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1.  Quantification of relevance of quality of life assessment for patients with cognitive impairment: the suitability indices 
BMC Neurology  2014;14:78.
Background
The extent to which MS patients with cognitive dysfunction can accurately self-report outcomes has been a crucial issue. The aim of this study was to quantify and compare the relevance of the quality of life (QoL) assessment between two populations with a high occurrence of cognitive dysfunction, specifically in individuals with multiple sclerosis (MS) and in individuals suffering from schizophrenia (SCZ).
Methods
Design: A cross-sectional study was performed using the following inclusion criteria: MS and SCZ patients were diagnosed according to the McDonald criteria and DSM-IV criteria, respectively. Data on sociodemographic (age, gender, education level) and clinical (disease severity, disease duration) factors, QoL (disease-specific questionnaires, MusiQoL and SQoL) and cognitive performance (executive, memory, and attention functions) were collected. Non-impaired and impaired populations were defined according to the French norms. Psychometric properties were compared to those reported in reference populations, which were assessed in the respective validation studies. Suitability indices were provided used to quantitatively compare how the structures in the different populations matched with the initial structure of the questionnaires (reference populations).
Results
One hundred and twenty-four MS patients and 113 SCZ patients were enrolled. Factor analysis was performed on the impaired populations and revealed that the questionnaire structure adequately matched the initial structure of the disease-specific QoL questionnaires. All of the suitability indices of construct and external validity in the non-impaired populations ranged from 70 to 100%.
Conclusions
Our study suggested that cognitive dysfunction did not compromise the reliability or validity of the self-reported QoL questionnaires among subjects with cognitive dysfunction, such as MS and SCZ. Thus, this report may clarify the relevance of using self-reported QoL assessments in clinical practice.
doi:10.1186/1471-2377-14-78
PMCID: PMC3984183  PMID: 24708665
Cognitive impairment; Multiple sclerosis; Schizophrenia; Quality of life; Validity; Reliability; MusiQoL; SQoL
2.  Deterioration after corticosteroids in CIDP may be associated with pure focal demyelination pattern 
BMC Neurology  2014;14:72.
Background
In the PREDICT study, a randomised controlled trial comparing dexamethasone with prednisolone in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), almost a quarter of patients deteriorated soon after starting treatment. The primary objective of this post-hoc analysis was to test the hypothesis that a focal demyelination pattern is associated with early deterioration after corticosteroid treatment and to explore whether various clinical characteristics are associated with deterioration after corticosteroid treatment.
Methods
Clinical outcome was categorised into early deterioration and non-early deterioration. A neurophysiologist blinded for treatment outcome scored electrophysiological data into following categories: pure focal versus non-focal distribution of demyelination and no/minor versus moderate/severe sensory involvement. Additionally, we compared electrophysiological and clinical baseline parameters, with emphasis on previously reported possible associations.
Results
Early deterioration was found in 7 out of 33 patients (21%). Ten patients had pure focal distribution of demyelination, of whom 5 had early deterioration; 23 patients had non-focal distribution, of whom 2 had early deterioration (p = 0.02). Higher mean median nerve sensory nerve conduction velocity (SNCV) was found in patients with early deterioration compared to patients with non-early deterioration (52.6 and respectively 40.8 m/s, p = 0.02).
Conclusion
Pure focal distribution of demyelination and lesser sensory electrophysiological abnormalities may be associated with early deterioration in CIDP patients treated with corticosteroids.
doi:10.1186/1471-2377-14-72
PMCID: PMC3977669
Chronic inflammatory demyelinating polyneuropathy; CIDP; Deterioration; Corticosteroids
3.  Impact of urinary incontinence on health-related quality of life, daily activities, and healthcare resource utilization in patients with neurogenic detrusor overactivity 
BMC Neurology  2014;14:74.
Background
Neurogenic detrusor overactivity (NDO) leads to impaired health-related quality of life (HRQoL), productivity, and greater healthcare resource burden. The humanistic and economic burden may be more apparent in NDO patients with urinary incontinence (UI). The objective of this study was to compare the HRQoL, productivity, and health resource use (HRU) between continent and incontinent NDO patients.
Methods
A retrospective database analysis was conducted using the Adelphi Overactive Bladder (OAB)/UI Disease Specific Programme, a multi-national, cross-sectional survey reported from both patients’ and physicians’ perspectives. The population for this analysis included NDO patients with or without UI. General and disease-specific HRQoL were assessed using the EuroQoL-5D (EQ-5D), Incontinence Quality of Life questionnaire (I-QOL), and the Overactive Bladder Questionnaire (OAB-q). Productivity and daily activity impairment were measured using the Work Productivity and Activity Impairment (WPAI) questionnaire. HRU indicators included OAB-related surgery, OAB-related hospitalizations, incontinence pad usage, switching anticholinergics used for OAB due to inadequate response or adverse effects, and OAB-related physician visits. Bivariate analyses, multivariate ordinary least squares (OLS) regression analyses and published minimal clinically important differences (MCID) were used to assess relationships between incontinent status and the aforementioned outcome measures.
Results
A total of 324 NDO patients with or without urinary incontinence were included, averaging 54 years of age (SD 16), of whom 43.8 percent were male. Bivariate analyses detected no significant relationship between incontinent status and HRU variables. Regression analyses revealed that incontinent patients had clinically and statistically lower disease-specific HRQoL and greater impairment in daily activities as compared to continent patients. On average, incontinent patients scored 10 points lower on the I-QOL total score, 9 points lower on the OAB-q HRQoL score, 15 points higher on OAB-q symptom severity, and experienced 8.2 percent higher activity impairment due to their bladder condition (all p < 0.001).
