Many patients with a diagnosis of neurological disease, such as multiple sclerosis, have symptoms or disability that is considered to be in excess of what would be expected from that disease. We aimed to describe the overall and relative frequency of symptoms 'unexplained by organic disease' in patients attending general neurology clinics with a range of neurological disease diagnoses. Newly referred outpatients attending neurology clinics in all the NHS neurological centres in Scotland, UK were recruited over a period of 15 months. The assessing neurologists recorded their initial neurological diagnoses and also the degree to which they considered the patient's symptoms to be explained by organic disease. Patients completed self report scales for both physical and psychological symptoms. The frequency of symptoms unexplained by organic disease was determined for each category of neurological disease diagnoses. 3,781 patients participated (91% of those eligible). 2,467 patients had a diagnosis of a neurological disease (excluding headache disorders). 293 patients (12%) of these patients were rated as having symptoms only "somewhat" or "not at all" explained by that disease. These patients self-reported more physical and more psychological symptoms than those with more explained symptoms. No category of neurological disease was more likely than the others to be associated with such symptoms although patients with epilepsy had fewer. A substantial proportion of new outpatients with diagnoses of neurological disease also have symptoms regarded by the assessing neurologist as being unexplained by that disease; no single neurological disease category was more likely than others to be associated with this phenomenon.

BACKGROUNDNitrous oxide has been associated with increased vascular risk in the perioperative period. Here, we conducted a secondary analysis of the GALA trial to ascertain the impact of nitrous oxide on outcomes after carotid surgery under general anaesthesia (GA).METHODSOne thousand seven hundred and seventy-three patients underwent GA, but 158 patients were excluded from this analysis as nitrous oxide use was unknown. The decision to use nitrous oxide was at the discretion of the anaesthetist and was not randomized. Six hundred and seventy-one patients received nitrous oxide and 944 patients did not. Logistic regression was used to analyse the same primary outcome as the original trial (risk of death, stroke, or myocardial infarction within 30 days of the operation).RESULTSPatients who received nitrous oxide were more likely to have had coronary artery disease, peripheral vascular disease, and atrial fibrillation (all P<0.05). Overall, there were 35 (5.2%) primary outcome events in patients receiving nitrous oxide compared with 44 (4.7%) in those who did not [relative risk 1.12, 95% confidence interval (CI: 0.73, 1.73); P=0.63]. The adjustment for the imbalanced baseline variables using logistic regression reduced the point estimate of harm for nitrous oxide [adjusted odds ratio 1.09, 95% CI (0.68, 1.74); P=0.73].CONCLUSIONSGiven the greater prevalence of vascular risk factors in the nitrous oxide group and the lack of any definite effect on the primary outcome measure, these data do not support a clinically meaningful adverse effect of nitrous oxide on our composite outcome in patients undergoing carotid surgery.

Background Findings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods.Methods 20 536 patients at high risk of vascular and non-vascular outcomes were allocated either 40 mg simvastatin daily or placebo, using minimised random isation. Mean in-trial follow-up was 5.3 years (SD 1.2), and post-trial follow-up of surviving patients yielded a mean total duration of 11.0 years (SD 0.6). The primary outcome of the long-term follow-up of HPS was first post-randomisation major vascular event, and analysis was by intention to treat. This trial is registered with ISRCTN, number 48489393.Findings During the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1.0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19-28; p<0.0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0.95 [0.89-1.02]) or vascular mortality (0.98 [0.90-1.07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0.98 [0.92-1.05]) or any particular site, or in mortality attributed to cancer (1.01 [0.92-1.11]) or to non-vascular causes (0.96 [0.89-1.03]).Interpretation More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards. These findings provide further support for the prompt initiation and long-term continuation of statin treatment.

