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Showing papers in "Journal of Neurology, Neurosurgery, and Psychiatry in 2009"


Journal ArticleDOI
TL;DR: In the general population, the use of statins, but not of non-statin cholesterol-lowering drugs, was associated with a lower risk of AD compared with never use of cholesterol- lowers drugs, and the protective effect was independent of the lipophilicity of statin.
Abstract: Background: Cross-sectional reports suggest that statin users are less likely to have Alzheimer disease (AD). Prospective studies have provided inconsistent evidence. Moreover, it is unclear whether the association differs for lipohilic statins, those that could more easily pass the blood–brain barrier and hydrophilic statins. Objectives: To prospectively evaluate whether use of statins is associated with the risk of AD, and to determine whether associations differ for lipophilic and hydrophilic statins. Method: 6992 participants of the prospective, population-based Rotterdam Study were followed, from baseline (1990–1993) until January 2005 for incident AD. Data on all filled prescriptions came from pharmacy records. For each date on which each event occurred, cholesterol-lowering drug use for the person who experienced the event and all remaining persons in the cohort was categorised as “any” or “never” use. A distinction was made between statin, lipophilic and hydrophilic statins, and non-statin cholesterol-lowering drugs. Data were analysed with the Cox regression analysis, adjusting for sex, age and potential confounders. Results: During follow-up (mean 9 years), 582 persons developed AD. Compared with never use of cholesterol-lowering drugs, statin use was associated with a decreased risk of AD (HR 0.57; 95% CI 0.37 to 0.90), but non-statin cholesterol-lowering drug use was not (HR 1.05; 95% CI 0.45 to 2.44). HRs were equal for lipophilic (HR 0.54; 95% CI 0.32 to 0.89) and hydrophilic statins (HR 0.54; 95% CI 0.26 to 1.11). Conclusion: In the general population, the use of statins, but not of non-statin cholesterol-lowering drugs, was associated with a lower risk of AD compared with never use of cholesterol-lowering drugs. The protective effect was independent of the lipophilicity of statins.

366 citations


Journal ArticleDOI
TL;DR: It was agreed that in the majority of cases, successful management could be based on a simple algorithm which includes using reagent sticks to test for urine infection and measurement of the post micturition residual urine volume, in contrast with published guidelines from other countries which recommend cystometry.
Abstract: Bladder symptoms in multiple sclerosis (MS) are common and distressing but also highly amenable to treatment. A meeting of stakeholders involved in patients' continence care, including neurologists, urologists, primary care, MS nurses and nursing groups was recently convened to formulate a UK consensus for management. National Institute for Health and Clinical Excellence (NICE) criteria were used for producing recommendations based on a review of the literature and expert opinion. It was agreed that in the majority of cases, successful management could be based on a simple algorithm which includes using reagent sticks to test for urine infection and measurement of the post micturition residual urine volume. This is in contrast with published guidelines from other countries which recommend cystometry. Throughout the course of their disease, patients should be offered appropriate management options for treatment of incontinence, the mainstay of which is antimuscarinic medications, in combination, if necessary, with clean intermittent self-catheterisation. The evidence for other measures, including physiotherapy, alternative strategies aimed at improving bladder emptying, other medications and detrusor injections of botulinum toxin A was reviewed. The management of urinary tract infections as well as the bladder problems as part of severe disability were discussed and recommendations agreed.

260 citations


Journal ArticleDOI
TL;DR: Female gender was associated with a considerably lower risk of PD and slightly delayed motor onset but had no impact on severity of parkinsonism or clinical phenotype in incident drug naïve PD, suggesting that the female gender influences on the nigrostriatal system are most pronounced in the preclinical phase of the disease.
Abstract: Objective: To present the incidence of Parkinson’s disease (PD) in Norway and to explore gender influences on incidence and age at onset, as well as severity and pattern of parkinsonism at the time of diagnosis in a representative drug naive cohort with newly diagnosed PD. Methods: In four Norwegian counties comprising a base population of 1 052 075 inhabitants, multiple sources of case ascertainment and a four step diagnostic procedure were used to establish a representative cohort of patients with incident PD at a high level of diagnostic accuracy. Of a total of 604 subjects referred to the study, 265 individuals fulfilled the clinical research criteria of PD at their latest clinical visit, at a mean 28 months after identification. Results: The incidence of PD in the study area, age standardised to the 1991 European standard population, was 12.6/10 5yr-1 (95% CI 11.1 to 14.2). The overall age standardised male to female ratio was 1.58 (95% CI 1.22 to 2.06), with a consistent male preponderance throughout all age groups. Clinical onset of PD was later in women than in men (68.6 vs 66.3 years; p = 0.062) whereas severity and pattern of parkinsonism in drug naive patients was not different between genders at the time of diagnosis. Conclusion: Incidence rates of PD in Norway are similar to those in other Western European and American countries. Female gender was associated with a considerably lower risk of PD and slightly delayed motor onset but had no impact on severity of parkinsonism or clinical phenotype in incident drug naive PD, suggesting that the female gender influences on the nigrostriatal system are most pronounced in the preclinical phase of the disease.