Conclusions
Incontinent NDO patients experience significantly lower HRQoL and activity impairment as compared to continent NDO patients.
doi:10.1186/1471-2377-14-74
PMCID: PMC3984584  PMID: 24708598
Neurogenic detrusor overactivity; Incontinence; Burden of illness; Quality of life; Productivity
4.  Self-Management education for adults with poorly controlled epILEpsy (SMILE (UK)): a randomised controlled trial protocol 
BMC Neurology  2014;14:69.
Background
Teaching people with epilepsy to identify and manage seizure triggers, implement strategies to remember to take antiepileptic drugs, implement precautions to minimize risks during seizures, tell others what to do during a seizure and learn what to do during recovery may lead to better self-management. No teaching programme exists for adults with epilepsy in the United Kingdom although a number of surveys have shown patients want more information.
Methods/Design
This is a multicentre, pragmatic, parallel group randomised controlled trial to evaluate the effectiveness and cost-effectiveness of a two-day Self-Management education for epILEpsy (SMILE (UK)), which was originally developed in Germany (MOSES).
Four hundred and twenty eight adult patients who attended specialist epilepsy outpatient clinics at 15 NHS participating sites in the previous 12 months, and who fulfil other eligibility criteria will be randomised to receive the intervention (SMILE (UK) course with treatment as usual- TAU) or to have TAU only (control). The primary outcome is the effect on patient reported quality of life (QoL). Secondary outcomes are seizure frequency and psychological distress (anxiety and depression), perceived impact of epilepsy, adherence to medication, management of adverse effects from medication, and improved self-efficacy in management (mastery/control) of epilepsy.
Within the trial there will be a nested qualitative study to explore users’ views of the intervention, including barriers to participation and the perceived benefits of the intervention. The cost-effectiveness of the intervention will also be assessed.
Discussion
This study will provide quantitative and qualitative evidence of the impact of a structured self management programme on quality of life and other aspects of clinical and cost effectiveness in adults with poorly controlled epilepsy.
Trial registration
Current Controlled Trials: ISRCTN57937389.
doi:10.1186/1471-2377-14-69
PMCID: PMC3976555  PMID: 24694207
Epilepsy; Seizures; Self-management education; Clinical trial; Quality of life
5.  Physical activity program for patients with dementia and their relative caregivers: randomized clinical trial in Primary Health Care (AFISDEMyF study) 
BMC Neurology  2014;14:63.
Background
The aging of the population has led to the increase of chronic diseases, especially dementia and cardiovascular diseases, and it has become necessary for their relatives to dedicate more time in caregiving.
The objective in the first phase of this study is to evaluate the effectiveness of a Primary Health Care procedure to increase the physical activity of people with dementia and their relative caregivers. Also the effect on the cognitive state and cardiovascular risk will be assessed.
Methods/Design
Design: Clinical, multicentric and randomized trial. A simple random sampling to select 134 patients diagnosed with dementia will be carried out. After contacting their relatives, his/her participation in the trial will be requested. A basal assessment will be made and the participants will be asigned to control or intervention group (1:1). Variables: The main measure will be the assessment of physical activity (podometer and 7-PAR) in patients and caregivers. In patients with dementia: ADAS-cog, functional degree and cardiovascular risk. In caregivers: cardiovascular risk, general health and quality of life. Intervention: For 3 months, participants will receive instructions to do physical activity with an adapted program. This program will be designed and applied by Primary Health Care professionals in patients with dementia and their caregivers. The control group will receive regular care. Analysis: An intention-to-treat analysis will be carried out by comparing the observed differences between basal, 6 and 12 months measures. Change in the mean of daily steps assessed with the podometer and 7-PAR will be the main result.
Discussion
If the main hypothesis is confirmed, it could be useful to improve the cognitive state of patients with dementia, as well as the cardiovascular risk of all of them. The results can be good to improve technical features of the devices that register the physical activity in the patients with dementia, and it could facilitate its commercialization.
Trial registration
Clinical Trials.gov Identifier: NCT02044887.
doi:10.1186/1471-2377-14-63
PMCID: PMC3972512  PMID: 24684948
Dementia; Caregivers; Physical activity; Pedometer; Cardiovascular risk
6.  Changes in cerebrospinal fluid and blood plasma levels of IGF-II and its binding proteins in Alzheimer’s disease: an observational study 
BMC Neurology  2014;14:64.
Background
The Insulin-like Growth Factor (IGF)-related system is implicated in neuroregeneration and cell repair, as well as regulating lifespan. IGF-II, one component of this system, has also been found to affect memory functions in a rat model. In this study we explored changes in the IGF-related system in patients with Alzheimer’s disease (AD), including changes in IGF-II levels.
Methods
We measured blood plasma and cerebrospinal fluid (CSF) levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in 72 healthy controls and 92 patients with AD.
Results
We found significantly lower blood plasma levels of IGF-II and IGFBP-3 in patients with AD, compared with controls. The levels of IGF-II and IGFBP-2 were significantly elevated in the CSF from patients with AD. We also found correlations between established CSF biomarkers for AD (tau and P-tau) and components of the IGF system.
Conclusions
CSF and blood plasma levels of IGF-II and some of its binding proteins are changed in patients with AD. Further investigation into this area may unravel important clues to the nature of this disease.
doi:10.1186/1471-2377-14-64
PMCID: PMC3973836  PMID: 24685003
Alzheimer Disease; Dementia; Cerebrospinal fluid; Blood plasma; IGF-I; IGF-II; IGFBP-2; IGFBP-3; Insulin
7.  Evaluation of coexistence of Alzheimer’s disease in idiopathic normal pressure hydrocephalus using ELISA analyses for CSF biomarkers 
BMC Neurology  2014;14:66.
