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Objective: To report the nature of stroke in patients infected with human immunodeficiency virus (HIV) in a region with high HIV seroprevalence and describe HIV associated vasculopathy. Methods: Patients with first ever stroke, infected with HIV and prospectively included in the stroke register of the Groote Schuur Hospital/University of Cape Town stroke unit were identified and reviewed. Results: Between 2000 and 2006, 67 of the 1087 (6,1%) stroke patients were HIV infected. Of these, 91% (n = 61) were younger than 46 years. Cerebral infarction occurred in 96% (n = 64) of the HIV positive patients and intracerebral haemorrhage in 4% (n = 3). HIV infected young stroke patients did not demonstrate hypertension, diabetes, hyperlipidaemia or smoking as significant risk factors for ischaemic stroke. Infection as a risk factor for stroke was significantly more common in HIV positive patients (p = 0.018, OR 6.4, CI 3.1 to 13.2). In 52 (81%) patients with ischaemic stroke, an aetiology was determined. Primary aetiologies comprised infectious meningitides/vasculitides in 18 (28%) patients, coagulopathy in 12 (19%) patients and cardioembolism in nine (14%) patients. Multiple aetiologies were present in seven (11%) patients with ischaemic stroke. HIV associated vasculopathy was identified in 13 (20%) patients. The HIV associated vasculopathy manifested either extracranially (seven patients) as total or significant carotid occlusion or intracranially (six patients) as medium vessel occlusion, with or without fusiform aneurysmal dilation, stenosis and vessel calibre variation. Conclusion: Investigation of HIV infected patients presenting with stroke will determine an aetiology in the majority of patients. In our cohort, 20% of patients demonstrated evidence of an HIV associated vasculopathy.

Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer's disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD.The MZ twins were identified and characterised by the University of Washington Alzheimer's Disease Research Center. We reviewed the available clinical and neuropathological records for all six cases looking specifically for concordance and discordance of clinical phenotype, neuritic amyloid plaques (NP), neurofibrillary tangles (NFT) and Lewy related pathology (LRP).Discordance in age of onset for developing AD in the MZ twins varied from 4 to 18 years. Clinical presentations also differed between twins. One twin presented with a dementia with Lewy Body clinical syndrome while the other presented with typical clinical AD. Neuropathology within the MZ twin pairs was concordant for NP and NFT, regardless of duration of disease, and was discordant for LRP. This difference was most marked in the late onset AD twin pair. One pair was found to have a mutation in presenilin-1 (PS1) (A79V) with remarkably late onset in a family member.MZ twins with AD can vary considerably in age of onset, presentation and disease duration. The concordance of NP and NFT pathological change and the discordance of LRP support the concept that, in AD, the former are primarily under genetic control whereas the latter (LRP) is more influenced by disease duration and environmental factors. The A79V mutation in PS1 can be associated with very late onset of dementia.

Background and purpose: Thrombolysis of acute ischaemic stroke is based strictly on body weight to ensure efficacy and to prevent bleeding complications. Many candidate stroke patients are unable to communicate their body weight, and there is often neither the means nor the time to weigh the patient. Instead, weight is estimated visually by the attending physician, but this is known to be inaccurate. Methods: Based on a large general population sample of nearly 7000 subjects, we constructed approximation formulae for estimating body weight from simple anthropometric measurements (body height, and waist and hip circumference). These formulae were validated in a sample of 178 consecutive inpatients admitted to our stroke unit, and their accuracy was compared with the best visual estimation of two experienced physicians. Results: The simplest formula gave the most accurate approximation (mean absolute difference 3.1 (2.6) kg), which was considerably better than the best visual estimation (physician 1: 6.5 (5.2) kg; physician 2: 7.4 (5.7) kg). It reduced the proportion of weight approximations mismatched by >10% from 31.5% and 40.4% (physicians 1 and 2, respectively) to 6.2% (anthropometric approximation). Only the patient’s own estimation was more accurate (mean absolute difference 2.7 (2.4) kg). Conclusions: By using an approximation formula based on simple anthropometric measurements (body height, and waist and hip circumference), it is possible to obtain a quick and accurate approximation of body weight. In situations where the exact weight of unresponsive patients cannot be ascertained quickly, we recommend using this approximation method rather than visual estimation.

Background: In clinical and research settings, the Mini-Mental State Examination (MMSE) is commonly used to measure cognitive change over time. The interpretation of changes in MMSE is often difficult. They do not necessarily result from true clinical change. Their interpretation requires comparison with normative data for change. However, MMSE change norms are lacking for long intervals. Objective: To examine what is a reliable change in MMSE for long follow-up periods commonly used in clinic. To provide normative data for change. Methods: A sample of 119 cognitively normal individuals, aged 75 years and over, who participated in the Leipzig Longitudinal Study of the Aged (LEILA 75+). All participants were tested six times at 1.5 year intervals with the MMSE over a mean period of 7.1 years. Reliable change indices were computed for a common confidence interval (90%). Results: In repeated assessments with 1.5 year intervals, a change in MMSE of at least 2–4 points indicated a reliable change at the 90% confidence level. Conclusion: Small changes in MMSE can be interpreted only with great uncertainty. They have a reasonable probability of being caused by measurement error, regression to the mean or practice.

Background: The 39 item Parkinson's disease questionnaire (PDQ-39) is the most widely used patient reported rating scale in Parkinson's disease. However, several fundamental measurement assumptions necessary for confident use and interpretation of the eight PDQ-39 scales have not been fully addressed. Methods: Postal survey PDQ-39 data from 202 people with Parkinson's disease (54% men; mean age 70 years) were analysed regarding psychometric properties using traditional and Rasch measurement methods. Results: Data quality was good ( mean missing item responses, 2%) and there was general support for the legitimacy of summing items within scales without weighting or standardisation. Score reliabilities were adequate (Cronbach's alpha 0.72-0.95; test-retest 0.76-0.93). The validity of the current grouping of items into scales was not supported by scaling success rates ( mean 56.2%), or factor and Rasch analyses. All scales represented more health problems than that experienced by the sample ( mean floor effect 15%) and showed compromised score precision towards the less severe end. Conclusions: Our results provide general support for the acceptability and reliability of the PDQ-39. However, they also demonstrate limitations that have implications for the use of the PDQ-39 in clinical research. The grouping of items into scales appears overly complex and the meaning of scale scores is unclear, which hampers their interpretation. Suboptimal targeting limits measurement precision and, therefore, probably also responsiveness. These observations have implications for the role of the PDQ-39 in clinical trials and evidence based medicine. PDQ-39 derived endpoints should be interpreted and selected cautiously, particularly regarding small but clinically important effects among people with less severe problems.

Background: Cluster headache (CH) is a relatively rare disease and episodic CH is more frequent than chronic CH. Few studies have described the characteristics of patients with chronic CH. Methods: This was a descriptive study carried out by eight tertiary care specialist headache centres in France participating in the Observatory of Migraine and Headaches (OMH). From 2002 to 2005, OMH collected data from 2074 patients with CH, of whom 316 had chronic CH. From January to June 2005, 113 patients with chronic CH were interviewed using standardised questionnaires during a consultation. Results: The male to female ratio was 4.65:1. Median age was 42 years. The majority of patients were smokers or former smokers (87%). 46% had primary chronic CH (chronic at onset) and 54% secondary chronic CH (evolving from episodic CH). Most patients had unilateral pain during attacks and 7% had sometimes bilateral pain during an attack. 48% reported a persisting painful state between attacks. Symptoms anteceding pain onset (mainly discomfort/diffuse pain, exhaustion, mood disorders) and auras were reported by 55% and 20% of patients, respectively. The functional impact of chronic CH was estimated as severe by 74% of patients, and 75.7% suffered from anxiety, as assessed by the Hospital Anxiety and Depression scale. There was no substantial difference in clinical presentation between primary and secondary CH. Discussion: This study confirms the existence of auras and interictal signs and symptoms in patients with chronic CH, and male sex and smoking as CH risk factors. Primary and secondary chronic CH appear equally prevalent. Male sex does not appear to favour the shift from episodic to chronic CH.

