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High dietary intake of salt is associated with elevated blood pressure, a major risk factor for cardiovascular disease.
Salt intake was reported to be associated with increased clinical and MRI activity in adult patients with relapsing-remitting multiple sclerosis (MS).
To determine if salt intake is associated with time to relapse in patients with paediatric-onset MS.
Paediatric-onset MS and patients with clinically isolated syndrome (CIS) within 4 years of disease onset were recruited from 15 paediatric MS centres in the USA as part of a case–control study. Patients with available prospective relapse data subsequent to enrolment were included in this project. Dietary sodium intake was assessed by self-report questionnaire using the validated Block Kids Food Screener. Cox proportional-hazards regression models were employed to determine the association of sodium density, excess sodium intake and sodium density tertiles with time to relapse following study enrolment, adjusting for several confounders.
174 relapsing-remitting MS/CIS patients were included in this analysis (mean age of 15.0 years, and 64.9% females). Median duration of follow-up was 1.8 years. In an unadjusted analysis, density of daily sodium intake was not associated with time to relapse, and patients with excess sodium intake had no decrease in time to relapse as compared with patients with non-excess sodium intake. The multivariable analysis demonstrated that patients in the medium and high tertile of sodium density had a HR of 0.69 (95% CI 0.37 to 1.30, p=0.25) and 1.37 (95% CI 0.74 to 2.51, p=0.32) compared with patients in the lowest tertile, respectively.
Higher salt intake was not associated with decreased time to relapse in patients with paediatric-onset MS.
Naturally occurring autoantibodies against amyloid β (Aβ) peptide exist in the serum and cerebrospinal fluid (CSF) of healthy individuals. Recently, it was reported that administration of intravenous immunoglobulin at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD) reduces brain atrophy.
To examine the association between naturally occurring anti-Aβ autoantibodies and brain atrophy in patients with cognitive impairment.
Serum and CSF levels of anti-Aβ autoantibodies and CSF biomarkers were evaluated in 68 patients with cognitive impairment, comprising 44 patients with AD, 19 patients with amnestic MCI and five patients with non-Alzheimer's dementia. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volume of interest (VOI) in medial temporal structures, including the whole hippocampus, entorhinal cortex and amygdala.
CSF levels of anti-Aβ autoantibodies were inversely correlated with the extent and severity of VOI atrophy, and the ratio of VOI/grey matter atrophy in patients with AD, but not in MCI or non-AD patients. Serum levels of anti-Aβ autoantibodies were not associated with these parameters in any of the patient groups.
These results indicate that CSF levels of naturally occurring anti-Aβ autoantibodies are inversely associated with the degree of the VOI atrophy in patients with AD. Although the mechanism is unclear, CSF levels of naturally occurring anti-Aβ autoantibodies may be implicated in the progression of atrophy of the whole hippocampus, entorhinal cortex and amygdala, in AD.
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterised by motor neuron degeneration in the primary motor cortex, brainstem and spinal cord. In two studies, >20 genes were associated with ALS and a number of patients carried potentially pathogenic variants in multiple ALS genes.
From 2009 to 2014, 254 Chinese patients diagnosed as having probable or definite ALS according to El Escorial criteria,
Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.
(1) To compare time to first relapse and disability progression among 'DMT stoppers' and propensity-score matched 'DMT stayers' in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.
Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.
Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.
Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.
There is no robust evidence that screening patients with acute stroke for dysphagia reduces the risk of stroke-associated pneumonia (SAP), or of how quickly it should be done after admission. We aimed to identify if delays in bedside dysphagia screening and comprehensive dysphagia assessments by a speech and language therapist (SALT) were associated with patients' risk of SAP.
Nationwide, registry-based, prospective cohort study of patients admitted with acute stroke in England and Wales. Multilevel multivariable logistic regression models were fitted, adjusting for patient variables and stroke severity. The exposures were time from (1) admission to bedside dysphagia screen, and (2) admission to comprehensive dysphagia assessment.
Of 63 650 patients admitted with acute stroke, 55 838 (88%) had a dysphagia screen, and 24 542 (39%) a comprehensive dysphagia assessment. Patients with the longest delays in dysphagia screening (4th quartile adjusted OR 1.14, 1.03 to 1.24) and SALT dysphagia assessment (4th quartile adjusted OR 2.01, 1.76 to 2.30) had a higher risk of SAP. The risk of SAP increased in a dose-response manner with delays in SALT dysphagia assessment, with an absolute increase of pneumonia incidence of 1% per day of delay.
Delays in screening for and assessing dysphagia after stroke, are associated with higher risk of SAP. Since SAP is one of the main causes of mortality after acute stroke, early dysphagia assessment may contribute to preventing deaths from acute stroke and could be implemented even in settings without access to high-technology specialist stroke care.
To evaluate the frequency of cerebral amyloid in early Parkinson's disease (ePD) and provide a multimodal assessment of the influence of cerebral amyloid on disease phenotype.
We performed a multicentre cohort study of the Parkinson's Progression Markers Initiative (PPMI), including 369 drug-naïve patients with ePD and 174 healthy controls (HC). Cerebrospinal fluid (CSF) amyloid-β levels were transformed using the linear regression procedure. A cut-off of >198 pg/mL was used to define amyloid-negative (PD–) and amyloid-positive (PD+) subgroups. Grey matter (GM) density and hippocampal volume from the MRI was measured using Advanced Normalisation Tools (ANTs). We compared demographic, genetic, CSF, behavioural, functional and imaging modalities across ePD– and ePD+ groups.
We observed that 16.5% of ePD have CSF evidence of amyloidosis. PD+ was significantly older than PD–, had a higher frequency of APOE e4 alleles and all CSF measures (total-tau, phosphorylated-tau and α-synuclein) were reduced. PD+ had reduced cognitive performance relative to PD– on Symbol–Digit Matching, Verbal Category Fluency and Delayed Recall tests. Imaging analysis in a subset of individuals (PD+ =43; PD– =241) revealed overlapping GM atrophy relative to HC in medial temporal, frontal and brainstem structures. Direct comparisons revealed PD+ GM reductions predominantly located in the frontal cortex while PD– had GM reductions in subcortical structures. These observations remain when controlling for age and APOE e4 allele status.
Cerebral amyloid in ePD yields a unique phenotype across all measured modalities that is consistent with a synergistic interaction between α-synuclein and amyloid pathology. Amyloid status should be considered when screening these individuals for trials involving disease-modifying agents.
Tweets from 2010–2015 that contained the words 'MS relapse' or 'multiple sclerosis relapse' were identified using the advanced search tool on Twitter. Retweets were excluded. The...]]>
Neuropsychiatric symptoms (NPS) are commonly found in patients with cerebral small vessel disease such as white matter hyperintensities and lacunar infarcts. However, the association between cerebral microbleeds (CMBs) and NPS has not been examined. Hence the present study sought to investigate the relation between CMBs and NPS in an elderly population.
This is a cross-sectional study of elderly Asians living in the community, who were assessed on a comprehensive neuropsychological battery and underwent clinical examinations as well as brain MRI scans. The 12-item neuropsychiatric inventory (NPI) was administered to a reliable informant. Total scores for individual symptoms and for NPI global performance were calculated and compared across three groups: no CMB, presence of 1 CMB and presence of multiple CMBs, controlling for demographics, vascular risk factors and other MRI markers.
A total of 802 participants were included in the analysis. Participants with multiple CMBs had higher NPI total score compared to those with no CMB (1.06 vs 2.66, p=0.03). On individual symptom scores, higher score on depression (0.16 vs 0.53, p=0.02) and disinhibition (0.01 vs 0.14, p=0.04) was found in those elderly with multiple CMBs, independent of demographic and vascular risk factors, history of stroke, and other small vessel and large vessel disease markers.
The presence of multiple CMBs is associated with high global neuropsychiatric disorder burden, in particular symptoms of depression and disinhibition. Future studies are recommended to investigate the importance of CMBs in the pathogenesis and longitudinal progression of neuropsychiatric disorders in the general elderly population.
Since then, dozens of clinical studies have shown that cognitive symptoms are frequent in so-called motor disorders and vice versa.
Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population.
To establish an updated natural history of ALSSOD1.
Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.
Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis.
Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02).
SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.
Existing literature suggests that the presence or absence of apraxia and associated parietal deficits may be clinically relevant in differential diagnosis of dementia syndromes.
This study investigated the profile of these features in Alzheimer's disease (AD) and frontotemporal dementia (FTD) spectrum disorders, at first presentation.