Background
We investigated levels of the β-amyloid 1–42 (Aβ42), total tau protein (T-tau) and tau phosphorylated at position threonine 181 (P-tau) in cerebrospinal fluid (CSF) of idiopathic normal pressure hydrocephalus (iNPH) patients and tried to find their clinical implications in the evaluation and treatment of iNPH.
Method
Twenty-five possible iNPH patients were prospectively enrolled and their CSF was collected to analyze levels of Aβ42, T-tau and P-tau using ELISA method. Gait disturbance, urinary incontinence, and cognitive impairment were semi-quantified and detailed neuropsychological (NP) test was performed.
Result
Eight iNPH patients were classified into the lower CSF Aβ42 group and 17 patients were classified into the higher CSF Aβ42 group. There was no difference in the iNPH grading score and its improvement after LP between the two groups. The lower CSF Aβ42 group showed more deficits in attention, visuospatial function and verbal memory in the baseline NP test and less improvement in phonemic categorical naming and frontal inhibitory function after LP.
Conclusions
Our study suggested that concomitant AD in iNPH patients might contribute to lumbar puncture or shunt unresponsiveness, especially in the field of cognitive dysfunction.
doi:10.1186/1471-2377-14-66
PMCID: PMC3976174  PMID: 24690253
Normal pressure hydrocephalus; Alzheimer’s disease; Cerebrospinal fluid; Lumbar puncture; Neuropsychological tests
8.  Protocol for a randomized comparison of integrated versus consecutive dual task practice in Parkinson’s disease: the DUALITY trial 
BMC Neurology  2014;14:61.
Background
Multiple tasking is an integral part of daily mobility. Patients with Parkinson’s disease have dual tasking difficulties due to their combined motor and cognitive deficits. Two contrasting physiotherapy interventions have been proposed to alleviate dual tasking difficulties: either to discourage simultaneous execution of dual tasks (consecutive training); or to practice their concurrent use (integrated training). It is currently unclear which of these training methods should be adopted to achieve safe and consolidated dual task performance in daily life. Therefore, the proposed randomized controlled trial will compare the effects of integrated versus consecutive training of dual tasking (tested by combining walking with cognitive exercises).
Methods and design
Hundred and twenty patients with Parkinson’s disease will be recruited to participate in this multi-centered, single blind, randomized controlled trial. Patients in Hoehn & Yahr stage II-III, with or without freezing of gait, and who report dual task difficulties will be included. All patients will undergo a six-week control period without intervention after which they will be randomized to integrated or consecutive task practice. Training will consist of standardized walking and cognitive exercises delivered at home four times a week during six weeks. Treatment is guided by a physiotherapist twice a week and consists of two sessions of self-practice using an MP3 player. Blinded testers will assess patients before and after the control period, after the intervention period and after a 12-week follow-up period. The primary outcome measure is dual task gait velocity, i.e. walking combined with a novel untrained cognitive task to evaluate the consolidation of learning. Secondary outcomes include several single and dual task gait and cognitive measures, functional outcomes and a quality of life scale. Falling will be recorded as a possible adverse event using a weekly phone call for the entire study period.
Discussion
This randomized study will evaluate the effectiveness and safety of integrated versus consecutive task training in patients with Parkinson’s disease. The study will also highlight whether dual task gait training leads to robust motor learning effects, and whether these can be retained and carried-over to untrained dual tasks and functional mobility.
Trial registration
Clinicaltrials.gov NCT01375413.
doi:10.1186/1471-2377-14-61
PMCID: PMC3974198  PMID: 24674594
Parkinson disease; Rehabilitation; Physical therapy; Neurologic gait disorder; Cognition; Dual task
9.  Therapy optimization in multiple sclerosis: a prospective observational study of therapy compliance and outcomes 
BMC Neurology  2014;14:49.
Background
Data sources for MS research are numerous but rarely provide an objective measure of drug therapy compliance coupled with patient-reported health outcomes. The objective of this paper is to describe the methods and baseline characteristics of the Therapy Optimization in MS (TOP MS) study designed to investigate the relationship between disease-modifying therapy compliance and health outcomes.
Methods
TOP MS was designed as a prospective, observational, nationwide patient-focused study using an internet portal for data entry. The protocol was reviewed and approved by Sterling IRB. The study was registered with ClinicalTrials.gov. It captured structured survey data monthly from MS patients recruited by specialty pharmacies. Data collection included the clinical characteristics of MS such as MS relapses. Disability, quality of life and work productivity and activity impairment were assessed quarterly with well-validated scales. When events like severe fatigue or new or worsening depression were reported, feedback was provided to treating physicians. The therapy compliance measure was derived from pharmacy drug shipment records uploaded to the study database. The data presented in this paper use descriptive statistics.
Results
The TOP MS Study enrolled 2966 participants receiving their disease-modifying therapy (DMT) from specialty pharmacies. The mean age of the sample was 49 years, 80.4% were female, 89.9% were Caucasian and 55.7% were employed full or part time. Mean time since first symptoms was 11.5 years; mean duration since diagnosis was 9.5 years. Patient-reported EDSS was 3.5; 72.2% had a relapsing-remitting disease course. The most commonly reported symptoms at the time of enrollment were fatigue (74.7%), impaired coordination or balance (61.8%) and numbness and tingling (61.2%). Half of the sample was using glatiramer acetate and half was using beta-interferons.
Conclusion
Demographic and clinical characteristics of the TOP MS sample at enrollment are consistent with other community-based MS samples, and the sample appears to be representative of DMT users in the US. TOP MS data can be used to explore the associations between disease-modifying therapy compliance and health outcomes.