While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuring activity dependent changes in axonal excitability following a maximum voluntary contraction (MVC).Nerve excitability changes were recorded before and after an MVC of the abductor pollicis brevis in 16 patients with ALS and 25 controls.In patients with ALS, there was a greater increase in threshold (36.5 (5.9)%; controls 19.6 (3.5)%; p0.05) as a result of MVC, with reduction in the amplitude of the compound muscle action potential generated by a submaximal stimulus (ALS 49 (7.6)%; controls 41.0 (5.4)%). These changes were associated with an increase in superexcitability (ALS 65.1 (25.4)%; controls 42.3 (5.7)%) and reduction in strength-duration time constant (ALS 20 (4.9)%; controls 10 (2.5)%; p0.01), indicative of axonal hyperpolarisation. The increase in threshold was more pronounced in patients with ALS with predominantly lower motor neuronal involvement.Higher firing rates of surviving motor axons attempting to compensate for neurogenic weakness are likely to explain the greater activity dependent changes in ALS. As such, the present study suggests a further peripheral factor underlying the development of fatigue in ALS.

The aims of this study were to determine the reliability, responsiveness and minimally important change score of the Multiple Sclerosis Impact Scale (MSIS)-29 physical using the Expanded Disability Status Scale (EDSS) as an anchor measure.214 patients with multiple sclerosis (MS) (EDSS 0-8.5) had concurrent MSIS-29 and EDSS assessments at baseline and at up to 4 years of follow-up.116 patients had unchanged EDSS scores. Stability of the MSIS-29 physical (mean change 0.1 points) was better in the 85 patients with EDSS 0-5.0 than in the 31 patients with EDSS 5.5-8.5 in whom the MSIS-29 physical score fell by 8 points, a response shift phenomenon. A floor effect for the MSIS-29 was observed in 5% of stable patients at both time points. 98 patients experienced EDSS change with moderately strong statistically significant correlations between change scores in the EDSS and the MSIS-29 physical (r = 0.523, p0.0001). Effect sizes for MSIS-29 physical change were moderate to large. Using receiver operating characteristic curves, the MSIS-29 change score which produced a combination of optimal sensitivity and specificity was chosen for both EDSS ranges. For EDSS range 5.5-8, a change score of 8 had a sensitivity of 87% and specificity of 67%. For EDSS 0-5.0, a change score of 7 had a sensitivity of 78% and a specificity of 51%.The MSIS-29 physical performs well over time, and is suitable for use in trials; a minimal change score of 8 points in the MSIS-29 is clinically significant.

Background: Diffusion tensor imaging (DTI) has detected secondary degeneration of the pyramidal tract distal (but not proximal) to, the primary lesion after a stroke. This finding and its potential clinical significance have received little attention. Methods: Twelve patients underwent DTI within the first week (W1), at 4 weeks (W4), and at 12 weeks (W12) following an isolated subcortical infarct. Twelve age- and gender-matched controls underwent DTI at baseline, and mean diffusivity (MD) and fractional anisotropy (FA) were measured. Two hours before each DTI examination, every patienti¯s neurological deficit (NIH Stroke Scale ), motor deficit (Fugl-Meyer scale) and life independence (Barthel index) were assessed. Results: Reduced signal in FA images was visible in the infarct regions and in sites located above and below the infarct in ipsilateral side. FA values decreased significantly from W1 to W12 in all regions above the internal capsule (derived from the mean FA value of the corona radiata and the centrum semiovale) , in the internal capsule and in all regions below the internal capsule (derived from the mean FA value of the cerebral peduncle, pons, and medulla) (,P©,0.01, respectively). However, the NIH Stroke Scale decreased and Fugl-Meyer scale and Barthel index increased significantly (P

We studied the level of distress in caregivers of patients with recently diagnosed multiple sclerosis (MS), and their relation to clinical characteristics.Caregivers of patients with MS and Parkinson's disease completed measures of distress and quality of life. MS patients underwent neurological, neuropsychiatric and neuropsychological examinations. Multivariate regression analyses were used to explore the relationship between patient variables and caregiver distress.Caregivers of patients with MS experienced high levels of distress and reduced quality of life related to caregiving. The level of distress was similar to that reported by elderly spouses of patients with longstanding Parkinson's disease. Psychiatric symptoms and cognitive impairment in patients with MS were associated with caregiver's distress and quality of life, even after controlling for level of disability (all p values0.01). Patients' physical impairment was associated with caregiver distress, but not with caregiver quality of life.Caregivers of patients with MS experience high levels of distress and reduced quality of life. Psychiatric symptoms and cognitive impairment contributed significantly to caregiver distress, over and above the effect of disability due to neurological symptoms.

Objective: To evaluate the effectiveness of a personalised home programme of exercises and strategies for repeat fallers with Parkinson’s disease (PD). Method: Patients with a confirmed diagnosis of idiopathic PD, independently mobile, living at home in the community, experiencing more than one fall in the previous 12 months and with intact gross cognitive function were invited to participate in this randomised controlled trial. Usual care was compared with a personalised 6 week, home based exercise and strategy programme. The primary outcomes were rates of falling at 8 weeks and 6 months. Whether participants had repeat fallen, nearly fallen or experienced injurious falls were also examined. Functional Reach, the Berg Balance Test, PD Self-assessment Scale and the Euro Quol were rated by a blinded assessor. Results: Participants were randomised to the exercise (n = 70) and control (n = 72) groups. There was a consistent trend towards lower fall rates in the exercise group at both 8 weeks and 6 months and lower rates of injurious falls needing medical attention at 6 months. Lower rates of repeat near falling were evident for the exercise group at 8 weeks (p = 0.004) and 6 months (p = 0.007). There was a positive effect of exercises at 6 months on Functional Reach (p = 0.009) and quality of life (p = 0.033). No significant differences were found on other secondary outcomes measures. Conclusion: There was a trend towards a reduction in fall events and injurious falls with a positive effect of exercises on near falls and quality of life.

Background: Individuals with Prader–Willi syndrome (PWS) exhibit severe disturbances in appetite regulation, including delayed meal termination, early return of hunger after a meal, seeking and hoarding food and eating of non-food substances. Brain pathways involved in the control of appetite in humans are thought to include the hypothalamus, frontal cortex (including the orbitofrontal, ventromedial prefrontal, dorsolateral prefrontal and anterior cingulate areas), insula, and limbic and paralimbic areas. We hypothesised that the abnormal appetite in PWS results from aberrant reward processing of food stimuli in these neural pathways. Methods: We compared functional MRI blood oxygen level dependent (BOLD) responses while viewing pictures of food in eight adults with PWS and eight normal weight adults after ingestion of an oral glucose load. Results: Subjects with PWS demonstrated significantly greater BOLD activation in the ventromedial prefrontal cortex than controls when viewing food pictures. No significant differences were found in serum insulin, glucose or triglyceride levels between the groups at the time of the scan. Conclusions: Individuals with PWS had an increased BOLD response in the ventromedial prefrontal cortex compared with normal weight controls when viewing pictures of food after an oral glucose load. These findings suggest that an increased reward value for food may underlie the excessive hunger in PWS, and support the significance of the frontal cortex in modulating the response to food in humans. Our findings in the extreme appetite phenotype of PWS support the importance of the neural pathways that guide reward related behaviour in modulating the response to food in humans.

Background: Arachnoid cysts (AC) can cause a wide spectrum of clinical symptoms. Only a limited number of studies have investigated intracranial pressure in patients with AC. We wished to investigate the relationship between intracystic pressure, preoperative complaints and postoperative symptom relief in adult patients operated on for a unilateral temporal AC. Material and methods: This was a prospective, population based study involving 38 adult (>18 years) patients (mean age 43 years; range 18–69) with a previously untreated unilateral temporal AC. Results: For all cyst types, mean pressure was 131 mm H 2 O. The main preoperative complaints were headache and dizziness/nausea. By median split, patients were divided into a low pressure ( 2 O) and a high pressure (>130 mm H 2 O) group. Patients with high intracystic pressure had a significantly higher preoperative visual analogue scale (VAS) score (54.7) than that found in patients with low intracystic pressure (39.4). Both pressure groups had a significant fall in VAS score after surgical decompression of the cyst. Intracystic pressure correlated significantly with arterial pCO 2 and mean arterial pressure. Conclusion: There was a significant correlation between intracystic pressure and the preoperative level of complaints. Mean intracystic pressure in adult patients with unilateral temporal AC seems to lie within the limits of normal intracranial pressure. We therefore hypothesise that factors other than absolute pressure, such as altered compliance and impedance of the brain, may be involved in the pathophysiology of intracranial AC.