Retrospective case note analysis was undertaken in 111 patients who presented to the Oxford Cognitive Disorders Clinic, Oxford, UK, including 29 amnestic AD, 12 posterior cortical atrophy (PCA), 12 logopenic primary progressive aphasia (lvPPA), 20 behavioural variant FTD (bvFTD), 7 non-fluent variant PPA (nfvPPA), 6 semantic variant PPA (svPPA) and 25 patients with subjective cognitive impairment (SCI). The clinical features of interest were: limb apraxia, apraxia of speech (AOS), and left parietal symptoms of dyslexia, dysgraphia, and dyscalculia.
The prevalence of limb apraxia was highest in PCA, amnestic AD, lvPPA and nfvPPA. AOS was only observed in nfvPPA. Associated parietal features were more prevalent in AD spectrum than FTD spectrum disorders. Group comparisons between key differential diagnostic challenges showed that lvPPA and nfvPPA could be significantly differentiated on the presence of left parietal features and AOS, and amnestic AD could be differentiated from bvFTD, svPPA and SCI by limb apraxia. Regression analysis showed that limb apraxia could successfully differentiate between AD and FTLD spectrum disorders with 83% accuracy.
Disease-specific profiles of limb apraxia and associated deficits can be observed. FTD and AD spectrum disorders can be difficult to differentiate due to overlapping cognitive symptoms, and measures of apraxia, in particular, appear to be a promising discriminator.
Frontotemporal dementia (FTD) is a devastating neurodegenerative disorder for which readily available biomarkers are needed to monitor disease progression and response to future therapies. Neurofilament light chain (NfL), a cytoskeletal protein, is elevated in the cerebrospinal fluid (CSF) of patients with FTD, correlating with disease severity.
CSF and serum samples of a consecutive series of 41 FTD, 25 ALS and 46 healthy control subjects were collected from 2009 until 2014 (see online supplement 1: Methodological and statistical details, see online supplement 2: Subject characteristics). Only participants with normal CSF white cell counts (cell count <5/µL) and...]]>
Antithrombotic agents increase risks of intracerebral haemorrhage (ICH) and associated adverse outcomes. We determined differential effects of early blood pressure (BP) lowering in patients with/without antithrombotic-associated ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trials (INTERACT1 and 2).
Post hoc pooled analyses of the INTERACT studies—international, multicentre, prospective, open, blinded end point trials of patients with ICH (<6 h) and elevated systolic BP (SBP 150–180 mm Hg) randomly assigned to intensive (target SBP <140 mm Hg) or guideline-based (SBP <180 mm Hg) BP management. Associations of antithrombotic use and (1) death or dependency (modified Rankin scale scores 3–6) were analysed using logistic regression, and (2) of increased haematoma+intraventricular haemorrhage volume (IVH) with/without intraventricular haemorrhage (IVH) over 24 h were estimated in analyses of covariance.
In all, 3184 patients were included in these analyses. Antithrombotic-associated ICH (364 patients, 11%) was not associated with a significantly increased risk of death or dependency (OR 1.38, 95% CI 0.93 to 2.04). There was no heterogeneity in the BP-lowering treatment effect on death or dependency. Among 1309 patients who underwent follow-up CT after 24 h, absolute increase in haematoma±IVH volume was larger (5.2/5.0 mL) in those with compared to those without prior antithrombotics (2.2/0.9 mL; p=0.022/0.031). Intensive BP lowering reduced haematoma±IVH growth by 4.7/7.1 mL in patients on antithrombotics versus 1.3/1.4 mL in those without, although these differences did not reach statistical significance (p homogeneity=0.104/0.059).
In patients with ICH, prior antithrombotic therapy is associated with greater haematoma growth, which may be reduced by early intensive BP-lowering treatment.
Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use.
A randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18–65 years, with migraine with or without aura, experiencing 2–8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups.
Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users.
Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.
Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).
Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).
Results of tests on 92 controls identified 12assays as highly specific (0–1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5–100%) of all 21 assays. The specificities (85.8–100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples.
The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.
The approval of 9--tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.
We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0–10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months.
A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3–2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%).
Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.
Amyotrophic lateral sclerosis (ALS) is characterised by a loss of motor neurons, leading to paralysis. Several autosomal dominant genes were implicated in ALS pathogenesis, such as SOD1, with over 180 reported mutations (http://alsod.iop.kcl.ac.uk/), including a p.T137A substitution.
Risk of ALS may be modulated by environmental factors, sex and ageing, which could be linked to epigenetic events (eg, DNA methylation). Monozygotic (MZ) twins provide the best opportunity to investigate environmental/epigenetic factors in disease development.
Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy characterised by length-dependent degeneration of the motor and sensory nerve fibres with consequent distal muscle weakness, atrophy and mild sensory loss, primarily in lower limbs. The historic prevalence of CMT in the general population is 1 in 2500 individuals,
In their JNNP paper, Rodriguez Cruz et al
Congenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission.
Review of case notes of patients with mutations in GMPPB to identify the associated clinical, neurophysiological, pathological and laboratory features. In addition, serum creatine kinase (CK) levels within the Oxford CMS cohort were retrospectively analysed to assess its usefulness in the differential diagnosis of this new entity.
All patients had prominent limb-girdle weakness with minimal or absent craniobulbar manifestations. Presentation was delayed beyond infancy with proximal muscle weakness and most patients recall poor performance in sports during childhood. Neurophysiology showed abnormal neuromuscular transmission only in the affected muscles and myopathic changes. Muscle biopsy showed dystrophic features and reduced α-dystroglycan glycosylation. In addition, myopathic changes were present on muscle MRI. CK was significantly increased in serum compared to other CMS subtypes. Patients were responsive to pyridostigimine alone or combined with 3,4-diaminopyridine and/or salbutamol.
Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised CK levels and variable mild cognitive delay. This syndrome underlines that CMS can occur in the absence of classic myasthenic manifestations such as ptosis and ophthalmoplegia or facial weakness, and links myasthenic disorders with dystroglycanopathies. This report should facilitate the recognition of this disorder, which is likely to be underdiagnosed and can benefit from symptomatic treatment.
To elucidate the common and distinct clinical features of immune-mediated necrotising myopathy (IMNM), also known as necrotising autoimmune myopathy associated with autoantibodies against signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR).
We examined a cohort of 460 patients with idiopathic inflammatory myopathies (IIMs) through a muscle biopsy-oriented registration study in Japan. Study entry was strictly determined by the comprehensive histological assessment to exclude other neuromuscular disorders. Anti-SRP and anti-HMGCR antibodies were detected by RNA immunoprecipitation and ELISA, respectively.
Of 460 patients with IIM, we diagnosed 73 (16%) as having inclusion body myositis (IBM). Of 387 patients with IIMs other than IBM, the frequencies of anti-SRP and anti-HMGCR antibodies were 18% and 12%, respectively. One patient had both autoantibodies. Severe limb muscle weakness, neck weakness, dysphagia, respiratory insufficiency and muscle atrophy were more frequently observed in patients with anti-SRP antibodies than in those with anti-HMGCR antibodies. Serum creatine levels were markedly higher in the patients with autoantibodies than in those without. Histology was characterised by necrosis and regeneration of muscle fibres and was consistent with IMNM except in 1 HMGCR-positive IBM patient. Most patients were initially treated with corticosteroids; however, additional immunosuppressive drugs were required, especially in the patients with anti-SRP antibodies. Rates of unsatisfactory neurological outcome were similar in the 2 autoantibody groups.
Anti-SRP antibodies are associated with severe neurological symptoms, more so than are anti-HMGCR antibodies. Although these autoantibodies are independent serological markers associated with IMNM, patients bearing either share common characteristics.
The phrase 'Please do not confuse your Google search for my medical degree' printed on a mug has been making the rounds on multiple social media forums and internet sites in recent times. This reflects the emerging use of the World Wide Web by patients to obtain information (and misinformation) and how the internet impacts the practising of...]]>
The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium.
The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10-05 or p<10–04 in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls.
The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort.
We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution.
Non-invasive ventilation (NIV) is part of standard care in amyotrophic lateral sclerosis (ALS). Intolerance or unavailability of NIV, as well as the quality of correction of nocturnal hypoventilation, has a direct impact on prognosis.
We describe the importance of NIV failure due to upper airway obstructive events, the clinical characteristics, as well as their impact on the prognosis of ALS.
Retrospective analysis of the data of 190 patients with ALS and NIV in a single centre for the period 2011–2014. 179 patients tolerating NIV for more than 4 h per night without leaks were analysed.
Among the 179 patients, after correction of leaks, 73 remained inadequately ventilated at night (defined as more than 5% of the night spent at <90% of SpO2), as a result of obstructive events in 67% of cases (n=48). Patients who remained inadequately ventilated after optimal adjustment of ventilator settings presented with shorter survival than adequately ventilated patients. Unexpectedly, patients with upper airway obstructive events without nocturnal desaturation and in whom no adjustment of treatment was therefore performed also presented with shorter survival. On initiation of NIV, no difference was demonstrated between patients with and without upper airway obstructive events. In all patients, upper airway obstruction was concomitant with reduction of ventilatory drive.