Trial registration
ClinicalTrials.gov (NCT00819000)
doi:10.1186/1471-2377-14-49
PMCID: PMC3984676  PMID: 24624979
Multiple sclerosis; Disease-modifying therapy; Compliance; Relapses; Disability; Quality of life; Work productivity
10.  Reviewer Acknowledgement 2013 
BMC Neurology  2014;14:28.
Contributing reviewers
The editors of BMC Neurology would like to thank all our reviewers who have contributed to the journal in Volume 13 (2013).
doi:10.1186/1471-2377-14-28
PMCID: PMC3973960
11.  Physical activity in subjects with multiple sclerosis with focus on gender differences: a survey 
BMC Neurology  2014;14:47.
Background
There is increasing research that examines gender-issues in multiple sclerosis (MS), but little focus has been placed on gender-issues regarding physical activity. The aim of the present study was to describe levels of physical activity, self-efficacy for physical activity, fall-related self-efficacy, social support for physical activity, fatigue levels and the impact of MS on daily life, in addition to investigating gender differences.
Methods
The sample for this cross-sectional cohort study consisted of 287 (84 men; 29.3%) adults with MS recruited from the Swedish Multiple Sclerosis Registry. A questionnaire was sent to the subjects consisting of the self-administrated measurements: Physical Activity Disability Survey – Revised, Exercise Self-Efficacy Scale, Falls- Efficacy Scale (Swedish version), Social Influences on Physical Activity, Fatigue Severity Scale and Multiple Sclerosis Impact Scale. Response rate was 58.2%.
Results
Men were less physically active, had lower self-efficacy for physical activity and lower fall-related self-efficacy than women. This was explained by men being more physically affected by the disease. Men also received less social support for physical activity from family members. The level of fatigue and psychological consequences of the disease were similar between the genders in the total sample, but subgroups of women with moderate MS and relapsing remitting MS experienced more fatigue than men.
Conclusions
Men were less physically active, probably a result of being more physically affected by the disease. Men being more physically affected explained most of the gender differences found in this study. However, the number of men in the subgroup analyses was small and more research is needed. A gender perspective should be considered in strategies for promoting physical activity in subjects with MS, e.g. men may need more support to be physically active.
doi:10.1186/1471-2377-14-47
PMCID: PMC3975577  PMID: 24612446
Multiple sclerosis; Gender; Physical activity; Self-efficacy; Fatigue; Social support
12.  Relation between aphasia and arcuate fasciculus in chronic stroke patients 
BMC Neurology  2014;14:46.
Background
The role of the arcuate fasciculus (AF) in the dominant hemisphere in stroke patients with aphasia has not been clearly elucidated. We investigated the relation between language function and diffusion tensor tractography (DTT) findings for the left AF in chronic stroke patients with aphasia.
Method
Twenty five consecutive right-handed stroke patients with aphasia following lesions in the left hemisphere were recruited for this study. The aphasia quotient (AQ) of Korean-Western Aphasia Battery was used for assessment of language function. We measured values of fractional anisotropy (FA), apparent diffusion coefficient (ADC), voxel number of the left AF. We classified patients into three groups: type A - the left AF was not reconstructed, type B - the left AF was discontinued between Wernicke’s and Broca’s areas, and type C – the left AF was preserved around the stroke lesion.
Results
Moderate positive correlation was observed between AQ and voxel number of the left AF (r = 0.471, p < 0.05). However, no correlation was observed between AQ and FA (r = 0.275, p > 0.05) and ADC values (r = -0.286, p > 0.05). Significant differences in AQ scores were observed between the three types (p < 0.05); the AQ score of type C was higher than those of type A and B, and that of type B was also higher than that of type A (p < 0.05).
Conclusion
According to our findings, the remaining volume of the left AF, irrespective of directionality and diffusivity, showed moderate positive correlation with language function in chronic stroke patients with aphasia. Discontinuation or non-construction of the left AF was also an important factor for language function.
doi:10.1186/1471-2377-14-46
PMCID: PMC3973830  PMID: 24607148
Aphasia; Stroke; Arcuate fasciculus; Diffusion tensor tractography
13.  Memory impairment caused by cerebral hematoma in the left medial temporal lobe due to ruptured posterior cerebral artery aneurysm 
BMC Neurology  2014;14:44.
Background
Cognitive disorders, such as memory disturbances, are often observed following a subarachnoid hemorrhage. We present a very rare case where rupture of a posterior cerebral artery aneurysm caused restricted damage to the hippocampus unilaterally, and caused memory disturbances.
Case presentation
A 56-year-old, right-handed man, with a formal education history of 16 years and company employees was admitted to our hospital because of a consciousness disturbance. He was diagnosed as having a subarachnoid hemorrhage due to a left posterior cerebral artery dissecting aneurysm, and coil embolization was performed. Subsequently, he had neither motor paresis nor sensory disturbances, but he showed disorientation, and both retrograde and anterograde amnesia. Although immediate recall and remote memory were almost intact, his recent memory was moderately impaired. Both verbal and non-verbal memories were impaired. Brain computed tomography (CT) and magnetic resonance imaging (MRI) revealed a cerebral hematoma in the left temporal lobe involving the hippocampus and parahippocampal gyrus, and single-photon emission computed tomography (SPECT) demonstrated low perfusion areas in the left medial temporal lobe.
Conclusions
We suggest that the memory impairment was caused by local tissue destruction of Papez’s circuit in the dominant hemisphere due to the cerebral hematoma.
doi:10.1186/1471-2377-14-44
PMCID: PMC3975334  PMID: 24602130
Amnesia; Subarachnoid hemorrhage; Ruptured cerebral aneurysm
14.  Lessons from everyday stroke care for clinical research and vice versa: comparison of a comprehensive and a research population of young stroke patients 
BMC Neurology  2014;14:45.