Background: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the commonest causes of presenile dementia. In the absence of a biological marker, diagnosis is reliant on clinical evaluation. Confirmation is often sought from neuroimaging, including single-photon emission computed tomography (SPECT). Most previous SPECT studies lack pathological validation. Aim: To examine the accuracy of SPECT in differentiating FTD from AD in patients with subsequent pathological confirmation. Methods: Technetium-99-labelled hexamethyl propylene amine oxime SPECT images obtained at initial evaluation in 25 pathologically confirmed cases of FTD were examined. These images were visually rated by an experienced blinded nuclear medicine consultant and compared with those of 31 patients with AD, also with pathological validation. Results: A reduction in frontal cerebral blood flow (CBF) was more common in FTD and was of diagnostic value (sensitivity 0.8, specificity 0.65 and likelihood ratio (LR) 2.25; 95% CI 1.35 to 3.77). A pattern of bilateral frontal CBF reduction without the presence of associated bilateral parietal CBF change is diagnostically more accurate (sensitivity 0.80, specificity 0.81 and +LR 4.13, 95% CI 1.96 to 8.71). Diagnostic categorisation (FTD or AD) on the basis of SPECT alone was less accurate than clinical diagnosis (based on neurology and detailed neuropsychological evaluation). One patient with FTD was initially clinically misdiagnosed as AD, owing to the lack of availability of full neuropsychological assessment. However, SPECT correctly diagnosed this patient, providing a diagnostic gain of 4%. Conclusion: Technetium-99-labelled hexamethyl propylene amine oxime SPECT CBF patterns provide valuable information in the diagnosis of FTD and AD. These data can be better used as an adjunct to clinical diagnosis if pathology is to be correctly predicted in life.

Loss of the alpha4beta2 nicotinic receptor subtype is found at autopsy in Alzheimer's disease.To investigate in vivo changes in this receptor using single-photon-emission CT (SPECT) with 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the alpha4beta2 receptor.32 non-smoking subjects (16 with Alzheimer's disease and 16 normal elderly controls) underwent 123I-5IA-85380 and perfusion (99mTc-hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation.Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both 123I-5IA-85380 and 99mTc-HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD.Using 123I-5IA-85380 SPECT we found changes consistent with significant reductions in the nicotinic alpha4beta2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases.

Background: Limbic encephalitis is a potentially treatable immunological condition. The presence of voltage-gated potassium channel antibodies (VGKC-Ab) in the cerebrospinal fluid (CSF) and serum of patients with the condition is a marker of the disease associated with a non-paraneoplastic form and good response to treatment. Recent work has highlighted absent serum VGKC-Ab and distinct immunology in patients with the paraneoplastic form of limbic encephalitis. Methods: The cases of four patients with the typical clinical presentation, neuropsychological features and brain imaging of acute limbic encephalitis, in the absence of any evidence for associated cancer during a follow-up of at least 18 months are described here. Results: All patients had negative testing for VGKC-Ab measured during their acute presentation. All patients made some recovery, although they were left with marked cognitive deficits and persistent seizures. Conclusion: These cases demonstrate that the absence of VGKC-Ab in limbic encephalitis does not necessarily imply a paraneoplastic form. Further work is required to establish the immunological basis for the disorder in these patients, and the optimal treatment regimen.

Acute-disseminated encephalomyelitis (ADEM) is a demyelinating disorder of the central nervous system, whose epidemiology, clinical presentations and functional outcome are incompletely understood in Asian populations.To assess the clinical presentations, predisposing factors and functional outcome of ADEM in Taiwan.50 patients initially diagnosed with ADEM (male, 19; female, 31) were enrolled from 1991 to 2005. Diagnosis of ADEM or multiple sclerosis was established during a follow-up period of 2-120 months. 8 adult patients were noted to have taken the immunomodulatory drug, levamisole, within 3 months before onset of symptoms. The remaining 42 patients (male, 17; female, 25) were categorised by age as children (16 years, n = 12), young adults (16-49 years, n = 21) and elderly adults (or =50 years, n = 9). The clinical manifestations, predisposing factors and radiological findings were compared between different age groups and adult patients with or without levamisole use. Functional outcome was compared by a log-rank test.Preceding upper respiratory tract infection was evident in 21 (50%) patients and only one young-adult patient had received Rubella vaccine immunisation. The frequency of fever was higher in children (p = 0.04) and psychiatric symptoms were more prevalent in elderly patients (p = 0.03). Functional recovery was faster in children than in adults (p = 0.002). Initial Expanded Disability Status Scale score (odds ratio (OR) 1.9, p = 0.03) and no fever (OR 0.04, p = 0.06) were associated with poor outcome (modified Rankin scaleor =2). After a mean (SD) follow-up of 31.8 (9.9) months, 4 (9.5%) patients developed multiple sclerosis (3 (25%) children, 1 (4.7%) young adult, p = 0.03). The neurological disability, radiological and cerebrospinal fluid findings did not differ between patients with and without levamisole use. One elderly adult patient previously receiving levamisole developed multiple sclerosis of relapse-remitting type after a mean follow-up period of 36.9 months.The clinical presentations, functional outcome and risk of developing multiple sclerosis differed between different age groups. Functional recovery was faster in children than in adults. Poor functional outcome was related to initial high Expanded Disability Status Scale score and absence of fever.

Background: Subjective visual vertical (SVV) perception can be perturbed after stroke, but its effect on balance recovery is not yet known. Aim: To evaluate the influence of SVV perturbations on balance recovery after stroke. Methods: 28 patients (14 with a right hemisphere lesion (RHL) and 14 with a left hemisphere lesion (LHL)) were included, 5 were lost to follow-up. SVV perception was initially tested within 3 months after stroke, then at 6 months, using a luminous line, which the patients adjusted to the vertical position in a dark room. Mean deviation (V) and uncertainty (U), defined as the standard deviation of the SVV, were calculated for eight trials. Balance was initially assessed by the Postural Assessment Scale for Stroke (PASS), and at 6 months by the PASS (PASS6), a force platform (lateral and sagittal stability limits (LSL6 and SSL6)), the Rivermead Mobility Index (RMI6) and gait velocity (v6). Functional outcome was also assessed by the Functional Independence Measure at 6 months (FIM6). Results: The scores for balance and for FIM6 were related to the initial V value: PASS6 (p = 0.01, τ = −0.38); RMI6 (p = 0.002, τ = −0.48), LSL6 (p = 0.06, τ = −0.29), SSL6 (p = 0.004, τ = −0.43), v6 (p = 0.01, τ = −0.36) and FIM6 (p = 0.001, τ = −0.49), as well as to the initial U value: PASS6 (p = 0.03, τ = −0.32), RMI6 (p = 0.02, τ = −0.35), SSL6 (p = 0.005, τ = −0.43) and FIM6 (p = 0.01, τ = −0.38). Conclusions: Initial misperception of verticality was related to a poor score for balance after stroke. This relationship seems to be independent of motricity and neglect. Rehabilitation programmes should take into account verticality misperceptions, which could be an important factors influencing balance recovery after stroke.

Background: Olfactory dysfunction is common in old age, but its basis is uncertain. Objective: To test the hypothesis that difficulty in identifying odours in old age is related to the accumulation of Alzheimer’s disease pathology. Methods: As part of the Rush Memory and Aging Project, participants completed the 12-item Brief Smell Identification Test, a standard measure of odour identification. During a mean (standred deviation (SD)) of 2.2 (1.2) years of follow-up (range 0.2–4.9), 166 people died, with brain autopsies performed on 129 (77.7%) people and neuropathological examinations completed on 77 (mean (SD) age at death 87.5 (5.9) years; median postmortem interval 6.1 h). From a uniform postmortem examination of multiple brain regions, summary measures of plaque and tangle pathology were derived on the basis of silver staining, and those of amyloid β burden, tangle density and Lewy bodies on the basis of immunohistochemistry. Results: Odour identification performance ranged from 0 to 12 correct (mean (SD) 8.0 (2.6)). In analyses adjusted for age, sex and education, a composite measure of plaques and tangles accounted for >12% of the variation in odour identification. The association remained after controlling for dementia or semantic memory. Density of τ tangles was inversely related to odour identification. A similar effect for amyloid burden was attenuated after controlling for tangles. The association with odour identification was robust for tangles in the entorhinal cortex and CA1/subiculum area of the hippocampus, but not for tangles in other cortical sites. Lewy bodies, identified in 12.5%, were not related to odour identification, probably partly due to to their relative infrequency. Conclusion: The results suggest that difficulty in identifying familiar odours in old age is partly due to the accumulation of neurofibrillar pathology in central olfactory regions.