This study shows that upper airway obstruction during NIV occurs in patients with ALS and is associated with poorer prognosis. Such events should be identified as they can be corrected by adjusting ventilator settings.
People with multiple sclerosis (MS) frequently use search engines, such as Google, to look for terms related to their disease, and its possible causes and symptoms.
Mutations in the HSJ1 (Heat-Shock Protein J1) gene, also called DNAJB2 (DnaJ (Hsp40) homologue, subfamily B, member 2), have been recently described as a cause of hereditary neuropathies. The HSJ1 c.352+1G>A mutation in homozygote state has been reported as the causative mutation in a single family with autosomal recessive distal hereditary motor neuropathy (dHMN).
We identified the HSJ1 c.352+1G>A mutation in 10 patients who underwent long-lasting follow-up. We describe their phenotype and clinical evolution.
Ten patients from five different Spanish families had been diagnosed with dHMN or CMT2 at two tertiary referral centres in Spain between 1976 and 2014. They all underwent neurological examination and electrophysiological studies using standard techniques.
The past few decades have seen the development of clinical and pathological diagnostic criteria for behavioural variant-frontotemporal dementia (bvFTD).
A 62-year-old retired man was referred to the memory clinic in 1992 with a 4-year history of insidious behavioural changes. Problems were first apparent when he became withdrawn and agitated following a number of minor...]]>
Impulse control disorders (ICD) are commonly associated with dopamine replacement therapy (DRT) in patients with Parkinson's disease (PD). Our aims were to estimate ICD heritability and to predict ICD by a candidate genetic multivariable panel in patients with PD.
Data from de novo patients with PD, drug-naïve and free of ICD behaviour at baseline, were obtained from the Parkinson's Progression Markers Initiative cohort. Incident ICD behaviour was defined as positive score on the Questionnaire for Impulsive-Compulsive Disorders in PD. ICD heritability was estimated by restricted maximum likelihood analysis on whole exome sequencing data. 13 candidate variants were selected from the DRD2, DRD3, DAT1, COMT, DDC, GRIN2B, ADRA2C, SERT, TPH2, HTR2A, OPRK1 and OPRM1 genes. ICD prediction was evaluated by the area under the curve (AUC) of receiver operating characteristic (ROC) curves.
Among 276 patients with PD included in the analysis, 86% started DRT, 40% were on dopamine agonists (DA), 19% reported incident ICD behaviour during follow-up. We found heritability of this symptom to be 57%. Adding genotypes from the 13 candidate variants significantly increased ICD predictability (AUC=76%, 95% CI (70% to 83%)) compared to prediction based on clinical variables only (AUC=65%, 95% CI (58% to 73%), p=0.002). The clinical-genetic prediction model reached highest accuracy in patients initiating DA therapy (AUC=87%, 95% CI (80% to 93%)). OPRK1, HTR2A and DDC genotypes were the strongest genetic predictive factors.
Our results show that adding a candidate genetic panel increases ICD predictability, suggesting potential for developing clinical-genetic models to identify patients with PD at increased risk of ICD development and guide DRT management.
Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy. Unfortunately, the clinical outcomes of TLE cannot be determined based only on current diagnostic modalities. A better understanding of white matter (WM) connectivity changes in TLE may aid the identification of network abnormalities associated with TLE and the phenotypic characterisation of the disease.
We implemented a novel approach for characterising microstructural changes along WM pathways using diffusional kurtosis imaging (DKI). Along-the-tract measures were compared for 32 subjects with left TLE and 36 age-matched and gender-matched controls along the left and right fimbria-fornix (FF), parahippocampal WM bundle (PWMB), arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF) and cingulum bundle (CB). Limbic pathways were investigated in relation to seizure burden and control with antiepileptic drugs.
By evaluating measures along each tract, it was possible to identify abnormalities localised to specific tract subregions. Compared with healthy controls, subjects with TLE demonstrated pathological changes in circumscribed regions of the FF, PWMB, UF, AF and ILF. Several of these abnormalities were detected only by kurtosis-based and not by diffusivity-based measures. Structural WM changes correlated with seizure burden in the bilateral PWMB and cingulum.
DKI improves the characterisation of network abnormalities associated with TLE by revealing connectivity abnormalities that are not disclosed by other modalities. Since TLE is a neuronal network disorder, DKI may be well suited to fully assess structural network abnormalities related to epilepsy and thus serve as a tool for phenotypic characterisation of epilepsy.
Screening for cognitive deficits is essential in neurodegenerative disease. Screening tests, such as the Montreal Cognitive Assessment (MoCA), are easily administered, correlate with neuropsychological performance and demonstrate diagnostic utility. Yet, administration time is too long for many clinical settings.
Item response theory and computerised adaptive testing simulation were employed to establish an abbreviated MoCA in 1850 well-characterised community-dwelling individuals with and without neurodegenerative disease.
8 MoCA items with high item discrimination and appropriate difficulty were identified for use in a short form (s-MoCA). The s-MoCA was highly correlated with the original MoCA, showed robust diagnostic classification and cross-validation procedures substantiated these items.
Early detection of cognitive impairment is an important clinical and public health concern, but administration of screening measures is limited by time constraints in demanding clinical settings. Here, we provide as-MoCA that is valid across neurological disorders and can be administered in approximately 5 min.
Dementia with Lewy bodies (DLB) is characterised by neuroleptic hypersensitivity. It is unclear, however, whether the neuroleptic hypersensitivity implies an increased incidence of neuroleptic malignant syndrome (NMS) or of akinetic crisis (AC), which are expressions of the same possibly lethal clinical event, and whether AC in DLB can appear independently of neuroleptic treatment. In our prospective study, we assessed the incidence of AC in a cohort of DLB as compared with that in patients with Parkinson disease (PD).
In total, 614 patients with PD and 236 DLB were recruited and followed during 2005–2013. AC was diagnosed as sudden akinetic state unresponsive to dopaminergic rescue drugs, dysphagia and serological alterations without recovery for 48 h or more requiring hospital admission. Exposure to neuroleptics was specifically evaluated, because of the high implicit risk in DLB.
24 patients with PD (3.9%) and 16 patients with DLB (6.8%) developed AC. 77 (32.6%) DLB and 32 (5.2%) PD were exposed to typical neuroleptics, but only 8 DLB and 3 PD presented with AC. Disease duration before AC was lower in DLB than in PD group (p<0.01). Outcome was fatal in 8 patients with (50%) DLB and 3 (12.5%) PD (p=0.05). When age and use of neuroleptics were adjusted for into a Cox proportional hazards model predicting time to AC, the HR of patients with DLB was 13.0 (95% CI 4.23 to 39.9; p<0.001).
AC in DLB can appear independently of neuroleptic treatment, occurs earlier and is more frequently fatal than in PD.
Subjective excessive daytime sleepiness (SEDS) is a common sequela following traumatic brain injury (TBI) and occupies 14–57% of patients with TBI.
TBI is classified as mild, moderate and severe according to the severity, and mild TBI has been reported in 75–85% of cases of TBI. Patients with...]]>
Friedreich ataxia (FRDA) is an autosomal recessive disorder defined by progressive motor incoordination. FRDA results from reduced expression of the protein, frataxin, which is involved in cellular iron homeostasis and metabolism, antioxidant protection, and iron-sulfur cluster biogenesis. Disruption of one or more of these processes putatively underpins the pathophysiology of FRDA, which manifests in cell death preferentially targeted to tissues with high rates of frataxin transcription.
In the brain, accumulation or redistribution of iron within, and atrophy of, the cerebellar dentate nuclei have been reported.
Non-invasive positive-pressure ventilation (NPPV) is an established, effective, long-term treatment for patients with amyotrophic lateral sclerosis (ALS), but the correct indicators for the establishment of NPPV have not been defined.
In this retrospective study, records (spirometry, nocturnal polygraphy, nocturnal blood gases) of 131 patients with ALS were reviewed in order to evaluate the role of polygraphy for prediction of respiratory failure in ALS.
The patient group reporting with versus without dyspnoea had significantly lower values on the revised ALS-Functional Rating Scale (ALSFRS-R), vital capacity (VC), forced VC (FVC), arterial oxygen saturation and arterial oxygen tension readings, including a higher apnoea–hypopnoea index. 23 patients, who did not report about dyspnoea, had an FVC of <75%. Nocturnal hypoventilation was observed in 67% of the patients with ALS independent of their ALSFRS-R. The patient group with nocturnal hypoventilation was characterised by a significantly lower VC, FVC and maximal static inspiratory pressure compared with the group without nocturnal hypoventilation. However, also in the absence of nocturnal hypoventilation, 8 patients had a VC <50% as predicted.
