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1.  Acute fatal posthypoxic leukoencephalopathy following benzodiazepine overdose: a case report and review of the literature 
BMC Neurology  2015;15:69.
Among the rare neurological complications of substances of abuse is the selective cerebral white matter injury (leukoencephalopathy). Of which, the syndrome of delayed post hypoxic encephalopathy (DPHL) that follows an acute drug overdose, in addition to “chasing the dragon” toxicity which results from chronic heroin vapor inhalation remain the most commonly described syndromes of toxic leukoencephalopathy. These syndromes are reported in association with opioid use. There are very few cases in the literature that described leukoencephalopathy following benzodiazepines, especially with an acute and progressive course. In this paper, we present a patient who developed an acute severe fatal leukoencephalopathy following hypoxic coma and systemic shock induced by benzodiazepine overdose.
Case presentation
A 19-year-old male was found comatose at home and brought to hospital in a deep coma, shock, hypoxia, and acidosis. Brain magnetic resonant imaging (MRI) revealed a strikingly selective white matter injury early in the course of the disease. The patient remained in a comatose state with no signs of neurologic recovery until he died few weeks later following an increase in the brain edema and herniation.
Toxic leukoencephalopathy can occur acutely following an overdose of benzodiazepine and respiratory failure. This is unlike the usual cases of toxic leukoencephalopathy where there is a period of lucidity between the overdose and the development of white matter disease. Unfortunately, this syndrome remains of an unclear pathophysiology and with no successful treatment.
PMCID: PMC4418099  PMID: 25925073
Delayed post-hypoxic leukoencephalopathy; Leukoencephalopathy; Benzodiazepines; Alprazolam; Coma; Hypoxia; Herniation; Demyelination; Acidosis; Toxin; Drugs of abuse
2.  Complex interventional treatment in a patient with atrial fibrillation and stroke caused by large carotid artery thrombus: a case report 
BMC Neurology  2015;15:62.
The treatment option for acute ischaemic stroke depends on the duration of symptoms, the dynamics of neurological condition changes, the aetiology, type of stroke, as well as the results of angiographic and neuroimaging tests.
Case presentation
A 60-year-old male patient presented with progressive left hemisphere stroke caused by extensive cardiogenic embolism of the common carotid artery and a thrombus closing the internal carotid artery from its ostium to the level of its intracranial division. The complex revascularisation therapy involving surgical embolectomy of the common carotid artery, thrombectomy of the internal carotid artery and intra-arterial thrombolysis has led to the improvement of arterial patency and has countered the progression of acute cerebral ischaemia.
Emergency carotid embolectomy together with thrombectomy and local thrombolytic rt-PA treatment may be a reasonable rescue therapy for carefully selected patients with large-vessel acute stroke. Further research is needed to establish the advantages and safety of surgical thrombectomy in patients with acute embolic occlusion of the carotid artery and ineffectiveness of or contraindications for systemic thrombolytic treatment.
PMCID: PMC4417224  PMID: 25902793
Stroke; Atrial fibrillation; Arterial thrombolysis; Embolectomy; Thrombectomy
3.  A study on the natural history of scanning behaviour in patients with visual field defects after stroke 
BMC Neurology  2015;15:64.
A visual field defect (VFD) is a common consequence of stroke with a detrimental effect upon the survivors’ functional ability and quality of life. The identification of effective treatments for VFD is a key priority relating to life post-stroke. Understanding the natural evolution of scanning compensation over time may have important ramifications for the development of efficacious therapies.
The study aims to unravel the natural history of visual scanning behaviour in patients with VFD. The assessment of scanning patterns in the acute to chronic stages of stroke will reveal who does and does not learn to compensate for vision loss.
Eye-tracking glasses are used to delineate eye movements in a cohort of 100 stroke patients immediately after stroke, and additionally at 6 and 12 months post-stroke. The longitudinal study will assess eye movements in static (sitting) and dynamic (walking) conditions.
The primary outcome constitutes the change of lateral eye movements from the acute to chronic stages of stroke. Secondary outcomes include changes of lateral eye movements over time as a function of subgroup characteristics, such as side of VFD, stroke location, stroke severity and cognitive functioning.
The longitudinal comparison of patients who do and do not learn compensatory scanning techniques may reveal important prognostic markers of natural recovery. Importantly, it may also help to determine the most effective treatment window for visual rehabilitation.
PMCID: PMC4417296  PMID: 25907452
Hemianopia; Eye tracking; Longitudinal; Stroke; Walking; Dynamic assessment
4.  DRD and GRIN2B polymorphisms and their association with the development of impulse control behaviour among Malaysian Parkinson’s disease patients 
BMC Neurology  2015;15:59.
Impulse control disorder (ICD) and behaviours (ICB) represent a group of behavioural disorders that have become increasingly recognised in Parkinson’s disease (PD) patients who previously used dopaminergic medications, particularly dopamine agonists and levodopa. It has been suggested that these medications can lead to the development of ICB through the abnormal modulation of dopaminergic transmission and signalling in the mesocorticolimbic dopaminergic system. Several studies have reported an association between polymorphisms in the dopamine receptor (DRD) and N-methyl-D-aspartate 2B (GRIN2B) genes with the development of ICB in PD (PD-ICB) patients. Thus, this study aimed to investigate the association of selected polymorphisms within the DRD and GRIN2B genes with the development of ICB among PD patients using high resolution melt (HRM) analysis.