Background: Tinnitus has been shown to respond to modulations of cortical activity by high-frequency and low-frequency repetitive transcranial magnetic stimulation (rTMS). Objective: To determine the tinnitus-attenuating effects of a 2-week daily regimen of rTMS, navigated to the maximum of tinnitus-related increase in regional cerebral blood flow. Methods: Six patients with chronic tinnitus were enrolled in this sham-controlled crossover study and treated with 2×2 weeks of suprathreshold 1 Hz rTMS (30 min) applied to the region with maximal tinnitus-related increase in regional cerebral blood flow delineated by functional imaging with [ 15 O]H 2 O positron emission tomography and a control area. Tinnitus-related distress was assessed before and after each treatment and 2 weeks after the end of the 4-week course of stimulation using a validated tinnitus questionnaire. Additional self-assessment scores of tinnitus change, loudness and annoyance were obtained. Results: In five of six patients, rTMS induced greater reduction of the tinnitus questionnaire score than sham stimulation. In two patients, all parameters measured (tinnitus change score, tinnitus loudness, tinnitus annoyance) showed unequivocal improvement. At the group level, the degree of response in the tinnitus questionnaire score was correlated with tinnitus-associated activation of the anterior cingulate cortex. Two weeks after the final stimulation, tinnitus had returned to baseline in all patients but one. Conclusion: Tinnitus can be attenuated by low-frequency rTMS navigated to each person’s maximum tinnitus-related cortical hyperactivity. The effects are only moderate; interindividual responsiveness varies and the attenuation seems to wear off within 2 weeks after the last stimulation session. Notably, tinnitus-related anterior cingulate cortex activation seems to predict the response to rTMS treatment.

International audience; BACKGROUND AND AIMS: To investigate the hypothesis that patients with a hemisphere stroke may perceive their longitudinal body axis (LBA) rotated in the frontal plane. This error in an egocentric frame of reference could be detrimental to posture, as tilted LBA would imply an unequal distribution of body mass about the true vertical. METHOD: 26 healthy subjects matched in age with 18 patients living with stroke participated in the study. The 18 patients were tested on average 80 days after a first left (n = 8) or right (n = 10) hemisphere stroke. Participants perceived their LBA by adjustments of the orientation of a luminous rod pivoting around a dorsonavel axis to the subjective direction of LBA. Participants were studied in the supine position to dissociate somaesthetic cues from graviceptive cues. RESULTS: Patients with stroke perceived their LBA rotated to the contralesional side in comparison with controls (p = 0.004). For all controls and 10 patients with stroke, the perceived LBA was very close to true LBA (mean (SD) 0.24 degrees (1.31 degrees)). For eight patients with stroke (six right stroke, two left stroke), the perceived LBA was rotated from true body orientation in the direction opposite to the lesioned side (range 3-9.5 degrees, mean 5.2 degrees). These eight patients provided similar estimates by tactile manipulation of the rod (without vision). The rotation of perceived LBA was more pronounced for right-hemisphere strokes. The magnitudes of perceptual rotations correlated with sensory loss, signs of spatial neglect and the degree of postural and gait disability. CONCLUSION: This is the first study showing that certain patients with a hemisphere stroke perceive their LBA rotated to the contralesional side. The consequences for perceptuomotor coordination have implications for their postural disorders.

To determine the relationship of cerebral degeneration with survival in amyotrophic lateral sclerosis (ALS).Patients with probable or definite ALS underwent magnetic resonance spectroscopic imaging (MRSI) of the brain between July 1996 and May 2002, and were followed prospectively until March 2004. Creatine (Cr), choline (Cho) and the neuronal marker N-acetylaspartate (NAA) were quantified as ratios in the motor cortex.In 63 patients compared with 18 healthy people, NAA/Cho was reduced by 13% (p0.001), NAA/Cr was reduced by 5% (p = 0.01) and Cho/Cr was increased by 8% (p = 0.01). NAA/Cho was used for survival analysis, given its larger effect size and superior test accuracy (a sensitivity of 67% and a specificity of 83%). Median survival after MRSI was 24 months. Multivariate analysis showed reduced survival for lower NAA/Cho (hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.08 to 0.72, p = 0.01), older age (HR 1.03, 95% CI 1.00 to 1.06, p = 0.04) and shorter symptom duration (HR 0.96, 95% CI 0.93 to 0.99, p = 0.01). Patients with NAA/Cho2.11 had a reduced survival of 19.4 v 31.9 months (HR 2.05, 95% CI 1.12 to 4.03, p = 0.02).Cerebral degeneration is predictive of reduced survival in ALS.

Background: The PROACT II trial showed that intra-arterial thrombolysis (IAT) is effective for treatment of acute ischaemic stroke attributable to M1 and M2 segment occlusions. Incidence of symptomatic intracranial haemorrhage (sICH) was 10%. Objective: : To evaluate the risk and predictors of sICH after IAT by using urokinase in a large number of patients presenting with the whole spectrum of cerebral vessel occlusions. Methods: 294 patients with stroke treated with intra-arterial urokinase were retrospectively analysed. The risk of sICH as well as bleeding characteristics were assessed. Demographic and radiological data, time to treatment, urokinase dose, recanalisation rates, stroke aetiology and severity were analysed for predictors. Results: sICH occurred in 14 of 294 (4.8%) patients. The median National Institute of Health Stroke Scale score of all patients was 15. All but one sICH were located in the infarcted brain tissue, and no sICH occurred in patients with peripheral vessel occlusions (M3 or M4 segments of the middle cerebral artery). Poor collaterals (p = 0.001), early signs of ischaemia on computed tomography (p = 0.003), higher urokinase dose (p = 0.019), lower recanalisation rate (p = 0.02) and higher diastolic blood pressure on admission (p = 0.04) were found to be correlated with sICH on univariate analysis. On multivariate analysis, poor collaterals (p = 0.004), urokinase dose (p = 0.021) and early signs on computed tomography (p = 0.026) remained predictors of sICH. Conclusions: With regard to the whole spectrum of cerebral vessel occlusions, an incidence of

Background: Although the aetiology of moyamoya disease (MMD) has not been fully clarified, genetic analysis of familial MMD (F-MMD) has considerable potential to disclose it. Objective: To determine the inheritance pattern and clinical characteristics of F-MMD to enable precise genetic analyses of the disease. Methods: 15 highly aggregated Japanese families (52 patients; 38 women and 14 men) with three or more affected members were examined. The difference in categories of age at onset (child onset, adult onset and asymptomatic) between paternal and maternal transmission was compared by χ 2 statistics. Results: In all families there had been three or more generations without consanguinity, and all types of transmission, including father-to-son, were observed. Among a total of 135 offspring of affected people, 59 (43.7%) were patients with MMD or obligatory carriers. Affected mothers were more likely to produce late-onset (adult-onset or asymptomatic) female offspring (p = 0.007). Conclusions: The mode of inheritance of F-MMD is autosomal dominant with incomplete penetrance. Thus, in future genetic studies on F-MMD, parametric linkage analyses using large families with an autosomal dominant mode of inheritance are recommended. Genomic imprinting may be associated with the disease.

Background: Horizontal gaze palsy and progressive scoliosis (HGPPS) is caused by mutations of the ROBO3 gene, which encodes a receptor associated with axonal guidance during development. Although there is evidence for uncrossed cuneatal and corticospinal tracts in HGPPS, it is unclear whether other central nervous system pathways are involved. Objective: To study two patients with HGPPS homozygotic for the ROBO3 E319K mutation using a variety of neurophysiological and neuropsychological tests. Methods: A battery of neuropsychological tests was applied to assess various cognitive and perceptual functions. The corticospinal, somatosensory and auditory pathways were evaluated using appropriate neurophysiological tests. To access motor pathways to the neck muscles, electromyographic recordings were obtained from the sternocleidomastoideus and splenius capitis muscle during active head rotation. Results: Both patients performed normally on manual dexterity, complex sensory and visuospatial functions, reading and general intelligence tests. Motor evoked potentials in both patients showed uncrossed corticospinal tracts for the extremities, although in one patient, electromyography indicated pyramidal tract crossing for the neck muscles. Although somatosensory evoked potentials showed uncrossed somatosensory fibres subserving proprioception and light touch, right median nerve somatosensory evoked potential in one patient indicated a partial lemniscal crossing. Sympathetic skin response and blink reflex showed a midline crossing of the spinothalamic and quintothalamic tracts. Brain stem auditory evoked potentials indicated a lack of crossing in the level of the trapezoid body. Conclusions: Our patients with the ROBO3 E319Κ mutation show normal perceptual and cognitive functions and have both crossed and uncrossed motor, sensory and auditory pathways.

