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1.  Impact of sex in stroke thrombolysis: a coarsened exact matching study 
BMC Neurology  2015;15:10.
It is not established whether sex influences outcome and safety following intravenous thrombolysis (IVT) in acute stroke. As a significant imbalance exists between the baseline conditions of women and men, regression analysis alone may be subject to bias. Here we aimed to overcome this methodical shortcoming by balancing both groups using coarsened exact matching (CEM) before evaluating outcome.
From our local prospective stroke database we analyzed consecutive patients who suffered anterior circulation stroke and received IVT from 1998 to 04/2013 (n = 1391, 668 female, 723 male). Data were preprocessed by CEM, balancing for age, NIHSS, lesion side, hypertension, diabetes, atrial fibrillation, smoking, coronary heart disease, and previous stroke, which yielded a matched cohort of 502 women and 436 men (n = 938). Outcome was estimated by adjusted binomial logistic regression analysis incorporating matched weights.
No effect of sex was seen to predict good outcome (OR 1.04, CI 0.76–1.43) or mortality (OR 1.13, CI 0.73–1.73). However, female sex was a strong independent predictor of symptomatic intracerebral hemorrhage (sICH – ECASS-II definition, OR 3.62, CI 1.77-7.41) and fatal ICH (OR 4.53, CI 1.61-12.7).
In balanced groups, the two sexes showed comparable outcomes following IVT. A novel finding was the higher rate of sICH and fatal ICH in women. In this analysis we also demonstrate how CEM can reduce multivariate imbalance and thereby improve estimates, already in crude, but more importantly, in adjusted regression analysis. Further investigations of multicentre data with improved analytical approaches that yield balanced sex-groups are therefore warranted.
PMCID: PMC4328713
Acute ischemic stroke; Intravenous thrombolysis; Coarsened exact matching; Sex; Intracerebral hemorrhage
2.  Personal and environmental factors to consider when aiming to improve participation in physical activity in children with Spina Bifida: a qualitative study 
BMC Neurology  2015;15:11.
Youth with spina bifida (SB) are less fit and active than other groups with childhood disability. While recent studies have shown benefits of exercise training, the increased fitness levels do not sustain or lead to increased levels of physical activity (PA) in these children. Therefore, it seems important to explore which factors are associated with participation in PA (or lack of) in youth with SB. The objective of this study is to describe both personal and environmental factors that are important for participation in physical activity as experienced by these children and their parents, in order to better develop intervention strategies to improve participation in PA in youth with SB.
Eleven semi-structured interviews with parents of children with SB aged 4–7 years, nine focus groups with youth with SB (n = 33, age 8–18 years) and eight focus groups with their parents (n = 31) were conducted, recorded and transcribed verbatim. Two independent researchers analyzed the data. Central themes for physical activity were constructed, using the model for Physical Activity for Persons with a Disability (PAD model) as a background scheme.
Data showed that youth with SB encountered both personal and environmental factors associated with participation in PA on all levels of the PAD model. Bowel and bladder care, competence in skills, sufficient fitness, medical events and self-efficacy were important personal factors. Environmental factors that were associated with physical activity included the contact with and support from other people, the use of assistive devices for mobility and care, adequate information regarding possibilities for adapted sports and accessibility of playgrounds and sports facilities.
Our findings suggest that a variety of both personal and environmental factors were either positively or negatively associated with participation in PA. An individual approach, assessing possibilities rather than overcoming barriers within and surrounding the child may be a good starting point when setting up intervention programs to improve participation in PA. Therefore, assessment of both personal and environmental factors associated with physical activity should be standard care within multidisciplinary intervention programs aimed to encourage healthy active lifestyles in youth with SB.
PMCID: PMC4336512
Youth; Spina bifida; Facilitators; Barriers; Physical activity
3.  Antibodies against phosphorylcholine are not altered in plasma of patients with Alzheimer’s disease 
BMC Neurology  2015;15:8.
Phosphorylcholine is one of the major epitopes of oxidised low density lipoprotein. Low levels of IgM antibodies against phosphorylcholine (anti-PC) are associated with development of myocardial infarction and stroke. It has been shown that patients with Alzheimer’s disease and other dementias have significantly lower serum anti-PC levels compared to controls, suggesting that low levels of atheroprotective anti-PC may play a role in AD and dementia.
We quantified levels of anti-PC levels using an ELISA in plasma from 176 controls, 125 patients with Alzheimer’s disease, 19 patients with vascular dementia and 63 patients with other dementias.
We observed similar plasma anti-PC levels in controls, patients with Alzheimer’s disease, and other dementias.
Our data suggests that anti-PC is not useful as a biomarker for Alzheimer’s disease.
PMCID: PMC4324431  PMID: 25651913
Anti-phosphorylcholine; Alzheimer’s disease; Dementia; Biomarker
4.  Comparing interventions and exploring neural mechanisms of exercise in Parkinson disease: a study protocol for a randomized controlled trial 
BMC Neurology  2015;15:9.
