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1.  Is Intracranial Atherosclerosis an Independent Risk Factor for Cerebral Atrophy? A Retrospective Evaluation 
BMC Neurology  2008;8:51.
Background
Our purpose was to study the association between the intracranial atherosclerosis as measured by cavernous carotid artery calcification (ICAC) observed on head CT and atrophic changes of supra-tentorial brain demonstrated by MRI.
Methods
Institutional review board approval was obtained for this retrospective study incorporating 65 consecutive patients presenting acutely who had both head CT and MRI. Arterial calcifications of the intracranial cavernous carotids (ICAC) were assigned a number (1 to 4) in the bone window images from CT scans. These 4 groups were then combined into high (grades 3 and 4) and low calcium (grades 1 and 2) subgroups. Brain MRI was independently evaluated to identify cortical and central atrophy. Demographics and cardiovascular risk factors were evaluated in subjects with high and low ICAC. Relationship between CT demonstrated ICAC and brain atrophy patterns were evaluated both without and with adjustment for cerebral ischemic scores and cardiovascular risk factors.
Results
Forty-six of the 65 (71%) patients had high ICAC on head CT. Subjects with high ICAC were older, and had higher prevalence of hypertension, diabetes, coronary artery disease (CAD), atrial fibrillation and history of previous stroke (CVA) compared to those with low ICAC. Age demonstrated strong correlation with both supratentorial atrophy patterns. There was no correlation between ICAC and cortical atrophy. There was correlation however between central atrophy and ICAC. This persisted even after adjustment for age.
Conclusion
Age is the most important determinant of atrophic cerebral changes. However, high ICAC demonstrated age independent association with central atrophy.
doi:10.1186/1471-2377-8-51
PMCID: PMC2630977  PMID: 19102733
2.  In-hospital cerebrovascular complications following orthotopic liver transplantation: A retrospective study 
BMC Neurology  2008;8:52.
Background
Cerebrovascular complications are severe events following orthotopic liver transplantation (OLT). This study aimed to observe the clinical and neuroimaging features and possible risk factors of in-hospital cerebrovascular complications in the patients who underwent OLT.
Patients and methods
We retrospectively reviewed 337 consecutive patients who underwent 358 OLTs. Cerebrovascular complications were determined by clinical and neuroimaging manifestations, and the possible risk factors were analyzed in the patients with intracranial hemorrhage.
Results
Ten of 337 (3.0%) patients developed in-hospital cerebrovascular complications (8 cases experienced intracranial hemorrhage and 2 cases had cerebral infarction), and 6 of them died. The clinical presentations were similar to common stroke, but with rapid deterioration at early stage. The hematomas on brain CT scan were massive, irregular, multifocal and diffuse, and most of them were located at brain lobes and might enlarge or rebleed. Infarcts presented lacunar and multifocal lesions in basal gangliar but with possible hemorrhagic transformation. The patients with intracranial hemorrhage had older age and a more frequency of systemic infection than non-intracranial hemorrhage patients. (P = 0.011 and 0.029, respectively).
Conclusion
Posttransplant cerebrovascular complications have severe impact on outcome of the patients who received OLT. Older age and systemic infection may be the possible risk factors of in-hospital intracranial hemorrhage following OLT.
doi:10.1186/1471-2377-8-52
PMCID: PMC2636841  PMID: 19102759
3.  Role of MAPT mutations and haplotype in frontotemporal lobar degeneration in Northern Finland 
BMC Neurology  2008;8:48.
Background
Frontotemporal lobar degeneration (FTLD) consists of a clinically and neuropathologically heterogeneous group of syndromes affecting the frontal and temporal lobes of the brain. Mutations in microtubule-associated protein tau (MAPT), progranulin (PGRN) and charged multi-vesicular body protein 2B (CHMP2B) are associated with familial forms of the disease. The prevalence of these mutations varies between populations. The H1 haplotype of MAPT has been found to be closely associated with tauopathies and with sporadic FTLD. Our aim was to investigate MAPT mutations and haplotype frequencies in a clinical series of patients with FTLD in Northern Finland.
Methods
MAPT exons 1, 2 and 9–13 were sequenced in 59 patients with FTLD, and MAPT haplotypes were analysed in these patients, 122 patients with early onset Alzheimer's disease (eoAD) and 198 healthy controls.
Results
No pathogenic mutations were found. The H2 allele frequency was 11.0% (P = 0.028) in the FTLD patients, 9.8% (P = 0.029) in the eoAD patients and 5.3% in the controls. The H2 allele was especially clustered in patients with a positive family history (P = 0.011) but did not lower the age at onset of the disease. The ApoE4 allele frequency was significantly increased in the patients with eoAD and in those with FTLD.
Conclusion
We conclude that although pathogenic MAPT mutations are rare in Northern Finland, the MAPT H2 allele may be associated with increased risks of FTLD and eoAD in the Finnish population.
doi:10.1186/1471-2377-8-48
PMCID: PMC2625345  PMID: 19091059
4.  Identifying people at high risk for developing sleep apnea syndrome (SAS): a cross-sectional study in a Pakistani population 
BMC Neurology  2008;8:50.