Objectives To determine the disability, distress and employment status of new neurology outpatients with physical symptoms unexplained by organic disease and to compare them with patients with symptoms explained by organic disease.Methods As part of a cohort study (the Scottish Neurological Symptoms Study) neurologists rated the extent to which each new patient's symptoms were explained by organic disease. Patients whose symptoms were rated as 'not at all' or only 'somewhat' explained by disease were considered cases, and those whose symptoms were 'largely' or 'completely' explained by disease were considered controls. All patients completed self-ratings of disability, health status (Medical Outcomes Study Short Form 12-Item Scale (SF-12)) and emotional distress (Hospital Anxiety and Depression Scale) and also reported their employment and state financial benefit status.Results 3781 patients were recruited: 1144 (30%) cases and 2637 (70%) controls. Cases had worse physical health status (SF-12 score 42 vs 44; difference in means 1.7 (95% CI -2.5 to 0.9)) and worse mental health status (SF-12 score 43 vs 47; difference in means -3.5 (95% CI -4.3 to to 2.7)). Unemployment was similar in cases and controls (50% vs 50%) but cases were more likely not to be working for health reasons (54% vs 37% of the 50% not working; OR 2.0 (95% CI 1.6 to 2.4)) and also more likely to be receiving disability-related state financial benefits (27% vs 22%; (OR 1.3, 95% CI 1.1 to 1.6)).Conclusions New neurology patients with symptoms unexplained by organic disease have more disability-, distress-and disability-related state financial benefits than patients with symptoms explained by disease.

It has been previously reported that a substantial proportion of newly referred neurology out-patients have symptoms that are considered by the assessing neurologist as unexplained by 'organic disease'. There has however been much controversy about how often such patients subsequently develop a disease diagnosis that, with hindsight, would have explained the symptoms. We aimed to determine in a large sample of new neurology out-patients: (i) what proportion are assessed as having symptoms unexplained by disease and the diagnoses given to them; and (ii) how often a neurological disorder emerged which, with hindsight, explained the original symptoms. We carried out a prospective cohort study of patients referred from primary care to National Health Service neurology clinics in Scotland, UK. Measures were: (i) the proportion of patients with symptoms rated by the assessing neurologist as 'not at all' or only 'somewhat explained' by 'organic disease' and the neurological diagnoses recorded at initial assessment; and (ii) the frequency of unexpected new diagnoses made over the following 18 months (according to the primary-care physician). One thousand four hundred and forty-four patients (30% of all new patients) were rated as having symptoms 'not at all' or only 'somewhat explained' by 'organic disease'. The most common categories of diagnosis were: (i) organic neurological disease but with symptoms unexplained by it (26%); (ii) headache disorders (26%); and (iii) conversion symptoms (motor, sensory or non-epileptic attacks) (18%). At follow-up only 4 out of 1030 patients (0.4%) had acquired an organic disease diagnosis that was unexpected at initial assessment and plausibly the cause of the patients' original symptoms. Eight patients had died at follow-up; five of whom had initial diagnoses of non-epileptic attacks. Seven other types of diagnostic change with very different implications to a 'missed diagnosis' were found and a new classification of diagnostic revision is presented. One-third of new neurology out-patients are assessed as having symptoms 'unexplained by organic disease'. A new diagnosis, which with hindsight explained the original symptoms, rarely became apparent to the patient's primary care doctor in the 18 months following the initial hospital consultation.

The aim is laudable: “To exploit the potential of the NHS [National Health Service] to improve national health and increase national wealth by creating a world class environment for research focused on the needs of patients”. So says Best research for best health: a new national health research strategy, the UK Department of Health document for which the consultation period recently ended. 1 Department of HealthBest research for best health: a new national health research strategy. http://www.dh.gov.uk/assetRoot/04/11/69/35/04116935.pdfDate: 2005 Google Scholar The strategy only applies to England, but Scotland, Wales, and Northern Ireland may, or may not, want to join in.

