A Time-Varying Connectivity Analysis from Distributed EEG Sources: A Simulation Study.

Time-varying connectivity analysis based on sources reconstructed using inverse modeling of electroencephalographic (EEG) data is important to understand the dynamic behaviour of the brain. We simulated cortical data from a visual spatial attention network with a time-varying connectivity structure, and then simulated the propagation to the scalp to obtain EEG data. Distributed EEG source modeling using sLORETA was applied. We compared different dipole (representing a source) selection strategies based on their time series in a region of interest. Next, we estimated multivariate autoregressive (MVAR) parameters using classical Kalman filter and general linear Kalman filter approaches followed by the calculation of partial directed coherence (PDC). MVAR parameters and PDC values for the selected sources were compared with the ground-truth. We found that the best strategy to extract the time series of a region of interest was to select a dipole with time series showing the highest correlation with the average time series in the region of interest. Dipole selection based on power or based on the largest singular value offer comparable alternatives. Among the different Kalman filter approaches, the use of a general linear Kalman filter was preferred to estimate PDC based connectivity except when only a small number of trials are available. In the latter case, the classical Kalman filter can be an alternative.

Chronometry of word and picture identification: common and modality-specific effects.

Based on a previous fMRI connectivity analysis, we previously proposed that long-distance connections between left inferior frontal sulcus and left occipitotemporal sulcus mediate access to visual short-term memory both for written words and pictures enhancing conscious perception and successful encoding in an amodal manner. Using a 64-channel event-related potential electrode system in 19 young cognitively intact volunteers, we determined the chronometry of common and input-modality specific effects of word and picture identification and subsequent memory retrieval. Stimulus durations were calibrated per subject, modality and run so as to reach a 50% positive identification report. The earliest main effect of a positive identification report occurred between 180 and 200 ms, was common for both input-modalities, had a positive polarity and was located at around CPz. This effect was followed between 270 and 450 ms by additional common positive-polarity effects at centrofrontal electrode sites and by common negative effects at P7/P8, TP7/TP8 and T8. Each of the later effects was closely associated not only with identification but also with subsequent memory retrieval. The earliest input-modality specific effect of conscious identification that we detected occurred from 280 till 440 ms at P8. Our findings are in line with a model where the initial stages of perceptual identification and visual short-term memory access rely on long-distance connections that are shared between written words and pictures.

Benefit of the Awaji diagnostic algorithm for amyotrophic lateral sclerosis: a prospective study.

OBJECTIVE: Early and accurate diagnosis of amyotrophic lateral sclerosis (ALS) is important for patient care and for entry in clinical trials. Retrospective studies suggest that the use of the Awaji algorithm for the diagnosis of ALS is more sensitive for early diagnosis than the currently used revised El Escorial criteria. METHODS: We prospectively compared the revised El Escorial criteria with the Awaji algorithm in patients seen with suspected ALS at the University Hospitals Leuven between January 2008 and April 2010. RESULTS: Out of 200 patients referred for the diagnosis of ALS, 66% and 85% could be categorized to definite or probable ALS at first presentation according to the revised El Escorial and the Awaji algorithm, respectively (p < 5.6 × 10(-17) ). This corresponds to a >50% reduction of patients not eligible for clinical trial entry. Application of the Awaji algorithm made the diagnosis of ALS more likely by at least 1 diagnostic category in 25.7% of patients and identified at least 1 additional region with electrodiagnostic signs of ongoing lower motor neuron loss in 46.4% of electrodiagnostic investigations. Application of the Awaji algorithm did not result in a single false-positive diagnosis of ALS in this study. INTERPRETATION: Our data demonstrate that the Awaji algorithm is significantly more sensitive compared to the revised El Escorial criteria, without resulting in false-positive diagnoses of ALS. It should therefore be used in clinical trials.

Mutations in PEX10 are a cause of autosomal recessive ataxia.

Peroxisomal biogenesis disorders typically cause severe multisystem disease and early death. We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense. Both patients had marked cerebellar atrophy. Peroxisomal studies revealed a peroxisomal biogenesis disorder. Two mutations in PEX10 were found in the child, c.992G>A (novel) and c.764_765insA, and in the adult, c.2T>C (novel) and c.790C>T. Transfection with wild-type PEX10 corrected the fibroblast phenotype. Bile acid supplements and dietary restriction of phytanic acid were started. Peroxisomal biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia.