Background: Intelligence was assessed in a group of 74 people with head injury, 16 years after injury (mean 16.77 years; range 10–32 years), and compared with their performance when assessed at an early stage in recovery (mean 1.05 years). Aims: To confirm the presence of long-term impairment relative to estimates of pre-accident ability, to confirm signs of deterioration between early (T1) and late (T2) measures, and to examine relationships between severity of injury, time since injury, length of education, sex and age, and performance on intelligence tests at T2. Expected outcomes: On the basis of evidence from other studies, a significant difference was expected between estimates of pre-accident intelligence and abilities measured at T1 and T2. Deterioration in performance between T1 and T2, and relationships between demographic variables, severity of injury and intellectual performance were also expected. Results and conclusion: The data supported long-term intellectual impairment, but there was no deterioration in abilities between T1 and T2. Performance on intelligence tests was associated with years of education but not with other factors.

Background: Camptocormia is defined as an abnormal flexion of the trunk that appears when standing or walking and disappears in the supine position. The origin of the disorder is unknown, but it is usually attributed either to a primary or a secondary paravertebral muscle myopathy or a motor neurone disorder. Camptocormia is also observed in a minority of patients with parkinsonism. Objective: To characterise the clinical and electrophysiological features of camptocormia and parkinsonian symptoms in patients with Parkinson’s disease and camptocormia compared with patients with Parkinson’s disease without camptocormia. Methods: Patients with parkinsonism and camptocormia (excluding patients with multiple system atrophy) prospectively underwent a multidisciplinary clinical (neurological, neuropsychological, psychological, rheumatological) and neurophysiological (electromyogram, ocular movement recording) examination and were compared with age-matched patients with Parkinson’s disease without camptocormia. Results: The camptocormia developed after 8.5 (SD 5.3) years of parkinsonism, responded poorly to levodopa treatment (20%) and displayed features consistent with axial dystonia. Patients with camptocormia were characterised by prominent levodopa-unresponsive axial symptoms (ie, axial rigidity, gait disorder and postural instability), along with a tendency for greater error in the antisaccade paradigm. Conclusion: We suggest that (1) the salient features of parkinsonism observed in patients with camptocormia are likely to represent a specific form of Parkinson’s disease and camptocormia is an axial dystonia and (2) both camptocormia and parkinsonism in these patients might result from additional, non-dopaminergic neuronal dysfunction in the basal ganglia.

Aim: To investigate whether the presence of serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome (CIS) predicts the interval to develop more frequently and earlier a first relapse (clinically definite multiple sclerosis: CDMS) than seronegative patients. Methods: Sera from 45 patients with a CIS and positive intrathecal IgG-synthesis were retrospectively tested for the presence of IgM antibodies against both MOG and MBP. Antibodies were detected by immunoblot using recombinant MOG (1–125) and human MBP antigen preparations. Clinical follow ups were performed retrospectively by telephone interviews and documented neurological examination. Results: Using the Cox proportional hazards model there was no significant increased risk for developing CDMS in anti-MOG and anti-MBP positive patients compared with negative. However regarding the median of the time span between CIS and CDMS over the whole follow up, antibody positive patients (MOG/MBP +/+) developed significantly earlier relapses (median 5.5 months (range 3–20)) than the antibody negative ones (median 25.0 months (range 7–43); p Conclusions: This study confirms previous data only in a subanalysis indicating that patients with positive anti-MOG/MBP antibodies develop earlier relapses than patients who are antibody negative. However, the authors could not verify that the presence of these antibodies anticipates the overall risk of developing CDMS—according to study criteria—after a first demyelinating event within the study period of 21–106 months (mean 60 (SD 25)).

The high coincidence of organic vestibular and somatoform vertigo syndromes has appeared to support pathogenic models showing a strong linkage between them. It was hypothesised that a persisting vestibular dysfunction causes the development of anxiety disorders.To determine the relation between vestibular deficits and somatoform vertigo disorders in an interdisciplinary prospective study.Participants were divided into eight diagnostic groups: healthy volunteers (n=26) and patients with benign paroxysmal positioning vertigo (BPPV, n=11), vestibular neuritis (n=11), Menière's disease (n=7), vestibular migraine (n=15), anxiety (n=23), depression (n=12), or somatoform disorders (n=22). Neuro-otological diagnostic procedures included electro-oculography with rotatory and caloric testing, orthoptic examination with measurements of subjective visual vertical (SVV) and ocular torsion, and a neurological examination. Psychosomatic diagnostic procedures comprised interviews and psychometric instruments.Patients with BPPV (35.3%) and with vestibular neuritis (52.2%) had pathological test values on caloric irrigation (p0.001). Otolith dysfunction with pathological tilts of SVV and ocular torsion was found only in patients with vestibular neuritis (p0.001). Patients with Menière's disease, vestibular migraine, and psychiatric disorders showed normal parameters for vestibular testing but pathological values for psychometric measures. There was no correlation between pathological neurological and pathological psychometric parameters.High anxiety scores are not a result of vestibular deficits or dysfunction. Patients with Menière's disease and vestibular migraine but not vestibular deficits showed the highest psychiatric comorbidity. Thus the course of vertigo syndromes and the possibility of a pre-existing psychopathological personality should be considered pathogenic factors in any linkage between organic and psychometric vertigo syndromes.

Background: Identification of outcome-predictive factors could lower risk of under- or over-treatment in status epilepticus (SE). Older age and acute symptomatic aetiology have been shown to predict mortality, but other variables are controversial and level of consciousness has received relatively little attention. The objective of this study was to assess variables predictive of mortality, particularly those available at presentation. Methods: The discharge database (1997–2004) of two university hospitals was screened for adult patients with EEG confirmed SE, excluding cerebral anoxia. Outcome at discharge (mortality, return to baseline clinical conditions) was analysed in relation to demographics, clinical features, and aetiology. Aetiologies were also classified based on whether or not they were potentially fatal independently of SE. Results: Mortality was 15.6% among 96 patients with a first SE episode, 10 of whom also experienced recurrent SE during the study period. Eleven other patients had only recurrent SE. Mortality was 4.8% among these 21 patients with recurrent SE. Return to baseline condition was more frequent after recurrent than incident SE (p = 0.02). For the first SE episode, death was associated with potentially fatal aetiology (p = 0.01), age ⩾65 (p = 0.02), and stupor or coma at presentation (p = 0.04), but not with gender, history of epilepsy, SE type, or time to treatment ⩾1 h. Conclusions: At initial evaluation, older age and marked impairment of consciousness are predictive of death. Surviving a first SE episode could lower the mortality and morbidity of subsequent episodes, suggesting that underlying aetiology, rather than SE per se, is the major determinant of outcome.

To examine functional outcomes from a rehabilitation programme and to compare two methods for evaluating cost efficiency of rehabilitation in patients with severe complex disability.Two hundred and ninety seven consecutive admissions to a specialist inpatient rehabilitation unit following severe acquired brain injury.Retrospective analysis of routinely collected data, including the Functional Independence Measure (FIM), Barthel Index, and Northwick Park Dependency Score and Care Needs Assessment (NPDS/NPCNA), which provides a generic estimation of dependency, care hours. and weekly cost of continuing care in the community. Patients were analysed in three groups according to dependency on admission: "low" (NPDS10 (n=83)); "medium" (NPDS10-24 (n=112)); "high" (NPDS24 (n=102)).Mean length of stay (LOS) 112 (SD 66) days. All groups showed significant reduction in dependency between admission and discharge on all measures (paired t tests: p0.001). Mean reduction in "weekly cost of care" was greatest in the high dependency group at pound639 per week (95% CI 488 to 789)), as compared with the medium (pound323/week (95% CI 217 to 428)), and low (pound111/week (95% CI 42 to 179)) dependency groups. Despite their longer LOS, time taken to offset the initial cost of rehabilitation was only 16.3 months in the high dependency group, compared with 21.5 months (medium dependency) and 38.8 months (low dependency). FIM efficiency (FIM gain/LOS) appeared greatest in the medium dependency group (0.25), compared with the low (0.17) and high (0.16) dependency groups.The NPDS/NPCNA detected changes in dependency potentially associated with substantial savings in the cost of ongoing care, especially in high dependency patients. Floor effects in responsiveness of the FIM may lead to underestimation of efficiency of rehabilitation in higher dependency patients.