Background
Obstructive Sleep Apnea (OSA) is associated with many cardiovascular and psychiatric diseases. Day-time sleepiness is a common consequence of sleep apnea and correlates with road-traffic accidents (RTA). Pakistan has a high prevalence of factors which predispose an individual to OSA and death from RTAs are a huge burden. However there is a dearth of prevalence studies in this regard. We aim to understand local relevance of the disease and estimate the prevalence of individuals high-risk for OSA.
Methods
This cross-sectional survey was conducted among 450 individuals at Aga Khan University Hospital (AKUH), which is a tertiary care teaching hospital in Pakistan. We used the BQ as our measurement tool. Based on the responses, participants were grouped into high or low-risk for OSA.
Results
Our study sample size was 418 with 63.2% males. Mean age of our study population was 30.4 SD +/- 12.3 years; and mean BMI was 23.2 SD +/- 5 kg/m2. Out of the total sample size 24.9% reported snoring and there were twice as many males who snored as compared to females. Forty-five individuals reported that they had nodded off to sleep while driving at least once in their lifetime. On the other hand, the highest proportion of high risk individuals 47.6% was found in the age group 60 or above. The overall prevalence of individuals who were high risk for sleep apnea was 10%.
Conclusion
A significant proportion of the population is at high-risk for OSA. Our study shows that despite low BMI and favorable craniofacial anatomy sleep apnea is still a locally relevant disease. Given the local relevance of OSAS, it is important to increase awareness among general population but more importantly among physicians of the developing countries, like Pakistan, about common clinical features and pertinent risk factors and complications of OSAS.
doi:10.1186/1471-2377-8-50
PMCID: PMC2615786  PMID: 19091126
5.  Impact of early applied upper limb stimulation: The EXPLICIT-stroke programme design 
BMC Neurology  2008;8:49.
Background
Main claims of the literature are that functional recovery of the paretic upper limb is mainly defined within the first month post stroke and that rehabilitation services should preferably be applied intensively and in a task-oriented way within this particular time window. EXplaining PLastICITy after stroke (acronym EXPLICIT-stroke) aims to explore the underlying mechanisms of post stroke upper limb recovery. Two randomized single blinded trials form the core of the programme, investigating the effects of early modified Constraint-Induced Movement Therapy (modified CIMT) and EMG-triggered Neuro-Muscular Stimulation (EMG-NMS) in patients with respectively a favourable or poor probability for recovery of dexterity.
Methods/design
180 participants suffering from an acute, first-ever ischemic stroke will be recruited. Functional prognosis at the end of the first week post stroke is used to stratify patient into a poor prognosis group for upper limb recovery (N = 120, A2 project) and a group with a favourable prognosis (N = 60, A1 project). Both groups will be randomized to an experimental arm receiving respectively modified CIMT (favourable prognosis) or EMG-NMS (poor prognosis) for 3 weeks or to a control arm receiving usual care. Primary outcome variable will be the Action Research Arm Test (ARAT), assessed at 1,2,3,4,5, 8, 12 and 26 weeks post stroke. To study the impact of modified CIMT or EMG-NMS on stroke recovery mechanisms i.e. neuroplasticity, compensatory movements and upper limb neuromechanics, 60 patients randomly selected from projects A1 and A2 will undergo TMS, kinematical and haptic robotic measurements within a repeated measurement design. Additionally, 30 patients from the A1 project will undergo fMRI at baseline, 5 and 26 weeks post stroke.
Conclusion
EXPLICIT stroke is a 5 year translational research programme which main aim is to investigate the effects of early applied intensive intervention for regaining dexterity and to explore the underlying mechanisms that are involved in regaining upper limb function after stroke. EXPLICIT-stroke will provide an answer to the key question whether therapy induced improvements are due to either a reduction of basic motor impairment by neural repair i.e. restitution of function and/or the use of behavioural compensation strategies i.e. substitution of function.
EXPLICIT is registered at the Netherlands Trial Register (NTR, ., TC 1424)
doi:10.1186/1471-2377-8-49
PMCID: PMC2630975  PMID: 19091088
6.  Significance of the parkin and PINK1 gene in Jordanian families with incidences of young-onset and juvenile parkinsonism 
BMC Neurology  2008;8:47.
Background
Parkinson's disease is a progressive neurodegenerative disorder, where most cases are sporadic with a late onset. In rare incidences familial forms of early-onset parkinsonism occur, and when recessively inherited, cases are often explained by mutations in either the parkin (PARK2) or PINK1 (PARK6) gene or on exceptional occasions the DJ-1 (PARK7) or ATP13A2 (PARK9) gene. Recessively inherited deletions/duplications and point mutations in the parkin gene are the most common cause of early-onset parkinsonism known so far, but in an increasing number of studies, genetic variations in the serine/threonine kinase domain of the PINK1 gene are found to explain early-onset parkinsonism.
Methods
In this study all families were from a population with a high incidence of consanguinity. We investigated 11 consanguineous families comprising 17 affected with recessively inherited young-onset parkinsonism for mutations both in the parkin and PINK1 gene. Exons and flanking regions were sequenced, and segregation patterns of genetic variation were assessed in members of the respective families. An exon dosage analysis was performed for all exons in both genes.