Microbleeds and the risk of recurrent stroke.

BACKGROUND AND PURPOSE: We studied the risk of recurrent cerebrovascular events in patients who had a transient ischemic attack or ischemic stroke and who had evidence of microbleeds on MRI. METHODS: A prospective follow-up study was performed on hospitalized patients who were at least 50 years old with a transient ischemic attack or an ischemic stroke. The presence and number of microbleeds were assessed on gradient echo MRI and the presence of white matter disease on fluid-attenuated inversion recovery imaging using a semiquantitative scale. Patients were followed up by phone every 6 months. End points were intracerebral hemorrhage, ischemic stroke, and unclassified stroke. Cerebral events were adjudicated by 2 independent neurologists blinded to the presence of microbleeds. Cox regression analysis was performed. RESULTS: A total of 487 patients with a mean age of 72 years were followed up for a median of 2.2 years (25th to 75th percentile 1.9 to 2.7 years). Microbleeds were identified in 129 patients (25.6%). Two patients developed intracerebral hemorrhage during follow-up, 32 patients developed recurrent ischemic stroke, and 3 patients had unclassified strokes. Microbleeds were not independent predictors of recurrent stroke (P=0.2) or intracerebral hemorrhage (P=0.43). Lobar microbleeds or combined lobar and deep microbleeds were independently associated with recurrent stroke (P=0.018). CONCLUSIONS: In this European cohort, patients with microbleeds who have had cerebral ischemia have a higher risk of developing new ischemic strokes than of intracerebral hemorrhage. Lobar microbleeds or combined lobar and deep microbleeds might be independent predictors of recurrent stroke.

Treatment time-specific number needed to treat estimates for tissue plasminogen activator therapy in acute stroke based on shifts over the entire range of the modified Rankin Scale.

BACKGROUND AND PURPOSE: To make informed treatment decisions, patients and physicians need to be aware of the benefits and risks of a proposed treatment. The number needed to treat (NNT) for benefit and harm are intuitive and statistically valid measures to describe a treatment effect. The aim of this study is to calculate treatment time-specific NNT estimates based on shifts over the entire spectrum of clinically relevant functional outcomes. METHODS: The pooled data set of the first 6 major randomized acute stroke trials of intravenous tissue plasminogen activator was used for this study. The data were stratified by 90-minute treatment time windows. NNT for benefit and NNT for harm estimates were determined based on expert generation of joint outcome distribution tables. NNT for benefit estimates were also calculated based on joint outcome distribution tables generated by a computer model. RESULTS: NNT for benefit estimates based on the expert panel were 3.6 for patients treated between 0 and 90 minutes, 4.3 with treatment between 91 and 180 minutes, 5.9 with treatment between 181 and 270 minutes, and 19.3 with treatment between 271 and 360 minutes. The computer simulation yielded very similar results. The NNT for harm estimates for the corresponding time intervals are 65, 38, 30, and 14. CONCLUSIONS: Up to 4(1/2) hours after symptom onset, tissue plasminogen activator therapy is associated with more benefit than harm, whereas there is no evidence of a net benefit in the 4(1/2)- to 6-hour time window. The NNT estimates for each 90-minute epoch provide useful and intuitive information based on which patients may be able to make better informed treatment decisions.

Benefits of intensive insulin therapy on neuromuscular complications in routine daily critical care practice: a retrospective study.