245 citations


Journal ArticleDOI
TL;DR: Depression, apathy and sleep disturbance are more common in patients than in people without PD, and both psychological stress and brain changes associated with PD are likely to contribute to the higher frequencies.
Abstract: Background: Neuropsychiatric symptoms are common in Parkinson’s disease (PD) and have important clinical consequences for patients, caregivers and society. Few studies of neuropsychiatric symptoms in early untreated PD exist. Objective: To explore the range, clustering and correlates of neuropsychiatric symptoms in an incidence cohort of untreated subjects with PD. Methods: All cases with incident PD identified during a 22 month period in four counties of Western and Southern Norway were included. Standardised criteria were used to diagnose PD. The Neuropsychiatric Inventory (NPI) was administered to 175 PD and 166 healthy control subjects with similar age and sex distributions. Cluster analysis was used to investigate the interrelationship of NPI items. Results: The proportion with any NPI symptoms was higher in PD (56%) than in controls (22%) (p Conclusions: Although the majority of patients with early untreated PD do not have clinical significant neuropsychiatric symptoms, these symptoms are more common in patients than in people without PD. Both psychological stress and brain changes associated with PD are likely to contribute to the higher frequencies.

243 citations


Journal ArticleDOI
TL;DR: The results are consistent with previous studies suggesting that therapeutic benefit is associated with electrode contacts near the dorsal border of the STN, and provide quantitative estimates of the electrical spread of the stimulation in a clinically relevant context.
Abstract: Objective: Despite the clinical success of deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD), little is known about the electrical spread of the stimulation. The primary goal of this study was to integrate neuroimaging, neurophysiology and neurostimulation data sets from 10 patients with PD, unilaterally implanted with subthalamic nucleus (STN) DBS electrodes, to identify the theoretical volume of tissue activated (VTA) by clinically defined therapeutic stimulation parameters. Methods: Each patient specific model was created with a series of five steps: (1) definition of the neurosurgical stereotactic coordinate system within the context of preoperative imaging data; (2) entry of intraoperative microelectrode recording locations from neurophysiologically defined thalamic, subthalamic and substantia nigra neurons into the context of the imaging data; (3) fitting a three dimensional brain atlas to the neuroanatomy and neurophysiology of the patient; (4) positioning the DBS electrode in the documented stereotactic location, verified by postoperative imaging data; and (5) calculation of the VTA using a diffusion tensor based finite element neurostimulation model. Results: The patient specific models show that therapeutic benefit was achieved with direct stimulation of a wide range of anatomical structures in the subthalamic region. Interestingly, of the five patients exhibiting a greater than 40% improvement in their Unified PD Rating Scale (UPDRS), all but one had the majority of their VTA outside the atlas defined borders of the STN. Furthermore, of the five patients with less than 40% UPDRS improvement, all but one had the majority of their VTA inside the STN. Conclusions: Our results are consistent with previous studies suggesting that therapeutic benefit is associated with electrode contacts near the dorsal border of the STN, and provide quantitative estimates of the electrical spread of the stimulation in a clinically relevant context.

240 citations


Journal ArticleDOI
TL;DR: The addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.
Abstract: Background: Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission. Methods: Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (45.0%) used only ChEIs, and 416 (40.1%) used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications). Results: Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death. Conclusions: This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.

235 citations


Journal ArticleDOI
TL;DR: A serological marker of periodontitis is associated with impaired delayed memory and calculation, and further exploration of relationships between oral health and cognition is warranted.
Abstract: Background: Periodontitis is ubiquitous and associated with serological evidence of exposure to periodontal organisms, systemic inflammation and vascular disease. Dementia is a major public health problem likely related to a complex interaction between genetics and diseases associated with systemic inflammation, including diabetes, smoking and stroke. Methods: To assess relationships between systemic exposure to periodontal pathogens and cognitive test outcomes, data were analysed from the Third National Health and Nutrition Examination Survey (NHANES-III), a nationally representative cross sectional observational study among older adults. We included 2355 participants ⩾60 years who completed measures of cognition and Poryphyromonas gingivalis IgG. Using SUDAAN, logistic regression models examined the association of P gingivalis IgG with cognitive test performance. Results: Poor immediate verbal memory ( P gingivalis IgG (>119 ELISA Units (EU)) were more likely to have poor delayed verbal recall (OR 2.89, 95% CI 1.14 to 7.29) and impaired subtraction (OR 1.95, 95% CI 1.22 to 3.11) than those with the lowest (⩽57 EU), with dose–response relationships for both (p trend, delayed memory = 0.045, subtraction = 0.04). After adjusting for socioeconomic and vascular variables, these relationships remained robust for the highest P gingivalis IgG group (delayed verbal memory OR 3.01 (95% CI 1.06 to 8.53); subtraction OR 2.00 (95% CI 1.19 to 3.36)). In contrast, immediate verbal memory was not significantly associated with P gingivalis . Conclusion: A serological marker of periodontitis is associated with impaired delayed memory and calculation. Further exploration of relationships between oral health and cognition is warranted.

235 citations


Journal ArticleDOI
TL;DR: The findings indicate that improvements in and more data on psychometric properties of (I)ADL questionnaires for dementia patients are necessary in order to justify their use.
Abstract: Background: Instrumental Activities of Daily Living (IADL) questionnaires can be helpful in diagnosing dementia and are often used for clinical follow-up and treatment evaluation in dementia patients. Despite the large number of questionnaires, their quality has received little attention. Objective: To systematically review the measurement properties of all available structured informant-based (I)ADL questionnaires, developed or validated for use in demented patients. Methods: A systematic literature search was conducted in MEDLINE, PsycINFO and EMBASE for psychometric articles on (I)ADL questionnaires. In addition, reference lists of all retrieved articles were screened. Standardised criteria were used to assess the quality of the measurement properties. When possible, investigators were contacted to obtain missing information. Two authors independently extracted studies and performed the quality assessment of the questionnaires. Findings: Thirty-two articles were selected, covering 12 (I)ADL questionnaires. Information on 52.3% of the quality aspects was not available, 32.4% of the ratings were indeterminate, 8.1% were positive, and 7.2% were negative. Out of eight measurement properties, two scales (the DAD and the Bristol ADL) received two positive ratings and were classified as of moderate quality. Five scales (ADL-PI, ADL-IS, B-ADL, CSADL and Lawton IADL) received one positive rating. Interpretation: The findings indicate that improvements in and more data on psychometric properties of (I)ADL questionnaires for dementia patients are necessary in order to justify their use.