Results
In the parkin gene, a three generation family was identified with an exon 4 deletion segregating with disease. Both affected were homozygous for the deletion that segregated on a haplotype that spanned the gene in a haplotype segregation analysis that was performed using additional markers. Exon dosage analysis confirmed the recessive pattern of inheritance with heterozygous deletions segregating in healthy family members. In the PINK1 gene we identified two novel putative pathogenic substitutions, P416R and S419P, located in a conserved motif of the serine/threonine kinase domain. Both substitutions segregated with disease in agreement with a recessive pattern of inheritance within respective families and both were present as homozygous in two affected each. We also discuss common polymorphisms in the two genes found to be co-segregating within families.
Conclusion
Our results further extend on the involvement of PINK1 mutations in recessive early-onset parkinsonism with clinical features similar to carriers of parkin mutations.
doi:10.1186/1471-2377-8-47
PMCID: PMC2635385  PMID: 19087301
7.  Plasma brain natriuretic peptide as a surrogate marker for cardioembolic stroke 
BMC Neurology  2008;8:45.
Background
Cardioembolic stroke generally results in more severe disability, since it typically has a larger ischemic area than the other types of ischemic stroke. However, it is difficult to differentiate cardioembolic stroke from non-cardioembolic stroke (atherothrombotic stroke and lacunar stroke). In this study, we evaluated the levels of plasma brain natriuretic peptide in acute ischemic stroke patients with cardioembolic stroke or non-cardioembolic stroke, and assessed the prediction factors of plasma brain natriuretic peptide and whether we could differentiate between stroke subtypes on the basis of plasma brain natriuretic peptide concentrations in addition to patient's clinical variables.
Methods
Our patient cohort consisted of 131 consecutive patients with acute cerebral infarction who were admitted to Kagawa University School of Medicine Hospital from January 1, 2005 to December 31, 2007. The mean age of patients (43 females, 88 males) was 69.6 ± 10.1 years. Sixty-two patients had cardioembolic stroke; the remaining 69 patients had non-cardioembolic stroke (including atherothrombotic stroke, lacunar stroke, or the other). Clinical variables and the plasma brain natriuretic peptide were evaluated in all patients.
Results
Plasma brain natriuretic peptide was linearly associated with atrial fibrillation, heart failure, chronic renal failure, and left atrial diameter, independently (F4,126 = 27.6, p < 0.0001; adjusted R2 = 0.45). Furthermore, atrial fibrillation, mitral regurgitation, plasma brain natriuretic peptide (> 77 pg/ml), and left atrial diameter (> 36 mm) were statistically significant independent predictors of cardioembolic stroke in the multivariable setting (Χ2 = 127.5, p < 0.001).
Conclusion
It was suggested that cardioembolic stroke was strongly predicted with atrial fibrillation and plasma brain natriuretic peptide. Plasma brain natriuretic peptide can be a surrogate marker for cardioembolic stroke.
doi:10.1186/1471-2377-8-45
PMCID: PMC2621245  PMID: 19077217
8.  A randomised controlled trial evaluating the effect of an individual auditory cueing device on freezing and gait speed in people with Parkinson's disease 
BMC Neurology  2008;8:46.
Background
Parkinson's disease is a progressive neurological disorder resulting from a degeneration of dopamine producing cells in the substantia nigra. Clinical symptoms typically affect gait pattern and motor performance. Evidence suggests that the use of individual auditory cueing devices may be used effectively for the management of gait and freezing in people with Parkinson's disease. The primary aim of the randomised controlled trial is to evaluate the effect of an individual auditory cueing device on freezing and gait speed in people with Parkinson's disease.
Methods
A prospective multi-centre randomised cross over design trial will be conducted. Forty-seven subjects will be randomised into either Group A or Group B, each with a control and intervention phase. Baseline measurements will be recorded using the Freezing of Gait Questionnaire as the primary outcome measure and 3 secondary outcome measures, the 10 m Walk Test, Timed "Up & Go" Test and the Modified Falls Efficacy Scale. Assessments are taken 3-times over a 3-week period. A follow-up assessment will be completed after three months. A secondary aim of the study is to evaluate the impact of such a device on the quality of life of people with Parkinson's disease using a qualitative methodology.
Conclusion
The Apple iPod-Shuffle™ and similar devices provide a cost effective and an innovative platform for integration of individual auditory cueing devices into clinical, social and home environments and are shown to have immediate effect on gait, with improvements in walking speed, stride length and freezing. It is evident that individual auditory cueing devices are of benefit to people with Parkinson's disease and the aim of this randomised controlled trial is to maximise the benefits by allowing the individual to use devices in both a clinical and social setting, with minimal disruption to their daily routine.
Trial registration
The protocol for this study is registered with the US NIH Clinical Trials Registry (NCT00727467).
doi:10.1186/1471-2377-8-46
PMCID: PMC2630976  PMID: 19077238
9.  Quantitative electroencephalography reveals different physiological profiles between benign and remitting-relapsing multiple sclerosis patients 
BMC Neurology  2008;8:44.
Background
A possible method of finding physiological markers of multiple sclerosis (MS) is the application of EEG quantification (QEEG) of brain activity when the subject is stressed by the demands of a cognitive task. In particular, modulations of the spectral content that take place in the EEG of patients with multiple sclerosis remitting-relapsing (RRMS) and benign multiple sclerosis (BMS) during a visuo-spatial task need to be observed.