Our study shows that in patients not reporting dyspnoea and having an FVC of >75%, nocturnal hypoventilation was observed in nearly every second patient. Therefore, for the question of whether NPPV should be initiated, polygraphy does not provide useful additional information if the FVC is already <75% as predicted. However, in patients with more or less normal lung function parameters or where lung spirometry cannot perform adequately (eg, bulbar ALS), it can provide sufficient evidence for the need of NPPV.
Development of new therapies for Alzheimer's disease (AD) is increasingly focused on more mildly affected populations, and requires new assessment and outcome strategies. Patients in early stages of AD have mild cognitive decline and no, or limited, functional impairment. To respond to these assessment challenges, we developed a measurement approach based on established scale items that exhibited change in previous amnestic Mild Cognitive Impairment (aMCI) trials.
Partial least squares regression with a longitudinal clinical decline model identified items from commonly used clinical scales with the highest combined sensitivity to change over time in aMCI and weighted these items according to their relative contribution to detecting clinical progression in patients' early stages of AD. The resultant AD Composite Score (ADCOMS) was assessed for its ability to detect treatment effect in aMCI/prodromal AD (pAD) clinical trial populations.
ADCOMS consists of 4 Alzheimer's Disease Assessment Scale–cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating—Sum of Boxes items. ADCOMS demonstrated improved sensitivity to clinical decline over individual scales in pAD, aMCI and in mild AD dementia. ADCOMS also detected treatment effects associated with the use of cholinesterase inhibitors in these populations. Improved sensitivity predicts smaller sample size requirements when ADCOMS is used in early AD trials.
ADCOMS is proposed as new standard outcome for pAD and mild AD dementia trials, and is progressing in a CAMD-sponsored qualification process for use in registration trials of pAD.
Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated.
We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case–control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH.
A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones.
Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions.
Natalizumab (NTZ), a monoclonal antibody to human α4β1/β7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days.
A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks.
17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort.
Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.
The pathophysiology underlying different types of dystonia is not yet understood. We report microelectrode data from the globus pallidus interna (GPi) and globus pallidus externa (GPe) in children undergoing deep brain stimulation (DBS) for dystonia and investigate whether GPi and GPe firing rates differ between dystonia types.
Single pass microelectrode data were obtained to guide electrode position in 44 children (3.3–18.1 years, median 10.7) with the following dystonia types: 14 primary, 22 secondary Static and 8 progressive secondary to neuronal brain iron accumulation (NBIA). Preoperative stereotactic MRI determined coordinates for the GPi target. Digitised spike trains were analysed offline, blind to clinical data. Electrode placement was confirmed by a postoperative stereotactic CT scan.
We identified 263 GPi and 87 GPe cells. Both GPi and GPe firing frequencies differed significantly with dystonia aetiology. The median GPi firing frequency was higher in the primary group than in the secondary static group (13.5 Hz vs 9.6 Hz; p=0.002) and higher in the NBIA group than in either the primary (25 Hz vs 13.5 Hz; p=0.006) or the secondary static group (25 Hz vs 9.6 Hz; p=0.00004). The median GPe firing frequency was higher in the NBIA group than in the secondary static group (15.9 Hz vs 7 Hz; p=0.013). The NBIA group also showed a higher proportion of regularly firing GPi cells compared with the other groups (p<0.001). A higher proportion of regular GPi cells was also seen in patients with fixed/tonic dystonia compared with a phasic/dynamic dystonia phenotype (p<0.001). The GPi firing frequency showed a positive correlation with 1-year outcome from DBS measured by improvement in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m) score (p=0.030). This association was stronger for the non-progressive patients (p=0.006).
Pallidal firing rates and patterns differ significantly with dystonia aetiology and phenotype. Identification of specific firing patterns may help determine targets and patient-specific protocols for neuromodulation therapy.
National Institute of Health Research, Guy's and St. Thomas' Charity, Dystonia Society UK, Action Medical Research, German National Academic Foundation.
Chromosome 1p/19q deletion is an established prognostic and predictive marker in the WHO grade III oligodendroglial tumours (OT). To estimate the genetic status preoperatively, the authors investigated the correlation between the uptake of 11C-methionine in positron emission tomography (PET) and the 1p/19q status in grades II and III OT.
We retrospectively reviewed 144 patients with gliomas who received 11C-methionine PET. 66 cases with grades II–III oligodendrogliomas or oligoastrocytomas underwent fluorescence in situ hybridisation to determine the 1p/19q status. The tissue uptake of 11C-methionine was expressed as the ratio of the maximum standardised uptake value (SUVmax) in tumour areas to the mean SUV (SUVmean) in the contralateral normal brain (tumour-to-normal tissue (T/N) ratio).
The T/N ratio in 11C-methionine PET was significantly higher in grade III OT than in grade II tumours. The mean T/N ratio of the grade II tumours without 1p/19q deletion was significantly higher than that of the grade II tumours with 1p/19q deletion (mean 2.67 vs 1.94, respectively; p=0.0457). In grade III tumours, the mean T/N ratio of the tumours without 1p/19q deletion was also significantly higher than that of the tumours with 1p/19q deletion (mean 4.83 vs 3.49, respectively; p=0.0261). The rate of IDH1 mutation was lower and the rate of contrast enhancement on MRIs was higher in the 1p/19q non-deleted OT than those with 1p/19q deletion, which may contribute to the high T/N ratio.
Among suspected OT, 11C-methionine PET may help us preoperatively discriminate tumours with and without 1p/19q deletion.
Recently, while writing our respective reviews on what has been called exploding head syndrome (EHS),
Case: A 60-year-old man reported of a sudden sensation of an explosion in the head with a bright flash of light just as he fell asleep. He was very clear that the sensation was not painful, but rather troublesome, as it was unexplained and frightening.
As described in the case, such patients have a sudden feeling that their head is exploding or of a...]]>
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterised by a triad of motor, psychiatric and cognitive deficits with the latter classically attributed to disruption of frontostriatal networks. However, emerging evidence from animal models of HD suggests that some of the early cognitive deficits may have a hippocampal basis. The objective of this study was to link previous rodent findings in this area to clinical practice.
In this study, 94 participants included patients with early HD, premanifest HD and age-matched controls underwent hippocampal-based cognitive assessments. These included a virtual reality version of the Morris water maze, a task involved participants having to swim through a virtual pool to find a submerged platform using a joystick, and the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning task, a test also known to rely on hippocampal integrity.
Patients with early HD showed impaired performance in both the virtual Morris water maze and the CANTAB paired associates learning. Such deficits were also correlated with estimated years to diagnosis in premanifest participants.
This study highlights the merit of using analogous tests in the laboratory and clinic and demonstrates that hippocampal impairments are an early feature of HD in patients as previously shown in rodent models of the disease. As such, they could be used not only to assist in the diagnosis of disease onset, but may also be useful as an outcome measure in future therapeutic trials.
Acute symptomatic seizure (AS) after ischaemic stroke is defined as a seizure occurring ≤7 days of the stroke. There remains a lack of information on the prognosis of AS after ischaemic stroke and how it should be treated.
We prospectively recruited patients after their incidents of ischaemic stroke from a population-based stroke registry. Stroke aetiology was defined according to Trial-of-ORG-10172 in acute-stroke treatment (TOAST). Patients were examined for any transient complete-occlusion with recanalisation (TCOR) and haemorrhagic transformation. The seizure outcomes were (1) acute clustering of seizures ≤7 days, (2) seizure recurrence associated with stroke recurrence beyond the 7-day period and (3) unprovoked seizure (US) >7 days.
104 patients (mean age 65 years/55% female) with AS after ischaemic stroke were identified (mean follow-up 6.17 years). Comparison of the group of patients with AS and those without seizures showed that patients with AS had significantly less large-vessel and small-vessel disease but more cardioembolisms (p<0.05) and a higher proportion of TCOR (p<0.01), multiple territory infarcts (p=0.007) and haemorrhagic transformations (p<0.01). Using Kaplan–Meier statistics, the risk of acute clustering of seizures ≤7 days was 22%, with a statistical trend for TCOR as a predictive factor (p=0.06). The risk of seizure recurrence associated with worsening/recurrence of stroke beyond 7 days was 13.5% at 2 years, 16.4% at 4 years and 18% at 8 years. Presence of >2 cardiovascular risk factors (p<0.05) and status epilepticus (P<0.05) are predictive risk factors on Cox regression model. The risk of US was 19% at 2 years, 25% at 4 years and 28% at 8 years with epileptiform EEG as a predictive factor (p<0.05).