INTRODUCTION: Intensive insulin therapy (IIT) reduced the incidence of critical illness polyneuropathy and/or myopathy (CIP/CIM) and the need for prolonged mechanical ventilation (MV >or= 14 days) in two randomised controlled trials (RCTs) on the effect of IIT in a surgical intensive care unit (SICU) and medical intensive care unit (MICU). In the present study, we investigated whether these effects are also present in daily clinical practice when IIT is implemented outside of a study protocol. METHODS: We retrospectively studied electrophysiological data from patients in the SICU and MICU, performed because of clinical weakness and/or weaning failure, before and after routine implementation of IIT. CIP/CIM was diagnosed by abundant spontaneous electrical activity on electromyography. Baseline and outcome variables were compared using Student's t-test, Chi-squared or Mann-Whitney U-test when appropriate. The effect of implementing IIT on CIP/CIM and prolonged MV was assessed using univariate analysis and multivariate logistic regression analysis (MVLR), correcting for baseline and ICU risk factors. RESULTS: IIT significantly lowered mean (+/- standard deviation) blood glucose levels (from 144 +/- 20 to 107 +/- 10 mg/dl, p < 0.0001) and significantly reduced the diagnosis of CIP/CIM in the screened long-stay patients (125/168 (74.4%) to 220/452 (48.7%), p < 0.0001). MVLR identified implementing IIT as an independent protective factor (p < 0.0001, odds ratio (OR): 0.25 (95% confidence interval (CI): 0.14 to 0.43)). MVLR confirmed the independent protective effect of IIT on prolonged MV (p = 0.002, OR:0.40 (95% CI: 0.22-0.72)). This effect was statistically only partially explained by the reduction in CIP/CIM. CONCLUSIONS: Implementing IIT in routine daily practice in critically ill patients evoked a similar beneficial effect on neuromuscular function as that observed in two RCTs. IIT significantly improved glycaemic control and significantly and independently reduced the electrophysiological incidence of CIP/CIM. This reduction partially explained the beneficial effect of IIT on prolonged MV.

Predictive value of JC virus PCR in cerebrospinal fluid in the diagnosis of PML.

OBJECTIVE: To assess the predictive value of JC virus (JCV) PCR in cerebrospinal fluid (CSF) in the diagnosis of progressive multifocal leukoencephalopathy (PML). METHODS: We conducted a retrospective database query to identify patients with positive CSF JCV PCR. Clinical features, final diagnosis and quantitative PCR results were obtained. RESULTS: A positive CSF JCV PCR had a PPV of 10.4% for the diagnosis of PML. A weakly positive PCR had a PPV of 1.6%, whereas a moderately to highly positive PCR had a PPV of 92.3%. A PPV of 0.0% was observed in immunocompetent patients and in patients without compatible clinical or radiological features. CONCLUSIONS: A false-positive CSF JCV PCR is highly prevalent in our clinical practice. This test should be reserved for patients with a clinical suspicion of PML and the quantitative result of the PCR should be taken into account when making the diagnosis of PML.

Assessment of the reliability of the motor unit size index (MUSIX) in single subject "round-robin" and multi-centre settings.

OBJECTIVE: The motor unit size index (MUSIX) is incorporated into the motor unit number index (MUNIX). Our objective was to assess the intra-/inter-rater reliability of MUSIX in healthy volunteers across single subject "round robin" and multi-centre settings. METHODS: Data were obtained from (i) a round-robin assessment in which 12 raters (6 with prior experience and 6 without) assessed six muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor digitorum brevis and abductor hallucis) and (ii) a multi-centre study with 6 centres studying the same muscles in 66 healthy volunteers. Intra/inter-rater data were provided by 5 centres, 1 centre provided only intra-rater data. Intra/inter-rater variability was assessed using the coefficient of variation (COV), Bland-Altman plots, bias and 95% limits of agreement. RESULTS: In the round-robin assessment intra-rater COVs for MUSIX ranged from 7.8% to 28.4%. Inter-rater variability was between 7.8% and 16.2%. Prior experience did not impact on MUSIX values. In the multi-centre study MUSIX was more consistent than the MUNIX. Abductor hallucis was the least reliable muscle. CONCLUSIONS: The MUSIX is a reliable neurophysiological biomarker of reinnervation. SIGNIFICANCE: MUSIX could provide insights into the pathophysiology of a range of neuromuscular disorders, providing a quantitative biomarker of reinnervation.

Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20-1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82-3·29) for intracranial haemorrhage and 1·23 (1·08-1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08-6·72] for intracranial haemorrhage vs 1·47 [1·19-1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36-9·05] vs 1·43 [1·07-1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69-15·81] vs 1·86 [1·23-1·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Normalization of 14-3-3 in CJD.

We report on a 47-year-old woman with autopsy proven Creutzfeldt-Jakob disease (CJD), who had a positive initial 14-3-3 test but a subsequent negative test under pharmacologic suppression of the periodic epileptiform discharges on EEG. Multiple factors associated with a subsequent 14-3-3 test becoming negative are known. However none of these circumstances were applicable to our patient. This case history suggests sedative therapy in CJD may induce false negative 14-3-3 testing. This appears to be a relevant finding, since the differential diagnosis between non-convulsive status epilepticus and CJD is not always evident in the initial stage of the disease and some patients with CJD present with seizures.