Methods
The sample consisted of 19 patients with RRMS, 10 with BMS, and 21 control subjects. All patients were free of medication and had not relapsed within the last month. The power spectral density (PSD) of different EEG bands was calculated by Fast-Fourier-Transformation (FFT), those analysed being delta, theta, alpha, beta and gamma. Z-transformation was performed to observe individual profiles in each experimental group for spectral modulations. Lastly, correlation analyses was performed between QEEG values and other variables from participants in the study (age, EDSS, years of evolution and cognitive performance).
Results
Nearly half (42%) the RRMS patients showed a statistically significant increase of two or more standard deviations (SD) compared to the control mean value for the beta-2 and gamma bands (F = 2.074, p = 0.004). These alterations were localized to the anterior regions of the right hemisphere, and bilaterally to the posterior areas of the scalp. None of the BMS patients or control subjects had values outside the range of ± 2 SD. There were no significant correlations between these values and the other variables analysed (age, EDSS, years of evolution or behavioural performance).
Conclusion
During the attentional processing, changes in the high EEG spectrum (beta-2 and gamma) in MS patients exhibit physiological alterations that are not normally detected by spontaneous EEG analysis. The different spectral pattern between pathological and controls groups could represent specific changes for the RRMS patients, indicative of compensatory mechanisms or cortical excitatory states representative of some phases during the RRMS course that are not present in the BMS group.
doi:10.1186/1471-2377-8-44
PMCID: PMC2628940  PMID: 19025654
10.  Long-term effects of STN DBS on mood: psychosocial profiles remain stable in a 3-year follow-up 
BMC Neurology  2008;8:43.
Background
Deep brain stimulation of the subthalamic nucleus significantly improves motor function in patients with severe Parkinson's disease. However, the effects on nonmotor aspects remain uncertain. The present study investigated the effects of subthalamic nucleus deep brain stimulation on mood and psychosocial functions in 33 patients with advanced Parkinson's disease in a three year follow-up.
Methods
Self-rating questionnaires were administered to 33 patients prior to surgery as well as three, six, twelve and 36 months after surgery.
Results
In the long run, motor function significantly improved after surgery. Mood and psychosocial functions transiently improved at one year but returned to baseline at 36 months after surgery. In addition, we performed cluster and discriminant function analyses and revealed four distinct psychosocial profiles, which remained relatively stable in the course of time. Two profiles featured impaired psychosocial functioning while the other two of them were characterized by greater psychosocial stability.
Conclusion
Compared to baseline no worsening in mood and psychosocial functions was found three years after electrode implantation. Moreover, patients can be assigned to four distinct psychosocial profiles that are relatively stable in the time course. Since these subtypes already exist preoperatively the extent of psychosocial support can be anticipatory adjusted to the patients' needs in order to enhance coping strategies and compliance. This would allow early detection and even prevention of potential psychiatric adverse events after surgery. Given adequate psychosocial support, these findings imply that patients with mild psychiatric disturbances should not be excluded from surgery.
doi:10.1186/1471-2377-8-43
PMCID: PMC2596774  PMID: 19014430
11.  The predictive value of transcranial duplex sonography for the clinical diagnosis in undiagnosed parkinsonian syndromes: comparison with SPECT scans 
BMC Neurology  2008;8:42.
Background
Transcranial duplex sonography (TCD) of the substantia nigra has emerged as a promising, non-invasive tool to diagnose idiopathic Parkinson's disease (IPD). However, its diagnostic accuracy in patients with undefined parkinsonism remains to be determined.
In this study we determined the predictive value of TCD for the clinical diagnosis in undiagnosed parkinsonian syndromes. Additionally we compared the predictive value of TCD with that of presynaptic and postsynaptic single photon emission computer tomography (SPECT) scans.
Methods
We studied 82 patients with an unclassified parkinsonian syndrome. All 82 patients were subjected to a TCD, 59 of them underwent a presynaptic SPECT scans and 32 underwent a postsynaptic SPECT scan.
We determined the diagnostic accuracy of TCD and SPECT scans in differentiating:
1) IPD patients from patients without nigrostriatal degeneration and 2) IPD patients from patients with atypical parkinsonian syndromes (APS).
To compare the diagnostic accuracy of TCD and SPECT scans, we used the clinical diagnosis after follow-up according to generally accepted clinical criteria as the gold standard. This clinical diagnosis was determined by a movement disorder specialist.
3) Finally, we ascertained the predictive value of the TCD for the SPECT result.
Results
The clinical diagnoses after follow-up resulted in 51 cases of IPD, 7 patients with APS and 17 patients without nigrostriatal degeneration. In total 7 patients remained undiagnosed.
1) The accuracy of TCD, assessed by sensitivity and specificity, to differentiate IPD patients from patients without nigrostriatal degeneration was 50% and 82% respectively.
For the presynaptic SPECT scans sensitivity was 97% and specificity 100%.
2) In differentiating IPD patients from APS patients, the sensitivity and specificity of TCD was 50% and 43% respectively. For presynaptic SPECT scans this was 97% and 0%. For the postsynaptic SPECT scans the sensitivity was 75% and the specificity 81%.
3) The positive predictive value (PPV) of an abnormal TCD for an abnormal presynaptic SPECT scan was 88%.