We used high resolution melt (HRM) analysis to genotype 11 polymorphisms in 5 DRD genes [DRD1 (rs4532, rs4867798 and rs265981), DRD2 (ANKK1 rs1800497, rs104894220 and rs144999500), DRD3 (rs3732783 and rs6280), DRD4 (rs1800443), and DRD5 (rs144132215)] and 1 polymorphism in GRIN2B (rs7301328) in PD patients with (cases, n = 52) and without (controls, n = 39) ICB. Cases were obtained from two tertiary movement disorder centres [UKMMC (n = 9) and UMMC (n = 43)]. At both centres, the diagnosis of ICB was made using the QUIP questionnaire. Controls were recruited from PD patients who attended UKMMC and were found to be negative for ICB using the QUIP questionnaire.
The HRM analysis showed that 7 of 11 polymorphisms [DRD1 (rs4532, rs4867798, and rs265981), DRD2 (ANKK1 rs1800497), DRD3 (rs3732783 and rs6280), and GRIN2B (rs7301328)] exhibited a clear distinction between wild-type and variant alleles. Variants of DRD2/ANKK1 rs1800497 (OR = 3.77; 95% CI, 1.38-10.30; p = 0.0044), DRD1 rs4867798 (OR = 24.53; 95% CI, 1.68-357.28; p = 0.0054), DRD1 rs4532 (OR = 21.33; 95% CI, 1.97-230.64; p = 0.0024), and GRIN2B rs7301328 (OR = 25.07; 95% CI, 1.30-483.41; p = 0.0097) were found to be associated with an increased risk of developing ICB among PD patients.
Our findings suggest that polymorphisms in dopamine [DRD1 (rs4532 and rs4867798) and DRD2/ANKK1 rs1800497] and glutamate (GRIN2B rs7301328) receptor genes confer increased risk of ICB development among PD patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0316-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4417293  PMID: 25896831
High resolution melt analysis; DNA polymorphism; N-methyl-D-aspartate 2B; Dopamine receptor
5.  Design of the Park-in-Shape study: a phase II double blind randomized controlled trial evaluating the effects of exercise on motor and non-motor symptoms in Parkinson’s disease 
BMC Neurology  2015;15:56.
Parkinson’s disease (PD) is a neurodegenerative disorder with a wide range of motor and non-motor symptoms. Despite optimal medical management, PD still results in a high disability rate and secondary complications and many patients lead a sedentary lifestyle, which in turn is also associated with a higher co-morbidity and mortality. Exercise has been explored as a strategy to reduce secondary complications and results suggests that it not only provides general health benefits, but may also provide symptomatic relief. If this holds true exercise would be a very attractive addition to the therapeutic arsenal in PD. The supportive evidence remains incomplete. Here, we describe the design of the Park-in-Shape study, which primarily aims to evaluate whether aerobic exercise affords clinically relevant improvements in motor symptoms in sedentary PD patients. A specific new element is the introduction of gaming to optimize compliance to the exercise intervention.
The Park-in-Shape study is a randomized controlled, assessor- and patient-blinded single center study. Two parallel groups will include a total of 130 patients, receiving either aerobic exercise on a home trainer equipped with gaming elements (“exergaming”), or a non-aerobic intervention (stretching, flexibility and relaxation exercises). Both groups are supported by a specifically designed motivational app that uses gaming elements to stimulate patients to exercise and rewards them after having completed the exercise. Both interventions are delivered at home at least 3 times a week for 30–45 minutes during 6 months. Eligible patients are community-dwelling, sedentary patients diagnosed with mild-moderate PD. The primary outcome is the MDS-UPDRS motor score (tested in the off state) after 6 months. Secondary outcomes include various motor and non-motor symptoms, quality of life, physical fitness, and adherence.
This Park-in-Shape study is anticipated to answer the question whether high intensity aerobic exercise combined with gaming elements (“exergaming”) provides symptomatic relief in PD. Strong elements include the double-blinded randomized controlled trial design, the MDS-UPDRS as valid primary outcome, the large sample size and unique combination of home-based pure aerobic exercise combined with gaming elements and motivational aspects.
Trial registration
Dutch trial register NTR4743
PMCID: PMC4418070  PMID: 25880966
Parkinson disease; Physical activity; Exergaming; RCT
6.  Short-term test-retest-reliability of conditioned pain modulation using the cold-heat-pain method in healthy subjects and its correlation to parameters of standardized quantitative sensory testing 
BMC Neurology  2016;16:125.
Conditioned Pain Modulation (CPM) is often used to assess human descending pain inhibition. Nine different studies on the test-retest-reliability of different CPM paradigms have been published, but none of them has investigated the commonly used heat-cold-pain method. The results vary widely and therefore, reliability measures cannot be extrapolated from one CPM paradigm to another. Aim of the present study was to analyse the test-retest-reliability of the common heat-cold-pain method and its correlation to pain thresholds.
We tested the short-term test-retest-reliability within 40 ± 19.9 h using a cold-water immersion (10 °C, left hand) as conditioning stimulus (CS) and heat pain (43-49 °C, pain intensity 60 ± 5 on the 101-point numeric rating scale, right forearm) as test stimulus (TS) in 25 healthy right-handed subjects (12females, 31.6 ± 14.1 years). The TS was applied 30s before (TSbefore), during (TSduring) and after (TSafter) the 60s CS. The difference between the pain ratings for TSbefore and TSduring represents the early CPM-effect, between TSbefore and TSafter the late CPM-effect. Quantitative sensory testing (QST, DFNS protocol) was performed on both sessions before the CPM assessment. Statistics: paired t-tests, Intraclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), Pearson’s correlation, Bland-Altman analysis, significance level p < 0.05 with Bonferroni correction for multiple comparisons, when necessary.