Background
Translating knowledge derived from medical research into the clinical setting is dependent on the representativeness of included patients. Therefore we compared baseline data of patients included in a recent large study addressing young stroke in comparison to a large representative stroke registry.
Methods
We analysed baseline data of 5023 patients (age 18-55 years) with an acute cerebrovascular event included in the sifap1 (Stroke in Young Fabry Patients) study. For comparison 17007 stroke patients (age 18-55 years) documented (2004-2010) in a statutory stroke registry of the Institute of Quality Assurance Hesse of the Federal State of Hesse (GQH), Germany.
Results
Among 17007 juvenile (18-55 years) patients identified in the GQH registry 15997 had an ischaemic stroke or TIA (91%) or an intracranial haemorrhage (9%). In sifap1 5023 subjects were included. Sex distribution was comparable (men: 59% sifap1 versus 60.5% GQH) whereas age differed between the groups: median age was 46 years in sifap1 versus 49 years in GQH. Slightly higher percentages for diabetes mellitus and hypertension in the GQH registry were noted. There were no differences in stroke severity as assessed by NIHSS (median 3) and mRS (median 2). In patients with ischaemic stroke or TIA (n = 4467 sifap1; n = 14522 GQH) higher rates of strokes due to small artery occlusion and atherosclerosis occurred in older age groups; cardioembolism and strokes of other determined cause occurred more frequently in younger patients.
Conclusions
The comparison of baseline characteristics between the sifap1 study and the GQH registry revealed differences mainly determined by age.
doi:10.1186/1471-2377-14-45
PMCID: PMC3984721  PMID: 24607068
Ischemic stroke; Stroke in the young; Stroke severity; Stroke registry
15.  Relevance of novel inflammatory markers in stroke-induced immunosuppression 
BMC Neurology  2014;14:41.
Background
Acute ischemic stroke (AIS) has a biphasic effect on the peripheral immune system. The initial inflammatory response is followed by systemic immunosuppression, referred to as stroke-induced immunosuppression (SIIS), leading to severe complications in stroke patients. We aimed to identify an inflammatory marker that best represents this biphasic immunological response after AIS.
Methods
We investigated the alteration of CRP, WBC, neutrophil count, suPAR levels, CD4+ CD25high Tregs, CD64+ and CD177+ neutrophils and monocytes in 12 acute ischemic stroke patients free of infection within 6 hours and one week after the insult. As controls, 14 age-matched healthy individuals were included.
Results
CRP, WBC and neutrophil count values were comparable in stroke patients within 6 hours and controls, however, they were elevated in stroke one week after the insult. suPAR levels were higher in both stroke groups compared to controls. The prevalence of CD64+ neutrophils was higher in stroke patients within 6 hours than in controls and it decreased in stroke one week after the insult below the level in controls (5.95 [5.41-8.75] % vs. 32.38 [9.21-43.93] % vs. 4.06 [1.73-6.77] %, p < 0.05).
Conclusions
Our pilot study identified that the prevalence of CD64+ neutrophils may reflect a biphasic alteration of the immune response following AIS. Since its level decreases below baseline after one week of the CNS insult in stroke patients without infection, it might serve as a reliable candidate to identify the developing inflammatory response due to infection after stroke in the future.
doi:10.1186/1471-2377-14-41
PMCID: PMC3948141  PMID: 24597828
CD4+ lymphocyte; CD64+ neutrophil; CRP; Stroke; suPAR; Treg
16.  Cerebrovascular function and cognition in childhood: a systematic review of transcranial doppler studies 
BMC Neurology  2014;14:43.
Background
The contribution of cerebrovascular function to cognitive performance is gaining increased attention. Transcranial doppler (TCD) is portable, reliable, inexpensive and extremely well tolerated by young and clinical samples. It enables measurement of blood flow velocity in major cerebral arteries at rest and during cognitive tasks.
Methods
We systematically reviewed evidence for associations between cognitive performance and cerebrovascular function in children (0-18 years), as measured using TCD. A total of 2778 articles were retrieved from PsychInfo, Pubmed, and EMBASE searches and 25 relevant articles were identified.
Results
Most studies investigated clinical groups, where decreased blood flow velocities in infants were associated with poor neurological functioning, and increased blood flow velocities in children with Sickle cell disease were typically associated with cognitive impairment and lower intelligence. Studies were also identified assessing autistic behaviour, mental retardation and sleep disordered breathing. In healthy children, the majority of studies reported cognitive processing produced lateralised changes in blood flow velocities however these physiological responses did not appear to correlate with behavioural cognitive performance.
Conclusion
Poor cognitive performance appears to be associated with decreased blood flow velocities in premature infants, and increased velocities in Sickle cell disease children using TCD methods. However knowledge in healthy samples is relatively limited. The technique is well tolerated by children, is portable and inexpensive. It therefore stands to make a valuable contribution to knowledge regarding the underlying functional biology of cognitive performance in childhood.
doi:10.1186/1471-2377-14-43
PMCID: PMC3975716  PMID: 24602446
Cognition; Infants; Children; Adolescents; Transcranial doppler; Cerebrovascular
17.  Study protocol: münster tinnitus randomized controlled clinical trial-2013 based on tailor-made notched music training (TMNMT) 
BMC Neurology  2014;14:40.
Background
Tinnitus is a result of hyper-activity/hyper-synchrony of auditory neurons coding the tinnitus frequency, which has developed to synchronous mass activity owing the lack of inhibition. We assume that removal of exactly these frequency components from an auditory stimulus will cause the brain to reorganize around tonotopic regions coding the tinnitus frequency. Based on this assumption a novel treatment for tonal tinnitus - tailor-made notched music training (TMNMT) (Proc Natl Acad Sci USA 107:1207–1210, 2010; Ann N Y Acad Sci 1252:253–258, 2012; Frontiers Syst Neurosci 6:50, 2012) has been introduced and will be tested in this clinical trial on a large number of tinnitus patients.