Conclusion
Presynaptic SPECT scanning has a higher predictive value for the clinical diagnosis than TCD. However, since the PPV of an abnormal TCD for parkinsonism with nigrostriatal degeneration is high, TCD might be used as screening tool, before ordering a presynaptic SPECT.
doi:10.1186/1471-2377-8-42
PMCID: PMC2628347  PMID: 18992168
12.  Skin-impedance in Fabry Disease: A prospective, controlled, non-randomized clinical study 
BMC Neurology  2008;8:41.
Background
We previously demonstrated improved sweating after enzyme replacement therapy (ERT) in Fabry disease using the thermo-regularity sweat and quantitative sudomotor axon reflex tests. Skin-impedance, a measure skin-moisture (sweating), has been used in the clinical evaluation of burns and pressure ulcers using the portable dynamic dermal impedance monitor (DDIM) system.
Methods
We compared skin impedance measurements in hemizygous patients with Fabry disease (22 post 3-years of bi-weekly ERT and 5 ERT naive) and 22 healthy controls. Force compensated skin-moisture values were used for statistical analysis. Outcome measures included 1) moisture reading of the 100th repetitive reading, 2) rate of change, 3) average of 60–110th reading and 4) overall average of all readings.
Results
All outcome measures showed a significant difference in skin-moisture between Fabry patients and control subjects (p < 0.0001). There was no difference between Fabry patients on ERT and patients naïve to ERT. Increased skin-impedance values for the four skin-impedance outcome measures were found in a small number of dermatome test-sites two days post-enzyme infusions.
Conclusion
The instrument portability, ease of its use, a relatively short time required for the assessment, and the fact that DDIM system was able to detect the difference in skin-moisture renders the instrument a useful clinical tool.
doi:10.1186/1471-2377-8-41
PMCID: PMC2585087  PMID: 18990229
13.  Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933] 
BMC Neurology  2008;8:40.
Background
The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question.
Design
GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage.
Conclusion
372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients.
Trial Registration
Current Controlled Trials
ISRCTN45122933
doi:10.1186/1471-2377-8-40
PMCID: PMC2605746  PMID: 18959773
14.  Risk factors for dementia in the epidemiological study of Munguialde County (Basque Country-Spain) 
BMC Neurology  2008;8:39.
Background
Prevalence of degenerative dementias and dementias associated with cerebrovascular disease is increasing. Dementia is one of the most significant public health problem. In recent years, the role of vascular risk factors (hypertension, diabetes mellitus and hypercholesterolemia) and depression has been evaluated.
The incidence of dementia and risk factors has not been fully investigated in Spain. The aim of this study was to identify the risk factors for dementia, Alzheimer's disease (AD) and vascular dementia (VD) in elderly people in Munguialde County (Spain).
Methods
A two phase, door-to-door populational study was performed. Demographic variables and the presence of vascular risk factors and depression were recorded. The MMSE, the DSM-IV and the conventional criteria for AD and VD were used in the evaluation. The odds ratio for each risk factor was calculated by logistic regression analysis.
Results
1756 healthy subjects and 175 patients with dementia participated in the study. Of these, 133 had AD, 15 VD and the remainder other dementias. The risk factors for dementia and AD were female sex (OR = 1.67 and 1.97, respectively); age (OR = 1.14 and 1.15); stroke (OR = 7.84 and 3); and depression (OR = 53.08 and 3.19). Stroke was the only risk factor for VD (OR = 119).
Conclusion
Greater age, female sex, stroke and depression increase the risk of suffering dementia, AD and VD. The relationship between depression, vascular risk factors and dementia has clear public health implications. Prevention and early treatment of vascular risk factors and depression may have an important impact in lowering the risk of dementia and could modify the natural history of the disease.
doi:10.1186/1471-2377-8-39
PMCID: PMC2584030  PMID: 18922150
15.  A novel needle for subcutaneous injection of interferon beta-1a: effect on pain in volunteers and satisfaction in patients with multiple sclerosis 
BMC Neurology  2008;8:38.
Background
To reduce injection pain and improve satisfaction, a thinner (29-gauge [29G]), sharper (5-bevel) needle than the 27G/3-bevel needle used previously to inject interferon (IFN) beta-1a, 44 or 22 mcg subcutaneously (sc) three times weekly (tiw), was developed for use in multiple sclerosis (MS).
Methods
Two clinical trials in healthy volunteers and five surveys of patients with MS were conducted to assess whether the 29G/5-bevel needle with a Thermo Plastic Elastomer (TPE) needle shield (a sleeve that houses the tip of the needle in a secure location) is an improvement over the 27G/3-bevel needle with a rubber shield for injection of IFN beta-1a, 44 or 22 mcg sc tiw. Parameters assessed were: pain and ease of insertion (healthy volunteer and nurse responses on subjective pain measurement scales); and patient satisfaction (surveys of patients with MS).
Results
In healthy volunteers, the 29G/5-bevel needle with TPE shield was associated with the least perceived pain on the Visual Analog Scale (VAS) and Verbal VAS (VB-VAS); mean VAS pain scores decreased by 40% and skin penetration improved by 69% compared with the 27G/3-bevel needle with standard rubber shield (p < 0.01). Pooled results from surveys of patients with MS indicated that 63% of patients thought that injections were less painful with the 29G/5-bevel needle than the 27G/3-bevel needle. Results from individual surveys indicated that the 29G/5-bevel needle was an improvement over the 27G/3-bevel needle for ease of insertion, injection-site reactions, bruising, burning and stinging.