232 citations


Journal ArticleDOI
TL;DR: Early intervention for memory difficulties in amnestic mild cognitive impairment, using cognitive rehabilitation in compensatory strategies, can assist in minimising everyday memory failures as evaluated by performance on prospective memory tasks and knowledge of memory strategies.
Abstract: Background: Positive effects are reported for memory training for healthy older adults, and yet there is limited information about the benefit of cognitive intervention for older adults with increasing memory difficulties—mild cognitive impairment. Objective: To investigate the usefulness of an early cognitive intervention for the memory difficulties experienced by people with amnestic mild cognitive impairment. Methods: Using a randomised control design, 52 participants with amnestic mild cognitive impairment and their family partners were randomly assigned to a cognitive intervention (memory rehabilitation group) or waitlist (control group). Participants were assessed on primary measures of everyday memory (prospective memory) and memory strategies at 2 weeks’ and 4 months’ follow-up; secondary measures of contentment with memory and the family participants’ knowledge of memory strategies were also assessed. Results: Everyday memory, measured by performance on prospective memory tasks, significantly improved following intervention, although self-appraisal of everyday memory did not demonstrate a similar intervention effect. Knowledge and use of memory strategies also significantly increased following intervention. Furthermore, family knowledge of memory strategies increased following intervention. There was a strong trend towards improvement in contentment with memory immediately following intervention, but this effect was not significant. Conclusions: Early intervention for memory difficulties in amnestic mild cognitive impairment, using cognitive rehabilitation in compensatory strategies, can assist in minimising everyday memory failures as evaluated by performance on prospective memory tasks and knowledge of memory strategies.

211 citations


Journal ArticleDOI
TL;DR: Examination of the extent and pattern of GM demyelination in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord in multiple sclerosis found there was substantial variation in the extent of demYelination between the different CNS regions.
Abstract: Background: Substantial grey matter (GM) demyelination occurs in both the cerebral cortex and spinal cord in multiple sclerosis (MS). GM demyelination also occurs in the cerebellar cortex and the deep GM nuclei of the brain. However, no study has made a direct “within subject” comparison of the extent of GM pathology between these regions. Aim: To examine the extent and pattern of GM demyelination in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord in MS. Methods: Postmortem study using material from 14 MS cases and three controls. Sections were taken from the five predetermined areas and stained for proteolipid protein. The extent of GM and white matter (WM) demyelination was assessed in each region. Results and conclusion: Overall, 28.8% of the GM was demyelinated compared with 15.6% of the WM (p

210 citations


Journal ArticleDOI
TL;DR: From a prognostic perspective, the reported association of seizures in NS with a poor long-term outcome was not supported, while the suggestion that myelopathy also predicts an adverse prognosis was confirmed.
Abstract: Methods The frequency, nature, relationship to systemic features, value of investigation findings and outcomes for a cohort of patients with neurosarcoidosis (NS) were studied by performing a retrospective survey of case records from nine District General or Regional Centre hospitals in south-west England and south Wales over a 12-year period (1990-2002). Thirty patients (29 Caucasians) were included--16 (53%) males and 14 (47%) females, including 13 with histological confirmation of CNS disease, making this one of the largest series of biopsy-confirmed NS; the remaining cases had "Probable" NS according to the Zajicek criteria. The male preponderance is of interest particularly considering the female predominance of systemic sarcoidosis. Results The indicative prevalence of NS in this geographical area was estimated at one per 100,000, given an approximate population of 3 million. The most frequent features were headaches, visual failure, ataxia and vomiting. Cranial neuropathy occurred in 80% of patients, and as a presenting feature in 50%--though facial nerve involvement was seen in only 23%, and in none of those with definite disease. Unsurprisingly, no diagnostic clinical patterns emerged overall when only definite cases were analysed, but within our definite group of patients, meningeal and/or parenchymal lesion enhancement was observed in all but one case, while distinction from multiple sclerosis might also be aided by the observation that in all NS cerebrospinal fluid (CSF) samples with positive oligoclonal bands (27%), banding was accompanied by elevations of CSF protein. Conclusion From a prognostic perspective, the reported association of seizures in NS with a poor long-term outcome was not supported, while the suggestion that myelopathy also predicts an adverse prognosis was confirmed.

Journal ArticleDOI
TL;DR: For the first time, the predictive validity of MTL and DGM atrophy were simultaneously compared with MS using reliable and validated neuropsychological measures and found that both compartments play significant but different roles in the amnesia of MS.
Abstract: Background: MRI research in multiple sclerosis (MS) samples reveals pathology in both the cerebral cortex and deep grey matter (DGM). The classical subcortical dementia hypothesis has been ascribed to MS and is supported by studies highlighting the role of thalamic atrophy in neuropsychological outcomes. However, the importance of mesial temporal lobe (MTL) atrophy in MS is largely untested and poorly understood. New structural imaging techniques permit volumetric measures of multiple regions within the MTL lobe and DGM. Objective: To determine the relative importance of MTL and DGM structures in predicting MS performance on memory tests presented in the auditory/verbal and visual/spatial spheres. Methods: Cross sectional analysis of 50 patients with MS undergoing structural brain MRI and neuropsychological testing. Using Freesurfer software, the volumes of the MTL (hippocampus, amygdala) and DGM (thalamus, caudate) structures were calculated and compared with control values. Neuropsychological testing contributed measures of new learning, delayed recall and recognition memory, in the auditory/verbal and visual/spatial memory modalities. Results: Significant correlations between lower regional volume and poorer test performance were observed across all memory tests. For measures of free recall or new learning, DGM volumes were most strongly predictive of outcomes. In contrast, measures of recognition memory were predicted only by MTL volumetric measures. Conclusion: For the first time, the predictive validity of MTL and DGM atrophy were simultaneously compared with MS using reliable and validated neuropsychological measures. This study found that both compartments play significant but different roles in the amnesia of MS.