Effective treatment of locomotor dysfunction in Parkinson disease (PD) is essential, as gait difficulty is an early and major contributor to disability. Exercise is recommended as an adjunct to traditional treatments for improving gait, balance, and quality of life. Among the exercise approaches known to improve walking, tango and treadmill training have recently emerged as two promising therapies for improving gait, disease severity and quality of life, yet these two interventions have not been directly compared to each other. Prior studies have been helpful in identifying interventions effective in improving gait function, but have done little to elucidate the neural mechanisms underlying functional improvements. The primary objective of the proposed work is to compare the effects of three community-based exercise programs, tango, treadmill training and stretching, on locomotor function in individuals with PD. In addition, we aim to determine whether and how these interventions alter functional connectivity of locomotor control networks in the brain.
One hundred and twenty right-handed individuals with idiopathic PD who are at least 30 years of age will be assigned in successive waves to one of three community-based exercise groups: tango dancing, treadmill training or stretching (control). Each group will receive three months of exercise training with twice weekly one-hour group classes. Each participant will be evaluated at three time points: pre-intervention (baseline), post-intervention (3 months), and follow-up (6 months). All evaluations will include assessment of gait, balance, disease severity, and quality of life. Baseline and post-intervention evaluations will also include task-based functional magnetic resonance imaging (fMRI) and resting state functional connectivity MRI. All MRI and behavioral measures will be conducted with participants OFF anti-Parkinson medication, with behavioral measures also assessed ON medication.
This study will provide important insights regarding the effects of different modes of exercise on locomotor function in PD. The protocol is innovative because it: 1) uses group exercise approaches for all conditions including treadmill training, 2) directly compares tango to treadmill training and stretching, 3) tests participants OFF medication, and 4) utilizes two distinct neuroimaging approaches to explore mechanisms of the effects of exercise on the brain.
Trial registration NCT01768832.
PMCID: PMC4326476  PMID: 25652002
Parkinson disease; Gait; Exercise; Magnetic resonance imaging; Functional connectivity; Rehabilitation
5.  Multicentric Castleman’s disease with voltage-gated potassium channel antibody-positive limbic encephalitis: a case report 
BMC Neurology  2015;15:4.
Castleman’s disease is a rare lymphoproliferative disorder which occurs in localized and multicentric forms and can mimic lymphoma. Despite its well-known association with certain autoimmune diseases, including paraneoplastic pemphigus and myasthenia gravis, Castleman’s disease has not previously been associated with limbic encephalitis.
Case presentation
We report the case of a 47-year old Caucasian man who presented with subacute onset of constitutional symptoms, diffuse lymphadenopathy, and stereotyped spells involving olfactory aura, nausea, disorientation, and unresponsiveness. He was found to have focal dyscognitive seizures of temporal lobe origin, cerebrospinal fluid with lymphocytic pleocytosis, hyponatremia, and serum positive for voltage-gated potassium channel antibodies, consistent with limbic encephalitis. An extensive infectious workup was unrevealing, but lymph node biopsy revealed multicentric Castleman’s disease. His symptoms improved with antiepileptic drugs and immunotherapy.
This case highlights the clinical diversity of voltage-gated potassium channel autoimmunity and expands the association of Castleman’s disease and autoimmune syndromes to include limbic encephalitis. Clinicians should be aware that paraneoplastic disorders of the central nervous system can be related to underlying hematologic disorders such as Castleman’s disease.
PMCID: PMC4320461  PMID: 25648431
Castleman’s disease; Lymphoproliferative; Limbic encephalitis; Voltage-gated potassium channel; VGKC; Paraneoplastic; Seizure
6.  Central fever in patients with spontaneous intracerebral hemorrhage: predicting factors and impact on outcome 
BMC Neurology  2015;15:6.
Central fever (CF) is defined as elevated temperature with no identifiable cause. We aimed to identify risk factors for developing CF among patients with spontaneous intracerebral hemorrhage (ICH) and to evaluate the impact of CF on outcome.
Patients included in our prospective stroke registry between 1/1/09 and 1/10/10 were studied. We identified patients with CF as those with a temperature ≥38.3°C without evidence for infection or drug fever. Patients with CF were compared to those without fever and those with infectious fever. Demographics, risk factors and imaging data as well as outcome parameters were reviewed.
We identified 95 patients with spontaneous ICH (median age 76, median admission NIHSS 9). CF was identified in 30 patients (32%), infectious etiology was found in 9 patients (9%) and the remaining patients did not develop fever. Baseline variables were similar between the groups except for intra-ventricular extension of the ICH (IVH) and larger ICH volumes that were more common in the CF group (OR = 4.667, 95% CI 1.658-13.135 and OR = 1.013/ml, 95% CI 1.004-1.021). Outcome analysis showed higher mortality rates (80% vs. 36%, p < 0.001) and lower rates of favorable functional outcome defined as a modified Rankin score ≤ 2 at 90 days (0% vs. 53%, p < 0.001) in the CF group.
