed epilepsy surgery were identified. Out of a total of 192 monthly questionnaires there was a response rate of 95%. A total of 289 surgical procedures for epilepsy were performed, suggesting an annual figure of 578 procedures.
Although there has been an almost twofold increase in curative epilepsy surgery in the last decade, this still falls far short of what is required from epidemiological estimates. The need for more surgical assessment units as well as trained epilepsy surgeons is emphasised by our study's figures.
DERMATITIS HERPETIFORMIS, COELIAC DISEASE, AND NEUROLOGICAL DYSFUNCTION
DSNA Pengiran Tengah, DJ Unsworth, L Fry, G Giovannoni, A Church, B Turner, GKT Holmes, AJ Wills Queens Medical Centre, Nottingham; Southmead Hospital, Bristol; Imperial College London; Institute of Neurology, London; Derbyshire Royal Infirmary, Derby, UK
Objective: To investigate the prevalence of neurological abnormalities in patients with dermatitis herpetiformis (DH) and coeliac disease (CD) based on previous data suggesting that gluten is neurotoxic via immune mechanisms.
Methods: 35 patients with biopsy proved DH and 38 patients with biopsy proved CD underwent thorough neurological examination and detailed case note review. Nerve conduction studies were requested where appropriate. The DH cohort was assessed for anti neuronal antibodies (Anti-Hu and Yo).
Results: Unexplained neurological abnormalities occurred in four patients with DH: chorea (one), essential tremor (one), and migraine (two); and nine patients with CD: epilepsy (one), migraine (six), benign fasciculations (one), and possible sensory neuropathy (one). Antineuronal antibodies were negative in all but one patient who had equivocally positive anti-Hu antibodies. An unexpected finding was the presence of a novel antispinal antibody in over 50% of these patients. The lifetime prevalence of essential tremor and migraine in these two cohorts was unremarkable. The patient with chorea had been on long term phenytoin, which is a reported association.
Conclusion: No cases of gluten ataxia were detected. The neurological abnormalities found in these patients are likely to be either chance or spurious associations contrasting with previous research. However, the unexpected discovery of this novel spinal antibody in DH patients requires further investigation, particularly in the light of previous studies suggesting an increased prevalence of sensory ataxia in patients with established gluten sensitivity.
WHITE MATTER T1 RELAXATION TIMES IN MULTIPLE SCLEROSIS ACQUIRED USING THREE DIMENSIONAL MAGNETIC RESONANCE IMAGING
L Vaithianathar, CR Tench, PS Morgan, LD Blumhardt Queen's Medical Centre, Nottingham, UK
T1 relaxation time (T1) mapping provides a quantitative method for assessing disease burden in multiple sclerosis (MS).
Previous studies have been limited to sampling small regions of normal appearing white matter or discrete lesions.
We compare total white matter T1 values in controls and MS patients from different clinical subgroups using histogram analysis. Relations between T1, disability, and T2 lesion volume are explored.
29 patients with MS (11 relapsing-remitting, RR; 11 secondary progressive, SP; seven primary progressive) and 11 healthy controls were recruited. High resolution T1 maps were acquired using a three dimensional fast low angle shot sequence. Dual echo T2 weighted images were also obtained. Disability was assessed using the expanded disability status scale (EDSS). Normalised white matter histograms were generated after extracting skull, cerebrospinal fluid and grey matter. T2 lesion volume was determined using a semiautomated technique.
Histogram standard deviation (SD) was significantly greater in each patient subgroup than in controls (p=0.0001), and in patients with SPMS compared with RRMS (p=0.02). In the overall patient cohort, histogram SD correlated significantly with T2 lesion volume (r=0.79, p<0.0001), and disability (r=0.53, p=0.004).
White matter T1 histograms evaluate global tissue damage in MS, and may provide a sensitive, objective measure for monitoring disease progression.
OLIGODENDROCYTES SECRETE FACTORS WHICH DECREASE NEURONAL APOPTOSIS IN VITRO VIA PI3-KINASE/AKT SIGNALLING PATHWAYS
A Wilkins, S Chandran, DAS Compston Cambridge Centre for Brain Repair, Cambridge, UK
There is increasing data both from experimental models and from pathological and clinical studies of multiple sclerosis showing that oligodendrocytes provide trophic support for neurons and withdrawal of that support may contribute to neuronal dysfunction. Understanding the nature of this support and underlying intracellular mechanisms may lead to development of therapeutic strategies to prevent neuronal/axonal abnormalities occurring in multiple sclerosis. We have used an in vitro model to study neuronal-oligodendrocyte interactions.
Rat embryonic cortical neurons were cultured in media conditioned by oligodendrocytes at different stages of their lineage. Neuronal survival was measured by immunocytochemistry and by 3H GABA uptake. Apoptosis was measured by TUNEL staining. Protein kinase analysis was studied by western blotting and immunocytochemistry.
Neurons showed a marked increase in survival when cultured in medium conditioned by oligodendrocyte precursor cells and differentiated oligodendrocytes, and a decrease in apoptosis, compared to non-conditioned media. This effect was blocked by inhibitors of PI3 kinase but not by MAP kinase inhibitors. Furthermore oligodendrocyte conditioned media caused an increase in Akt (protein kinase B) phosphorylation in neurons consistent with an anti-apoptotic effect.
This study provides evidence that soluble factors from oligodendrocytes support neuronal survival and decrease apoptosis via PI3 kinase/Akt signalling pathways.
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