Proceedings of the Association of British Neurologists and Societe Suisse de Neurologie Joint meeting, The Commonwealth Institute, London, 20-22 September 2000.(Statistical Data Included)

Analysis of pooled individual patient data from randomised controlled trials of carotid endarterectomy for symptomatic Stenosis

PM ROTHWELL, SA GUTNIKOV, MR MAYBERG, CP WARLOW, HJM BARNElT

Radcliffe Infirmary, Oxford, UK

Carotid endarterectomy (CEA) is indicated for symptomatic "severe" carotid stenosis. However, because of differences between trials in the method of measurement of stenosis, and insufficient numbers of patients in individual trials, there is uncertainty about the exact benefit at different degrees of stenosis. Moreover, no trial has had the power to determine the effect of CEA in important clinical and pathological subgroups. We therefore combined individual patient data (300 variables and 2 million data fields) from the three main RCTs (ECST, NASCET, and VA309), remeasuring stenosis using the same method (that used in NASCET and VA309).

Stenosis was categorised as [less than]30% (n1775); 30-49% (n=1441); 50-69% (n 1546); 70-99% (n=1118); and near occlusion (n=219). All analyses were intention to treat and used Kaplan-Meier survival techniques. Surgery was beneficial in patients with 50-69% stenosis and 70-99% stenosis: absolute reductions in the 5 year risk of any stroke or death were 9% (p[less than]0.001) and 13% (p[less than]0.001) respectively. However, there was no evidence of benefit in patients with near occlusion (2%, p=0.5). Surgery was ineffective in patients with 30-49% stenosis (0%, pO.7) and harmful in patients with [less than]30% stenosis (-4%, p[less than].0.05). There was clinically important heterogeneity of treatment effect between the different predefined subgroups within both the 50-69% and 70-99% stenosis groups.

CEA is beneficial in patients with 50-99% symptomatic stenosis, but there is no evidence of benefit in patients with near occlusion. Several other clinical and angiographic characteristics also influence the efficacy of surgery.

Thrombolysis for acute stroke: single centre United Kingdom experience with rtPA

KW MUIR

Institute of Neurological Sciences, Glasgow

Background--Recombinant tissue plasminogen activator (rtPA) is licensed for ischaemic stroke treatment in North America. Postlicensing experience indicates benefit consistent with trial results, but potential hazard of non-protocol treatment. United Kingdom experience is limited.

Methods--Patients received open rtPA for ischaemic MCA stroke [less than]3 hours after onset, with pretreatment CT excluding haemorrhage or early infarct changes in [greater than]1/3 of MCA territory. CT was repeated at 24[+ or -]12 hours. Outcome was assessed by NIH stroke scale, and Barthel and Rankin scales.

Results--Twelve patients, mean age 69 years (range 57-86), received rtPA from December 1996-April 2000. Median NIHSS pretreatment was 17. All had TACS. Aetiology was carotid stenosis (four), AF (six), and undetermined in two. 2/12 received nonNINDS protocol therapy: intra-arterial rtPA 5 hours postonset in one; IV rtPA for recurrent Ml MCA stroke 48 hours after ipsilateral branch MCA infarct in one. 10/12 improved substantially. Median 24 hour NIHSS was 5. Three had asymptomatic haemorrhage on repeat CT. One patient died (of bronchopneumonia) 4 weeks after stroke. Six were discharged home in [less than]7 days; two remained in hospital at 3 months.

Conclusions--Local experience supports benefit of rtPA for ischaemic stroke despite use in a population with more severe strokes than those included in the NINDS trial.

Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomised trials

C SUDLOW, G HANKEY, D DUNBABIN

University of Oxford, Oxford, UK

Aspirin is the most widely prescribed antiplatelet drug, and acts by irreversibly inhibiting platelet cyclo-oxygenase. The thienopyridines ticlopidine and clopidogrel act by inhibiting the binding of ADP to its platelet receptor. We aimed to establish how the thienopyridines compare with aspirin in terms of effectiveness and safety.

Methods--We did a systematic review of all unconfounded, randomised trials comparing ticlopidine or clopidogrel with aspirin among high vascular risk patients. The primary Outcome was vascular events (stroke, myocardial infarction, or vascular death). Adverse outcomes were intracranial and extracranial haemorrhage, upper and lower gastrointestinal disturbances, neutropenia, thrombocytopenia, and skin rash.