Seizure recurrence following AS after ischaemic stroke may appear as acute clustering. Afterwards, seizures may occur as often with a recurrent stroke as without one within 4.2 years. We recommend the use of antiepileptic agents for up to 4 years if the underlying stroke aetiology cannot be fully treated.
Acquired inflammatory central nervous system (CNS) disorders include multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis and other less prevalent disorders.
Antibodies against aquaporin-4 (AQP4-Ab) suggest the diagnosis of NMOSD and promote severe immune-mediated astrocyte damage. However, some patients who are clinically diagnosed with NMOSD are AQP4-Ab-seronegative despite the use of highly sensitive cell-based assays (CBAs); therefore, other CNS molecules may be implicated as autoimmune targets in such cases.
Recently, we reported the presence of conformational-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG-Ab) in a portion of AQP4-Ab-seronegative NMOSD,
Thus, it is interesting to study how MOG-Ab+ cases pathologically and immunologically differ from AQP4-Ab+ cases and...]]>
Despite the increasing global importance of Parkinson's disease (PD), its exact incidence in the general population is not known. Comparing published studies, incidence rates from 1.5 to 19/100 000 person-years have been reported but such differences cannot simply be attributed to between-population differences in PD risk as no two studies have used the same case ascertainment strategy.
The PICNICS...]]>
To compare two modes of natalizumab cessation interventions: immediate versus tapered down, as measured by serial MRI and the occurrence of relapses during a 12-month period.
Weighing progressive multifocal encephalopathy risk associated with ≥24 months of natalizumab therapy against the benefits of disease control, we initiated a natalizumab discontinuation study.
A phase IV, 12-month, single-blinded randomised (MRI) study. Fifty relapsing patients with multiple sclerosis (MS) who had been on natalizumab therapy ≥24 months and were contemplating natalizumab discontinuation were enrolled. Participants were randomised to either the immediate discontinuation group (IDG) or the tapered group (TG). IDG discontinued natalizumab at once and initiated another disease modifying therapy (DMT) following the last natalizumab infusion, while the TG received two more natalizumab infusions, at 6 and 8 weeks (14 weeks from study entry) before initiating another DMT. Standardised MRI was performed at baseline, 6 and 12 months from the last natalizumab infusion.
A higher rate of relapses in the IDG (n=28) compared to the TG (n=8) over 12 months from the last infusion (p=0.007) was observed, most relapses occurred within 3 months of discontinuation (20 vs 7 relapses, p=0.012). The IDG showed a higher number of new T2 lesions within 6–12 months of discontinuation (p=0.025), a higher mean absolute T2-LV change from 0 to 12 months (1.1 vs 0.1 mL, p=0.024) and a higher number of new T1-hypointense lesions over 0–12 months (p=0.005) as well as from baseline to 6 months (p=0.026) compared to the TG.
Natalizumab discontinuation therapy was associated with development of new disease activity. Our tapered protocol showed benefits, as patients in the TG experienced less relapses and lower accumulation of MRI lesions compared to those in the IDG.
We investigated long-term (to 25 years) seizure prognosis and survival in people with newly diagnosed epilepsy in the community. We explored whether prognosis is different in those with epilepsy (
This is a prospective observational cohort study of people with newly diagnosed seizures. We investigated seizure outcome and survival in people presenting with a single seizure and in those presenting with
695 people (median follow-up 23.6 years) had unprovoked epileptic seizures. For seizure analysis we excluded 38 people with missing data leaving 657 (309 male, and 249 aged <18 years). Seizures recurred in 67%. The 354 people with epilepsy were only slightly more likely to have further seizure recurrence than the 302 people with a single seizure at presentation (HR 1.32, 95% CI 1.09 to 1.59). In 327 people with complete follow-up, 268 (82%, 95% CI 77% to 86%) were in terminal remission; (80%, (95% CI 73% to 85%) in those with epilepsy at presentation). Premature mortality was increased in people with epilepsy (standardised mortality ratio 1.67; 95% CI 1.40 to 1.99) and those with a single seizure at presentation (standardised mortality ratio 2.65; 95% CI 2.23 to 3.15). It is also high in those with early remission.
People with epilepsy and with single seizures at presentation in the community generally have good prognosis for seizure control with prolonged follow-up. The risk of premature mortality is significantly increased in both groups.
Intraventricular extension of intracerebral haemorrhage (ICH) predicts poor outcome, but the significance of delayed intraventricular haemorrhage (dIVH) is less well defined. We determined the prognostic significance of dIVH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trials (INTERACT 1 and 2).
Pooled analyses of the INTERACT CT substudies—international, multicentre, prospective, open, blinded end point, randomised controlled trials of patients with acute spontaneous ICH and elevated systolic blood pressure (SBP)—randomly assigned to intensive (<140 mm Hg) or guideline-based (<180 mm Hg) SBP management. Participants had blinded central analyses of baseline and 24 h CTs, with dIVH defined as new intraventricular haemorrhage (IVH) on the latter scan. Outcomes of death and major disability were defined by modified Rankin Scale scores at 90 days.
There were 349 (27%) of 1310 patients with baseline IVH, and 107 (11%) of 961 initially IVH-free patients who developed dIVH. Significant associations of dIVH were prior warfarin anticoagulation, high (≥15) baseline National Institutes of Health Stroke Scale score, larger (≥15 mL) ICH volume, greater ICH growth and higher achieved SBP over 24 h. Compared with those who were IVH-free, dIVH had greater odds of 90-day death or major disability versus initial IVH (adjusted ORs 2.84 (95% CI 1.52 to 5.28) and 1.87 (1.36 to 2.56), respectively (p trend <0.0001)).
Although linked to factors determining greater ICH growth including poor SBP control, dIVH is independently associated with poor outcome in acute small to moderate-size ICH.
NCT00226096 and NCT00716079.
To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns.
We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs.
We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47–8.34x10–8). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6x10–10–1.1x10–7). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002).
We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.
Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome, typically due to Alzheimer pathology, characterised by impairments in higher-order visual function and other parieto-occipital skills.
Five patients fulfilling clinical diagnostic criteria for PCA,
Parkinson's disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M–F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies.
We used French national drug claims databases to identify PD cases using a validated algorithm. We computed M–F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M–F ratios.
On the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M–F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M–F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M–F ratio <1.2, p>0.20), and over 1.6 (p<0.001) times higher in men than women above 80 years (p trend <0.001). A meta-analysis of 22 incidence studies (14 126 cases, 46% women) confirmed that M– F ratios increased with age (0.26 per 10 years, p trend=0.005).
Age-increasing M–F ratios suggest that PD aetiology changes with age. Sex-related risk/protective factors may play a different role across the continuum of age at onset. This finding may inform aetiological PD research.
Resting-state functional MRI (rs-fMRI) of the brain has been successfully used to identify altered functional connectivity in the motor network in multiple sclerosis (MS).
To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms.
Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays.
45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016).
67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.
Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterised by atrophy of the frontal and temporal lobes and progressive behavioural and cognitive impairment. Some behavioural symptoms such as craving for food, alcohol or drugs, and hypersexuality are suggestive of abnormal reward processing. The reward circuit is formed by a number of different structures including the orbitofrontal cortex, ventral striatum (in particular the nucleus accumbens), ventral pallidum, anterior cingulate cortex, thalamus, hypothalamus, midbrain and habenula.
To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA).
73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology.
Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed.
Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients.
To describe the incidence of, and clinical and neurobiological risk factors for, new-onset impulse control disorder (ICD) symptoms and related behaviours in early Parkinson disease (PD).
The Parkinson's Progression Markers Initiative is an international, multicenter, prospective study of de novo patients with PD untreated at baseline and assessed annually, including serial dopamine transporter imaging (DAT-SPECT) and ICD assessment (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease short form, QUIP). Participants were included if they screened negative on the QUIP at baseline. Kaplan-Meier curves and generalised estimating equations examined frequency and predictors of incident ICD symptoms.
Participants were seen at baseline (n=320), year 1 (n=284), year 2 (n=217) and year 3 (n=96). Estimated cumulative incident rates of ICD symptoms and related behaviours were 8% (year 1), 18% (year 2) and 25% (year 3) and increased each year in those on dopamine replacement therapy (DRT) and decreased in those not on DRT. In participants on DRT, risk factors for incident ICD symptoms were younger age (OR=0.97, p=0.05), a greater decrease in right caudate (OR=4.03, p=0.01) and mean striatal (OR=6.90, p=0.04) DAT availability over the first year, and lower right putamen (OR=0.06, p=0.01) and mean total striatal (OR=0.25, p=0.04) DAT availability at any post-baseline visit.