The risk of CF is increased in patients with larger ICH and in those with IVH. CF negatively impacts outcome in patients with ICH.
PMCID: PMC4324842  PMID: 25648165
Stroke; Cerebrovascular disease; Intracerebral hemorrhage; Fever
7.  Study protocol of ‘Prism Adaptation in Rehabilitation’: a randomized controlled trial in stroke patients with neglect 
BMC Neurology  2015;15:5.
A frequent disorder after stroke is neglect, resulting in a failure to report or respond to contralesional stimuli. Rehabilitation of neglect is important, given the negative influence on motor recovery, independence in self-care, transfers, and locomotion. Effects of prism adaptation (PA) to alleviate neglect have been reported. However, either small groups or no control group were included and few studies reported outcome measurements on the level of activities of daily living (ADL). The current ongoing RCT investigates the short- and long-term effects of PA in a large population in a realistic clinical setting. Measures range from the level of function to the level of ADL.
Neglect patients in the sub-acute phase after stroke are randomly assigned to PA (n = 35) or sham adaptation (SA; n = 35). Adaptation is performed for 10 consecutive weekdays. Patients are tested at start of the study, 1 and 2 weeks after starting, and 1, 2, 4 and 12 weeks after ending treatment. Primary objectives are changes in performance on neuropsychological tests and neglect in ADL. Secondary objectives are changes in simulated driving, eye movements, balance, visual scanning and mobility, subjective experience of neglect in ADL and independence during ADL.
If effective, PA could be implemented as a treatment for neglect.
Trial registration
This trial is registered at the Dutch Trial Register #NTR3278.
PMCID: PMC4326203  PMID: 25648350
Unilateral neglect; Prism adaptation; Treatment; Clinical trial; Intervention; Stroke
8.  Defining pediatric traumatic brain injury using International Classification of Diseases Version 10 Codes: A systematic review 
BMC Neurology  2015;15:7.
Although healthcare administrative data are commonly used for traumatic brain injury (TBI) research, there is currently no consensus or consistency on the International Classification of Diseases Version 10 (ICD-10) codes used to define TBI among children and youth internationally. This study systematically reviewed the literature to explore the range of ICD-10 codes that are used to define TBI in this population. The identification of the range of ICD-10 codes to define this population in administrative data is crucial, as it has implications for policy, resource allocation, planning of healthcare services, and prevention strategies.
The databases MEDLINE, MEDLINE In-Process, Embase, PsychINFO, CINAHL, SPORTDiscus, and Cochrane Database of Systematic Reviews were systematically searched. Grey literature was searched using Grey Matters and Google. Reference lists of included articles were also searched for relevant studies. Two reviewers independently screened all titles and abstracts using pre-defined inclusion and exclusion criteria. A full text screen was conducted on articles that met the first screen inclusion criteria. All full text articles that met the pre-defined inclusion criteria were included for analysis in this systematic review.
A total of 1,326 publications were identified through the predetermined search strategy and 32 articles/reports met all eligibility criteria for inclusion in this review. Five articles specifically examined children and youth aged 19 years or under with TBI. ICD-10 case definitions ranged from the broad injuries to the head codes (ICD-10 S00 to S09) to concussion only (S06.0). There was overwhelming consensus on the inclusion of ICD-10 code S06, intracranial injury, while codes S00 (superficial injury of the head), S03 (dislocation, sprain, and strain of joints and ligaments of head), and S05 (injury of eye and orbit) were only used by articles that examined head injury, none of which specifically examined children and youth.
This review provides evidence for discussion on how best to use ICD codes for different goals. This is an important first step in reaching an appropriate definition and can inform future work on reaching consensus on the ICD-10 codes to define TBI for this vulnerable population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0259-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4335539  PMID: 25648197
Coding; International Classification of Diseases; Pediatric brain injury
9.  Prospective assessment of subjective sleep benefit in Parkinson’s disease 
BMC Neurology  2015;15:2.
Parkinson’s disease (PD) patients may experience ‘sleep benefit’ (SB): a temporarily improved mobility upon awakening. SB has mainly been studied retrospectively using questionnaires, but it remains unclear whether it is associated with actual changes in motor functioning.
We performed a prospective study on sleep-related changes in motor functioning, using a PD symptom diary during 7 days in 240 randomly selected PD patients (140 men; 66.8 ± 9.6 years; disease duration 9.3 ± 6.2 years). Afterwards, patients received a questionnaire on the possible subjective experience of SB.