Conclusion
Together these studies indicate that the 29G/5-bevel needle with the TPE shield is an improvement over the 27G/3-bevel needle with standard rubber shield in terms of pain, ease of insertion and patient satisfaction. These improvements are expected to result in improved compliance in patients with MS treated with IFN beta-1a, 44 or 22 mcg sc tiw.
doi:10.1186/1471-2377-8-38
PMCID: PMC2577094  PMID: 18845005
16.  The effect of coaching on the simulated malingering of memory impairment 
BMC Neurology  2008;8:37.
Background
Detecting malingering or exaggeration of impairments in brain function after traumatic brain injury is of increasing importance in neuropsychological assessment. Lawyers involved in brain injury litigation cases routinely coach their clients how to approach neuropsychological testing to their advantage. Thus, it is important to know how robust assessment methods are with respect to symptom malingering or exaggeration.
Methods
The influence of different coaching methods on the simulated malingering of memory impairments is investigated in neurologically healthy participants using the Short-Term-Memory Test from the Bremer Symptom-Validierung (STM-BSV). Cut-offs were derived from patients with mild to severe traumatic brain injury. For comparison purposes, the German adaptation of the Rey Auditory Verbal Learning Test (AVLT), and the Rey 15 Items Test (FIT) were additionally administered. Four groups of neurologically healthy subjects were instructed to (1) perform as best as they can, (2) simulate brain injury, (3) simulate brain injury and received additional information about the sequelae of head trauma, (4) simulate brain injury and received additional information on how to avoid detection. Furthermore, a group of patients with mild to severe closed head injury performed the tests with best effort.
Results
The naïve simulator and the symptom coached groups were the easiest to detect, whereas the symptom plus test coached group was the hardest to detect. The AVLT and the FIT were not suited to detect simulators (sensitivities from 0% to 50.8% at 75% specificity) whereas the STM-BSV detected simulators with 67% – 88% sensitivity at a specificity of 73%. However, the STM-BSV was not robust to coaching.
Conclusion
The present investigation shows that symptom validity testing as implemented in the BSV-STM is one clinically useful element in the detection of memory malingering. However, clinicians have to be aware that coaching influences performance in the test.
doi:10.1186/1471-2377-8-37
PMCID: PMC2569062  PMID: 18838010
17.  Perceived needs and satisfaction with care in people with multiple sclerosis: A two-year prospective study 
BMC Neurology  2008;8:36.
Background
Considering the costs of multiple sclerosis (MS), it is crucial that the health-related services supplied are in accordance with needs as they are perceived by people with MS (PwMS). Satisfaction with care is related to quality of care and can provide health care providers with the means for improvement. The aim was to explore the perceived needs and satisfaction with care amongst PwMS over a two-year period, also taking sex and disease severity into consideration.
Methods
The sample consisted of 219 outpatients at a MS specialist clinic. Data on perceived needs and satisfaction with care were collected every six months using a questionnaire which included various dimensions of care. The data was analysed for the whole sample and on an individual level, as well as in subgroups with regard to sex and disease severity.
Results
There were no statistically significant variations in the proportion of PwMS with perceived needs concerning different health-related services during the study period. However, individual variations were found with regard to both perceived needs and satisfaction with care. Few PwMS perceived a continuous need for a specific service. However, the majority perceived a need for rehabilitation, assistive devices, transportation service for the disabled, psychosocial support/counselling and information on social insurance/vocational rehabilitation at least sometimes. Severe MS was associated with a greater perceived need for almost all the services studied and women experienced a need for psychosocial support/counselling to a greater extent than men. In relation to the different categories of health care staff, PwMS were most satisfied with nurses with regard to all dimensions of care. They were least satisfied with the availability of psychosocial support/counselling; and information about social insurance/vocational rehabilitation.
Conclusion
Despite the large proportion of individuals with mild disease severity in our sample, a considerable number of needs were identified of which many, on an individual level, varied over time. Key services demanded by PwMS were identified. Also the level of satisfaction with care varied and areas with a potential for improvement were identified such as the availability of rehabilitation services including an increase in the supply of psychosocial support and counselling.
doi:10.1186/1471-2377-8-36
PMCID: PMC2569963  PMID: 18823543
18.  Cross-modal deactivations during modality-specific selective attention 
BMC Neurology  2008;8:35.
Background
Processing stimuli in one sensory modality is known to result in suppression of other sensory-specific cortices. Additionally, behavioral experiments suggest that the primary consequence of paying attention to a specific sensory modality is poorer task performance in the unattended sensory modality. This study was designed to determine how focusing attention on the auditory or visual modality impacts neural activity in cortical regions responsible for processing stimuli in the unattended modality.
Methods
Functional MRI data were collected in 15 participants who completed a cued detection paradigm. This task allowed us to assess the effects of modality-specific attention both during the presence and the absence of targets in the attended modality.
Results
The results of this experiment demonstrate that attention to a single sensory modality can result in decreased activity in cortical regions that process information from an unattended sensory modality (cross-modal deactivations). The effects of attention are likely additive with stimulus-driven effects with the largest deactivations being observed during modality-specific selective attention, in the presence of a stimulus in that modality.