BACKGROUNDBrain arteriovenous malformations (AVMs) are the single most common cause of intracerebral haemorrhage in young adults. Brain AVMs also cause seizure(s) and focal neurological deficits (in the absence of haemorrhage, migraine or an epileptic seizure); approximately one fifth are incidental discoveries. Various interventions are used in an attempt to eradicate brain AVMs: neurosurgical excision, stereotactic radiotherapy/'radiosurgery' (using gamma knife, linear accelerator or proton beam), endovascular embolisation (using glues, particles, fibres, coils, or balloons), and staged combinations of these interventions.OBJECTIVESTo assess the clinical effects of interventions to treat brain AVMs in adults (with the aim of either partial obliteration or total eradication), using data published in randomised controlled trials.SEARCH STRATEGYWe searched: (1) the Cochrane Stroke Group Register (last searched December 2004); (2) medical literature databases (MEDLINE 1966 to 31 December 2004 and EMBASE 1980 to 31 December 2004); (3) on-line and paper journal surveillance; (4) the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005); (5) international registers of clinical trials; (6) bibliographies of relevant articles identified by (1) to (5); and (7) we sought unpublished data from manufacturers of interventional treatments for brain AVMs.SELECTION CRITERIAWe sought randomised trials of any or all of the interventions for brain AVMs, compared against each other or against usual medical therapy, with relevant clinical outcome measures.DATA COLLECTION AND ANALYSISTwo authors independently applied the inclusion criteria and reviewed the relevant studies.MAIN RESULTSWe did not find any randomised trials meeting our selection criteria. We found two randomised trials which tested the equivalence of two embolic agents for the pre-operative embolisation of brain AVMs (one published, one unpublished), but none of the primary or secondary outcome measures in these trials met our desired criteria; although important clinical outcomes were reported, meaningful comparison of the two treatment arms was impossible. We also excluded a third RCT which studied three different blood pressure lowering treatments to induce deliberate hypotension during surgical resection of brain AVMs, because the intervention was not the focus of this review.AUTHORS' CONCLUSIONSThere is no evidence from randomised trials with clear clinical outcomes, comparing different interventional treatments for brain AVMs against each other or against usual medical therapy, to guide the interventional treatment of brain AVMs in adults. One such trial (ARUBA), comparing interventional versus conservative management for unruptured brain AVMs, is being planned.

OBJECTIVE:Paralysis, seizures, and sensory symptoms that are unexplained by organic disease are commonly referred to as "conversion" symptoms. Some patients who receive this diagnosis subsequently turn out to have a disease that explains their initial presentation. We aimed to determine how frequently this misdiagnosis occurs, and whether it has become less common since the widespread availability of brain imaging. DESIGN:Systematic review. DATA SOURCES:Medline, Embase, PsycINFO, Cinahl databases, and searches of reference lists. REVIEW METHODS:We included studies published since 1965 on the diagnostic outcome of adults with motor and sensory symptoms unexplained by disease. We critically appraised these papers, and carried out a multivariate, random effect, meta-analysis of the data. RESULTS:Twenty seven studies including a total of 1466 patients and a median duration of follow-up of five years were eligible for inclusion. Early studies were of poor quality. There was a significant (P < 0.02) decline in the mean rate of misdiagnosis from the 1950s to the present day; 29% (95% confidence interval 23% to 36%) in the 1950s; 17% (12% to 24%) in the 1960s; 4% (2% to 7%) in the 1970s; 4% (2% to 6%) in the 1980s; and 4% (2% to 6%) in the 1990s. This decline was independent of age, sex, and duration of symptom in people included in the studies. CONCLUSIONS:A high rate of misdiagnosis of conversion symptoms was reported in early studies but this rate has been only 4% on average in studies of this diagnosis since 1970. This decline is probably due to improvements in study quality rather than improved diagnostic accuracy arising from the introduction of computed tomography of the brain.