Using the PD symptom diary, a positive change in motor function was observed after 267 nights (17.8%) and after 138 daytime naps (23.4%). Based on these results, 75 patients (32%) were classified as having SB. In response to the subsequent questionnaire, 73 patients (31%) reported SB. Interestingly, the groups with SB according to either the diary or the questionnaire overlapped only partially: outcomes were congruent in 63% of subjects (both negative 49%, both positive 14%). In both the diary and questionnaire, patients with SB showed a longer disease duration and longer medication use. According to the questionnaire, there was a trend towards a shorter sleep duration and lower sleep efficiency in the SB group. The mean change in motor function after sleep as assessed using the diary was higher in patients reporting subjective SB.
We show that the subjective experience of SB in PD is not always related to an actual increase in reported motor function after sleep. Defining SB using either a symptom diary or a questionnaire on subjective experience, results in only partly overlapping groups. These data suggest that SB may be a more heterogeneous phenomenon than previously thought and that subjective experience of symptom severity is not necessarily related to actual motor function.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-014-0256-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4300997  PMID: 25591551
Sleep; Parkinson’s disease; Sleep benefit; Nap; Questionnaire
10.  Temporal trends and risk factors for readmission for infections, gastrointestinal and immobility complications after an incident hospitalisation for stroke in Scotland between 1997 and 2005 
BMC Neurology  2015;15:3.
Improvements in stroke management have led to increases in the numbers of stroke survivors over the last decade and there has been a corresponding increase of hospital readmissions after an initial stroke hospitalisation. The aim of this study was to examine the one year risk of having a readmission due to infective, gastrointestinal or immobility (IGI) complications and to identify temporal trends and any risk factors.
Using a cohort of first hospitalised for stroke patients who were discharged alive, time to first event (readmission for IGI complications or death) within 1 year was analysed in a competing risks framework using cumulative incidence methods. Regression on the cumulative incidence function was used to model the risks of having an outcome using the covariates age, sex, socioeconomic status, comorbidity, discharge destination and length of hospital stay.
There were a total of 51,182 patients discharged alive after an incident stroke hospitalisation in Scotland between 1997–2005, and 7,747 (15.1%) were readmitted for IGI complications within a year of the discharge. Comparing incident stroke hospitalisations in 2005 with 1997, the adjusted risk of IGI readmission did not increase (HR = 1.00 95% CI (0.90, 1.11). However, there was a higher risk of IGI readmission with increasing levels of deprivation (most deprived fifth vs. least deprived fifth HR = 1.16 (1.08, 1.26).
Approximately 15 in 100 patients discharged alive after an incident hospitalisation for stroke in Scotland between 1997 and 2005 went on to have an IGI readmission within one year. The proportion of readmissions did not change over the study period but those living in deprived areas had an increased risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-014-0257-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4320501  PMID: 25591718
Incident stroke hospitalisation; Readmission; Cumulative incidence; Competing risks
11.  Intramedullary spinal cord neurocysticercosis presenting as Brown-Séquard syndrome 
BMC Neurology  2015;15:1.
Cysticercosis is a parasitic disease caused by the larval stage of Taenia Solium. Involvement of the central nervous system by this tapeworm is endemic in developing countries. However, isolated spinal involvement by Taenia Solium is uncommon and having clinical presentation of Brown-Séquard syndrome is even rarer.
Case presentation
A 43-year-old male who came to the emergency department with clinical presentation of complete Brown-Séquard syndrome. Computed tomography scan of the brain was normal. Magnetic resonance imaging of the thoracic spine revealed an intramedullary mass of the spinal cord at C-7/T-l level. Patient underwent surgery that revealed a cystic lesion and was resected. Histopathological report confirmed the diagnosis of neurocysticercosis. Postoperatively, oral steroid therapy and a four week course of albendazol were administered.
Intramedullary neurcysticercosis represents a diagnostic challenge and should be considered in intramedullary lesions in settings where Taenia solium is endemic. Clinical, pathophysiological and diagnostic aspects of spinal cord intramedullary neurocysticercosis are discussed.
PMCID: PMC4320533  PMID: 25595849
Intramedullary; Neurocysticercosis; Spinal cord
12.  Heat exposure and bicycling trigger recurrent aseptic meningitis: a case report 
BMC Neurology  2014;14(1):230.
Aseptic meningitis associated with herpes simplex virus type 2 often has a relapsing-remitting clinical phenotype. Factors that lead to disease activation and reactivation are currently incompletely understood.
Case presentation
We describe the case of a 49-year-old Caucasian man who developed recurrent episodes of herpes simplex virus type 2-associated aseptic meningitis in the setting of heat exposure and bicycling. This case is compelling in that substantial data were available to the examining physicians on the amount of physical exercise and heat exposure. Strenuous physical activities or heat exposure in isolation did not cause re-occurrence of clinical signs and symptoms.
This case illustrates that the dual activation of mechanical and temperature receptors in dorsal root ganglia may lead to the recurrent reactivation and afferent dissemination of latent herpes simplex virus type 2 in some patients.
PMCID: PMC4301064  PMID: 25551438
13.  The Dutch Parelsnoer Institute - Neurodegenerative diseases; methods, design and baseline results 
BMC Neurology  2014;14(1):254.