Conclusion
Modality-specific selective attention results in behavioral decrements in unattended sensory modalities. The imaging results presented here provide a neural signature (cross-modal deactivation) for modality-specific selective attention.
doi:10.1186/1471-2377-8-35
PMCID: PMC2569962  PMID: 18817554
19.  A pilot study of rivastigmine in the treatment of delirium after stroke: A safe alternative 
BMC Neurology  2008;8:34.
Background
Delirium is a common disorder in the early phase of stroke. Given the presumed cholinergic deficiency in delirium, we tested treatment with the acetylcholinesterase inhibitor rivastigmine.
Methods
This pilot study was performed within an epidemiological study. In 527 consecutive stroke patients presence of delirium was assessed during the first week with the confusion assessment method. Severity was scored with the delirium rating scale (DRS). Sixty-two patients developed a delirium in the acute phase of stroke. Only patients with a severe and persistent delirium (defined as a DRS of 12 or more for more than 24 hours) were enrolled in the present study. In total 26 fulfilled these criteria of whom 17 were treated with orally administered rivastigmine with a total dose between 3 and 12 mg a day. Eight patients could not be treated because of dysphagia and one because of early discharge.
Results
No major side effects were recorded. In 16 patients there was a considerable decrease in severity of delirium. The mean DRS declined from 14.8 on day one to 8.5 after therapy and 5.6 after tapering. The mean duration of delirium was 6.7 days (range; 2–17).
Conclusion
Rivastigmine is safe in stroke patients with delirium even after rapid titration. In the majority of patients the delirium improved after treatment. A randomized controlled trial is needed to establish the usefulness of rivastigmine in delirium after stroke.
Trial registration
Nederlands Trial Register NTR1395
doi:10.1186/1471-2377-8-34
PMCID: PMC2556687  PMID: 18803862
20.  Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: A double-blind placebo-controlled trial 
BMC Neurology  2008;8:33.
Background
Recent consensus guidelines recommend pregabalin as a first-tier treatment for painful diabetic peripheral neuropathy (DPN). We evaluated the efficacy of pregabalin 600 mg/d (300 mg dosed BID) versus placebo for relieving DPN-associated neuropathic pain, and assessed its safety using objective measures of nerve conduction (NC).
Methods
In this randomized, double-blind, placebo-controlled trial, the primary efficacy measure was endpoint mean pain score (MPS) from daily pain diaries (11-point scale). NC velocity and sensory and motor amplitudes were assessed at baseline, endpoint, and end of follow-up (2 weeks post-treatment). At each timepoint, the median-motor, median-sensory, ulnar-sensory, and peroneal-motor nerves were evaluated. Secondary efficacy measures included weekly MPS and proportion of responders (patients achieving ≥50% reduction in MPS from baseline to endpoint). After 1-weeks' dosage escalation, pregabalin-treated patients received 300 mg BID for 12 weeks.
Results
Eighty-two patients received pregabalin and 85 placebo. Mean durations were 10 years for diabetes and ~5 years for painful DPN. Pregabalin-treated patients had lower MPS than controls (mean difference, -1.28; p <.001). For all four nerves, 95% CIs for median differences in amplitude and velocity from baseline to endpoint and baseline to follow-up included 0 (ie, no significant difference vs. placebo). Significant pain improvement among pregabalin-treated patients was evident at week 1 and sustained at every weekly timepoint. More pregabalin-treated patients (49%) than controls (23%) were responders (p <.001).
Conclusion
Pregabalin 600 mg/d (300 mg BID) effectively reduced pain, was well tolerated, and had no statistically significant or clinically meaningful effect on NC in patients with painful DPN.
Trial registration
ClinicalTrials.gov NCT00159679
doi:10.1186/1471-2377-8-33
PMCID: PMC2565674  PMID: 18796160
21.  Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9 
BMC Neurology  2008;8:32.
Background
Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND.
Methods
Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing.
Results
Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree.
Conclusion
Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.
doi:10.1186/1471-2377-8-32
PMCID: PMC2553097  PMID: 18755042
22.  The leukoaraiosis is more prevalent in the large artery atherosclerosis stroke subtype among Korean patients with ischemic stroke 
BMC Neurology  2008;8:31.
Background
Several studies have suggested that the specific stroke subtype may influence the presence of leukoaraiosis in patients with ischemic stroke. We investigated the association between stroke subtype and leukoaraiosis in Korean patients with ischemic stroke by MRI.
Methods
There were 594 patients included in this study that were classified as large artery disease, lacune and cardioembolic stroke. For large-artery disease, the analysis focused on the intracranial or extracranial location of the stenosis, and the multiplicity of the stenotic lesions. Leukoaraiosis grading was performed according to the Atherosclerosis Risk in Communities Study.
Results
There was a significant association between leukoaraiosis and the stroke subtypes; the large-artery-disease group had a higher prevalence of leukoaraiosis than did the other groups (55.4% in the large-artery-disease group, 30.3% in the lacunar group and 14.3% in the cardioembolic group, P = 0.016 by chi-square test). On the multivariate linear regression analysis, age, the presence of hypertension, previous stroke and stroke subtype were independently associated with the presence of leukoaraiosis. In the sub analysis of the large-artery-disease group, the leukoaraiosis had a tendency to be more prevalent in the mixed and intracranial stenosis group than did the extracranial stenosis group (45.5% in the mixed group, 40.3% in the intracranial group and 26.9% in the extracranial group, P = 0.08 by chi-square test).