Background: Antipsychotic treatment in schizophrenia is frequently associated with extrapyramidal side effects. Objective behavioural measures to evaluate the severity of extrapyramidal side effects in the clinical setting do not exist. Objectives: This study was designed to investigate grasping movements in five drug naive and 13 medicated subjects with schizophrenia and to compare their performance with that of 18 healthy control subjects. Deficits of grip force performance were correlated with clinical scores of both parkinson-like motor disability and psychiatric symptom severity Methods: Participants performed vertical arm movements with a handheld instrumented object and caught a weight that was dropped into a handheld cup either expectedly from the opposite hand or unexpectedly from the experimenter’s hand. The scaling of grip force and the temporospatial coupling between grip and load force profiles was analysed. The psychiatric symptom severity was assessed by the positive and negative symptom score of schizophrenia and the brief psychiatric rating scale. Extrapyramidal symptoms were assessed by the unified Parkinson’s disease rating scale. Results: Drug naive subjects with schizophrenia performed similar to healthy controls. In contrast, medicated subjects with schizophrenia exhibited excessive grip force scaling and impaired coupling between grip and load force profiles. These performance deficits were strongly correlated with the severity of both extrapyramidal side effects related to antipsychotic therapy and negative symptoms related to the underlying pathology. Conclusions: These data provide preliminary evidence that deficits of sensorimotor performance in schizophrenia are, at least in part, related to the side effects of antipsychotic treatment. The investigation of grasping movements may provide a sensitive measure to objectively evaluate extrapyramidal side effects related to antipsychotic therapy.

Objective: To examine anxiety related seizure symptoms and avoidance behaviour in adults with dissociative (psychogenic non-epileptic) seizures (DS) in comparison with a group suffering from partial epilepsy. Methods: 25 DS and 19 epilepsy patients completed an attack symptom measure, the hospital anxiety and depression scale, the dissociative experiences scale, and the fear questionnaire. Results: DS patients reported the presence of significantly greater numbers of somatic symptoms of anxiety during their attacks than the epilepsy group, despite not reporting subjectively higher levels of anxiety. The DS patients also reported higher levels of agoraphobic-type avoidance behaviour than the epilepsy group. Measures of dissociation were higher in the DS group, who also reported greater symptoms of depression. Conclusions: The findings support a model whereby DS occur as a paroxysmal, dissociative response to heightened arousal in the absence of raised general anxiety levels. The model has practical implications for clinical assessment and treatment: in clinical practice, inquiry about these symptoms may help in the diagnosis of DS; with respect to treatment, the anxiety related symptoms and avoidance behaviour prevalent in DS are a potential focus for a cognitive behavioural approach analogous to that used in the treatment of other anxiety disorders.

Background and aims: An important part is played by inflammation in intracranial aneurysm formation. The hypothesis that there is an association of the proinflammatory cytokine interleukin-6 (IL-6) genotypes (−572G>C and −174G>C) with intracranial aneurysms was tested. Methods: IL-6 genotypes were determined in 91 Caucasian patients with aneurysms and compared with 2720 healthy UK controls. Results: For both polymorphisms, the distribution of the genotypes and estimated allele frequency were different between the control group and the aneurysm group. For −572G>C, a higher frequency of the C allele (p = 0.001) and more people homozygous for the C allele were found among those with aneurysms than among the controls (4.4% v 0.3%, p = 0.001). For −174G>C, more people homozygous for the C allele were found among the controls than among those with aneurysm (18% v 7%, p = 0.007). The 572C/174G haplotype was associated with an increased risk of aneurysms, with the relative risk compared with the common haplotype being 1.89 and that for the −572G/174C haplotype being 0.58 (p Conclusion: This is the first study to show that IL-6 promoter polymorphisms are associated with intracranial aneurysmal disease. Whether this association is with the development, progression or rupture of such aneurysms, or represents survivor bias, is unclear.

Background: The number of elderly patients being admitted with aneurysmal subarachnoid haemorrhage (SAH) has been increasing. Treatment of the aneurysm may be offset by the higher rate of surgical or endovascular complications. Aim: To study the clinical condition at onset, complications during clinical course, treatment and outcome in a consecutive series of elderly patients. Methods: Patients who were ⩾75 years at the onset of SAH were selected from the databases of two hospitals. Data on clinical condition at onset (poor condition defined as World Federation of Neurological Surgeons (WFNS) Scale IV and V), clinical course, treatment and outcome were extracted. Univariate and multivariate regression analyses were carried out to identify predictors for in-hospital death and poor outcome, defined as death or dependency. Results: The data of 170 patients were retrieved, of whom 25 (15%) patients were independent at discharge; none of these patients had been admitted in a poor condition. Poor clinical condition on admission (odds ratio (OR) 7.9; 95% confidence interval (CI) 3.7 to 17) and recurrent haemorrhage (OR 7.5; 95% CI 2.5 to 23) were the strongest predictors for in-hospital death. Recurrent haemorrhage was the strongest predictor for poor outcome in the subset of patients who were admitted in good clinical condition. In all, 10 of 47 (21%) patients were independent at discharge after neurosurgical clipping (n = 34) or endovascular coiling (n = 13). Conclusion: Elderly patients with SAH have a poor prognosis. The effect of the initial haemorrhage is the most common reason for poor outcome. For patients who are admitted in good clinical condition, the most important complication leading to poor outcome is recurrent haemorrhage. Treatment of the aneurysm in patients ⩾75 years is feasible, may improve the outcome and should be strongly considered in patients who are admitted in a good condition.

Objective: To determine whether it is worth pursuing surgery for the treatment of epilepsy in patients with normal neuroimaging. Methods: Two patient populations were studied: (1) 136 consecutive patients who were surgically treated; (2) 105 consecutive patients assessed with chronically implanted intracranial electrodes within the same period. Sixty patients belonged to both groups, and included all 21 patients who had normal neuroimaging. Results: There were no differences in the proportion of patients with favourable outcome between those with normal and those with abnormal neuroimaging, irrespective of whether intracranial recordings were required. Among the 19 operated patients with normal neuroimaging, 74% had a favourable outcome (Engel’s seizure outcome grades I and II), and among the 93 patients with abnormal neuroimaging, 73% had favourable outcome (p = 0.96). In patients with temporal resections, 92% of the 13 patients with normal neuroimaging had a favourable outcome, whereas among the 70 patients with abnormal neuroimaging, 80% had a favourable outcome (p = 0.44). In patients with extratemporal resections, two of the six patients with normal neuroimaging had a favourable outcome, while 12 of the 23 patients with abnormal neuroimaging had a favourable outcome (p = 0.65). Among the 105 patients studied with intracranial electrodes, five suffered transitory deficits as a result of implantation, and two suffered permanent deficits (one hemiplegia caused by haematoma and one mild dysphasia resulting from haemorrhage). Conclusions: It is worth pursuing surgery in patients with normal neuroimaging because it results in good seizure control and the incidence of permanent deficits associated with intracranial studies is low.

Objective: Abnormal thalamo-cortical oscillations underlie idiopathic generalised epilepsy (IGE). Although thalamic involvement has long been indicated by electrophysiological data, it has only recently become feasible to test this with independent methods. In this magnetic resonance (MR) study, we investigated the metabolic and structural integrity of the thalamus. Possible changes in glutamine and glutamate concentrations and signs of neuronal damage were of particular interest. Method: Forty three IGE patients and 38 age and sex matched healthy controls were investigated. Quantitative single volume MR spectroscopy (MRS, 1.5 T) was used to measure concentrations of glutamate and glutamine (Glx) and N -acetyl aspartate (NAA) in thalamus and occipital cortex. We also measured thalamic volumes on high resolution gradient-echo images and estimated fractions of thalamic grey and white matter with voxel based morphometry (VBM). Results: IGE patients showed elevated Glx and reduced NAA concentrations in the thalamus compared to controls (12.2±2.6 v 8.9±4.1 mM, p = 0.0022 for Glx, and 9.9±1.0 v 10.7±0.9 mM, p = 0.017 for NAA). Thalamic grey matter fraction was reduced in IGE patients, and white matter fraction was increased with the greatest increase in the dorso-medial thalamus. Mean thalamic volume was reduced in patients (6.7±0.7 v 7.2±0.6 ml in controls, p = 0.0001), as was mean cerebral volume (1163±128 v 1250±102 ml, p = 0.0003). Patients’ thalamus/whole brain ratios were normal. Conclusion: Quantitative MRS and VBM provide further evidence for involvement of the thalamus in IGE. The observed elevation of Glx levels together with reductions in NAA levels and grey matter fractions are consistent with epilepsy related excitoxicity as a possible underlying mechanism.