Pain ratings during CPM correlated significantly (ICC: 0.411…0.962) between both days, though ratings for TSafter were lower on day 2 (p < 0.005). The early (day 1: 16.7 ± 11.7; day 2: 19.5 ± 11.9; ICC: 0.618, SRD: 20.2) and late (day 1: 1.7 ± 9.2; day 2: 7.6 ± 11.5; ICC: 0.178, SRD: 27.0) CPM effect did not differ significantly between both days. Both early and late CPM-effects did not correlate with the pain thresholds.
The short-term test-retest-reliability of the early CPM-effect using the heat-cold-pain method in healthy subjects achieved satisfying results in terms of the ICC. The SRD of the early CPM effect showed that an individual change of > 20 NRS can be attributed to a real change rather than chance. The late CPM-effect was weaker and not reliable.
PMCID: PMC4974731  PMID: 27495743
Conditioned pain modulation; Test-retest reliability; Quantitative sensory test; Heat-cold-pain method; Early CPM effect; Late CPM effect
7.  T1- vs. T2-based MRI measures of spinal cord volume in healthy subjects and patients with multiple sclerosis 
BMC Neurology  2015;15:124.
The reliable and efficient measurement of spinal cord atrophy is of growing interest in monitoring disease progression in multiple sclerosis (MS).
We compared T1- and T2-weighted MRI for measuring cervical spinal cord volume in 31 patients with MS and 18 age-matched controls (NC) from T1-weighted gradient recalled echo and T2-weighted fast spin-echo 1.5 T axial acquisitions. The two sequences were matched on slice thickness, signal averages and voxel size. An active surface software tool determined the normalized mean cervical cord cross-sectional area.
T1-derived cord areas were higher than T2 areas in the whole cohort (estimated mean difference = 7.03 mm2 (8.89 %); 95 % Confidence Interval (CI): 5.91, 8.14; p < 0.0001) and in both groups separately. There were trends for lower spinal cord areas in MS vs. NC with both sequences. For the T1 cord area, the mean difference was 3.7 mm2 (4.55 %) (95 % CI: −1.36, 8.78; p = 0.15). For the T2 cord area, the difference was larger [mean difference 4.9 mm2 (6.52 %) (95 % CI: −0.83, 10.67); p = 0.091]. The T1 and T2 cord areas showed similar weak to moderate correlations with measures of clinical status and T2 spinal cord lesion volume in the MS group. Superficial spinal cord T2 lesions had no apparent confounding effect on the outlining tool. The mean intra-rater and inter-rater coefficients of variation ranged from 0.27 to 0.91 % for T1- and 0.66 to 0.99 % for T2-derived cord areas.
T2-weighted images may prove efficient for measuring cervical spinal cord atrophy in MS, with the added advantage of lesion detectability.
PMCID: PMC4521382  PMID: 26227960
Multiple sclerosis; Spinal cord; MRI; Atrophy; Physical disability
8.  Dramatic recovery of steroid-refractory relapsed multiple sclerosis following Fingolimod discontinuation using selective immune adsorption 
BMC Neurology  2015;15:125.
Selective immune adsorption (SIA) is an emerging method for treating immune-mediated neurological diseases, given its superior safety profile compared to plasma exchange (PEX). However, the available literature concerning Multiple Sclerosis includes no cases of SIA applied to steroid-refractory rebound after Fingolimod discontinuation.
Case presentation
Here we report the case of a 32-year-old woman suffering from multiple sclerosis treated with Fingolimod and admitted to a Multiple Sclerosis Centre after drug discontinuation due to the occurrence of lymphopenia.
During the few weeks preceding admission, the patient experienced progressive and severe neurological deterioration that did not respond to an initial cycle of pulsed high doses of intravenous 6-methyl prednisolone (IVMP). Given the ineffectiveness of a second cycle of IVMP, the patient was treated with plasma immunoadsorption, leading to dramatic functional recovery. The patient then started a neuro-rehabilitation program.
About one month after the final SIA procedure the patient started Natalizumab-based therapy, while maintaning a stable neurological condition.
We noted significant modification of C3/C4 complement components and total gamma globulin concentrations (IgG) during SIA.
Our observations show that however serious, steroid-refractory neurological deterioration occurring after Fingolimod discontinuation in multiple sclerosis can be treated with selective immune-adsorption therapy which thus represents a good alternative in these cases.
It could be speculated that this clinical condition was associated with pattern II of demyelination, given the good response to a form of treatment that acts on autoantibodies. Thus, SIA represented an effective therapeutic strategy for this case of relapsed MS as steroid-resistent rebound post Fingolimod cessation.
PMCID: PMC4521477  PMID: 26227815
Multiple sclerosis; Selective immuno adsorption (SIA); Fingolimod; Steroid-refractory rebound; Intravenous 6-methyl prednisolone (IVMP)
9.  Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer’s disease cybrid cells 
BMC Neurology  2015;15:127.
Alzheimer’s disease (AD) is associated with vascular risk factors; brain ischemia facilitates the pathogenesis of AD. Recent studies have suggested that the reduction of AD risk with statin was achieved by decreased amyloidogenic amyloid precursor protein.
We used mitochondrial transgenic neuronal cell (cybrid) models to investigate changes in the levels of intracellular hypoxia inducible factor 1α (HIF-1α) and β-site amyloid precursor protein cleaving enzyme (BACE) in the presence of simvastatin. Sporadic AD (SAD) and age-matched control (CTL) cybrids were exposed to 2 % O2 and incubated with 1 μM or 10 μM simvastatin.