Background Undernutrition is common inpatients admitted with stroke. We aimed to establish whether the timing and route of enteral tube feeding after stroke affected patients' outcomes at 6 months.Methods The FOOD trials consist of three pragmatic multicentre randomised controlled trials, two of which included dysphagic stroke patients. In one trial, patients enrolled within 7 days of admission were randomly allocated to early enteral tube feeding or no tube feeding for more than 7 days (early versus avoid). In the other, patients were allocated percutaneous endoscopic gastrostomy (PEG) or nasogastric feeding. The primary outcome was death or poor outcome at 6 months. Analysis was by intention to treat.Findings Between Nov 1, 1996, and July 31, 2003, 859 patients were enrolled by 83 hospitals in 15 countries into the early versus avoid trial. Early tube feeding was associated with an absolute reduction in risk of death of 5 . 8% (95% CI -0 . 8 to 12 . 5, p=0.09) and a reduction in death or poor outcome of 1 . 2% (-4.2 to 6.6, p=0.7). In the PEG versus nasogastric tube trial, 321 patients were enrolled by 47 hospitals in 11 countries. PEG feeding was associated with an absolute increase in risk of death of 1 . 0% (-10 . 0 to 11 . 9, p=0 . 9) and an increased risk of death or poor outcome of 7.8% (0 . 0 to 15 . 5, p=0 . 05).Interpretation Early tube feeding might reduce case fatality, but at the expense of increasing the proportion surviving with poor outcome. Our data do not support a policy of early initiation of PEG feeding in dysphagic stroke patients.

The degree of aggregation among the particles of a suspension of virus is one of the parameters upon which the plaque titer depends. Careful workers have always recognized this fact and they have employed various means to insure maximum dispersion of virus on which critical plaque titrations were to be made. Still, we are not aware of any published work which sets out clearly in experimental or theoretical form the relationship between plaque titer and degree of particle aggregation. Our first effort (1) in this direction provided evidence that vaccinia virus, which was released from infected L cells by the freeze-thaw procedure, as well as virus that had been pelleted one or more times in a centrifuge, was highly aggregated. It showed that the plaque titer of such preparations could be increased by treatment of the virus with 9-kc sonic waves.

Background Undernutrition is common in hospital patients with stroke, can develop or worsen in hospital, and is associated with poor outcomes. We aimed to establish whether routine oral nutritional supplements improve outcome after stroke.Methods The FOOD trials are a family of three pragmatic, multicentre, randomised controlled trials. We measured the outcomes of stroke patients who could swallow and who were randomly allocated normal hospital diet or normal hospital diet plus oral nutritional supplements until hospital discharge. The primary outcome was death or poor outcome (modified Rankin scale [MRS] grade 3-5), 6 months after enrolment, measured unaware of treatment allocation. Analysis was by intention to treat.Findings Between Nov 1, 1996, and July 31, 2003, 4023 patients were enrolled by 125 hospitals in 15 countries. Only 314 (8%) patients were judged to be undernourished at baseline. Vital status and MRS at the end of the trial were known for 4012 and 4004 patients, respectively. Supplemented diet was associated with an absolute reduction in risk of death of 0 . 7% (95% Cl -1 . 4 to 2 . 7) and an increased risk of death or poor outcome of 0 . 7% (-2.3 to 3.8).Interpretation We could not confirm the anticipated 4% absolute benefit for death or poor outcome from routine oral nutritional supplements for mainly well nourished stroke patients in hospital. Our results would be compatible with a 1% or 2% absolute benefit or harm from oral supplements. These results do not support a policy of routine oral supplementation after stroke.

Abstract Objective To evaluate the differences between adults who consent to participate in observational research, and those who do not. Design Prospective, population based cohort study. Setting Primary and secondary care throughout Scotland. Participants 187 adults (aged ≥16 years) resident in Scotland at the time of their first diagnosis of a brain arteriovenous malformation in 1999-2002. Intervention Postal consent form sent via participants' general practitioner. Main outcome measures Differences between consenters and non-consenters in demographic and clinical features at first presentation, and outcome during follow-up. Results 111 adults (59%) consented to participate in the study. These consenters were not significantly different from non-consenters in age, sex, or socioeconomic status at first presentation. However, consenters were significantly more likely than non-consenters to present alive and independent, and with a seizure. During follow-up, consenters were significantly more likely to receive interventional treatment. Although consenters' survival was significantly better, they were more likely to have a seizure during follow-up. Presentation with intracranial haemorrhage conferred a higher risk of subsequent haemorrhage when the whole cohort was analysed, but not when it was restricted to consenters. Conclusions We have found differences between adults who consent to participate in observational records-based research and those who do not, or cannot, consent. Blanket requirements for explicit consent for the use of individuals' identifiable data can bias disease registers, epidemiological studies, and health services research.