Journal ArticleDOI
TL;DR: Risk factors prior to initial stroke have a significant role in predicting stroke recurrence up to 10 years, and different predictors for stroke Recurrence were identified throughout the follow-up period.
Abstract: Background: Data estimating the risk of, and predictors for, long-term stroke recurrence are lacking. Methods: Data were collected from the population-based South London Stroke Register. Patients were followed up for a maximum of 10 years. Kaplan–Meier estimates and Cox proportional hazards models were used to assess the cumulative risk of and predictors for first stroke recurrence. Variables analysed included sociodemographic factors, stroke subtype (defined as cerebral infarction, intracerebral haemorrhage and subarachnoid haemorrhage), stroke severity markers and prior-to-stroke risk factors. Results: Between 1995 and 2004, 2874 patients with first-ever stroke were included. The mean follow-up period was 2.9 years. During 8311 person-years of follow-up, 303 recurrent events occurred. The cumulative risk of stroke recurrence at 1 year, 5 years and 10 years was 7.1%, 16.2% and 24.5% respectively. No differences in stroke recurrence were noted between the stroke subtypes. Factors increasing the risk of recurrence at 1 year were previous myocardial infarction (HR 1.73; 95% CI 1.08 to 2.78) and atrial fibrillation (HR 1.61; 95% CI 1.04 to 4.27); at 5 years, hypertension (HR 1.47; 95% CI 1.08 to 1.99) and atrial fibrillation (HR 1.79; 95% CI 1.29 to 2.49); and at 10 years, older age (p = 0.04), and hypertension (HR 1.38, 95% CI 1.04 to 1.82), myocardial infarction (HR 1.50, 95% CI 1.06 to 2.11) and atrial fibrillation (HR 1.51, 95% CI 1.09 to 2.09). Conclusions: Very-long-term risk of stroke recurrence is substantial. Different predictors for stroke recurrence were identified throughout the follow-up period. Risk factors prior to initial stroke have a significant role in predicting stroke recurrence up to 10 years.

Journal ArticleDOI
TL;DR: While some white-matter bundles are affected equally in both forms of TLE, abnormalities of the bundles directly related to the mesial temporal structures appear to be unique to TLE+uMTS.
Abstract: Background: Although epilepsy is considered a grey-matter disorder, changes in the underlying brain connectivity have important implications in seizure generation and propagation. Abnormalities in the temporal and extratemporal white matter of patients with temporal-lobe epilepsy (TLE) and mesial temporal sclerosis (MTS) have previously been identified. Patients with TLE but without MTS often show a different course of the disorder and worse surgical outcome than patients with MTS. The purpose of this study was to determine if said white-matter abnormalities are related to the presence of MTS or if they are also present in non-lesional TLE. Methods: Seventeen patients with TLE and MTS (TLE+uMTS), 13 patients with non-lesional TLE (nl-TLE) and 25 controls were included in the study. Diffusion tensor imaging (DTI) was used to assess tract integrity of the fornix, cingulum, external capsules and the corpus callosum. Results: The white-matter abnormalities seen in the fornix appear to be exclusive to patients with MTS. Although the cingulum showed an abnormally high overall diffusivity in both TLE groups, its anisotropy was decreased only in the TLE+uMTS group in a pattern similar to the fornix. The frontal and temporal components of the corpus callosum, as well as the external capsules, demonstrated reduced anisotropy in TLE regardless of MTS. Conclusions: While some white-matter bundles are affected equally in both forms of TLE, abnormalities of the bundles directly related to the mesial temporal structures (ie, the fornix and cingulum) appear to be unique to TLE+uMTS.

Journal ArticleDOI
TL;DR: Detailed observations of the progression of physical disability, dependence on care and respiratory impairment in patients with DMD from childhood to adult life is valuable for predicting the clinical course with current medical care.
Abstract: Background: Duchenne muscular dystrophy (DMD) leads to progressive impairment of muscle function, respiratory failure and premature death. Longitudinal data on the course of physical disability and respiratory function are sparse. Objectives: To assess prospectively physical impairment and disability, respiratory function and survival in patients with DMD over several years to describe the course of the disease with current care. Methods: In 43 patients with DMD, aged 5–35 years, yearly assessments of physical disability by the Duchenne muscular dystrophy physical Impairment and Dependence on care (DID) score, ranging from 9 (no disability) to 80 (complete dependence), and forced vital capacity (FVC), were obtained over a mean time interval of 5.4 (SD 2.1) years. Results: DID scores were correlated with age according to a hyperbolic function (f = 85.3×age/(10.05+age), R = 0.62, p Conclusions: Our detailed observations of the progression of physical disability, dependence on care and respiratory impairment in patients with DMD from childhood to adult life is valuable for predicting the clinical course with current medical care. Compared with historical data, survival has improved considerably.