Results--In four trials involving 22 656 patients (including 9840 presenting with a TIA/ischaemic stroke), the thienopyridines produced a 9% reduction in vascular events (OR 0.91; 95% CI 0.84 to 0.98; 2p=0.01), preventing 11 (2 to 19) events per 1000 patients treated for about 2 years. The thienopyridines produced significantly less gastrointestinal haemorrhage and upper gastrointestinal upset than aspirin, but increased the odds of skin rash and diarrhoea-- ticlopidine by about twofold and clopidogrel by about one third. Only ticlopidine increased the odds of neutropenia.

Conclusions--The thienopyridines seem modestly more effective than aspirin in preventing serious vascular events in high risk patients, but the size of the additional benefit is substantially uncertain. Clopidogrel seems to be safer than ticlopidine and as safe as aspirin, making it an appropriate alternative anriplatelet drug for patients unable to tolerate aspirin.

Acute stroke in childhood: a retrospective study

M STEINLIN, K ROELLIN, K-O LOVBLAD

University Children's Hospital, Inselspital, Bern, Switzerland

Cerebral stroke is a rare disease in childhood differing in aetiology and prognosis from adult stroke.

Methods--Retrospective chard review of children with acute stroke between 1985 and 1999, retrieved by computer analyses at our hospital.

Results-22 children (15 boys) aged 1 day so 16 years presenting the following symptoms: 19 hemiplegia (with aphasia eight); two seizures or diplopia alone; one apnoea and lethargy. Localisation was MCA in 14 (nine left sided), PCA in two, multiple in three and sinus venous in three. Follow up (mean 3.4 years) showed residual hemiparesis in eight, with neuropsychological problems in four; tetraspasticity with developmental problems in two, mild neurological/neuropsychological problems in four. Four were healthy, and two were lost to follow up. Recurrence was noted in two aetiologies: two x Moya Maya disease, two x vasculitis, three x heart disease, one x asparaginase therapy, and two x infectious problems. There was strong suspicion of focal vasculitis in two, fibromuscular dysplasia in one; coagulation problems were present in two. In one child polyglobuly after sports, in another trauma and secondary thrombosis, and in three thromboembolism might have been the cause. In two aetiology was unrecognised.

Conclusions--Most show mild residual neurological and/or neuropsychological problems. Recurrence rate is low. Aetiology was detected in half, with a strong suspicion in another third.

Variation in the management of physiological perameters after ischaemic stroke: a European perspective

A BHALLA, R HOWARO,CD WOLFE, AO RUDD

Guy's, King's and St Thomas' School of Medicine, London, UK

Significant variations in case fatality from stroke have been demonstrated in hospitalised patients in Europe. A population based study has also shown variation in case fatality at 3 months between three regions of Europe, with the United Kingdom having the poorest outcome (Dijon Stroke Register-France, 27%, Erlangen Stroke Register- Germany, 34%, and South London Stroke Register, 41%). We hypothesise that differences in acute supportive care in the first week after stroke may contribute to this.

Standardised data were collected in centres over 6 months. These included baseline characteristics, clinical status, and management of acute physiology such as hydration, oxygenation, nutrition, hypertension, hyperglycaemia, and temperature in the first week of stroke. Differences in acute supportive care between centres were adjusted for case mix in the multivariate analysis.

Patients admitted to London (n=105), Dijon (n=95), and Er]angen (n=91) who survived the first week of stroke were studied. Statistically significant differences existed between centres in enteral feeding (p=0.02), artificial ventilation (p[less than]0.05), management of hypertension (p[less than]0.05), use of insulin (p=0.03), and the use of antipyretics or antibiotics (p=0.03). There were significant differences in the case mix of admissions for incontinence, dysphasia, dysphagia, level of consciousness, pyrexia ([greater than or equal to] 37.5[degrees]C), diabetes, and hyperglycaemia ([greater than or equal to]7mmol/l). After adjusting for confounding factors, there were significant differences in enteral feeding, continuation of previous antihypertensive therapy, initiation of new antihypertensive therapy, and insulin therapy between centres (p[less than]0.000l), with the United Kingdom having the poorest uptake of such interventions.

There is significant variation in acute supportive care across three European centres, which remains unexplained by case mix differences. Further research is required to link variation in acute care with stroke outcome, to identify which interventions seem to be the most effective.

