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.

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.

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.

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.

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.

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.

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.

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.

Quality Control of Motor Unit Number Index (MUNIX) Measurements in 6 Muscles in a Single-Subject "Round-Robin" Setup.

BACKGROUND: Motor Unit Number Index (MUNIX) is a neurophysiological measure that provides an index of the number of lower motor neurons in a muscle. Its performance across centres in healthy subjects and patients with Amyotrophic Lateral Sclerosis (ALS) has been established, but inter-rater variability between multiple raters in one single subject has not been investigated. OBJECTIVE: To assess reliability in a set of 6 muscles in a single subject among 12 examiners (6 experienced with MUNIX, 6 less experienced) and to determine variables associated with variability of measurements. METHODS: Twelve raters applied MUNIX in six different muscles (abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), tibialis anterior (TA), extensor dig. brevis (EDB), abductor hallucis (AH)) twice in one single volunteer on consecutive days. All raters visited at least one training course prior to measurements. Intra- and inter-rater variability as determined by the coefficient of variation (COV) between different raters and their levels of experience with MUNIX were compared. RESULTS: Mean intra-rater COV of MUNIX was 14.0% (±6.4) ranging from 5.8 (APB) to 30.3% (EDB). Mean inter-rater COV was 18.1 (±5.4) ranging from 8.0 (BB) to 31.7 (AH). No significant differences of variability between experienced and less experienced raters were detected. CONCLUSION: We provide evidence that quality control for neurophysiological methods can be performed with similar standards as in laboratory medicine. Intra- and inter-rater variability of MUNIX is muscle-dependent and mainly below 20%. Experienced neurophysiologists can easily adopt MUNIX and adequate teaching ensures reliable utilization of this method.

Awaji criteria improves the diagnostic sensitivity in amyotrophic lateral sclerosis: A systematic review using individual patient data.

OBJECTIVE: To determine the utility of the Awaji criteria in diagnosing amyotrophic lateral sclerosis (ALS) and to propose a novel modification so as to enhance sensitivity based on results of individual patient data (IPD). METHODS: Individual patient data were available from 8 studies comparing the diagnostic accuracy of Awaji and revised El Escorial (rEEC) criteria. The sensitivity of a novel updated Awaji criteria, incorporating a "probable-laboratory supported" category, was also tested. RESULTS: Individual patient data were available from 1086 patients, consisting of 881 ALS and 205 patients with disorders mimicking ALS. Summary sensitivities based on random effects logistic regression modelling disclosed a higher sensitivity of the Awaji criteria (0.70, 95% confidence interval [CI] 0.51-0.83) and updated Awaji criteria (0.73, 95% CI 0.56-0.85) when compared to rEEC (0.58, 95% CI 0.48-0.68). Paired analysis revealed higher sensitivities of Awaji criteria in 4 studies, and of updated Awaji criteria in 7 studies, when compared to rEEC. CONCLUSION: Individual patient data analysis established a higher sensitivity of Awaji criteria when compared to rEEC. The updated Awaji criteria enhanced the diagnostic sensitivity in limb-onset ALS. SIGNIFICANCE: The updated Awaji criteria should be considered in clinical practice and future therapeutic trials.

Voxel-based lesion-symptom mapping of stroke lesions underlying somatosensory deficits.

The aim of this study was to investigate the relationship between stroke lesion location and the resulting somatosensory deficit. We studied exteroceptive and proprioceptive somatosensory symptoms and stroke lesions in 38 patients with first-ever acute stroke. The Erasmus modified Nottingham Sensory Assessment was used to clinically evaluate somatosensory functioning in the arm and hand within the first week after stroke onset. Additionally, more objective measures such as the perceptual threshold of touch and somatosensory evoked potentials were recorded. Non-parametric voxel-based lesion-symptom mapping was performed to investigate lesion contribution to different somatosensory deficits in the upper limb. Additionally, structural connectivity of brain areas that demonstrated the strongest association with somatosensory symptoms was determined, using probabilistic fiber tracking based on diffusion tensor imaging data from a healthy age-matched sample. Voxels with a significant association to somatosensory deficits were clustered in two core brain regions: the central parietal white matter, also referred to as the sensory component of the superior thalamic radiation, and the parietal operculum close to the insular cortex, representing the secondary somatosensory cortex. Our objective recordings confirmed findings from clinical assessments. Probabilistic tracking connected the first region to thalamus, internal capsule, brain stem, postcentral gyrus, cerebellum, and frontal pathways, while the second region demonstrated structural connections to thalamus, insular and primary somatosensory cortex. This study reveals that stroke lesions in the sensory fibers of the superior thalamocortical radiation and the parietal operculum are significantly associated with multiple exteroceptive and proprioceptive deficits in the arm and hand.

Comparison of different Kalman filter approaches in deriving time varying connectivity from EEG data.

Kalman filter approaches are widely applied to derive time varying effective connectivity from electroencephalographic (EEG) data. For multi-trial data, a classical Kalman filter (CKF) designed for the estimation of single trial data, can be implemented by trial-averaging the data or by averaging single trial estimates. A general linear Kalman filter (GLKF) provides an extension for multi-trial data. In this work, we studied the performance of the different Kalman filtering approaches for different values of signal-to-noise ratio (SNR), number of trials and number of EEG channels. We used a simulated model from which we calculated scalp recordings. From these recordings, we estimated cortical sources. Multivariate autoregressive model parameters and partial directed coherence was calculated for these estimated sources and compared with the ground-truth. The results showed an overall superior performance of GLKF except for low levels of SNR and number of trials.

A venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and re-challenge.

CASE DESCRIPTION: A 85 year old woman with a history of severe depression treated with mirtazapine and venlafaxine was admitted to the hospital twice after progressive deterioration of her general condition evolving to unconsciousness. Clinicians diagnosed a metabolic encephalopathy caused by a urinary tract infection which was treated appropriately. Although mirtazapine was stopped during the first hospitalization, the patient's general practitioner restarted mirtazapine four days before readmission. During rehospitalization, she developed extreme restlessness, hyperreflexia and an increased tone in the lower limbs. She was hypertensive and tachycardic. Excessive sweating, elevated creatine kinase levels and bilateral mydriasis were noticed. Urinary analysis showed positive levels of mirtazapine and venlafaxine and both drugs were withdrawn. Symptoms resolved within 48 h after discontinuation of her antidepressants. Conclusion To our knowledge, this is the first case of the serotonin syndrome confirmed by a positive challenge, de-challenge and re-challenge.

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.