The Parelsnoer Institute is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called “Pearls”) are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer’s disease.
The objective of this paper is to describe the design and methods of the Pearl Neurodegenerative Diseases, as well as baseline descriptive variables, including their biomarker profile.
The Pearl Neurodegenerative Diseases is a 3-year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%).
The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset.
PMCID: PMC4301568  PMID: 25551191
Dementia; Alzheimer’s disease; Design; Biobank; Research infrastructure
14.  Influence of morphology and hemodynamic factors on rupture of multiple intracranial aneurysms: matched-pairs of ruptured-unruptured aneurysms located unilaterally on the anterior circulation 
BMC Neurology  2014;14(1):253.
The authors evaluated the impact of morphological and hemodynamic factors on the rupture of matched-pairs of ruptured-unruptured intracranial aneurysms on one patient’s ipsilateral anterior circulation with 3D reconstruction model and computational fluid dynamic method simulation.
20 patients with intracranial aneurysms pairs on the same-side of anterior circulation but with different rupture status were retrospectively collected. Each pair was divided into ruptured-unruptured group. Patient-specific models based on their 3D-DSA images were constructed and analyzed. The relative locations, morphologic and hemodynamic factors of these two groups were compared.
There was no significant difference in the relative bleeding location. The morphological factors analysis found that the ruptured aneurysms more often had irregular shape and had significantly higher maximum height and aspect ratio. The hemodynamic factors analysis found lower minimum wall shear stress (WSSmin) and more low-wall shear stress-area (LSA) in the ruptured aneurysms than that of the unruptured ones. The ruptured aneurysms more often had WSSmin on the dome.
Intracranial aneurysms pairs with different rupture status on unilateral side of anterior circulation may be a good disease model to investigate possible characteristics linked to rupture independent of patient characteristics. Irregular shape, larger size, higher aspect ratio, lower WSSmin and more LSA may indicate a higher risk for their rupture.
PMCID: PMC4301794  PMID: 25551809
Intracranial aneurysms; Multiple aneurysm; Anterior circulation; Rupture; Computational fluid dynamics
15.  Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: results from a randomized controlled trial in relapsing-remitting multiple sclerosis 
BMC Neurology  2014;14(1):240.
Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1.
RRMS patients (18–65 years; Expanded Disability Status Scale score ≤5) were randomized to double-blind placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted.
1512 patients were randomized and dosed (placebo n = 500; peginterferon beta-1a every 2 [n = 512] or 4 [n = 500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p < 0.0001. Every 2 week dosing also provided significant reductions versus placebo and every 4 week dosing in the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium-enhancing plus non-enhancing new T2) lesions (all p < 0.0001), as well as the volume of T2 and T1 lesions (p < 0.05) at Weeks 24 and 48. Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p < 0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]). Consistent results were seen when allowing for minimal MRI activity.
During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4 week dosing. NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders.
Trial registration NCT00906399
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-014-0240-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4311432  PMID: 25551571
Clinical trial; Multiple sclerosis; Pegylation; Interferon
16.  (Cost)-effectiveness of a multi-component intervention for adults with epilepsy: study protocol of a Dutch randomized controlled trial (ZMILE study) 
BMC Neurology  2014;14(1):255.
In patients with epilepsy, poor adherence to anti-epileptic drugs has been shown to be the most important cause of poorly controlled epilepsy. Furthermore, it has been noted that the quality of life among patients with epilepsy can be improved by counseling and treatments aimed at increasing their self-efficacy and concordance, thus stimulating self-management skills. However, there is a need for evidence on the effectiveness of such programs, especially within epilepsy care. Therefore, we have developed a multi-component intervention (MCI) which combines a self-management/education program with e-Health interventions. Accordingly, the overall objective of this study is to assess the (cost)-effectiveness and feasibility of the MCI, aiming to improve self-efficacy and concordance in patients with epilepsy.
A RCT in two parallel groups will be conducted to compare the MCI with a control condition in epilepsy patients. One hundred eligible epilepsy patients will be recruited and allocated to either the intervention or control group. The intervention group will receive the MCI consisting of a self-management/education program of six meetings, including e-Health interventions, and will be followed for 12 months. The control group will receive care as usual and will be followed for 6 months, after which patients will be offered the possibility of participating in the MCI. The study will consist of three parts: 1) a clinical effectiveness study, 2) a cost-effectiveness study, and 3) process evaluation. The primary outcome will be self-efficacy. Secondary outcomes include adherence, side effects, change in seizure severity & frequency, improved quality of life, proactive coping, and societal costs. Outcome assessments will be done using questionnaires at baseline and after 3, 6, 9, and 12 months (last two applicable only for intervention group).
In times of budget constraints, MCI could be a valuable addition to the current healthcare provision for epilepsy, as it is expected that higher concordance and self-efficacy will result in reduced use of healthcare resources and an increased QOL. Accordingly, this study is aimed helping patients to be their own provider of health care, shifting epilepsy management from professionals to self-care by patients equipped with appropriate skills and tools.