There was no significant difference between cell survival by 1 or 10 μM simvastatin in both SAD and CTL cybrids. In the presence of 1 μM simvastatin, intracellular levels of HIF-1α and BACE decreased by 40–70 % in SAD, but not CTL cybrids. However, 10 μM simvastatin increased HIF-1α and BACE expression in both cybrid models.
Our results suggest demonstrate differential dose-dependent effects of simvastatin on HIF-1α and BACE in cultured Alzheimer’s disease cybrid cells.
PMCID: PMC4521481  PMID: 26228060
Alzheimer’s disease; Cybrid cell; Statin; Hypoxia; HIF-1α; BACE
10.  Trust behavior in Parkinson’s disease: results of a trust game experiment 
BMC Neurology  2015;15:126.
Parkinson’s Disease (PD) is a neurodegenerative disease characterized by motor symptoms, but in which behavioral and cognitive disturbances are also common. Trust, due to its pervasiveness in society, has become a major research topic in several scientific disciplines. However, empirical evidence for trust behavior in neurological patients, and specifically for movement disorders such as PD, is missing. Evidence from healthy subjects, however, indicates that three brain regions are involved in trust perceptions and behavior, namely the limbic system, basal ganglia, and frontal cortex. PD affects all these brain regions. Therefore, we hypothesized that PD patients and healthy controls show differences in trust behavior.
We conducted an experiment using the trust game, an established paradigm to investigate trust behavior in both patient and healthy populations alike, controlling for risky decision making. Twenty patients suffering from PD diagnosed according to UK PDS Brain Bank criteria and twenty healthy controls (matched for age, gender, education, and income) were recruited. We excluded those suffering from clinically relevant neuropsychiatric comorbidities.
We found that PD patients exhibit significantly lower levels of trust than do healthy controls. Importantly, our results cannot be explained by lower levels of risk-taking. Moreover, our results indicate that the trust deficit is independent of medication, disease duration, and severity of motor symptoms.
Application of a standard procedure for measuring trust behavior revealed that PD patients exhibit lower levels of trust in other humans than do healthy controls. Against this background we make a call for further research to determine the underlying pathophysiology of reduced trust in PD.
PMCID: PMC4521483  PMID: 26227627
Parkinson; Trust game; Risk; Behavior; Non-motor symptoms; Game-of-dice task; Behavioral neurology
11.  Effect of pre-stroke statin use on stroke severity and early functional recovery: a retrospective cohort study 
BMC Neurology  2015;15:120.
Experimental studies suggest that pre-stroke statin treatment has a dual effect of neuroprotection during ischemia and neurorestoration after ischemic injury. The aim of this study was to evaluate the effect of pre-stroke statin use on initial stroke severity and early clinical outcome.
We used a prospective database enrolling patients with acute ischemic stroke from 12 hospitals in Korea between April 2008 and January 2012. Primary endpoint was the initial stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS) score. Secondary endpoints were good outcome (modified Rankin Scale [mRS], 0–2) and overall mRS distribution at discharge. Multivariable regression model and propensity score (PS) matching were used for statistical analyses.
Among the 8340 patients included in this study, 964 patients (11.6 %) were pre-stroke statin users. The initial NIHSS score (mean [95 % CI]) was lower among pre-stroke statin users vs. non-users in multivariable analysis (5.7 [5.2–6.3] versus 6.4 [5.9–6.9], p = 0.002) and PS analysis (5.2 [4.7–5.7] versus 5.7 [5.4–6.0], p = 0.043). Pre-stroke statin use was associated with increased achievement of mRS 0–2 outcome (multivariable analysis: OR [95 % CI], 1.55 [1.25–1.92], p < 0.001; PS matching: OR [95 % CI], 1.47 [1.16-1.88]; p = 0.002) and favorable shift on the overall mRS distribution (multivariable analysis: OR [95 % CI], 1.29 [1.12-1.51], p = 0.001; PS matching: OR [95 % CI], 1.31 [1.11-1.54]; p = 0.001).
Pre-stroke statin use was independently associated with lesser stroke severity at presentation and better early functional recovery in patients with acute ischemic stroke.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0376-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4520077  PMID: 26224123
Acute stroke; Statins; Outcomes
12.  Early statin use in ischemic stroke patients treated with recanalization therapy: retrospective observational study 
BMC Neurology  2015;15:122.
We aimed to determine whether early statin use following recanalization therapy improves the functional outcome of ischemic stroke.
Using a prospective stroke registry database, we identified a consecutive 337 patients within 6 h of onset who had symptomatic stenosis or occlusion of major cerebral arteries and received recanalization therapy. Based on commencement of statin therapy, patients were categorized into administration on the first (D1, 13.4 %), second (D2, 20.8 %) and third day or later (D ≥ 3, 15.4 %) after recanalization therapy, and no use (NU, 50.4 %). The primary efficacy outcome was a 3-month modified Rankin Scale score of 0–1, and the secondary outcomes were neurologic improvement, neurologic deterioration and symptomatic hemorrhagic transformation during hospitalization.
Earlier use of statin was associated with a better primary outcome in a dose-response relationship (P for trend = 0.01) independent of premorbid statin use, stroke history, atrial fibrillation, stroke subtype, calendar year, and methods of recanalization therapy. The odds of a better primary outcome increased in D1 compared to NU (adjusted odds ratio, 2.96; 95 % confidence interval, 1.19–7.37). Earlier statin use was significantly associated with less neurologic deterioration and symptomatic hemorrhagic transformation in bivariate analyses but not in multivariable analyses. Interaction analysis revealed that the effect of early statin use was not altered by stroke subtype and recanalization modality (P for interaction = 0.97 and 0.26, respectively).