Background Corticosteroids have been used to treat head injuries for more than 30 years. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1-2%. The CRASH trial-a multicentre international collaboration-aimed to confirm or refute such an effect by recruiting 20 000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment.Methods 10 008 adults with head injury and a Glasgow coma score (GCS) of 14 or less within 8 h of injury were randomly allocated 48 h infusion of corticosteroids (methylprednisolone) or placebo. Primary outcomes were death within 2 weeks of injury and death or disability at 6 months. Prespecified subgroup analyses were based on injury severity (GCS) at randomisation and on time from injury to randomisation. Analysis was by intention to treat. Effects on outcomes within 2 weeks of randomisation are presented in this report. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN74459797.Findings Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21.1%] vs 893 [17.9%] deaths; relative risk 1.18 [95% CI 1.09-1.27]; p=0.0001). The relative increase in deaths due to corticosteroids did not differ by injury severity (p=0.22) or time since injury (p=0.05).Interpretation Our results show there is no reduction in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks is unclear.

Background and Purpose - The Perindopril Protection Against Recurrent Stroke Study ( PROGRESS) showed that blood pressure lowering reduced stroke risk in patients with a history of cerebrovascular events. Here, we report the consistency of treatment effects across different stroke subtypes and among major clinical subgroups.Methods - PROGRESS was a randomized, double-blind trial among 6105 people with a prior history of cerebrovascular events. Participants were assigned to active treatment (perindopril for all participants and indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s).Results - During a mean of 3.9 years of follow-up, active treatment reduced the absolute rates of ischemic stroke from 10% to 8% ( relative risk reduction [RRR], 24%; 95% confidence interval [CI], 10 to 35) and the absolute rates of intracerebral hemorrhage from 2% to 1% (RRR, 50%; 95% CI, 26 to 67). The relative risk of any stroke during follow-up was reduced by 26% ( 95% CI, 12 to 38) among patients whose baseline cerebrovascular event was an ischemic stroke and by 49% ( 95% CI, 18 to 68) among those whose baseline event was an intracerebral hemorrhage. There was no evidence that treatment effects were modified by other drug therapies ( antiplatelet or other antihypertensive agents), residual neurological signs, atrial fibrillation, or the time since the last cerebrovascular event.Conclusions - Beneficial effects of a perindopril-based treatment regimen were observed for all stroke types and all major clinical subgroups studied. These data suggest that effective blood pressure - lowering therapy should be routinely considered for all patients with a history of cerebrovascular events.

BACKGROUND:All doctors recognise that some patients are more "difficult to help" than others, but the issue has received little systematic investigation in neurological practice.OBJECTIVE:To test the hypothesis that patients whose symptoms were less explained by organic disease would be perceived as more difficult to help.METHODS:In a consecutive series of 300 new neurology outpatients, neurologists indicated on four point Likert-type scales how "difficult to help" they found the patient and to what extent the patient's symptoms were explained by organic disease. The patients' demographics, health status, number of somatic symptoms, and mental state were also assessed.RESULTS:The neurologists rated 143 patients (48%) as "not at all difficult" to help, 111 (37%) as "somewhat difficult", 27 (9%) as "very difficult", and 18 (6%) as "extremely difficult". A logistic regression model was constructed and the hypothesis that patients whose symptoms were less explained by organic disease would be perceived as more difficult to help was supported. The only other measured variable that contributed to perceived difficulty was physical disability, but it explained only a small amount of the variance.CONCLUSIONS:Neurologists find patients whose symptoms are not explained by organic disease more difficult to help than their other patients.