Background: The cerebral metabolism of patients in the chronic stage of traumatic diffuse brain injury (TDBI) has not been fully investigated. Aim: To study the relationship between regional cerebral metabolism (rCM) and consciousness disturbance in patients with TDBI. Methods: 52 patients with TDBI in the chronic stage without large focal lesions were enrolled, and rCM was evaluated by fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) with statistical parametric mapping (SPM). All the patients were found to have disturbed consciousness or cognitive function and were divided into the following three groups: group A (n = 22), patients in a state with higher brain dysfunction; group B (n = 13), patients in a minimally conscious state; and group C (n = 17), patients in a vegetative state. rCM patterns on FDG-PET among these groups were evaluated and compared with those of normal control subjects on statistical parametric maps. Results: Hypometabolism was consistently indicated bilaterally in the medial prefrontal regions, the medial frontobasal regions, the cingulate gyrus and the thalamus. Hypometabolism in these regions was the most widespread and prominent in group C, and that in group B was more widespread and prominent than that in group A. Conclusions: Bilateral hypometabolism in the medial prefrontal regions, the medial frontobasal regions, the cingulate gyrus and the thalamus may reflect the clinical deterioration of TDBI, which is due to functional and structural disconnections of neural networks rather than due to direct cerebral focal contusion.

To study the association of pain with motor complications in 117 patients with Parkinson's disease.Patients were asked to refer any pain they experienced at the time of study and lasting since at least 2 months. Basic parkinsonian signs and motor complications (including motor fluctuations and dyskinesia) were assessed and Unified Parkinson's Disease Rating Scale (UPDRS) motor score part III (during on) and part IV were calculated. Information on age, sex, duration of disease, use of dopamine agonists and levodopa, years of levodopa treatment and current levodopa dosage, medical conditions possibly associated with pain, and depression were collected. Single and multiple explanatory variable logistic regression models were used to check the association of pain with the investigated variables.Pain was described by 47 patients (40%) and could be classified into dystonic (n.19) and non dystonic pain (n.16); in 12 patients both types coexisted. Multiple explanatory variable logistic regression models indicated a significant association of pain with motor complications (adjusted OR, 5.7; 95% CI, 2 to 16.5; p = 0.001). No association was found between pain, dystonic or non dystonic, and the other investigated variables including medical conditions known to be associated to pain in the general population. There was a significant correlation (r = 0.31, p0.05) between severity of pain (measured on a Visual Analogue Scale) and severity of motor complications (UPDRS part IV).Pain may be a representative feature of Parkinson's disease frequently associated with motor complications. The association is independent of a number of potentially relevant demographic and clinical variables.

Background: Previous studies have found the e4 allele of the apolipoprotein E gene ( APOE e4) is associated with an unfavourable outcome after head injury, but this has not been related to specific pathological features. Objectives: This study tested the postulate that head injured patients with APOE e4, amounting to approximately a third of the population, are selectively predisposed to one or more of the different pathological features that constitute the response to traumatic brain injury (TBI), and that this underlies the association of APOE e4 with poor clinical outcome. Methods: Included in the study were 239 fatal cases of TBI (1987–1999) for which APOE genotypes were determined from archival tissue. For each case, specific pathological features of trauma were recorded by researchers blinded to the APOE e4 status. Of the 239 cases examined, 83 (35%) were APOE e4 carriers and 156 (65%) were non-carriers. Results: Possession of APOE e4 was associated with a greater incidence of moderate or severe contusions (42% v 30% for carriers versus e4 non-carriers; p = 0.05) and there was a trend towards a greater incidence of severe ischaemic brain damage (54% v 42%; p = 0.08). Significant differences were not noted between the other pathological features examined. Conclusions: Possession of APOE e4 is associated with a greater incidence of moderate/severe contusional injury and severe ischaemic brain damage in fatal cases of TBI. This may be relevant to the relatively poor outcome from traumatic brain injury in patients with APOE e4 identified in clinical studies.

Background: Retinal infarction and transient monocular blindness (TMB) are associated with an increased risk of future ischaemic stroke. Little information is available on the type of subsequent ischaemic strokes that may occur (anterior or posterior circulation and small vessel or large vessel). Aim: To analyse the type of stroke after TMB. Methods: Patients with transient or permanent retinal ischaemia were selected from three prospective studies: the Dutch TIA Trial, the Dutch Amaurosis Fugax Study and the European/Australian Stroke Prevention in Reversible Ischaemia Trial. On follow-up the type of stroke was classified according to the supply territory and the type of vessel involved. Results: 654 patients were included. During a mean follow-up of 5.2 years, 42 patients were found to have had a cerebral or retinal infarct, of which 27 occurred in the carotid territory ipsilateral to the symptomatic eye, 9 in the territory of the contralateral carotid artery and 6 were infratentorial strokes. Thirty patients had a large-vessel infarct, four had a small-vessel infarct and eight had a retinal infarct. Characteristics associated with a notable increased risk for subsequent stroke or retinal infarction were age ⩾65 years, a history of stroke, a history of intermittent claudication, diabetes mellitus, Rankin score ⩾3, more than three attacks of retinal ischaemia and any degree of ipsilateral carotid stenosis on duplex ultrasonography observation. Conclusion: Ischaemic strokes after TMB or retinal infarction were found to be mainly large-vessel infarcts in the territory of the ipsilateral carotid artery. TMB and retinal infarction are probably manifestations of large-vessel disease.

Background: Adhesion molecules and matrix metalloproteinases (MMPs) are known to be relevant to the ongoing development and disappearance of areas of demyelination in the white matter of the CNS of multiple sclerosis (MS) patients. This study examined whether serum matrix metalloproteinase-3 (MMP-3) levels correlate with disease activity in MS. Methods: Serum MMP-3 levels in 47 consecutive patients with relapsing-remitting MS were measured by immunoassay every 4 weeks over a 15 month period. Results: During the study period, 48 clinical relapses occurred. Serum MMP-3 levels within 1 month of relapse were significantly higher than during the remission phase. Sequential analysis showed that serum MMP-3 levels had increased transiently at the time of clinical relapse but returned to the normal range within a month. Conclusions: Circulatory MMP-3 levels are correlated with disease activity in relapsing-remitting MS. This may contribute to the breakdown of the blood-brain barrier at the time of relapse.

We sought to determine the prevalence, clinical features, and laboratory characteristics of polyneuropathies in Waldenström's macroglobulinaemia (WM), a malignant bone marrow disorder with lymphocytes that produce monoclonal IgM.We prospectively studied 119 patients with WM and 58 controls. Medical history was taken, and neurological examinations, electrodiagnostic tests, and serum studies were performed by different examiners who were blinded to results except the diagnosis of WM.Polyneuropathy symptoms, including discomfort and sensory loss in the legs, occurred more frequently (p0.001) in patients with WM (47%) than in controls (9%). Patients with WM had 35% lower quantitative vibration scores, and more frequent pin loss (3.4 times) and gait disorders (5.5 times) than controls (all p0.001). Patients with IgM binding to sulphatide (5% of WM) had sensory axon loss; those with IgM binding to myelin associated glycoprotein (MAG) (4% of WM) had sensorimotor axon loss and demyelination. Patients with WM with IgM binding to sulphatide (p0.005) or MAG (p0.001) had more severe sensory axon loss than other patients with WM. Demyelination occurred in 4% of patients with WM with no IgM binding to MAG. Age related reductions in vibration sense and sural SNAP amplitudes were similar ( approximately 30%) in WM and controls.Peripheral nerve symptoms and signs occur more frequently in patients with WM than controls, involve sensory modalities, and are often associated with gait disorders. IgM binding to MAG or sulphatide is associated with a further increase in the frequency and severity of peripheral nerve involvement. Age related changes, similar to those in controls, add to the degree of reduced nerve function in patients with WM.

Background: The National Institute for Clinical Excellence in the UK has issued guidelines stating all individuals with epilepsy be given information about sudden unexpected death in epilepsy (SUDEP). Methods: We conducted a survey of current practice among UK neurologists, using a questionnaire sent to all practising neurologists in the UK listed on the Association of British Neurologists database, asking under what circumstances they told patients about SUDEP. Results: Of the validated respondents, 5% discussed SUDEP with all patients, 26% with a majority, 61% with a few, and 7.5% with none. The commonest reasons for SUDEP to be discussed were the patient asking about it and the neurologist counselling people with known risk factors for SUDEP. Conclusions: The variation we found, although not necessarily in tune with the guidelines, reflects the variation in patients’ need for knowledge about their condition.