Early statin use after recanalization therapy in ischemic stroke may improve the likelihood of a better functional outcome without increasing the risk of intracranial hemorrhage.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0367-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4520147  PMID: 26224069
Stroke; Recanalization; Statin; Stenosis and occlusion
13.  Misdiagnosed murine typhus in a patient with multiple cerebral infarctions and hemorrhage: a case report 
BMC Neurology  2015;15:121.
Rickettsias cause a wide spectrum of tick-, flea-, or mite-borne infections. Rickettsial infections have no classical manifestations and can often lead to encephalitis, which can be fatal if improperly diagnosed.
Case presentation
A 74-year-old male farmer was admitted to the hospital with fevers and a headache that had lasted for 10 days, followed by 4 days of unconsciousness, and his condition continued to deteriorate. Images showed multiple acute lesions in the brain stem, and bilateral cerebral and cerebellar hemispheres. He was finally diagnosed with endemic typhus and treated with antibiotics that resulted in improvement.
The present report describes a patient with a rickettsial infection and subsequent deterioration to coma because of an initial misdiagnosis. Because of the similarity to other infectious diseases, physicians should be more vigilant towards the history and radiologic results to ensure early detection and avoid complications which may prove to be fatal.
PMCID: PMC4520183  PMID: 26223226
Endemic or murine typhus; Cerebral infarction; Cerebral hemorrhage; Multiple lesions
14.  Spinal cord hemorrhage in a patient with neurosarcoidosis on long-term corticosteroid therapy: case report 
BMC Neurology  2015;15:123.
Central nervous system bleeding is a rare complication of neurosarcoidosis: only 18 cases of spontaneous cerebral hematoma have been reported. We present the first recorded case of spinal cord hemorrhage in neurosarcoidosis.
Case presentation
A 48-year-old Caucasian woman had relapsing neurosarcoidosis for 5 years, with inflammatory spinal and cerebral lesions. While on 20 mg corticosteroids, she experienced subacute paraparesia with right leg pain. A spine MRI revealed a low thoracic hematomyelia at the T10-T11 level. Despite high doses of corticosteroids, her condition continued to worsen. Surgical evacuation of the hematoma was performed 10 days after the onset of bleeding, and she partially recovered.
This report highlights the possibility of spinal cord hemorrhage secondary to sarcoid vasculitis. The patient improved after surgical evacuation of the intramedullary hematoma. Immuno-modulating agents must be envisaged in severe neurosarcoidosis, to prevent complications.
PMCID: PMC4520197  PMID: 26224095
Hematomyelia; Hemorrhage; Spinal cord; Neurosarcoidosis; Magnetic resonance imaging; Corticosteroid
15.  D-dimer for the exclusion of cerebral venous thrombosis: a meta-analysis of low risk patients with isolated headache 
BMC Neurology  2015;15:118.
Patients with isolated headache may have cerebral venous thrombosis (CVT). D-dimers are proven sensitive in excluding deep venous thrombosis (DVT) and pulmonary embolism (PE) in low risk patients. We aimed to determine whether D-dimer may play the same role in low risk CVT patients with isolated headache.
We included consecutive patients suspected of CVT from our teaching hospital with isolated headache, a normal neurological examination and normal standard head CT in whom D-dimer was determined. Additionally we did a systematic review on articles describing consecutive patients suspected of CVT with isolated headache and their D-dimer values. CVT was investigated with CT or MR venography in all patients.
A total of 636 consecutive patients were collected from our own data and the literature search. Of 45 CVT patients one had a negative D-dimer (7.5 %). Sensitivity of D-dimer for diagnosing CVT was 97.8 % (95 % CI: 88.2–99.6 %), specificity was 84.9 % (95 % CI: 81.8–87.7 %), positive predictive value was 33.1 % (95 % CI: 25.2–41.7 %), negative predictive value was 99.8 % (95 % CI: 98.9–100 %). Another 56 isolated headache CVT patients were identified in literature, lacking consecutive isolated headache controls. Sensitivity of D-dimer for diagnosing CVT including these patients was 87.1 % (95 % CI: 79.0–93.0 %).
D-dimers have a high negative predictive value in patients with isolated headache for excluding CVT. Sensitivity is lower but comparable to the values accepted in PE and DVT. Low risk patients were defined as headache patients with a normal neurological examination, normal standard head CT and absence of risk factors such as pregnancy or puerperium. Normal D-dimers in these patients may reduce unnecessary imaging, making it a potential valuable marker.
PMCID: PMC4517419  PMID: 26215857
Cerebral sinus thrombosis; D-dimer; Isolated headache; Diagnostic marker; Meta-analysis
16.  Serum biomarkers for the early diagnosis of TIA: The MIND-TIA study protocol 
BMC Neurology  2015;15:119.
A Transient Ischaemic Attack (TIA) bears a high risk of a subsequent ischaemic stroke. Adequate diagnosis of a TIA should be followed immediately by the start of appropriate preventive therapy, including antiplatelets. The diagnosis of a TIA based on symptoms and signs only is notoriously difficult and biomarkers of brain ischaemia might improve the recognition, and target management and prognosis of TIA patients. Our aim is to quantify the added diagnostic value of serum biomarkers of brain ischaemia in patients suspected of TIA.
Study design: a cross-sectional diagnostic accuracy study with an additional six month follow-up period.