Trial registration number
PMCID: PMC4301056  PMID: 25540089
17.  Incidence of multiple sclerosis in Northern Lisbon, Portugal: 1998–2007 
BMC Neurology  2014;14(1):249.
There are few, recent, well assessed, multiple sclerosis (MS) incidence surveys on European populations. This study sought to measure MS incidence in a Northern Lisbon population and assess it using capture-recapture methods (CRMs).
Among the population residing in the Northern Lisbon Health Area, registered MS diagnoses were obtained from general practitioners in three primary-care districts covering a population of 196,300, and a neurology unit at the main referral hospital. Cases with onset during the periods 1978–1997 and 2008–2012 were excluded due to perceived poor access to image-supported neurological diagnosis and administrative changes in patient referral respectively. Age- and sex-specific incidences for the period 1998–2007 were calculated using McDonald diagnostic criteria, and CRMs were used to correct age-specific incidence rates. The corrected figures were also adjusted for age using the European Standard Population as reference.
When applied to 62 MS patients with onset in the period 1998–2007, the rates per 100,000 population were as follows for both sexes: crude, 3.16; age-adjusted, 3.09 (95% CI 2.32 to 3.87); CRM-adjusted, 4.53 (95% CI 3.13 to 5.94); and age- and CRM-adjusted, 4.48 (3.54-5.41). In general, the rates were 3-fold higher among women than among men. Negative source dependency and CRM impact were highest at ages 35–44 years, where a 60% rise led to a peak incidence.
MS incidence in Northern Lisbon, Portugal, is moderately lower than that yielded by surveys on European populations. CRMs, which in this instance suggest undercounts, are a potentially useful tool for case-finding assessment but their application may introduce bias.
PMCID: PMC4300835  PMID: 25528357
Capture-recapture; Epidemiology; Methods; Multiple sclerosis; Public health
18.  Early supported discharge after stroke in Bergen (ESD Stroke Bergen): three and six months results of a randomised controlled trial comparing two early supported discharge schemes with treatment as usual 
BMC Neurology  2014;14(1):239.
Stroke causes lasting disability and the burden of stroke is expected to increase substantially during the next decades. Optimal rehabilitation is therefore mandatory. Early supported discharge (ESD) has previously shown beneficial, but all major studies were carried out more than ten years ago. We wanted to implement and study the results of ESD in our community today with comparisons between ESD and treatment as usual, as well as between two different ESD models.
Patients with acute stroke were included during a three year period (2008–11) in a randomised controlled study comparing two different ESD models to treatment as usual. The two ESD models differed by the location of treatment: either in a day unit or in the patients’ homes. Patients in the ESD groups were followed by a multi-disciplinary ambulatory team in the stroke unit and discharged home as early as possible. The ESD models also comprised treatment by a multi-disciplinary community health team for up to five weeks and follow-up controls after 3 and 6 months. Primary outcome was modified Rankin Scale (mRS) at six months.
Three-hundred-and-six patients were included. mRS scores and change scores were non-significantly better in the two ESD groups at 3 and 6 months. Within-group improvement from baseline to 3 months was significant in the ESD 1 (p = 0.042) and ESD 2 (p = 0.001) groups, but not in the controls. More patients in the pooled ESD groups were independent at 3 (p = 0.086) and 6 months (p = 0.122) compared to controls and there also was a significant difference in 3 month change score between them (p = 0.049). There were no differences between the two ESD groups. Length of stay in the stroke unit was 11 days in all groups.
Patients in the ESD groups tended to be more independent than controls at 3 and 6 months, but no clear statistically significant differences were found. The added effect of supported discharge and improved follow-up seems to be rather modest. The improved stroke treatment of today may necessitate larger patient samples to demonstrate additional benefit of ESD.
Clinical trial registration
Unique identifier: NCT00771771
PMCID: PMC4301654  PMID: 25528166
Stroke; Randomised controlled trial; Rehabilitation; Early supported discharge; ESD; Community rehabilitation
19.  Interactions between cognitive and sensory load while planning and controlling complex gait adaptations in Parkinson’s disease 
BMC Neurology  2014;14(1):250.
Recent research has argued that removal of relevant sensory information during the planning and control of simple, self-paced walking can result in increased demand on central processing resources in Parkinson’s disease (PD). However, little is known about more complex gait tasks that require planning of gait adaptations to cross over an obstacle in PD.
In order to understand the interaction between availability of visual information relevant for self-motion and cognitive load, the current study evaluated PD participants and healthy controls while walking toward and stepping over an obstacle in three visual feedback conditions: (i) no visual restrictions; (ii) vision of the obstacle and their lower limbs while in complete darkness; (iii) vision of the obstacle only while in complete darkness; as well as two conditions including a cognitive load (with a dual task versus without a dual task). Each walk trial was divided into an early and late phase to examine changes associated with planning of step adjustments when approaching the obstacle.