Methods and design
A randomized controlled trial (RCT) in parallel group design will be performed in a double-blinded manner. The choice of the intervention we are going to apply is based on two “proof of concept” studies in humans (Proc Natl Acad Sci USA 107:1207–1210, 2010; Ann N Y Acad Sci 1252:253–258, 2012; Frontiers Syst Neurosci 6:50, 2012; PloS One 6(9):e24685, 2011) and on a recent animal study (Front Syst Neurosci 7:21, 2013).
The RCT includes 100 participants with chronic, tonal tinnitus who listened to tailor-made notched music (TMNM) for two hours a day for three months. The effect of TMNMT is assessed by the tinnitus handicap questionnaire and visual analogue scales (VAS) measuring perceived tinnitus loudness, distress and handicap.
Discussion
This is the first randomized controlled trial applying TMNMT on a larger number of patients with tonal tinnitus. Our data will verify more securely and reliably the effectiveness of this kind of completely non-invasive and low-cost treatment approach on tonal tinnitus.
Trial registration
Current Controlled Trials ISRCTN04840953
doi:10.1186/1471-2377-14-40
PMCID: PMC3942518  PMID: 24581050
Tinnitus; Tailor-made notched music training (TMNMT); Münster Tinnitus randomized controlled Clinical Trial-2013
18.  Oxfordshire community stroke project classification improves prediction of post-thrombolysis symptomatic intracerebral hemorrhage 
BMC Neurology  2014;14:39.
Background
The Oxfordshire Community Stroke Project (OCSP) classification is a simple stroke classification system with value in predicting clinical outcomes. We investigated whether and how the addition of OCSP classification to the Safe Implementation of Thrombolysis in Stroke (SITS) symptomatic intracerebral hemorrhage (SICH) risk score improved the predictive performance.
Methods
We constructed an extended risk score by adding an OCSP component, which assigns 3 points for total anterior circulation infarcts, 0 point for partial anterior circulation infarcts or lacunar infarcts. Patients with posterior circulation infarcts were assigned an extended risk score of zero. We analyzed prospectively collected data from 4 hospitals to compare the predictive performance between the original and the extended scores, using area under the receiver operating characteristic curve (AUC) and net reclassification improvement (NRI).
Results
In a total of 548 patients, the rates of SICH were 7.3% per the National Institute of Neurological Diseases and Stroke (NINDS) definition, 5.3% per the European-Australasian Cooperative Acute Stroke Study (ECASS) II, and 3.5% per the SITS-Monitoring Study (SITS-MOST). Both scores effectively predicted SICH across all three definitions. The extended score had a higher AUC for SICH per NINDS (0.704 versus 0.624, P = 0.015) and per ECASS II (0.703 versus 0.612, P = 0.016) compared with the SITS SICH risk score. NRI for the extended risk score was 22.3% (P = 0.011) for SICH per NINDS, 21.2% (P = 0.018) per ECASS II, and 24.5% (P = 0.024) per SITS-MOST.
Conclusions
Incorporation of the OCSP classification into the SITS SICH risk score improves risk prediction for post-thrombolysis SICH.
doi:10.1186/1471-2377-14-39
PMCID: PMC3941257  PMID: 24581034
19.  Treatment satisfaction, adherence and behavioral assessment in patients de – escalating from natalizumab to interferon beta 
BMC Neurology  2014;14:38.
Background
De-escalating natalizumab (NTZ) to interferon beta 1b (IFN B 1B) is a possible treatment option in multiple sclerosis (MS) patients interrupting NTZ because of increased risk of progressive multifocal leukoencephalopathy (PML). The aim of this study was to evaluate satisfaction and adherence to treatment, behavioral and fatigue changes in patients switched to IFN B 1B compared to continued NTZ treatment.
Methods
A 1 year, prospective, randomized, rater-blinded, parallel-group study. Nineteen relapsing remitting (RR) MS patients, randomly assigned to undergo either NTZ (n = 10) or IFN B 1B (n = 9) treatment, who had previously received NTZ for at least 12 months with disease stability and fearing or at risk for PML were included. Patients underwent behavioral and treatment assessments at baseline, after 24-week and 1 year follow-up. Behavioral assessment included measures of cognition, fatigue and quality of life. Treatment assessment included measures of satisfaction, persistence and adherence to treatment. Clinical-radiological disease activity and safety were also assessed.
Results
Baseline characteristics of patients were similar between groups except for Euro Quality Visual Analogue Scale, being higher in the NTZ group (p = 0.04). Within-group comparisons at the three time points, as well as interaction analysis of treatment effect over time did not show any statistically significant differences in behavioral or treatment assessments, but a coherent trend favoring NTZ over IFN B 1B.
Conclusions
De-escalating NTZ to IFN B 1B is feasible and associated with overall good patient related outcome and persistently stable behavioral measures.
doi:10.1186/1471-2377-14-38
PMCID: PMC3940251  PMID: 24576156
Adherence; Fatigue; Cognition; Quality of life; Multiple sclerosis; Natalizumab; Interferon beta-1b
20.  The effect of obstructive sleep apnea and treatment with continuous positive airway pressure on stroke rehabilitation: rationale, design and methods of the TOROS study 
BMC Neurology  2014;14:36.