Study population: 350 patients suspected of TIA in the primary care setting.
Patients suspected of a TIA will be recruited by at least 200 general practitioners (GPs) in the catchment area of seven TIA outpatient clinics willing to participate in the study. In all patients a blood sample will be drawn as soon as possible after the patient has contacted the GP, but at least within 72 h after onset of symptoms. Participants will be referred by the GP to the regional TIA outpatient clinic for additional investigations, including brain imaging. The ‘definite’ diagnosis (reference standard) will be made by a panel consisting of three experienced neurologists who will use all available diagnostic information and the clinical information obtained during the outpatient clinic assessment, and a six month follow-up period. The diagnostic accuracy, and value in addition to signs and symptoms of candidate serum biomarkers will be assessed in terms of discrimination with C statistics, and calibration with plots.
We aim to include 350 suspected cases, with 250 patients with indeed definite TIA (or minor stroke) according to the panel.
We hope to find novel biomarkers that will enable a rapid and accurate diagnosis of TIA. This would largely improve the management and prognosis of such patients.
Trial registration Identifier NCT01954329
PMCID: PMC4517631  PMID: 26215720
TIA; Minor stroke; Diagnosis; Biomarkers
17.  Morphometric variability of neuroimaging features in Children with Agenesis of the Corpus Callosum 
BMC Neurology  2015;15:116.
Agenesis of the corpus callosum (ACC) is a developmental brain malformation associated with a wide spectrum of structural brain abnormalities and genetic loci. To characterize the diverse callosal morphologies and malformations of brain development associated with ACC, we report on the neuroimaging findings of 201 individuals diagnosed with corpus callosal abnormalities.
We searched through medical records of individuals seen at New York Presbyterian Hospital between 2002 and 2013 and thought to have ACC. We confirmed 201 individuals meeting criteria and used magnetic resonance imaging to characterize morphological variants of the corpus callosum and associated brain malformations.
The majority of individuals displayed hypoplasia or dysplasia of the corpus callosum (N = 160, 80 %). Forty-one (20 %) displayed complete agenesis of the corpus callosum with other abnormalities, while only 18 (9 %) displayed complete agenesis without associated brain abnormalities. White matter abnormalities were more frequent in hypoplasia or dysplasia group than complete agenesis (28.2 % vs 9.8 %, p < 0.05). In contrast, hippocampal abnormalities, colpocephaly, and Probst bundles were significantly more frequent in complete agenesis compared to hypoplasia or dysplasia group.
Collectively, our results underscore the broad diversity of morphological variants of the corpus callosum and associated brain abnormalities in individuals with ACC.
PMCID: PMC4515020  PMID: 26209096
Agenesis; Dysplasia; Corpus callosum; Brain development; Neuroradiology
18.  Total antioxidant capacity is associated with mortality of patients with severe traumatic brain injury 
BMC Neurology  2015;15:115.
Previously, circulating total antioxidant capacity (TAC) in traumatic brain injury (TBI) patients has been scarcely studied and only in studies of small sample size (lower than 55 TBI patients). In one study were found higher serum TAC in non-survivor than in survivor TBI patients; however, an association between circulating TAC and mortality in patients with TBI has not been previously reported. Thus, the objective of this study was to determine whether there is an association between circulating TAC, peroxidation state and mortality in patients with severe TBI.
This was a multicenter, observational and prospective study was carried out in six Spanish Intensive Care Units. We included patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9. We excluded patients with Injury Severity Score (ISS) in non-cranial aspects higher than 9. We measured serum TAC on day 1 of TBI. The 30-day mortality was established as endpoint.
Non-surviving TBI patients (N = 27) showed higher serum TAC (P < 0.001) than survivor ones (N = 73). Logistic regression analyses showed that serum TAC higher than 2.59 nmol/mL were associated with 30-day mortality controlling for APACHE-II and CT classification (OR = 4.40; 95 % CI = 1.14–16.98; P = 0.03), controlling for GCS and age (OR = 5.88; 95 % CI = 1.57–22.06; P = 0.009), and controlling for CT classification and admission abnormal pupils (OR = 3.89; 95 % CI = 1.30–11.61; P = 0.02). There was an association between serum TAC and malondialdehyde (a biomarker of lipid peroxidation) levels (rho = 0.25; p = 0.01), APACHE-II score (rho = 0.23; p = 0.03) and GCS (rho = −0.21; p = 0.04).
To our knowledge, our series is the largest reporting data on circulating TAC in patients with severe TBI. The most relevant and new findings of our study were that there is an association between circulating TAC and peroxidation state and mortality in patients with severe TBI.
PMCID: PMC4513627  PMID: 26205136
Total antioxidant capacity; Brain trauma; Patients; Mortality; Injury
19.  A novel compound heterozygous mutation in a Chinese boy with L-2-hydroxyglutaric aciduria: a case study 
BMC Neurology  2015;15:117.
L-2-hydroxyglutaric aciduria is a rare autosomal recessive encephalopathy caused by mutations in the L-2-hydroxyglutarate dehydrogenase gene. We describe some novel clinical and molecular characteristics found in a boy with L-2-hydroxyglutaric aciduria.
Case presentation
We report an 8-year-old Chinese boy, who had characteristic developmental delay, ataxia and acrocephaly as the main symptoms. He also complained of paroxysmal headache and palpitation. Brain image revealed a symmetrical, extensive subcortical white matter lesion. Urine test for organic acids showed a significantly increased level of 2-hydroxyglutaric acid (106.74 mmol/mol cre, normal range 0.6 ~ 5.9 mmol/mol cre), leading to the diagnosis of L-2-hydroxyglutaric aciduria. Genetic testing uncovered two heterozygous missense mutations in L-2-hydroxyglutarate dehydrogenase gene: c.169G > A in exon 2 and c.542G > T in exon 5, not hitherto been described.