The rate of incident ICD symptoms increases with time and initiation of DRT in early PD. In this preliminary study, a greater decrease or lower DAT binding over time increases risk of incident ICD symptoms, conferring additional risk to those taking DRT.
Since 1993, more than 20 genes have been found to be implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS).
The study enrolled 20 familial ALS (FALS) index cases, 324 patients with sporadic ALS (SALS) and 355 control subjects from Peking Union Medical College Hospital, between July 2011 and June 2012. The clinical characteristics of the patients with ALS...]]>
Prevalence of atrial fibrillation (AF) is increasing, due partly to the ageing population. The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) Trial, published in 2007, provided strong evidence of the effectiveness of warfarin at age≥80 years, but the impact on incidence of AF-related stroke and peripheral embolic vascular events is uncertain.
We studied age-specific incidence and outcome of all AF-related incident strokes and systemic emboli from 2002 to 2012 in the Oxford Vascular Study.
Of 3096 acute cerebral or peripheral vascular events, 748 (24.2%) were AF-related. Of the 597 disabling/fatal incident ischaemic strokes, 369 occurred at age ≥80 years, of which 124 (33.6%) were in non-anticoagulated patients with known prior AF. There was no reduction in incident AF-related events after 2007 at all ages (n=231 vs 211; adjusted RR=1.11, 0.91 to 1.36, p=0.29) or at age ≥80 (137 vs 135, RR=1.15, 0.94 to 1.40, p=0.17). Scope for improved prevention at older ages was considerable. Among 208 patients with incident AF-related events at age ≥80 and known prior AF, only 19 (9.1%) were anticoagulated. Of the 189 patients not anticoagulated, 166 (87.8%) had no major disability prior to the event and 167 (88·4%) had a high embolism risk score, of whom 139 (83.2%) were also at low risk of complications. Yet, 125/167 (74.9%) were dead or institutionalised after the event. Potentially preventable embolic events outnumbered warfarin-related intracerebral haemorrhages by about 15-fold (280 vs 19), rising to 50-fold (189 vs 4) at age ≥80 years.
We found no reduction in incidence of AF-related vascular events since publication of the BAFTA trial. A third of all disabling/fatal strokes occur in non-anticoagulated patients with known prior AF.
Executive dysfunctions are a key clinical feature of behavioural-variant frontotemporal dementia (bvFTD). Such deficits are also found in Alzheimer's disease (AD), making the differentiation between these two diseases difficult at times, particularly in the absence of extensive cognitive assessments. To address this issue, we developed the FRONTIER Executive Screen (FES), which combines three abbreviated measures of verbal fluency, inhibitory control and working memory.
We administered the FES to 28 patients with dementia (14 bvFTD, 14 AD) matched for disease severity and 33 age-matched and education-matched healthy controls. We also administered traditional tests of executive function to establish the concurrent validity of the FES.
Both patient groups obtained lower FES scores (total and subscores) compared to controls. Correct classification into patient or control groups was reached in over 90% of study participants based on the FES total score. Only two patients with bvFTD obtained FES scores within 2 SDs of the control group. Receiver operating characteristic analyses on the patient groups showed that a cut-off FES total score of 7/15 achieved 71% sensitivity and 73% specificity for a diagnosis of bvFTD. In addition, the FES showed high correlations with traditional measures of executive function.
The FES is a brief (5–10 min) bedside screening measure which is simple to administer and score, and demonstrates good discriminative validity to differentiate bvFTD from AD. It is a useful addendum to general cognitive screening measures and can help with the differential diagnosis of dementia.
To determine the effect of intravenous immunoglobulin (IVIG) on brain atrophy and cognitive function in mild cognitive impairment (MCI) due to Alzheimer's disease (AD).
50 participant 50–84 years of age with amnestic MCI were administered 0.4 g/kg 10% IVIG or 0.9% saline every 2 weeks for a total of 5 infusions (2 g/kg total dose) in a randomised double-blinded design. MRI brain was completed at baseline, 12 and 24 months. Cognitive testing was completed at baseline and every 4 months. Participants were stratified into early and late (LMCI) MCI stages. Average annualised per cent change in ventricular volume was computed as a measure of brain atrophy.
There was significantly less brain atrophy (p=0.037, adjusted for MCI status) in the IVIG group (5.87%) when compared with placebo (8.14%) at 12 months; at 24 months, the reduction in brain atrophy no longer reached statistical significance. The LMCI participants who received IVIG performed better on Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog; p=0.011) and Mini-Mental State Examination (MMSE; p=0.004) at 1 year; these differences were not present after 2 years. There was no difference in conversion to AD dementia between the treatment and control groups after 2 years; however, at 1 year, there were fewer conversions from LMCI to AD dementia in the IVIG group (33.3%) when compared with control group (58.3%).
This exploratory study provides limited evidence that a short course of IVIG administered in the MCI stage of AD reduces brain atrophy, prevents cognitive decline in LMCI and delays conversion to AD dementia for at least 1 year; however, this effect of IVIG appears to wane by 2 years.
ClinicalTrials.gov, NCT01300728.
Several studies have suggested an asymmetry in Meyer's loop in individuals, with the left loop anterior to the right. In this study we test the hypothesis that there is an association between Meyer's loop asymmetry (MLA) and language lateralisation.
57 patients with epilepsy were identified with language functional MRI (fMRI) and diffusion MRI acquisition. Language lateralisation indices from fMRI(LI) and optic radiation and arcuate fasciculus probabilistic tractography was performed for each subject. The subjects were divided into left language dominant (LI>0.4) and non-left language groups (LI<0.4) according to their LI.
A negative linear correlation was identified between language lateralisation and MLA, with greater left lateralised language associated with more anteriorly placed left Meyer's loops (R value –0.34, p=0.01). There was a significant difference in mean MLA between the two groups, with the left loop being anterior to the right loop in the LI>0.4 group and posterior to the right loop in the LI<0.4 group (p=0.003). No correlation was found between language lateralisation and arcuate fasciculus volume.
This study suggests an association between the extent of Meyer's loop asymmetry and the lateralisation of language determined by fMRI in patients with epilepsy. Further studies should be carried out to evaluate this association in control subjects and with other measures of language lateralisation.
Anticollapsin response mediator protein 5 antibody (anti-CRMP5 antibody, also known as anti-CV2 antibody) is usually associated with small-cell lung carcinoma (SCLC) or thymoma.
A 72-year-old man presented with a 6-month history of ambulatory disturbance. After the patient noticed sialorrhoea in September 2010, he began to develop a stooped posture, and short-stepped and propulsive gait. In January 2011, he noted gradual onset of dysarthria and constipation. His gait instability became severe, and by April 2011, he was only able to walk with assistance. He reported to our hospital in May...]]>
The early detection of MRI findings suggestive of immune reconstitution inflammatory syndrome (IRIS) in natalizumab-associated progressive multifocal leukoencephalopathy (PML) is of crucial clinical relevance in terms of treatment decision-making and clinical outcome. The aim of this study was to investigate the earliest imaging characteristics of PML-IRIS manifestation in natalizumab-treated patients with multiple sclerosis and describe an imaging pattern that might aid in the early and specific diagnosis.
This was a retrospective study assessing brain MRI of 26 patients with natalizumab-associated PML presenting with lesions suggestive of PML-IRIS during follow-up. MRI findings were evaluated considering the imaging findings such as mass effect, swelling, contrast enhancement, new perivascular T2 lesions and signs suggestive of meningeal inflammation.
Contrast enhancement was the most common imaging sign suggestive of PML-IRIS, seen in 92.3% of the patients (with patchy and/or punctuate pattern in 70.8% and 45.8% respectively), followed by new T2 lesions with a perivascular distribution pattern (34.6%). In those patients with contrast enhancement, the enhancement was present in the lesion periphery in 95.8% of the patients. Contrast-enhancing lesions with a perivascular distribution pattern outside of the PML lesion were observed in 33.3% of the patients. The most common overall pattern was contrast enhancement in the border of the PML lesion with either a patchy or punctuate appearance in 88.5% of all patients.
Contrast enhancement is the most common earliest sign of natalizumab-associated PML-IRIS with a frequent imaging pattern of contrast-enhancing lesions with either a patchy or punctuate appearance in the border of the PML lesion.
Idiopathic REM (rapid eye movement) sleep behaviour disorder (iRBD) has been implicated in cognitive impairments, but there is little evidence about progression of cognitive dysfunction in iRBD.
A retrospective follow-up study with patients with iRBD was performed. Conversion to neurodegenerative disorders was analysed by Kaplan-Meier survival analysis. Neuropsychological test results at baseline were compared between patients with iRBD and healthy controls. 57 patients with iRBD were successfully followed up for changes of cognitive performance over time (follow-up duration 50.84±25.38 months; range 12–108 months). Factors affecting cognitive decline were evaluated with multiple regression analysis and the subgroup analysis for groups with and without conversion was carried out.