Quantitative Analyses Help in Choosing Between Simultaneous vs. Separate EEG and fMRI.

Simultaneous registration of scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is considered an attractive approach for studying brain function non-invasively. It combines the better spatial resolution of fMRI with the better temporal resolution of EEG, but comes at the cost of increased measurement artifact and the accompanying artifact preprocessing. This paper presents a study of the residual signal quality based on temporal signal to noise ratio (TSNR) for fMRI and fast Fourier transform (FFT) for EEG, after optimized conventional signal preprocessing. Measurements outside the magnetic resonance imaging scanner and inside the scanner prior to and during image acquisition were compared. For EEG, frequency and region dependent significant effects on FFT squared amplitudes were observed between separately vs. simultaneously recorded EEG and fMRI, with larger effects during image acquisition than without image acquisition inside the scanner bore. A graphical user interface was developed to aid in quality checking these measurements. For fMRI, separately recorded EEG-fMRI revealed relatively large areas with a significantly higher TSNR in right occipital and parietal regions and in the cingulum, compared to separately recorded EEG-fMRI. Simultaneously recorded EEG-fMRI showed significantly higher TSNR in inferior occipital cortex, diencephalon and brainstem, compared to separately recorded EEG-fMRI. Quantification of EEG and fMRI signals showed significant, but sometimes subtle, changes between separate compared to simultaneous EEG-fMRI measurements. To avoid interference with the experiment of interest in a simultaneous EEG-fMRI measurement, it seems warranted to perform a quantitative evaluation to ensure that there are no such uncorrectable effects present in regions or frequencies that are of special interest to the research question at hand.

Association of apolipoprotein E epsilon2 with white matter disease but not with microbleeds.

BACKGROUND AND PURPOSE: Apolipoprotein E (apoE) alleles (epsilon2 and epsilon4) are associated with cerebral amyloid angiopathy, in which white matter disease and microbleeds are prominent features. The role of apoE in patients with microbleeds or white matter disease but no evidence of cerebral amyloid angiopathy has not been elucidated. We studied apoE alleles in relation to white matter disease and microbleeds in patients with transient ischemic attack or ischemic stroke. METHODS: We obtained brain MRI scans and apoE genotypes in 334 transient ischemic attack or ischemic stroke patients. Microbleeds were scored on a gradient echo MRI and white matter disease was examined on fluid attenuated inversion recovery MRI using a semiquantitative rating scale. RESULTS: Patients with moderate to severe white matter disease more frequently carried apoE epsilon2 alleles (25.2% versus 11.3%, P=0.001), but not apoE epsilon4 (26.6% in apoE epsilon4 carriers versus 25.9%; P=0.98). Adjustment for traditional risk factors did not modify this relationship (odds ratio, 2.9; 95% confidence interval, 1.5 to 5.3). There was no association between the presence of microbleeds and the apoE epsilon4 or apoE epsilon2 alleles. CONCLUSIONS: ApoE alleles do not exert a major influence on the development of microbleeds, but apoE epsilon2 may be associated with development of moderate to severe white matter disease in transient ischemic attack and stroke patients.

is leukoaraiosis on CT an accurate surrogate marker for the presence of microbleeds in acute stroke patients?

UNLABELLED: Microbleeds (MB) detected on gradient echo magnetic resonance images (GRE) are a potential risk factor for intracerebral hemorrhage after thrombolysis or oral anticoagulation. We assessed whether the presence of MB could be predicted from the extent of white matter disease (WMD) on computed tomography (CT). METHODS: We studied consecutive TIA or ischemic stroke patients who presented to the ER and who underwent both CT and GRE. WMD was rated on CT using a three point scale by two independent observers. The presence of MB was assessed on GRE. Logistic regression was used to predict the presence of MB on GRE. RESULTS: 199 consecutive patients underwent both CT and GRE. MB were identified on GRE in 56 patients (28.1%). After adjustment for age and sex, MB were more frequent in patients with leukoaraiosis (OR 2.8 per 1-point increase on the Van Swieten scale, p<0.001) and in patients presenting with a lacunar or posterior circulation syndrome (OR 2.0, p=0.048). The area under the ROC-curve derived from the logistic model was 0.70 (95% CI 0.61-0.79). Age, sex, hypertension, diabetes or the presence of left ventricular hypertrophy on ECG were not different in patients with or without MB. CONCLUSION: White matter disease on CT is associated with the presence of microbleeds on GRE. However, leukoaraiosis does not detect the presence of MB accurately enough to be considered a surrogate marker.