Interactions between visual feedback and dual task conditions during the obstacle approach were not significant. Patients with PD had greater deceleration and step time variability in the late phase of the obstacle approach phase while walking in both dark conditions compared to control participants. Additionally, participants with PD had a greater number of obstacle contacts when vision of their lower limbs was not available specifically during the dual task condition. Dual task performance was worse in PD compared to healthy control participants, but notably only while walking in the dark regardless of visual feedback.
These results suggest that reducing visual feedback while approaching an obstacle shifts processing to somatosensory feedback to guide movement which imposes a greater demand on planning resources. These results are key to fully understanding why trips and falls occur in those with PD.
PMCID: PMC4302136  PMID: 25528474
Parkinson’s disease; Visual feedback; Dual task; Gait with obstacle; Cognitive load
20.  A randomised controlled trial of an exercise plus behaviour change intervention in people with multiple sclerosis: the step it up study protocol 
BMC Neurology  2014;14(1):241.
Exercise has consistently yielded short-term, positive effects on health outcomes in people with multiple sclerosis (MS). However, these effects have not been maintained in the long-term. Behaviour change interventions aim to promote long-term positive lifestyle change. This study, namely, “Step it Up” will compare the effect of an exercise plus Social Cognitive Theory (SCT)-based behaviour change intervention with an exercise plus control education intervention on walking mobility among people with MS.
People with a diagnosis of MS who walk independently, score of 0–3 on the Patient Determined Disease Steps, who have not experienced an MS relapse or change in their MS medication in the last 12 weeks and who are physically inactive will be randomised to one of two study conditions. The experimental group will undergo a 10-week exercise plus SCT-based behavioural change intervention. The control group will undergo a 10-week exercise plus education intervention to control for contact. Participants will be assessed at weeks 1, 12, 24 and 36. The primary outcome will be walking mobility. Secondary outcomes will include: aerobic capacity, lower extremity muscle strength, participant adherence to the exercise programme, self-report exercise intensity, self-report enjoyment of exercise, exercise self-efficacy, outcome expectations for exercise, goal-setting for exercise, perceived benefits and barriers to exercise, perceptions of social support, physical and psychological impact of MS and fatigue. A qualitative evaluation of Step it Up will be completed among participants post-intervention.
This randomised controlled trial will examine the effectiveness of an exercise plus SCT-based behaviour change intervention on walking mobility among people with MS. To this end, Step it Up will serve to inform future directions of research and clinical practice with regard to sustainable exercise interventions for people with MS.
Trial registration, NCT02301442
PMCID: PMC4311502  PMID: 25528262
Exercise; Physical activity; Social cognitive theory; Behaviour change; Physiotherapy
21.  Post-stroke memory impairment among patients with vascular mild cognitive impairment 
BMC Neurology  2014;14(1):244.
The American Stroke Association/American Heart Association recommended the criteria for diagnosis of vascular cognitive impairment and memory impairment (MI) is a feature in the classification of vascular mild cognitive impairment (VaMCI). VaMCI patients with MI may differ in terms of infarct location or demographic features, so we evaluated the clinical characteristics associated with MI in patients with VaMCI.
A prospective multicenter study enrolled 353 acute ischemic stroke patients who underwent evaluation using the Korean Vascular Cognitive Impairment Harmonization Standard Neuropsychological Protocol at three months after onset. The association between MI and demographic features, stroke risk factors, and infarct location was assessed.
VaMCI was diagnosed in 141 patients, and 58 (41.1%) exhibited MI. Proportions of men and of left side infarcts were higher in VaMCI with MI than those without (75.9 vs. 57.8%, P = 0.03, 66.7 vs. 47%, P = 0.02). Multiple logistic analyses revealed that male sex (odds ratio [OR] 3.07, 95% confidence interval [95% CI] 1.12-8.42), left-side infarcts (OR 3.14, 95% CI 1.37-7.20), and basal ganglia/internal capsule infarcts (OR 4.53, 95% CI 1.55-13.22) were associated with MI after adjusting other demographic variables, vascular risk factors, and subtypes of stroke.
MI is associated with sex and infarct location in VaMCI patients.
PMCID: PMC4300833
22.  The efficacy and safety of cilostazol for the secondary prevention of ischemic stroke in acute and chronic phases in Asian population- an updated meta-analysis 
BMC Neurology  2014;14(1):251.
While previous meta-analysis have investigated the efficacy of cilostazol in the secondary prevention of ischemic stroke, they were criticized for their methodology, which confused the acute and chronic phases of stroke. We present a new systematic review, which differs from previous meta-analysis by distinguishing between the different phases of stroke, and includes two new randomized, controlled trials (RCTs).
All RCTs investigating the effect of cilostazol on secondary prevention of ischemic stroke were obtained. Outcomes were analyzed by Review Manager, including recurrence of cerebral infarction (ROCI), hemorrhage stroke or subarachnoid hemorrhage (HSSH), all-cause death (ACD), and modified Rankin Scale score (mRS). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessed the quality of the evidence.