Novel gene mutation and associated clinical symptoms can contribute for the understanding and identification of this rare disease. Possible genotype-phenotype correlation waits for further study.
PMCID: PMC4514984  PMID: 26208971
L-2-hydroxyglutaric aciduria; L-2-hydroxyglutarate dehydrogenase gene; Mutation; Phenotype
20.  Bent spine syndrome as an initial manifestation of late-onset multiple acyl-CoA dehydrogenase deficiency: a case report and literature review 
BMC Neurology  2015;15:114.
Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive inherited disease of metabolic dysfunction clinically characterized by fluctuating proximal muscle weakness, excise intolerance, and dramatic riboflavin responsiveness. Dropped head syndrome can occasionally be observed in some severe patients with late-onset MADD; however, bent spine syndrome as an initial symptom had not been reported in patients with late-onset MADD.
Case presentation
A 46-year-old man lost the ability to hold his trunk upright, and had difficulty in raising his head, but he had no obvious symptoms of limb weakness. Meanwhile, he developed persistent numbness of limbs and lips around. Myopathological features and combined elevation of multiple acylcarnitines indicated that the axial myopathy might be caused by lipid storage myopathy. Cervical and lumbosacral MRI revealed a lot of abnormal signals diffusing along paravertebral muscles, while the abnormal signals almost disappeared after riboflavin treatment. Nerve conduction study indicated the patient suffering from predominantly sensory neuropathy and mildly motor neuropathy. Muscle pathology also demonstrated no typical neurogenic change, which was consistent with the electrophysiological findings. Causative mutations were found in the ETFDH gene.
We report the first case of late-onset MADD with sensory neuropathy initially manifesting as bent spine syndrome and dropped head syndrome.
PMCID: PMC4513616  PMID: 26205240
Late-onset multiple acyl-CoA dehydrogenase deficiency; Bent spine syndrome; Dropped head syndrome; Lipid storage myopathy; Peripheral neuropathy
21.  When battery exhaustion lets the lame walk: a case report on the importance of long-term stimulator monitoring in deep brain stimulation 
BMC Neurology  2015;15:113.
Deep brain stimulation is increasingly used in the treatment of advanced Parkinson’s disease. While its short-term effectiveness is well documented, there are only few reports on long-term outcomes, and the need to repeatedly reprogram the stimulator is seldom reported.
Case presentation
We present a 74-year-old man with gait impairment, which had been mistaken for worsening of the disease and only remitted when the stimulator battery was exhausted indicating that the stimulator itself had been the cause.
This case highlights the need to repeatedly monitor not only battery capacity, but also stimulator-related side-effects for an extended period after implantation and, if necessary, to refer to centres capable of systematically reprogramming the device.
PMCID: PMC4506586  PMID: 26187628
Deep brain stimulation; Subthalamic nucleus; Parkinson’s disease; Gait; Device misprogramming
22.  Geminate consonant grapheme-colour synaesthesia (ideaesthesia) 
BMC Neurology  2015;15:112.
Synaesthesia is a neurological condition which manifests clinically as an involuntary experience of a sensory or cognitive pathway upon stimulation of a second unrelated sensory or cognitive pathway
Case presentation
We report a 55 year old male who presented with a life-long history of grapheme-colour synaesthesia in which the triggering grapheme was the double letter ‘ll’ (a geminate consonant), but not ‘l’ as a single letter. This patient’s synaesthesia was also font specific (becoming more evident with serif fonts) and influenced by migraine headache (being suppressed during the prodrome and aura of a migraine headache)
These results suggest that geminate consonants are uniquely processed rather than treated as two individual consonants. Also, the existence of a mechanistic relationship between synesthetic and migrainous events sequence was verified.
PMCID: PMC4501105  PMID: 26174314
Synaesthesia; Ideaesthesia; Double letter perception
23.  Serum tissue inhibitor of matrix metalloproteinase-1 levels are associated with mortality in patients with malignant middle cerebral artery infarction 
BMC Neurology  2015;15:111.
In the last years, circulating matrix metalloproteinases (MMP)-9 levels have been associated with functional outcome in ischemic stroke patients. However the prognostic value of circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and MMP-10 in functional outcome of ischemic stroke patients has been scarcely studied. In addition, to our knowledge, serum MMP-9, MMP-10 and TIMP-1 levels in patients with malignant middle cerebral artery infarction (MMCAI) for mortality prediction have not been studied, and these were the objectives of this study.
This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We included patients with severe MMCAI defined as Glasgow Coma Scale (GCS) lower than 9. We measured circulating levels of MMP-9, MMP-10, TIMP-1, in 50 patients with severe MMCAI at diagnosis and in 50 healthy subjects. Endpoint was 30-day mortality.
Patients with severe MMCAI showed higher serum levels of MMP-9 (p = 0.001), MMP-10 (p < 0.001), and TIMP-1 (p = 0.02) than healthy subjects. Non-surviving MMCAI patients (n = 26) compared to survivor ones (n = 24) showed higher circulating levels of TIMP-1 (p < 0.001), MMP-10 (p = 0.02) and PAI-1(p = 0.02), and lower MMP-9 levels (p = 0.04). Multiple binomial logistic regression analysis showed that serum TIMP-1 levels > 239 ng/mL are associated with 30-day mortality (OR = 5.82; 95 % CI = 1.37-24.73; P = 0.02) controlling for GCS and age. The area under the curve for TIMP-1 as predictor of 30-day mortality was 0.81 (95 % CI = 0.67-0.91; P < 0.001). We found an association between circulating levels of TIMP-1 and MMP-10 (rho = 0.45; P = 0.001), plasminogen activator inhibitor (PAI)-1 (rho = 0.53; P < 0.001), and tumor necrosis factor (TNF)-alpha (rho = 0.70; P < 0.001).