Background
Obstructive sleep apnea is a common sleep disorder in stroke patients. Obstructive sleep apnea is associated with stroke severity and poor functional outcome. Continuous positive airway pressure seems to improve functional recovery in stroke rehabilitation. To date, the effect of continuous positive airway pressure on cognitive functioning in stroke patients is not well established. The current study will investigate the effectiveness of continuous positive airway pressure on both cognitive and functional outcomes in stroke patients with obstructive sleep apnea.
Methods/Design
A randomized controlled trial will be conducted on the neurorehabilitation unit of Heliomare, a rehabilitation center in the Netherlands. Seventy stroke patients with obstructive sleep apnea will be randomly allocated to an intervention or control group (n = 2×35). The intervention will consist of four weeks of continuous positive airway pressure treatment. Patients allocated to the control group will receive four weeks of treatment as usual. Outcomes will be assessed at baseline, immediately after the intervention and at two-month follow-up.
In a supplementary study, these 70 patients with obstructive sleep apnea will be compared to 70 stroke patients without obstructive sleep apnea with respect to cognitive and functional status at rehabilitation admission. Additionally, the societal participation of both groups will be assessed at six months and one year after inclusion.
Discussion
This study will provide novel information on the effects of obstructive sleep apnea and its treatment with continuous positive airway pressure on rehabilitation outcomes after stroke.
Trial registration
Trial registration number: Dutch Trial Register NTR3412
doi:10.1186/1471-2377-14-36
PMCID: PMC3938083  PMID: 24568360
Stroke; Rehabilitation outcome; Obstructive sleep apnea; CPAP; Randomized controlled trial; Cognition; Functional status
21.  Prediction of outcome in patients with suspected acute ischaemic stroke with CT perfusion and CT angiography: the Dutch acute stroke trial (DUST) study protocol 
BMC Neurology  2014;14:37.
Background
Prediction of clinical outcome in the acute stage of ischaemic stroke can be difficult when based on patient characteristics, clinical findings and on non-contrast CT. CT perfusion and CT angiography may provide additional prognostic information and guide treatment in the early stage. We present the study protocol of the Dutch acute Stroke Trial (DUST). The DUST aims to assess the prognostic value of CT perfusion and CT angiography in predicting stroke outcome, in addition to patient characteristics and non-contrast CT. For this purpose, individualised prediction models for clinical outcome after stroke based on the best predictors from patient characteristics and CT imaging will be developed and validated.
Methods/design
The DUST is a prospective multi-centre cohort study in 1500 patients with suspected acute ischaemic stroke. All patients undergo non-contrast CT, CT perfusion and CT angiography within 9 hours after onset of the neurological deficits, and, if possible, follow-up imaging after 3 days. The primary outcome is a dichotomised score on the modified Rankin Scale, assessed at 90 days. A score of 0–2 represents good outcome, and a score of 3–6 represents poor outcome. Three logistic regression models will be developed, including patient characteristics and non-contrast CT (model A), with addition of CT angiography (model B), and CT perfusion parameters (model C). Model derivation will be performed in 60% of the study population, and model validation in the remaining 40% of the patients. Additional prognostic value of the models will be determined with the area under the curve (AUC) from the receiver operating characteristic (ROC) curve, calibration plots, assessment of goodness-of-fit, and likelihood ratio tests.
Discussion
This study will provide insight in the added prognostic value of CTP and CTA parameters in outcome prediction of acute stroke patients. The prediction models that will be developed in this study may help guide future treatment decisions in the acute stage of ischaemic stroke.
doi:10.1186/1471-2377-14-37
PMCID: PMC3939816  PMID: 24568540
Stroke; Ischaemia; Infarct; Prediction; CT perfusion; CT angiography
22.  A retrospective analysis of hand tapping as a longitudinal marker of disease progression in Huntington’s disease 
BMC Neurology  2014;14:35.
Background
Current clinical assessments of motor function in Huntington’s Disease (HD) rely on subjective ratings such as the Unified Huntington’s Disease Rating scale (UHDRS). The ability to track disease progression using simple, objective, inexpensive, and robust measures would be beneficial.
Methods
One objective measure of motor performance is hand-tapping. Over the last 14 years we have routinely collected, using a simple device, the number of taps made by the right and left hand over 30 seconds in HD patients attending our NHS clinics.
Results
Here we report on a longitudinal cohort of 237 patients, which includes patients at all stages of the disease on a wide range of drug therapies. Hand tapping in these patients declines linearly at a rate of 5.1 taps per year (p < 0.0001; 95% CI = 3.8 to 6.3 taps), and for each additional year of age patients could perform 0.9 fewer taps (main effect of age: p = 0.0007; 95% CI = 0.4 to 1.4). Individual trajectories can vary widely around this average rate of decline, and much of this variation could be attributed to CAG repeat length. Genotype information was available for a subset of 151 patients, and for each additional repeat, patients could perform 5.6 fewer taps (p < 0.0001; 95% CI = 3.3 to 8.0 taps), and progressed at a faster rate of 0.45 fewer taps per year (CAG by time interaction: p = 0.008; 95% CI = 0.12 to 0.78 taps). In addition, for each unit decrease in Total Functional Capacity (TFC) within individuals, the number of taps decreased by 6.3 (95% CI = 5.4 to 7.1, p < 0.0001).
Conclusions
Hand tapping is a simple, robust, and reliable marker of disease progression. As such, this simple motor task could be a useful tool by which to assess disease progression as well therapies designed to slow it down.
doi:10.1186/1471-2377-14-35
PMCID: PMC3937529  PMID: 24564568
Huntington’s disease; Biomarker; Hand tapping
23.  Outcome of MRSA carriers in neurological early rehabilitation 
BMC Neurology  2014;14:34.
Background
Colonization with MRSA is believed to have deteriorating effects on neurological rehabilitation patients because MRSA carriers need to be isolated.