Objective: To determine prevalence and intensity of pain after stroke, focusing on patients’ perspectives. Methods: During a one year period, 416 first-ever stroke patients were included in the population based Lund Stroke Register. After 4 and 16 months (median), 297 patients (98% of survivors) were followed up. Worst pain intensity during the previous 48 hours was assessed on a visual analogue scale (VAS), range 0 to 100: a score of 0 to 30 was defined as no or mild pain; 40 to 100 as moderate to severe pain. NIH stroke scale (NIHSS) score and HbA1c were assessed at baseline. At 16 months, screening for depression was done using the geriatric depression scale (GDS-20), and cognition with the mini-mental state examination (MMSE). Predictors of pain were determined by multivariate analyses. Results: Moderate to severe pain was reported by 96 patients (32%) after four months (VAS median = 60). Predictors of pain were younger age (p = 0.01), female sex (p = 0.006), higher NIHSS score (p Conclusions: Although prevalence of pain after stroke decreased with time, after 16 months 21% had moderate to severe pain. Late pain after stroke was on average more severe, and profoundly affected the patients’ wellbeing.

Background: There is a paucity of literature from India on metachromatic leucodystrophy (MLD), a rare metabolic disorder of childhood resulting from aryl sulfatase A (ASA) deficiency. Patients/Methods: Case records of histopathologically verified cases of MLD, evaluated over a period of 12 years at the National Institute of Mental Health and Neurosciences, Bangalore, India, were reviewed. Results: The late infantile group (36) manifested with regression of milestones (all), delayed mile stones (14), gait abnormalities (14), and seizures (11). Despite spasticity (29), there was hypo/areflexia in 25 patients. Optic atrophy (six) was rare. Consanguinity was noted in 25 children and four had a history of similar illness in siblings. Behavioural problems dominated in the juvenile group (four), but associated cognitive decline and hyporeflexia provided a clue to the diagnosis. Low serum ASA (seven of 20), raised cerebrospinal fluid protein (five of 12), and urinary metachromatic granules (two of 32) were infrequent. Electrophysiological evidence of severe demyelinating and length dependent sensory motor neuropathy was observed in all, even in the presence of hyper-reflexia. In addition to metachromatic dysmyelinating neuropathy in all patients, sural nerve biopsy in 20 patients revealed orthochromatic deposits within perivascular macrophages, particularly among those patients with normal ASA values (11 of 14), suggesting the accumulation of other glycosphingolipids. Conclusions: This study produced some noteworthy observations: the high degree of consanguinity associated with MLD in India, the existence of MLD with normal serum concentrations of ASA, the deposition of orthochromatic lipids, and electrophysiological evidence of a partial conduction block.

Objective: To document and critically analyse the impact of the revised WHO 2000 histological classification for meningiomas on postoperative radiotherapy/radiosurgery indications and MRI follow up protocols. Methods: The current (2000) WHO classification was used to grade 57 meningiomas treated surgically at one institution. These had been reviewed previously in 1999. All German neurosurgical departments carrying out intracranial microsurgery were asked to detail their guidelines for radiation therapy and follow up for meningiomas of different WHO grades. Results: Use of the current criteria downgraded seven of 15 atypical meningiomas (WHO grade II, MII) to grade I (MI), and four of six anaplastic tumours (WHO grade III, MIII) to grade II. Indications for radiotherapy/radiosurgery and MRI follow up protocols varied substantially with the histological grade and between institutions—for example, after an incomplete resection, radiotherapy/radiosurgery recommendations differed between MI and MII in 30 of 58 units (52%), and between MII and MIII in 34 of 56 units (61%). Conclusions: Correlative studies combining treatment and outcome data with a standardised histopathological analysis are warranted to define properly the indications for radiotherapy/radiosurgery and follow up protocols after surgery for meningiomas of different histological grades. The use of changing grading paradigms during recent years renders decision making based on local and published experience difficult. The relatively large number of meningiomas classified as atypical/WHO grade II in current practice would argue against an uncritically aggressive approach to these tumours.

Objective: To assess the associations of medial temporal lobe atrophy (MTA) and white matter hyperintensities (WMH) with cognitive function in a large group of independently functioning elderly people. Methods: Data were drawn from the multicentre, multinational leukoaraiosis and disability (LADIS) project which is studying prospectively the role of WMH as an independent predictor of the transition to disability in non-disabled elderly people. In all, 639 participants were enrolled in the LADIS study. For the present analysis, data on 581 subjects were available. Cognitive function was assessed by the mini-mental state examination (MMSE). Visual ratings of WMH and MTA were undertaken on magnetic resonance images (MRI). Results: The presence of either severe WMH or MTA was associated with a modest but non-significant increase in frequency of mild cognitive deficits (severe WMH: odds ratio (OR) = 1.9 (95% confidence interval (CI), 1.0 to 3.7); MTA present: OR = 1.5 (95% CI, 0.8 to 2.8)). However, subjects with the combination of MTA and severe WMH had a more than fourfold increase in frequency of mild cognitive deficits (OR = 4.1 (95% CI, 2.3 to 7.4)). Analysis of variance with post hoc Bonferroni t tests showed that subjects with both MTA and severe WMH performed worse on MMSE than those with either no MRI abnormality or a single MRI abnormality (p Conclusions: These results provide further evidence for the combined involvement of both Alzheimer type pathology and vascular pathology in the earliest stages of cognitive decline and suggest an additive effect of WMH and MTA.

Objectives: To determine the long term survival and predictors of death in patients with primary intracerebral haemorrhage (ICH) in Central Finland. Methods: Data were collected retrospectively on all adult patients with first ever ICH in Central Finland county between September 1985 and December 1991. The survival of all patients at the end of December 2002 was investigated. Kaplan–Meier survival curves were constructed and factors associated with both early (⩽28 days) and late deaths determined. Long term survival was compared with the general Finnish population of the same age and sex distribution. The causes of death were compared with those of the population of Central Finland. Results: 411 patients with first ever ICH were identified, 199 men (mean age 64.9 years) and 212 women (mean age 69.5); 30 died before hospital admission, and 208 (50.6%) within the first 28 days. In Kaplan–Meier analysis, at 16 years the cumulative survival was 3.2% for men and 9.8% for women. The 28 day survivors had a 4.5-fold increased annual risk of dying during the first year after ICH, and 2.2-fold during years 2 to 6. On admission, significant independent predictors of death within the first four weeks were unconsciousness, lateral shift of cerebral midline structures, mean arterial pressure ⩾134 mm Hg, hyperglycaemia, anticoagulant treatment, and ventricular extrasystoles. Predictors of late death for the 28 day survivors were old age, male sex, and heart failure. Conclusions: Primary intracerebral haemorrhage has a poor short and long term outcome. The results emphasise the importance of primary and secondary prevention for ICH.

Objectives: To compare the responsiveness of the Multiple Sclerosis Impact Scale (MSIS-29) with other self report scales in three multiple sclerosis (MS) samples using a range of methods. To estimate the impact on clinical trials of differing scale responsiveness. Methods: We studied three discrete MS samples: consecutive admissions for rehabilitation; consecutive admissions for steroid treatment of relapses; and a cohort with primary progressive MS (PPMS). All patients completed four scales at two time points: MSIS-29; Short Form 36 (SF-36); Functional Assessment of MS (FAMS); and General Health Questionnaire (GHQ-12). We determined: (1) the responsiveness of each scale in each sample (effect sizes): (2) the relative responsiveness of competing scales within each sample (relative efficiency): (3) the differential responsiveness of competing scales across the three samples (relative precision); and (4) the implications for clinical trials (samples size estimates scales to produce the same effect size). Results: We studied 245 people (64 rehabilitation; 77 steroids; 104 PPMS). The most responsive physical and psychological scales in both rehabilitation and steroids samples were the MSIS-29 physical scale and the GHQ-12. However, the relative ability of different scales to detect change in the two samples was variable. Differing responsiveness implied more than a twofold impact on sample size estimates. Conclusions: The MSIS-29 was the most responsive physical and second most responsive psychological scale. Scale responsiveness differs notably within and across samples, which affects sample size calculations. Results of clinical trials are scale dependent.