S-Nitrosoglutathione, a platelet specific nitric oxide donor, and L-arginine reduce embolisation post-carotid endarterectomy

Z KAFOSZTA, PA RASKERVILLE, SCA FRASsER, D MADGE, JF MARTIN, HS MARKUS

St George's Hospital Medical School; GKT; UCL, London, UK

Introduction--Asymptomatic cerebral embolic signals (ES) are common after carotid endarterectomy (CEA). A high frequency of ES during the early postoperative phase predicts early stroke and TIA risk. 5-Nitrosoglutathione (GSNO) is a nitric oxide (NO) donor which may have relative platelet specificity. GSNO administered during CEA, starting from the induction of anaesthesia until 2 hours after skin closure reduced the rate of embolisation. However it caused some intraoperative hypotensive episodes. L-Arginine (L-Arg) is a NO precursor, which may inhibit platelet aggregation by the formation of cyclic GMP. The aims of this study were to determine whether (1) GSNO reduced embolisation when administered postoperatively only and, (2) L-Arg also reduced embolisation.

Methods and results---Transcranial Doppler ultrasound (TCD) recordings from the ipsilateral middle cerebral artery were made in patients randomised double-blind to placebo (n=14), GSNO (n=14), or L-Arg (n=14) given IV from 30 minutes to 2 hours after skin closure. Data were recorded onto digital tape for blinded analysis. Both GSNO and L-Arg reduced the frequency of ES for up to 24 hours. GSNO almost abolished embolic signals (table).

Mean (SD) ES intensity was lower with GSNO (12.12 (2.38) dB), than the L-Arg group (14.60 (4.41) dB), p=0.002) and was lower in both active arms than with placebo (16.07 (4.94) dB, p[less than]0.0001 for both).

Conclusions+-GSNO is effective when administered postoperatively, and the hypotensive episodes seen with intraoperative administration were not seen. L-Arg also reduced the rate of embolisation. This indicates that L-Arg has a clinically significant antiplatelet effect in humans. The lower signal intensity is consistent with emboli being smaller in the treated groups. Our results suggest the potential use drugs which modulate NO release in the treatment of thromboembolic disease.

Multiple sclerosis in sibling pairs: an analysis of 250 families

J CHATAWAY, A MANDER, N ROEERTSON, S SAWCER,

J DEANS, M FRASER, S EROADLEY, D CLAYTON, A COMPSTON University of Cambridge Neurology unit; MRC Institute of Public Health, Cambridge; ED Adrian Building, Cambridge, UK

An analysis of 250 sets of coaffected siblings with multiple sclerosis was carried out, primarily using a kappa function able to incorporate potentially confounding variables and generate 95% confidence intervals, through a novel bootstrap simulation process.

There were 238 sibling pairs and 12 trios (an effective number of 262 sibling pairs). Adjusted intraclass correlation coefficients were not significant for either age of onset or for year of first symptom (both p values [sim]0.06). One third of sibling pairs were concordant for presenting symptom (81/262), a result that was non-significant, kappa=0.02 (95% CI -0.07 to 0.15). However, identical course type was found in 50% of the sibling pairs with k0. 17 (95% CI 0.08 to 0.26) indicating a significant result. Severity of the disease at assessment using the Kurtzke and CAMBS scales, demonstrated that while there was no agreement for relapse rate in the previous year within the sibship, there was significant concordance for measures of disability (k=0.11(0.04 to 0.19), progression k0.09 (0.01 to 0.18), and handicap k=0.08 (0.02 to 0.14)).

What do these results reveal about multiple scleroris as a disease entity? Within a sibship, the initial presentation is more likely to be different than the same. However, once established, concordance is more likely to be seen for the ultimate course, culminating in similar disability and handicap scores. As the process becomes established, measures of disease outcome are more likely to equilibrate within a sibship than not. These results are consistent with the hypothesis that genes influence both susceptibility and the course of multiple sclerosis.

Genotype-phenotype correlation in hereditary spastic paraparesis

CJ MCDERMOT', K WHITE, JC UNDSEY, ME LUSHER, KMD EUSHEY, PJ SHAW

University of Newcastle upon Tyne, Newcastle, UK

Introduction--Hereditary spastic paraparesis (HSP) comprises a group of clinically and genetically heterogeneous disorders. Recently, the genetic bases for two autosomal forms of HSP have been identified with mutations detected in the spastin and paraplegin genes on chromosome 2 and 16 respectively.

Aims--To analyse pedigrees, from the northeast of England for mutations in the spastin and paraplegin genes To correlate genotype with phenotype.