Journal ArticleDOI
TL;DR: Locally weighted and spline regressions suggested the relationship between 25(OH)D concentration and cognitive function was most pronounced at 25( OH)D concentrations below 35 nmol/l, and lower 25(oh)D levels were associated with poorer performance on the DSST.
Abstract: Background: Although there is evidence that vitamin D inadequacy may be linked to adverse cognitive outcomes, results from studies on this topic have been inconsistent. The aim of this trial was to examine the association between 25-hydroxyvitamin D (25(OH)D) levels and cognitive performance in middle-aged and older European men. Methods: This population-based cross-sectional study included 3,369 men aged 40–79 years from eight centres enrolled in the European Male Ageing Study. Cognitive function was assessed using the Rey–Osterrieth Complex Figure (ROCF) test, the Camden Topographical Recognition Memory (CTRM) test and the Digit Symbol Substitution Test (DSST). Serum 25(OH)D levels were measured by radioimmunoassay. Additional assessments included measurement of physical activity, functional performance and mood/depression. Associations between cognitive function and 25(OH)D levels were explored using locally weighted and linear regression models. Results: In total, 3,133 men (mean (±SD) age 60±11 years) were included in the analysis. The mean (±SD) 25(OH)D concentration was 63±31 nmol/l. In age-adjusted linear regressions, high levels of 25(OH)D were associated with high scores on the copy component of the ROCF test (β per 10 nmol/l = 0.096; 95% CI 0.049 to 0.144), the CTRM test (β per 10 nmol/l = 0.075; 95% CI 0.026 to 0.124) and the DSST (β per 10 nmol/l = 0.318; 95% CI 0.235 to 0.401). After adjusting for additional confounders, 25(OH)D levels were associated with only score on the DSST (β per 10 nmol/l = 0.152; 95% CI 0.051 to 0.253). Locally weighted and spline regressions suggested the relationship between 25(OH)D concentration and cognitive function was most pronounced at 25(OH)D concentrations below 35 nmol/l. Conclusion: In this study, lower 25(OH)D levels were associated with poorer performance on the DSST. Further research is warranted to determine whether vitamin D sufficiency might have a role in preserving cognitive function in older adults.

Journal ArticleDOI
TL;DR: In patients with severe TBI and elevated ICP refractory to previous mannitol treatment, 7.5% hypertonic saline administered as second tier therapy is associated with a significant increase in brain oxygenation, and improved cerebral and systemic haemodynamics.
Abstract: Background: The impact of osmotic therapies on brain oxygen has not been extensively studied in humans. We examined the effects on brain tissue oxygen tension (PbtO 2 ) of mannitol and hypertonic saline (HTS) in patients with severe traumatic brain injury (TBI) and refractory intracranial hypertension. Methods: 12 consecutive patients with severe TBI who underwent intracranial pressure (ICP) and PbtO 2 monitoring were studied. Patients were treated with mannitol (25%, 0.75 g/kg) for episodes of elevated ICP (>20 mm Hg) or HTS (7.5%, 250 ml) if ICP was not controlled with mannitol. PbtO 2 , ICP, mean arterial pressure, cerebral perfusion pressure (CPP), central venous pressure and cardiac output were monitored continuously. Results: 42 episodes of intracranial hypertension, treated with mannitol (n = 28 boluses) or HTS (n = 14 boluses), were analysed. HTS treatment was associated with an increase in PbtO 2 (from baseline 28.3 (13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min; all p 2 (baseline 30.4 (11.4) vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; all p>0.1). Compared with mannitol, HTS was associated with lower ICP and higher CPP and cardiac output. Conclusions: In patients with severe TBI and elevated ICP refractory to previous mannitol treatment, 7.5% hypertonic saline administered as second tier therapy is associated with a significant increase in brain oxygenation, and improved cerebral and systemic haemodynamics.

Journal ArticleDOI
TL;DR: An approach to the diagnosis of the genetic neuropathies is suggested, an update on new therapies is provided and the most common types are Charcot–Marie–Tooth disease, the hereditary sensory and autonomic Neuropathies and the distal hereditary motor neuropathie.
Abstract: The genetic neuropathies are a clinically and genetically heterogeneous group of diseases of which the most common types are Charcot-Marie-Tooth disease (CMT), the hereditary sensory and autonomic neuropathies and the distal hereditary motor neuropathies. More than 30 causative genes have been described, making an accurate genetic diagnosis increasingly possible. Although no specific therapies are yet available, research into their pathogenesis has revolutionised our understanding of the peripheral nervous system and allowed the development of rational approaches to therapy. The first therapeutic trials in CMT are currently underway. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.

Journal ArticleDOI
TL;DR: CAS were present in half of migraine patients and the clinical features may help differentiate migraine from CH, and the prevalence of ⩾1 CAS in migraine patients was 56% and did not differ among migraine subtypes.
Abstract: Background: Cranial autonomic symptoms (CAS) are distinguishing features of trigeminal autonomic cephalalgias, of which cluster headache (CH) is the most common, but they can occur in patients with migraine. For migraine with strictly unilateral headache, the presence of CAS might cause diagnostic confusion with CH. Characteristics of CAS in migraine and comparisons with those in CH have rarely been reported. Methods: This study prospectively recruited consecutive patients with migraine and CH treated at a headache clinic. Six CAS items were surveyed, including: conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, eyelid oedema and forehead/facial sweating. The CAS characteristics recorded included: laterality, intensity, time sequence and consistency with headache attacks. Results: A total of 786 migraine patients (625 women/161 men, mean age 40 (13) years) and 98 CH patients (11 women/87 men, mean age 36 (11) years) were recruited. The prevalence of ⩾1 CAS in migraine patients was 56% and did not differ among migraine subtypes. Except for forehead/facial sweating, the features of the other CAS differed between patients with migraine and CH: CAS in migraine tended to be bilateral (OR 5.8–23.8 among different CAS), be unrestricted to the headache sides (OR 5.0–20.4), appear with mild to moderate intensity (OR 1.7–7.7) and be inconsistent with headache attacks (OR 2.8–6.7). Conclusions: CAS were present in half of our migraine patients and the clinical features may help differentiate migraine from CH.