5491 patients from six studies were included in the current study. In secondary prevention of ischemic stroke in chronic phase, cilostazol was associated with a 47% reduction in ROCI (relative risk [RR] 0.53, 95% confidence interval [CI] 0.34 to 0.81, p = 0.003), while no significant difference in HSSH and ACD compared with placebo; and 71% reduction in HSSH (RR 0.29, 95% CI 0.15 to 0.56, p = 0.0002) compared with aspirin, but not in ROCI and ACD. In the secondary prevention of ischemic stroke in acute phase, cilostazol did not show any effect in the ROCI, HSSH, ACD and mRS compared to placebo or aspirin. The quality of the evidence from chronic phase was high or moderate, and those from acute phase were moderate or low when analyzed by GRADE approach.
Cilostazol provided a protective effect in the secondary prevention of the chronic phase of ischemic stroke.
PMCID: PMC4301843  PMID: 25527141
Acute Phase; Chronic phase; Cilostazol; Meta-analysis; Stroke
23.  Comparison of clinical characteristics between neuromyelitis optica spectrum disorders with and without spinal cord atrophy 
BMC Neurology  2014;14(1):246.
Spinal cord lesions is one of the predominant characteristics in patients with neuromyelitis optica spectrum disorders (NMOSD). Interestingly, mounting evidence indicates that spinal cord atrophy (SCA) is one of common clinical features in multiple sclerosis (MS) patients, and correlates closely with the neurological disability. However, Clinical studies related to the SCA aspects of NMOSD are still scarce.
We retrospectively analyzed 185 patients with NMOSD, including 23 patients with SCA and 162 patients without SCA. Data were collected regarding clinical characteristics, laboratory tests, and magnetic resonance imaging findings.
12.4% of patients had SCA in NMOSD. Patients with SCA had a longer disease duration and higher EDSS at clinical onset and last visit. More importantly, SCA patients were more prone to reach disability milestones (EDSS ≥ 6.0). Bowel or bladder dysfunction, movement disorders, and sensory disturbances symptoms were more common in patients with SCA. ESR and CRP were significantly higher in patients with SCA than those without SCA. Patients with SCA were more frequently complicated with cervical cord lesions. However, the ARR, progression index, seropositive rate of NMO-IgG and OCB were similar in the two groups. Futhermore, LETM did not differ significantly between patients with SCA and without SCA in NMOSD patients.
Patients with SCA might have longer disease duration, more severe clinical disability, and more frequently complicated with cervical spinal cord lesions. SCA might be predictive of the more severe neurologic dysfunction and worse prognosis in NMOSD. Inflammation contributes to the development of SCA in NMOSD.
PMCID: PMC4302083  PMID: 25526927
Neuromyelitis optica spectrum disorders; Spinal cord atrophy; Longitudinally extensive transverse myelitis; Magnetic resonance imaging
24.  Behavioral disorders as unusual presentation of pediatric extraventricular neurocytoma: report on two cases and review of the literature 
BMC Neurology  2014;14(1):242.
Extraventricular neurocytomas (EVNs) are rare parenchymal brain tumors, distinct from central neurocytomas that are typically located within the supratentorial ventricular system. Seizures and headache represent the most common symptoms of extraventricular neurocytomas in the cerebral hemisphere both in adult and pediatric population.
Case presentation
We describe two cases of pediatric EVN with clinical onset characterized by behavioral and attention deficit/ hyperactivity disorders. The association between behavioral/attention disorders in childhood and the presence of a frontal neurocytoma has never been described before. Furthermore, inappropriate levels of inattention, hyperactivity and impulsivity are common among the neurobehavioral and developmental disorders in childhood. We reviewed 43 pediatric cases of extraventricular neurocytoma included in the PubMed database and their clinical presentation, and we never found this unusual relationship.
In childhood, the attention/hyperactivity disorders seem to be often over-diagnosed. When these deficits are more subtle and do not well-fit in a specific neurocognitive disorder, the clinicians should have a suspicion that they might mask the clinical features of a frontal lesion. This paper is focused on the clinical presentation of the extraventricular neurocytoma and the possible organic etiology of an attention and hyperactivity deficit.
PMCID: PMC4276055  PMID: 25524219
Extraventricular neurocytoma; Pediatric brain tumors; Behavioral disorder; Attention deficit/hyperactivity disorders
25.  Trigeminal isolated sensory neuropathy (TISN) and FOSMN syndrome: despite a dissimilar disease course do they share common pathophysiological mechanisms? 
BMC Neurology  2014;14(1):248.
Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms.
Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain.
The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex.
Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms.
PMCID: PMC4301795  PMID: 25527047
Trigeminal nerve; Neuronopathy; Trigeminal neuropathy; FOSMN; Facial pain

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