Among 84 patients with iRBD, conversion occurred in 18 patients and conversion rates were estimated to be 9%, 18% and 35% at 3, 5 and 6 years from diagnosis of iRBD. Individuals with iRBD showed lower z-scores at baseline than controls in Mini-Mental Status Examination, Trail Making Test A, constructional praxis and Executive Clock Drawing Task (CLOX2). Patients with non-converting iRBD showed significant performance decline in memory (p=0.003, Digit span forward) and a worsening tendency of executive functions (p=0.007, frontal assessment battery; p=0.012, Stroop test) at follow-up tests. Cognitive decline was associated with disease duration or follow-up duration, and lower executive function at baseline increased conversion risk (p=0.031).
Patients with iRBD have cognitive impairments at baseline and progressive cognitive decline over time. Even in idiopathic cases without development of any neurodegenerative disease, degenerative changes in cognition seem to be under way.
We retrospectively examined whether a history of traumatic brain injury (TBI) is associated with an earlier age of symptom onset and diagnosis in a large sample of patients with behavioural variant frontotemporal dementia (bvFTD).
Data on patients with bvFTD (n=678) were obtained from the National Alzheimer's Coordinating Center Uniform Data Set. TBI was categorised based on reported lifetime history of TBI with loss of consciousness (LOC) but no chronic deficits occurring more than 1 year prior to diagnosis of bvFTD. Analysis of covariance (ANCOVA) was used to determine if clinician-estimated age of symptom onset and age at diagnosis of bvFTD differed between those who reported a history of TBI with LOC (TBI+) and those who did not (TBI–).
Controlling for sex, the TBI+ bvFTD group had an age of symptom onset and age of diagnosis that was on average 2.8 and 3.2 years earlier (p<0.01) than the TBI– bvFTD group.
TBI history with LOC occurring more than 1 year prior to diagnosis is associated with an earlier age of symptom onset and diagnosis in patients with bvFTD. TBI may be related to the underlying neurodegenerative processes in bvFTD, but the implications of age at time of injury, severity and repetitive injuries remain unclear.
A MRI T2-weighted three-dimensional (3D)-Fast Recovery Fast Spin Echo (FRFSE) sequence revealed a hyperintensity filling the left internal jugular vein (
The effect of the variability of electrode placement on outcomes after bilateral deep brain stimulation of subthalamic nucleus has not been sufficiently studied, especially with respect to the sequence of hemisphere implantation.
We retrospectively analysed the clinical and radiographic data of all the consecutive patients with Parkinson's disease who underwent surgery at our centre and completed at least 1 year follow-up. The dispersion in electrode location was calculated by the square of deviation from population mean, and the direction of deviation was analysed by comparing the intended and final implantation coordinates. Linear regression analysis was performed to analyse the predictors of postoperative improvement of the motor condition, also controlling for the sequence of implanted hemisphere.
76 patients (mean age 58±7.2 years) were studied. Compared with the first side, the second side electrode tip had significantly higher dispersion as an overall effect (5.6±21.6 vs 2.2±4.9 mm2, p=0.04), or along the X-axis (4.1±15.6 vs 1.4±2.4 mm2, p=0.03) and Z-axis (4.9±11.5 vs 2.9±3.6 mm2, p=0.02); the second side stimulation was also associated with a lower threshold for side effects (contact 0, p<0.001 and contact 3, p=0.004). In the linear regression analysis, the significant predictors of outcome were baseline activities of daily living (p=0.010) and dispersion of electrode on the second side (p=0.005).
We observed a higher dispersion for the electrode on the second implanted side, which also resulted to be a significant predictor of motor outcome at 1 year.
Over 150 mutations in the coding region of SOD1 have been found in patients with ALS worldwide, with variation of the frequency of SOD1 mutations in different populations. However, not all SOD1 mutations are pathogenic and there is a variety of clinical presentations of patients with pathogenic mutations. Furthermore, the different mutations have diverse effects on the structure of the SOD1 protein, and some cause no...]]>
Some patients admitted to acute stroke units are diagnosed as stroke mimics. A minority have a functional neurological disorder ('functional mimics').
To determine the incidence of functional stroke mimics admitted to a hyperacute stroke unit (HASU); to compare their clinical characteristics with medical mimics and stroke cases and obtain information about outcomes.
Patients admitted to the King's College Hospital HASU between 2011 and 2012 were analysed. Data were obtained from the Stroke Improvement National Audit Programme (SINAP) database. Expert consensus diagnosis was used to classify functional mimics. Follow-up information was obtained from a retrospective case series in primary care over the year following discharge.
1165 patients were admitted to the HASU; 904 patients with stroke (77.6%), 163 medical mimics (14%) and 98 functional mimics (8.4%). Functional mimics were significantly more likely to be female (63.3%) versus 49.7% medical mimics and 45.5% stroke, and younger (mean age (SD)) 49.1 (18.8) than medical mimic (63.5 years (16.7)) and stroke cases (71 years (15.5)). Weakness and slurred speech were the commonest presentations of functional mimics and diagnostic MRI was used more often. Clinician recorded visual and speech symptoms and neglect were significantly more frequent in patients with stroke than either mimic group. Of the 68 functional mimics on whom follow-up information was obtained, 40 (59%) were referred to another service most often for a psychologically-based intervention.
Functional stroke mimics are an important subgroup admitted to acute stroke services and have a distinct demographic and clinical profile. Their outcomes are poorly monitored. Services should be developed to better diagnose and manage these patients.
The limitations of the current WHO classification of astrocytomas call for a sustained effort to improve diagnostic and prognostic accuracy. The relationship between tumour growth and clinical outcome suggests that proliferative activity should be examined. The objective of this study was to evaluate the diagnostic and prognostic value of the proliferation markers mitosin and phosphohistone H3 (pHH3) in infiltrative astrocytomas WHO grades II and III and compare the findings with mitotic count and Ki-67/MiB-1 immunostaining.
Fifty-nine and thirty-three infiltrative astrocytomas WHO grades II and III, respectively, were immunostained with the proliferation markers mitosin and pHH3 using standard immunohistochemical procedures. The expression was quantified as a proliferative index (PI) and statistically evaluated with Spearman's rank correlation test, Wilcoxon-Mann-Whitney U test, and univariable and multivariable COX regression survival analyses.
Significant positive correlations were found between these proliferation markers. The number of mitoses, pHH3 mitotic figures (MFs), the Ki-67/MiB-1 PI and the mitosin PI were greater in WHOgrade III anaplastic astrocytomas compared to WHO grade II diffuse astrocytomas, while pHH3 PI only showed a trend. All proliferation markers were associated with poorer prognosis, but mitotic count was not. Ki-67/MiB-1, mitosin and pHH3 MF achieved statistical significance in the univariable analyses of both time to relapse (TTR) and overall survival (OS). Only mitosin remained significant in both multivariable analyses. pHH3 was significant in the multivariable analysis of OS but not of TTR. Clinical factors including age, extent of surgical resection and WHO performance status were also significantly correlated with survival.
In conclusion, mitosin and pHH3 immunostaining have prognostic and diagnostic value in the clinical assessment of patients with infiltrative astrocytomas. The inclusion of proliferation markers in a layered diagnosis should be considered in the upcoming revision of the WHO classification system.


text:
- AirAsia India's aircraft dedicated to 'Kabali'Kapil's on-screen lover Sumona Chakravarti caught smokingSalman Khan possessive for his girlfriend Iulia VanturPorsche launched 911 range in IndiaDebina Bonnerjee to join 'The Kapil Sharma Show'Painted stages of a woman's lifeAfter Sushant's stardom, Ankita Lokhande to make Bollywood debutDivyanka Tripathi confess about her weddingB'day Special: Lesser known facts about Chhoti AnandiKeep frizzy hair at bay this monsoon
AC Milan's new head coach Vincenzo Montella has said that the Italian football club must r
Watch: Brazil Bigg Boss dress slip Last Updated : 12 Sep 2011 02:07:19 PM IST Brazil Bigg Boss dress slip
The Bigg Boss house in Brazil witnessed a wardrobe malfunction.
One of the contestant of Brazil's TV reality show Bigg Boss suffered a wardrobe malfunction when she was trying to change her dress.
It was an 'Oops' moment for her when her dress slipped and she exposed more than she wanted.
The hidden camera captured the moment and the video clip is doing rounds on the internet these days.