Journal ArticleDOI
TL;DR: The data confirmed the high frequency of depressive symptoms and the major impact of central hypersomnias on health related quality of life, especially in patients with cataplexy and recommends a more thorough assessment of mood impairment in central hypersOMnias,especially in narcolepsy–cataplexY.
Abstract: Background: A large observational French study of central hypersomnia, including narcolepsy with cataplexy (C+), without cataplexy (C−) and idiopathic hypersomnia (IH), was conducted to clarify the relationships between the severity of the condition, psychological health and treatment response. Methods: 601 consecutive patients over 15 years of age suffering from central hypersomnia were recruited on excessive daytime sleepiness, polysomnography and Multiple Sleep Latency Test (MSLT) results. 517 (47.6% men, 52.4% women) were finally included: 82.0% C+, 13.2% C− and 4.8% IH. Face to face standardised clinical interviews plus questionnaires (Epworth Sleepiness Scale (ESS), short version Beck Depression Inventory (S-BDI), Pittsburgh Sleep Quality Index (PSQI) and 36-item Short Form Health Survey (SF-36)) were performed. Patients affected with a different diagnosis and with and without depressive symptoms were compared. Results: Mean ESS and body mass index were higher in C+ compared with C−/IH patients. Half of the patients (44.9%) had no depressive symptoms while 26.3% had mild, 23.2% moderate and 5.6% severe depressive symptoms. C+ patients had higher S-BDI and PSQI and lower SF-36 scores than C−/IH patients. Depressed patients had higher ESS scores than non-depressed patients, with no difference in age, gender, duration of disease or MSLT parameters. Finally, C+ patients treated with anticataplectic drugs (38.7%) had higher S-BDI and lower SF-36 scores than C+ patients treated with stimulants alone. Conclusion: Our data confirmed the high frequency of depressive symptoms and the major impact of central hypersomnias on health related quality of life, especially in patients with cataplexy. We recommend a more thorough assessment of mood impairment in central hypersomnias, especially in narcolepsy–cataplexy.

Journal ArticleDOI
TL;DR: Unequal VA flow is an important haemodynamic contributor of BA curvature and development of peri-vertebrobasilar junctional infarcts.
Abstract: Objectives: The diameters of the vertebral arteries (VAs) are very often unequal. Therefore, this study investigated if unequal VA flow contributes to the development of basilar artery (BA) curvature and if it is a link to the laterality of pontine or cerebellar infarcts occurring around the vertebrobasilar junction. Methods: Radiological factors were analysed (infarct laterality, VA dominance, BA curvature and their directional relationships) in 91 patients with acute unilateral pontine or posterior inferior cerebellar artery (PICA) territory infarcts. The “dominant” VA side was defined as either that the VA was larger in diameter or the VA was connected with the BA in more of a straight line, if both VAs looked similar in diameter on CT angiography. Multiple regression analysis was performed to predict moderate to severe BA curvature. Results: The dominant VA was more frequent on the left side (p Conclusions: Unequal VA flow is an important haemodynamic contributor of BA curvature and development of peri-vertebrobasilar junctional infarcts.

Journal ArticleDOI
TL;DR: Camptocormia, a relatively common sign in Parkinson disease, seems to be related to the clinical severity of PD.
Abstract: Background: Camptocormia is an abnormal flexion of the thoracolumbar spine during standing and walking that abates in the recumbent position. Methods: In a single-centre epidemiological and clinical study, the prevalence of camptocormia in Parkinson disease (PD) and its relationship with the clinical features of PD were investigated. A total of 275 consecutive outpatients were systematically screened for camptocormia with a clinical evaluation. Patients who screened positive for camptocormia were subsequently reassessed by formal goniometric analysis. The demographic and clinical features of the patients with and without camptocormia were then compared. Results: A 6.9% (19/275, 95% CI, 4.2 to 10.6) prevalence of camptocormia was found. Camptocormia was found in patients with more severe PD, as clinically assessed by the Hoehn–Yahr (HY) staging and the motor Unified Parkinson Disease Rating Scale (UPDRS) part III, longer l-dopa treatment duration and greater l-dopa daily dose and presence of DSM-IV dementia. Camptocormia was reported to develop after the clinical onset of PD. No correlation was found between the degree of trunk flexion and age, duration of PD, UPDRS motor score, HY staging, and l-dopa treatment duration and dose. As a risk factor, the study identified previous vertebral surgery. Conclusions: Camptocormia, a relatively common sign in PD seems to be related to the clinical severity of PD.

Journal ArticleDOI
TL;DR: The association of frontal and periventricular ARW MC with falls supports the hypothesis that interruption of frontal subcortical motor circuits lead to balance disturbances and hence to an increased risk for falls in ARWMC.
Abstract: Background: Global age related white matter changes (ARWMC) are associated with progressive gait disturbances and falls, hypothesised to result from interruptions of cortico-subcortical circuits controlling balance, posture and locomotion Methods: The location of ARWMC in a large cohort of elderly non-disabled individuals with reported falls was analysed, using the cross sectional data of the Leukoaraiosis and Disability (LADIS) study Detailed anatomical distributions of ARWMC assessed by MRI studies were analysed with respect to falls and balance performance Results: The severity of global ARWMC was significantly associated with a history of falls in the year prior to study inclusion (222% in the mild, 316% in the moderate and 373% in the severe ARWMC group according to the Fazekas scale; p = 0002) Analysing the anatomical distribution of ARWMC, using the semiquantitative Scheltens scale, in multivariate analysis, periventricular (p = 0006) and frontal deep (p = 0033) ARWMC were independently associated with falls Furthermore, logistic regression identified frontal deep (p = 0003) ARWMC, but not basal ganglia and infratentorial hyperintensities, as significantly associated with balance disturbances Conclusion: The association of frontal and periventricular ARWMC with falls supports the hypothesis that interruption of frontal subcortical motor circuits lead to balance disturbances and hence to an increased risk for falls in ARWMC