Conclusion
The association of leukoaraiosis with large-artery disease in this study might be due to the relatively high prevalence of intracranial occlusive lesions in Korean stroke patients compared to other ethnic groups.
doi:10.1186/1471-2377-8-31
PMCID: PMC2532686  PMID: 18687146
23.  No effect of preterm birth on the risk of multiple sclerosis: a population based study 
BMC Neurology  2008;8:30.
Background
Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. A clear parent of origin effect has been shown in several populations, perhaps resulting from factors operating during gestation. Preterm birth (birth at less than 37 weeks gestational age) has been shown to result in long-term health problems, including impaired neurological development. Here, in a population-based cohort, we investigate whether preterm birth increases the risk to subsequently develop MS.
Methods
We identified 6585 MS index cases and 2509 spousal controls with preterm birth information from the Canadian Collaborative Project on Genetic Susceptibility to MS. Rates of individuals born preterm were compared for index cases and controls.
Results
There were no significant differences between cases and controls with respect to preterm births. 370 (5.6%) MS index cases and 130 (5.2%) spousal controls were born preterm, p = 0.41.
Conclusion
Preterm birth does not appear to contribute to MS aetiology. Other factors involved in foetal and early development need to be explored to elucidate the mechanism of the increased risk conferred by the apparent maternal effect.
doi:10.1186/1471-2377-8-30
PMCID: PMC2518551  PMID: 18673559
24.  Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials 
BMC Neurology  2008;8:29.
Background
Duloxetine hydrochloride is a reuptake inhibitor of 5-hydroxytryptamine and norepinephrine used to treat depression, generalized anxiety disorder, neuropathic pain, and stress incontinence in women. We investigated the efficacy of duloxetine in painful diabetic neuropathy and fibromyalgia to allow comparison with other antidepressants.
Methods
We searched PubMed, EMBASE (via Ovid), and Cochrane CENTRAL up to June 2008 for randomised controlled trials using duloxetine to treat neuropathic pain.
Results
We identified six trials with 1,696 patients: 1,510 were treated with duloxetine and 706 with placebo. All patients had established baseline pain of at least moderate severity. Trial duration was 12 to 13 weeks. Three trials enrolled patients with painful diabetic neuropathy (PDN) and three enrolled patients with fibromyalgia. The number needed to treat (NNT) for at least 50% pain relief at 12 to 13 weeks with duloxetine 60 mg versus placebo (1,211 patients in the total comparison) was 5.8 (95% CI 4.5 to 8.4), and for duloxetine 120 mg (1,410 patients) was 5.7 (4.5 to 5.7). There was no difference in NNTs between PDN and fibromyalgia. With all doses of duloxetine combined (20/60/120 mg) there were fewer withdrawals for lack of efficacy than with placebo (number needed to treat to prevent one withdrawal 20 (13 to 42)), but more withdrawals due to adverse events (number needed to harm (NNH) 15 (11 to 25)). Nausea, somnolence, constipation, and reduced appetite were all more common with duloxetine than placebo (NNH values 6.3, 11, 11, and 18 respectively). The results for duloxetine are compared with published data for other antidepressants in neuropathic pain.
Conclusion
Duloxetine is equally effective for the treatment of PDN and fibromyalgia, judged by the outcome of at least 50% pain relief over 12 weeks, and is well tolerated. The NNT of 6 for 50% pain relief suggests that this is likely to be a useful drug in these difficult-to-treat conditions, where typically only a minority of patients respond. Comparing duloxetine with antidepressants for pain relief in DPN shows inadequacies in the evidence for efficacy of antidepressants, which are currently recommended in PDN care pathways.
doi:10.1186/1471-2377-8-29
PMCID: PMC2529342  PMID: 18673529
25.  Do nasogastric tubes worsen dysphagia in patients with acute stroke? 
BMC Neurology  2008;8:28.
Background
Early feeding via a nasogastric tube (NGT) is recommended as safe way of supplying nutrition in patients with acute dysphagic stroke. However, preliminary evidence suggests that NGTs themselves may interfere with swallowing physiology. In the present study we therefore investigated the impact of NGTs on swallowing function in acute stroke patients.
Methods
In the first part of the study the incidence and consequences of pharyngeal misplacement of NGTs were examined in 100 stroke patients by fiberoptic endoscopic evaluation of swallowing (FEES). In the second part, the effect of correctly placed NGTs on swallowing function was evaluated by serially examining 25 individual patients with and without a NGT in place.
Results
A correctly placed NGT did not cause a worsening of stroke-related dysphagia. Except for two cases, in which swallowing material got stuck to the NGT and penetrated into the laryngeal vestibule after the swallow, no changes of the amount of penetration and aspiration were noted with the NGT in place as compared to the no-tube condition. Pharyngeal misplacement of the NGT was identified in 5 of 100 patients. All these patients showed worsening of dysphagia caused by the malpositioned NGT with an increase of pre-, intra-, and postdeglutitive penetration.
Conclusion
Based on these findings, there are no principle obstacles to start limited and supervised oral feeding in stroke patients with a NGT in place.
doi:10.1186/1471-2377-8-28
PMCID: PMC2507716  PMID: 18651972

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