You can also watch the Bigg Boss dress slip:
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Filmmaker A.R. Murugadoss, who presented Aamir Khan in the famous eight-pack abs look in "
- Johnny Depp gets $11 mn from Basquiat artworks
- B-town impressed with Akshay's 'Rustom' trailer
- AirAsia India's aircraft dedicated to 'Kabali'
- Ileana D'Cruz holidaying with her boyfriend: View PICS
- Kapil's on-screen lover Sumona Chakravarti caught smoking
- Salman Khan possessive for his girlfriend Iulia Vantur
- Debina Bonnerjee to join 'The Kapil Sharma Show'
- TV good way to start as actor: Mohit Abrol
A man in the US has taken his love for smartness to a whole new level - by marrying it in
Creating a ripple in the flagship smartphone market, Reliance Retail on Monday unveiled th
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...At college level he has tutored students from the Universities of Princeton, Oxford, Pennsylvania State, Drexel, Temple, Phoenix, and the College of New Jersey. Dr. Peter offers algebra, pre-calculus, SAT, AP calculus, college calculus 1, 2 and 3, GMAT and GRE.
Richboro, PAView Tutor
Education is the key to success in whatever you choose in your life long journey. Science and math (music and language also) are indispensable in a modern society. Educate yourself, and you will be rewarded.
Allentown, PAView Tutor
...In between formal tutoring sessions, I offer my students FREE email support to keep them moving past particularly tough problems. In addition, I offer FREE ALL NIGHT email/phone support just before the ?big" exam, for students who pull "all nighters". One quick note about my cancellation policy...
Havertown, PAView Tutor
...I owe to him that I scored A+ grades in my Bachelors and Masters program. I am manager with fortune 100 company and I believe with correct tutoring anyone can get better in mathematics. There are four ingredients for success will, skill, equipment and mentorship.
Doylestown, PAView Tutor
...Good for you! I can help you do that too. Throughout my many years of school I always helped and tutored other students as I went along - my little brother, my friends, classmates, etc. - and I really enjoyed it.
Lancaster, PAView Tutor


text:
Easily compose music and visual art with Emacs via ReneFroger.
Tag: Programming Language
GNU APL mode for Emacs
APL might pique your interest, but not enough for you take final step forward to start hacking with it. GNU APL is there, waiting for you. Still not enough?
Set up GNU APL mode for Emacs using use-package
(use-package gnu-apl-mode :ensure t)
or download it, extract it, and load it with a
(add-to-list 'load-path "~/path-to/gnu-apl-mode") (require 'gnu-apl-mode)
Do you have any more reasons not to start hacking with GNU APL and Emacs?!
Never having studied a package like this before, it is educational. It is also revealing how much love and labor went into this delightful package.
Thanks you Elias Mårtenson; hear, hear!
New Google+ APL Group
Google+ has an APL Group now!
Prettifying Org-Mode Code Blocks for Presentations
Org-Mode code blocks are verbose and lovable for literate programming. Rasmus wants to use the raw literate document for a presentation though, so that verbosity won't do. He explains here how to prettify code blocks. The value-add here is that he doesn't have to weave (export) the document for it to look great in the presentation; it already does directly in the Emacs buffer.
(Screencast) The Best Emacs Modifier Key Setup for OS X
Here is an easy way to use both Emacs and OS X modifier keys when you are inside Emacs:
Toggle the right-option and function key to switch between using them inside Emacs and using them for OS X.
I used Karabiner to make
ENTER send
LEFT CONTROL when chorded. I used OS X to make
CAPS LOCK be
CONTROL. I didn't change
OPTION and
COMMAND. I made this change because Emacs couldn't ignore the key-event when it was coming from Karabiner.
Here is the code:
(help/on-osx (setq mac-control-modifier 'control) (setq mac-right-control-modifier 'left) (setq mac-command-modifier 'meta) (setq mac-right-command-modifier 'left) (setq mac-option-modifier 'super) (setq mac-right-option-modifier 'left) (setq mac-function-modifier 'hyper) (defun help/toggle-mac-right-option-modifier () "Toggle between passing option modifier either to Emacs or OS X." (interactive) (let ((old-ropt mac-right-option-modifier)) (setq mac-right-option-modifier (if (eq mac-right-option-modifier 'left) 'none 'left)) (message "Toggled `mac-right-option-modifier' from %s to %s." old-ropt mac-right-option-modifier))) (defun help/toggle-mac-function-modifier () "Toggle between passing function modifier either to Emacs or OS X." (interactive) (let ((old-func mac-function-modifier)) (setq mac-function-modifier (if (eq mac-function-modifier 'hyper) 'none 'hyper)) (message "Toggled `mac-function-modifier' from %s to %s." old-func mac-function-modifier))))
Zark's Dyalog APL Tutorial
Just went through most of Zark's Dyalog APL Tutorial
- Nice to pick and choose topic areas
- Seems to serve both inexperienced and experienced programmers
- Lots of examples
- Funny
- Great for virtual input from an experienced APL programmer for you
Aaron Hsu on APL
Aaron Hsu blogs on APL here; all good reads.
(Screencast) Three Ways to Quote in your Notes with Org-Mode
Here are three ways that I might want to quote content in my personal notes with Org-Mode:
My friends really might want to know how.
The GNU APL Mailing List bug-apl is For Everything (not only bugs)
bug-apl Mailing List Everything (not only bugs) related to GNU APL
To see the collection of prior posting to the list, visit the bug-apl archives.
(APL) A Mathematics of Arrays
Paper here.


text:
I have had the pleasure of visiting the salon twice over the past 3 months. I had never been there before, but it was recommended by a friend since I was new to Tucson and looking for a new stylist. From the time I made the appointment on the phone to the time I left after receiving a shampoo, cut & style, I was treated with courtesy from a cheering staff. The male receptionist took all necessary information, repeated it back to confirm it was accuate. Upon arrival, I was greeted by name, offered a cold beverage (choice of soda, water, etc.) and barely sat down when I was greeted by the stylist who I had not yet met. She warmly introduced herself and gave me a tour of the facility since I had not been there before. She was competent and patient as we discussed what I wanted done and she made sure she had a full understanding before she preceeded. I was so pleased with the experience and care I was given that I have gone back a second time and received the same warm treatment as the first. I was impressed that a file had been kept on me and the stylist even knew what products I had purchased the time before and asked how I liked them. I have not used the spa or nail services as of yet, but plan to in the near future. The price of the service was well within the average of most salons, $35.
Tucson Tanyas
1. Hill, Tanya Y
5225 E Pima StTucson, AZ 85712
2. Tanya Nielsen
5504 E 22nd St Ste 140Tucson, AZ 85711
3. Nielsen, Tanya L, DDS
2990 S 6th AveTucson, AZ 85713
4. Barnett, Tanya R
6410 E Tanque Verde RdTucson, AZ 85715
5. Mulford, Tanya L
7423 E Tanque Verde RdTucson, AZ 85715
6. Bowman, Tanya L
4051 E Sunrise Dr # 101Tucson, AZ 85718
7. Underwood, Tanya
39580 S Lago Del Oro PkwyTucson, AZ 85739
8. Underwood, Tanya, MD
3100 N 1st AveTucson, AZ 85719
Showing1-8 of 8results
Svetlana Burtman at Renewed Beauty Medical Spa & Salon is excellent at what she does and has many years of experience to prove it. She stays current on new procedures and techniques, is friendly, easy to talk to, and answered all of my questions regarding my Botox and The Vampire Facelift procedures. I was referred to her by a close friend. Svetlana Burtman has a friendly and funny personality, so she made me feel at ease during the procedures. Svetlana is very prompt on appointments and I am seen within 5 minutes of arriving at her office. Svetlana Burtman's office staff is very friendly and is knowledgeable about the procedures and products that Svetlana Burtman offers in her practice. She is very caring and takes her time during the procedure, which I think is important in achieving great results. I have received so many compliments from my friends and colleagues, and my confidence has boosted since having the Botox and The Vampire Facelift . If you are looking to have these procedures Svetlana Burtman at Renewed Beauty Medical Spa & Salon should be your go to Medical Spa! Svetlana is excellent and I couldn't have asked for a better Medical Spa to go to!
I had to do research on salons and stylist because my mom is older with long hair she has trimmed herself for years, she was very nervous about who's hands she would be in. Joe had great reviews and a great detailed website, so we went for it. Everything Joe states on his website is true, we are so happy with his services and the result of my moms new look. He listened intently to what my mom said she wanted for a cut and color, and gave similar suggestions so she could make the best decision possible, all the while making her feel comfortable in taking her time, and answering questions and asking them. As a bystander I can tell he loves his job and has a fun and caring personality, so no matter what age you are he would take great care of you. I don't normally write in reviews but to see my mom so happy, I cryed, and I think everyone should know there are still people who love their job and dont treat you like your just another number in the day. My mom will only go to Joe now.