Journal ArticleDOI
TL;DR: The study describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specificlevodopa-resistant symptoms.
Abstract: An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower limb dystonia, diurnal fluctuations, and excellent response to levodopa has been well recognized in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow up of genetically proven cases. We present a detailed clinical evaluation of 34 patients (19 women, 15 men) with confirmed mutations in the GCH1 gene. We found that the classic phenotype was most frequent (n=23), with female predominance (F:M=16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n=4), or with an adult-onset (mean 37 years) Parkinson's disease-like phenotype (n=4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. We also describe a number of supplementary features including restless legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder, and specific levodopa-resistant symptoms (writer's cramp, dysphonia, truncal dystonia). We report that levodopa was used effectively and safely in 20 pregnancies, and did not cause any foetal abnormalities.

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TL;DR: Self-report of ’no difficulty’ is not a reliable indicator of swallowing ability and studies employing more-objective assessment of aspiration risk to compare with water swallow test performance are advocated.
Abstract: Background: Changes to the efficiency and integrity of swallowing mechanisms are inevitable in Parkinson disease (PD); however, it remains unclear how many people with PD are at risk of dysphagia. The aim of this study was to establish the frequency of impaired swallowing in people with PD and the relationship between swallowing performance and indicators of disease progression. Methods: A community-based and hospital-based cohort of 137 individuals with PD were asked to drink 150 ml of water as quickly as possible while in an ‘off drug’ state. Results: Thirty-one (23%) patients could not completely drink the full 150 ml. Swallowing rate (ml/sec) fell to more than 1SD below published norms for 115 (84%) patients and to more than 2SD below for 44 (32%) individuals. There were moderate correlations between rate of swallowing and disease severity, depression and cognition, but not between swallowing speed and disease duration. There was poor correlation between subjective reports of dysphagia and performance on the water swallow test. Conclusions: Swallowing problems are frequent in PD. Self-report of ’no difficulty’ is not a reliable indicator of swallowing ability. Studies employing more-objective assessment of aspiration risk to compare with water swallow test performance are advocated.

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TL;DR: There are clear clinical differences between OCB negative and OCB positive multiple sclerosis, in particular a better prognosis for disability, consistent with a secondary but nonetheless contributory role in disease process for intrathecally synthesised immunoglobulins.
Abstract: Objective: Oligoclonal band (OCB) negative multiple sclerosis (MS) is well recognised but uncommon, studied in only a few usually small case series. These reached differing conclusions on whether its clinical features or course differ from OCB positive disease. The study hypothesis was that a definitive study would not only be of clinical and prognostic value but also potentially offer information about the possible role of CSF oligoclonal immunoglobulins in MS disease processes. Methods: A collaborative cohort of well documented patients in southwest England and south Wales was used to identify and analyse a large group of patients with OCB negative MS and make comparisons with age and sex matched OCB positive controls. Results: An approximate minimum 3% of patients with MS were OCB negative. They were significantly more likely to exhibit neurological or systemic clinical features atypical of MS (headaches, neuropsychiatric features and skin changes). Non-specific MRI, blood and (other) CSF abnormalities were also more common, emphasising the need for continued diagnostic vigilance, although the incautious application of McDonald diagnostic criteria in OCB negative cases renders categorisation as ‘‘definite’’ MS more likely. Studying the uniformly assessed Cardiff group (69 patients), we found the prognosis for neurological disability was significantly better for OCB negative cases. The age adjusted hazard ratio for OCB negative and OCB positive subjects to reach Disability Scale Status (DSS) 4 and DSS 6 was, respectively, 0.60 (95% CI 0.39 to 0.93; p=0.02) and 0.51 (95% CI 0.27 to 0.94; p=0.03). Conclusion: There are clear clinical differences between OCB negative and OCB positive MS, in particular a better prognosis for disability. This is consistent with a secondary but nonetheless contributory role in disease process for intrathecally synthesised immunoglobulins.

Journal ArticleDOI
TL;DR: CSF-GFAP and S100B may be clinically useful biomarkers in NMO, and astrocytic damage is strongly suggested in the acute phase of NMO.
Abstract: Background: Neuromyelitis optica (NMO) is a neurological inflammatory disease associated with autoimmunity to aquaporin 4, predominantly localised in astrocytic foot processes. Recent studies have revealed that loss of aquaporin 4 and glial fibrillar acidic protein (GFAP) is a prominent feature of NMO lesions, suggesting astrocytic impairment. Objective: To reveal a useful clinical biomarker of NMO. Methods: Enzyme-linked immunosorbent assays were carried out for astrocytic markers GFAP and S100B in CSFs, obtained from the patients with NMO (n = 10) and multiple sclerosis (MS) (n = 10) manifesting acute myelitis, acute disseminated encephalomyelitis (ADEM) (n = 3), spinal infarction (n = 3), and other neurological diseases (OND) (n = 5). Results: The CSF-GFAP levels during relapse in NMO (7666.0 (SD 15 266.5) ng/ml) were significantly over several thousand times higher than those in MS (0.7 (1.5)) or OND (0.6 (0.3)), and considerably higher than those in spinal infarction (354.7 (459.0)) and ADEM (0.4 (0.2)). They returned close to normal levels along with clinical improvement soon after corticosteroid therapy in NMO. There were strong correlations between the CSF-GFAP or S100B levels and expanded disability status scales or spinal lesion length in NMO (r>0.9). Conclusions: CSF-GFAP and S100B may be clinically useful biomarkers in NMO, and astrocytic damage is strongly suggested in the acute phase of NMO.