Methods--Affected patients from 29 HSP pedigrees have been identified in the northeast of England. Mutation detection using single stranded confirmation polymorphism and heteroduplex analysis was carried out on genomic DNA from a representative member of each of these pedigrees, after amplification of the individual exons for spastin and paraplegin with the appropriate primers.

Results--Spastin. We have identified seven novel mutations one of which seems to behave in a recessive manner. The overall phenotype of HSP associated with spastin in our families tends to be pure HSP of mild severity.

Paraplegin. We have identified one family with a deletion, which seems to be transmitted dominantly. The phenotype in this family was complicated by amyotrophy, OXPHOS muscle defect, raised serum creatine kinase, and mixed motor sensory neuropathy.

Conclusions--Spastin mutations account for 29% of HSP in the northeast of England. We have identified the first example of autosomal recessive inheritance of mutation in the spastin gene. The phenotype associated with spastin mutations is of pure HSP without specific clinical features that would alert to the possibility of a spastin mutation.

Paraplegin mutations are not a common cause of HSP in the northeast of England. We have identified the first example of apparent autosomal dominant transmission of a parEplegin mutation. A rather characteristic phenotype was present in this family, but given the rarity of paraplegin mutations it remains to be seen whether these clinical features will apply to other SPG7 pedigrees.

Phenotypic heterogeneity in a United Kingdom CADASIL prevalence study

RI MARTIN, JP POWELL, HS MARKUS

St George's Hospital Medical School; Institute of Psychiatry, London, UK

During a United Kingdom prevalence study of CADASIL (cerebral autosomal dominant arteriopathy with subeortical infarcts and leukoencephalopathy) we have collected detailed clinical information on 32 cases from 20 families with the disease (established by mutation analysis (26), or by the presence of granular osmiophilic material, GOM (six)). We have found greater heterogeneity in presentation than commonly recognised. The age at first clinical manifestation can be advanced: one non-smoking woman without a history of migraine or depression had her first vascular symptoms at age 65, her smoking sister had had her first event at age 51; both carry the R141C mutation in the notch3 gene. A 47 year old woman presented with nocturnal generalised epilepsy without any history of vascular events, MRI was suggestive of the disease and led to sequencing which showed the R153C mutation. A 53 year old man presented with an encephalitic-like illness, without a history of stroke, but with classic migraine from the age of 45. His MRI is typical of the disease, and GOM was detected on skin biopsy. The clinical phenotype of CADASIL seems to be more variable than currently appreciated.

The natural history of mitochondrial DNA disease provides new insight into the pathogenetic mechanisms

PP CHINNERY, DT BROWN, MA JOHNSON, DM TURNBULL

University of Newcastle upon Tyne, Newcastle, UK

Mitochondrial DNA (mtDNA) defects cause debilitating neurological disease, but very little is known about their natural history. Establishing the mechanism of disease progression is an essential step in the development of novel therapeutic strategies, and an accurate picture of the clinical course is an essential prerequisite for therapeutic clinical trials.

We have studied the natural history of mtDNA disease in 150 patients over a 10 year period. We have correlated the clinical findings with sequential assessment of the muscle histopathology and molecular genetic defects. Most patients deteriorated clinically, although there was considerable variation between individual cases. Clinical progression was often accompanied by an accumulation of cytochrome c oxidase negative and ragged-red fibres. This was associated with an increase in the proportion of mutant mtDNA. Morphological and genetic studies of single muscle fibres support a novel mechanism for the late onset and relentless progression of mtDNA disease: clinical deterioration is due to an intrinsic property of the intracellular mitochondrial gene pool.

Progressive frontal "disconnection": a mechanism for cognitive decline in normal aging

M O'SULLIVAN, DK JONES, PE SUMMERS, MA HORSFIELD, SCR WILLIAMS, JIM JAROSZ, HS MARKUS

St George's Hospital Medical School; GKT, London; University of Leicester, Leicester, UK

Frontal/executive cognitive functions are known to deteriorate with normal aging, although the mechanisms of decline remain obscure. Diffusion tensor MRI produces images sensitive to water motion in tissues. In cerebral white matter, myelin and axonal membranes are the major barriers to diffusion. Thus diffusion tensor imaging allows demonstration of white matter tracts and assessment of their integrity. We used this technique to look for changes in white matter structure that may accompany normal aging.

Methods and results--Diffusion tensor MRI was performed …