The most relevant and new findings of our study, were that serum TIMP-1 levels in MMCAI patients were associated with mortality, and could be used as a prognostic biomarker of mortality in MMCAI patients.
PMCID: PMC4499187  PMID: 26162891
TIMP-1; Ischemic stroke; Patients; Mortality; Injury
24.  A pragmatic approach to sonothrombolysis in acute ischaemic stroke: the Norwegian randomised controlled sonothrombolysis in acute stroke study (NOR-SASS) 
BMC Neurology  2015;15:110.
Ultrasound accelerates thrombolysis with tPA (sonothrombolysis). Ultrasound in the absence of tPA also accelerates clot break-up (sonolysis). Adding intravenous gaseous microbubbles may potentiate the effect of ultrasound in both sonothrombolysis and sonolysis. The Norwegian Sonothrombolysis in Acute Stroke Study aims in a pragmatic approach to assess the effect and safety of contrast enhanced ultrasound treatment in unselected acute ischaemic stroke patients.
Acute ischaemic stroke patients ≥18 years, with or without visible arterial occlusion on computed tomography angiography (CTA) and treatable ≤ 4½ hours after symptom onset, are included in NOR-SASS. NOR-SASS is superimposed on a separate trial randomising patients with acute ischemic stroke to either tenecteplase or alteplase (The Norwegian Tenecteplase Stroke Trial NOR-TEST). The NOR-SASS trial has two arms: 1) the thrombolysis-arms (NOR-SASS A and B) includes patients given intravenous thrombolysis (tenecteplase or alteplase), and 2) the no-thrombolysis-arm (NOR-SASS C) includes patients with contraindications to thrombolysis. First step randomisation of NOR-SASS A is embedded in NOR-TEST as a 1:1 randomisation to either tenecteplase or alteplase. Second step NOR-SASS randomisation is 1:1 to either contrast enhanced sonothrombolysis (CEST) or sham CEST. Randomisation in NOR-SASS B (routine alteplase group) is 1:1 to either CEST or sham CEST. Randomisation of NOR-SASS C is 1:1 to either contrast enhanced sonolysis (CES) or sham CES. Ultrasound is given for one hour using a 2-MHz pulsed-wave diagnostic ultrasound probe. Microbubble contrast (SonoVue®) is given as a continuous infusion for ~30 min. Recanalisation is assessed at 60 min after start of CEST/CES. Magnetic resonance imaging and angiography is performed after 24 h of stroke onset. Primary study endpoints are 1) major neurological improvement measured with NIHSS score at 24 h and 2) favourable functional outcome defined as mRS 0–1 at 90 days.
NOR-SASS is the first randomised controlled trial designed to test the superiority of contrast enhanced ultrasound treatment given ≤4½ hours after stroke onset in an unselected acute ischaemic stroke population eligible or not eligible for intravenous thrombolysis, with or without a defined arterial occlusion on CTA. If a positive effect and safety can be proven, contrast enhanced ultrasound treatment will be an option for all acute ischaemic stroke patients. EudraCT No 201200032341; NCT01949961.
PMCID: PMC4499181  PMID: 26162826
Randomised controlled trial; Acute ischemic stroke; Arterial occlusion; Contrast; Recanalisation; Outcome; Safety; Sonolysis; Sonothrombolysis; Thrombolysis; Transcranial ultrasound
25.  Case report of a patient with progressive multifocal leukoencephalopathy under treatment with dimethyl fumarate 
BMC Neurology  2015;15:108.
Progressive multifocal leukoencephalopathy is a severe demyelinating disease caused by the polyoma JC virus in patients with reduced immunocompetence. A few cases of progressive multifocal leukoencephalopathy have been reported in patients treated with fumaric acid esters.
Case presentation
A 53-year-old Caucasian woman reported to our clinic with a first focal epileptic seizure and mild cognitive impairment. Since 1.5 years, she was treated with fumaderm for her psoriasis. During that time, her lymphocyte counts ranged between 450 and 700/μl. Cerebral magnet resonance imaging showed multifocal subcortical T2 hyperintense lesions with partial gadolinium enhancement. She did not have antibodies against human immunodeficiency virus 1 and 2 and cerebrospinal fluid-polymerase chain reaction for viral infections including a sensitive JC-virus polymerase chain reaction were negative. The diagnosis of progressive multifocal leukoencephalopathy was established by histological analysis and detection of JC-virus desoxyribonucleic acid in brain biopsy specimens. Dimethyl fumarate was stopped and Mirtazapin and Mefloquin were initiated. Neurological examination and imaging remained stable.
Progressive multifocal leukoencephalopathy can occur in patients with lymphocyte counts between 450 and 700/μl, produce only faint symptoms and is not excluded by negative JC-virus-polymerase chain reaction in cerebrospinal fluid. The incidence of progressive multifocal leukoencephalopathy may thus be underestimated and a more careful surveillance of patients would be necessary.
PMCID: PMC4495627  PMID: 26152311
PML; dimethyl fumarate; Psoriasis treatment

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