Methods
Medical records of neurological early rehabilitation patients (most of them after stroke) admitted to a large rehabilitation facility in Northern Germany in 2010 have been carefully reviewed with respect to MRSA status, outcome variables (functional independence), morbidity, and length of stay (LOS).
Results
74/569 (13.0%) patients were MRSA positive on admission. MRSA carriers had a significantly longer LOS in early neurological rehabilitation (63.7 (37.1) vs. 25.8 (24.5) days, p < 0.001), worse functional status on admission (Barthel index (BI) 13.6 (9.9) vs. 25.6 (24.1), p < 0.001), worse Glasgow Coma Scale (9.5 (3.2) vs. 12.0 (3.3), p < 0.001), more co-diagnoses (20.5 (5.1) vs. 13.3 (5.5), p < 0.001), and higher Patient Clinical Complexity Levels (PCCL). The outcome was significantly worse among MRSA positive patients (BI 25.5 (21.2) vs. 47.4 (31.0), p < 0.001; Early Rehabilitation Index −47.3 (51.4) vs. -26.0 (35.4), p < 0.001). Isolated patients had slightly less therapy per day (131.6 (16.6) vs. 140.2 (18.7) min/day, p < 0.001), but the overall sum of therapy was significantly larger in the MRSA positive group due to longer LOS.
Conclusions
Functional recovery of MRSA carriers in early neurological rehabilitation is worse than in MRSA negative patients. Poorer outcome is not resulting from isolation (less therapy) but from functional status and higher morbidity on admission.
doi:10.1186/1471-2377-14-34
PMCID: PMC3932788  PMID: 24555811
24.  Multicystic meningioangiomatosis 
BMC Neurology  2014;14:32.
Background
Meningioangiomatosis (MA) is a rare hamartomatous lesion. Only six cases of cystic MA have been reported in the literature.
Case presentation
We present a case of multicystic MA. A 21-year-old woman without any stigmata of neurofibromatosis type 2 presented with intractable seizures since 10 years. Brain magnetic resonance imaging revealed a well-defined, multicystic mass with heterogeneous signal intensity in the right temporal lobe. The patient underwent resection of the lesion and of the epileptogenic cortex under intraoperative electrocorticography (ECoG) assistance. Histopathological examination showed proliferation of perivascular cells that were arranged in a cuff pattern and were positive for vimentin, D2-40 and smooth muscle actin. Mutiple microcysts and enlarged perivascular spaces were present, which was similar to the structure of the arachnoid cavity. Hyalinized collagen fibers with round concentric acellular eosinophilic lamellae within areas of reactive gliosis were noted for the first time in MA. The patient was followed up without any clinical symptoms or recurrence for 2 years.
Conclusion
MA may originate from arachnoid and vascular tissue trapped in the cortical parenchyma during brain development, and the cysts may have resulted from the gradual accumulation of cerebrospinal fluid in the perivascular spaces of the trapped tissue. Resection of the lesion and of the epileptogenic cortex is important not only for pathological diagnosis but also for seizure control, and intraoperative ECoG assistance is recommended.
doi:10.1186/1471-2377-14-32
PMCID: PMC3931926  PMID: 24555776
Meningioangiomatosis; Multicystic; Seizure; Hamartomatous lesion
25.  Relations of low contrast visual acuity, quality of life and multiple sclerosis functional composite: a cross-sectional analysis 
BMC Neurology  2014;14:31.
Background
Although common and often disabling in multiple sclerosis (MS), visual dysfunction is currently not adequately accounted for in both clinical routine and MS trials. Sloan low contrast letter acuity (SLCLA) is a standardised chart-based measure of visual function particular at low contrast and has been suggested as additional visual component to the Multiple Sclerosis Functional Composite (MSFC). Here, we evaluate the relations between SLCLA, retinal integrity, MSFC, and quality of life (QoL) in MS patients.
Methods
Cross-sectional analysis of retinal nerve fibre layer (RNFL) thickness, MSFC, SLCLA (2.5% and 1.25% contrast levels), visual evoked potentials, and QoL (Short Form (SF) 36, National Eye Institute Visual Functioning Questionnaire (NEIVFQ)) using baseline data of 92 MS patients from an ongoing prospective longitudinal trial. Relations between RNFL thickness or P100 latency and SLCLA were analysed using generalised estimating equations (GEE) accounting for intra-individual inter-eye dependencies and corrected for age, gender, and history of optic neuritis. Pearson’s correlations were used to assess relations between SLCLA, MSFC, and QoL.
Results
SLCLA reflected RNFL thickness (p = 0.021) and P100 latency (p = 0.004) and predicted vision-related QoL, reflected by the NEIVFQ39 subscores “general vision” and “near activities” (p < 0.008 for both). SLCLA did not predict general QoL reflected by SF36. Implementing SLCLA into MSFC, thus creating a four-dimensional MSFC4, captured aspects of disability reflected by the NEIVFQ39 subscores “general vision” (r = 0.42, p < 0.0001) and “near activity” (r = 0.3, p = 0.014) which were not captured by standard MSFC3.
Conclusions
SLCLA at 2.5% and 1.25% contrast levels correlates with retinal morphology and P100 latency and predicts some aspects of vision-related QoL in MS. More importantly, using a prospective cross-sectional approach we provide evidence that extending the MSFC by SLCLA as an additional visual component increases the performance of MSFC to capture MS-related disability. Longitudinal data on the relation between SLCLA, MSFC, and QoL will be available in the near future.
doi:10.1186/1471-2377-14-31
PMCID: PMC3932139  PMID: 24555757
Multiple sclerosis; Low contrast visual acuity; Sloan low contrast letter acuity; Multiple sclerosis functional composite; Quality of life; Retinal nerve fibre layer thickness

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