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TL;DR: Finding the NFR threshold to be decreased in addition to the decreased electrical and heat pain thresholds indicates that the pathophysiological changes either already reside at or reach down to the spinal level.
Abstract: Background: Patients suffering from Parkinson’s disease (PD) often complain about painful sensations. Recent studies detected increased subjective pain sensitivity and increased spinal nociception, which appeared to be reversible by dopaminergic treatment. Possibly, reduced descending pain inhibition contributes to this finding. Objective: Subjective pain thresholds as well as nociceptive reflex thresholds were investigated to isolate potential loci of the pathophysiological changes within the pain pathway. In addition, the diffuse noxious inhibitory control (DNIC) system as one form of descending control was assessed. Method: 15 patients with PD and 18 controls participated in the study. Electrical and heat pain thresholds as well as the nociceptive flexion reflex (NFR) thresholds were determined. Thereafter, the electrical pain thresholds were measured once during painful heat stimulation (conditioning stimulation) and twice during innocuous stimulation (control stimulation). Results: Patients with PD exhibited lower electrical and heat pain thresholds as well as lower NFR thresholds. Suppression of the electrical pain thresholds during painful heat stimulation (conditioning stimulation) compared with control stimulation did not differ significantly between the groups. No differences in the thresholds between patients with PD with and without clinical pain were seen. Conclusions: Finding the NFR threshold to be decreased in addition to the decreased electrical and heat pain thresholds indicates that the pathophysiological changes either already reside at or reach down to the spinal level. Reduced activation of the DNIC system was apparently not associated with increased pain sensitivity, suggesting that DNIC-like mechanisms do not significantly contribute to clinical pain in PD.

Journal ArticleDOI
TL;DR: Smoking, hypertension and diabetes were strongly associated with subsequent risk of hospitalisation with dementia, particularly in middle-aged individuals, and the importance of early lifestyle modification and risk factor treatment to prevent dementia is emphasised.
Abstract: Background: Cardiovascular risk factors are associated with a higher risk of developing dementia. Studies in older populations, however, have often failed to show this relationship. We assessed the association between cardiovascular risk factors measured in midlife and risk of being hospitalised with dementia and determined whether this association was modified by age and ethnicity. Methods: We studied 11 151 participants in the population-based Atherosclerosis Risk in Communities cohort, aged 46–70 (23% African–Americans) in 1990–2, when participants underwent a physical exam and cognitive testing. Hospitalisations with dementia were ascertained through December 2004. Results: During follow-up, 203 cases of hospitalisation with dementia were identified. Smoking (hazard ratio (HR), 95% CI 1.7, 1.2 to 2.5), hypertension (HR, 95% CI 1.6, 1.2 to 2.2) and diabetes (HR, 95% CI 2.2, 1.6 to 3.0) were strongly associated with dementia, in Caucasians and African–Americans. These associations were stronger when risk factors were measured at a younger age than at an older age. In analyses including updated information on risk factors during follow-up, the HR of dementia in hypertensive versus non-hypertensive participants was 1.8 at age ,55 years compared with 1.0 at age 70+ years. Parallel results were observed for diabetes (HR 3.4 in ,55, 2.0 in >70), smoking (4.8 in ,55, 0.5 in >70) and hypercholesterolaemia (HR 1.7 in ,55, 0.9 in >70) Conclusion: In this prospective study, smoking, hypertension and diabetes were strongly associated with subsequent risk of hospitalisation with dementia, particularly in middle-aged individuals. Our results emphasise the importance of early lifestyle modification and risk factor treatment to prevent dementia.

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TL;DR: This study shows that progressive tissue loss and injury to the remaining tissue occur in the cervical cord of ALS patients and that these two features of ALS-related pathology are not strictly interrelated.
Abstract: Objective: To define the temporal evolution of intrinsic tissue damage and atrophy in the cervical cord and the brain portion of the corticospinal tracts (CST) from patients with amyotrophic lateral sclerosis (ALS). Methods: Conventional and diffusion tensor (DT) magnetic resonance imaging (MRI) of the cervical cord and brain were obtained from 17 ALS patients and 20 controls, at baseline and after a mean follow-up of 9 months. The following measurements were assessed: (a) cervical cord cross-sectional area, average mean diffusivity (MD) and average fractional anisotropy (FA); and (b) CST T2-visible hyperintensities, average MD and FA. Results: During the follow-up, ALS patients showed a significant decrease in cord area (p = 0.003) and cord average FA (p = 0.01), and a significant increase in cord average MD (p = 0.01). In ALS patients, longitudinal changes of diffusivity measurements were not associated with cord area changes. At baseline, brain CST average MD was significantly higher in ALS patients compared with controls (p = 0.001). Brain CST diffusivity measurements remained stable over time in ALS patients and did not correlate with cord damage. Conclusions: This study shows that progressive tissue loss and injury to the remaining tissue occur in the cervical cord of ALS patients and that these two features of ALS-related pathology are not strictly interrelated. Cord pathology in ALS patients is likely to be independent of brain changes, indicating that imaging the cervical cord may be a useful adjunctive tool to monitor ALS evolution.