Minimal EEG montage with high yield for the detection of status epilepticus in the setting of postanoxic brain damage.

For the diagnosis of electrographic seizures or status epilepticus, we reduced the number of EEG-electrodes to make urgent EEG monitoring more feasible. Unlike the current existing research, with mixed results, we studied a specific population with postanoxic brain damage, expecting a higher yield of detection of ictal EEG patterns. In a population treated with therapeutic hypothermia post-cardiac arrest, the initial EEGs were reformatted in a longitudinal, a hairline and an 8-lead montage, and independently reviewed by two investigators. The EEGs were categorized into three categories: one without ictal EEG activity, one with interictal activity and one with probable electrographic seizure(s). Generalized ictal EEG activity was the most frequently observed EEG pattern. The average sensitivity for the detection of probable electrographic seizure(s) was 100 % for the 8-lead montage and 92 % in the hairline montage. In comparison to the routine longitudinal montage, the 8-lead montage proved to be reliable for the detection of electrographic seizure activity in a postanoxic population even with limited training in EEG interpretation. The hairline montage did not suffice with regard to the differential diagnosis of triphasic waves associated with metabolic encephalopathy and generalized nonconvulsive status epilepticus, but nonetheless detected the vast majority of probable electrographic seizure(s). Our results support the use of EEG monitoring with fewer electrodes for the detection of ictal EEG activity in the postanoxic population.

Electrocorticography of Spatial Shifting and Attentional Selection in Human Superior Parietal Cortex.

Spatial-attentional reorienting and selection between competing stimuli are two distinct attentional processes of clinical and fundamental relevance. In the past, reorienting has been mainly associated with inferior parietal cortex. In a patient with a subdural grid covering the upper and lower bank of the left anterior and middle intraparietal sulcus (IPS) and the superior parietal lobule (SPL), we examined the involvement of superior parietal cortex using a hybrid spatial cueing paradigm identical to that previously applied in stroke and in healthy controls. In SPL, as early as 164 ms following target onset, an invalidly compared to a validly cued target elicited a positive event-related potential (ERP) and an increase in intertrial coherence (ITC) in the theta band, regardless of the direction of attention. From around 400-650 ms, functional connectivity [weighted phase lag index (wPLI) analysis] between SPL and IPS briefly inverted such that SPL activity was driving IPS activity. In contrast, the presence of a competing distracter elicited a robust change mainly in IPS from 300 to 600 ms. Within superior parietal cortex reorienting of attention is associated with a distinct and early electrophysiological response in SPL while attentional selection is indexed by a relatively late electrophysiological response in the IPS. The long latency suggests a role of IPS in working memory or cognitive control rather than early selection.

Prognostic value of clinical and electrodiagnostic parameters at time of diagnosis in patients with amyotrophic lateral sclerosis.

OBJECTIVE: To assess the added prognostic value of the aggregated clinical and electrodiagnostic data, which define a given diagnostic category according to the Awaji or revised El Escorial criteria at time of diagnosis in patients with amyotrophic lateral sclerosis (ALS). METHODS: Clinical signs and electrodiagnostic test results were collected at time of diagnosis in 396 patients with ALS between January 2009 and January 2016. Significant predictors of prognosis were identified using a univariate model, and later combined in a multivariate Cox regression model. RESULTS: Known factors associated with reduced survival included older age at onset, shorter diagnostic delay, higher ALSFRS-R slope and presence of C9orf72 mutation (all p < 0.05). Diagnostic category according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0177) criteria, definite ALS according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0343) and number of regions with LMN involvement (p < 0.0001) were all associated with shorter survival. DISCUSSION: Clinical and electrodiagnostic data at time of diagnosis provide additional prognostic information compared to other known prognostic factors. Diagnostic category according to Awaji and the extensiveness of LMN involvement contain the most additional value.