Publications by authors named "Anne-Fleur van Rootselaar"

58 Publications

Reply to Scarpino et al., SSEP amplitude for prognostication in post-anoxic coma: A further step towards standardization.

Resuscitation 2021 10 23;167:432. Epub 2021 Aug 23.

Department of Intensive Care, Amsterdam UMC and University of Amsterdam, the Netherlands; Amsterdam Neuroscience, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1016/j.resuscitation.2021.08.030DOI Listing
October 2021

GABA, Glutamate, and NAA Levels in the Deep Cerebellar Nuclei of Essential Tremor Patients.

Front Neurol 2021 6;12:664735. Epub 2021 May 6.

Department of Neurology and Clinical Neurophysiology, Amsterdam University Medical Centers, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands.

Essential tremor is among the commonly observed movement disorders in clinical practice, however the exact pathophysiological mechanisms underlying tremor are unknown. It has been suggested that Purkinje cell alterations play a causal factor in tremorgenesis. Altered levels of inhibitory (GABA) and excitatory (glutamate+glutamine, Glx) neurotransmitters could be markers for Purkinje cell alterations. We hypothesize that GABA and Glx levels in the dentate nuclei could be differentially altered in patients responsive to either anticonvulsants or β-adrenergic blockers. In this explorative study in patients with essential tremor, we measured gamma-aminobutyric acid (GABA) and glutamate+glutamine (Glx) levels in the dentate nucleus region using H-magnetic resonance spectroscopy (MRS) in seven patients using propranolol, five patients using anticonvulsants, and eight healthy controls. There were no group differences with respect to GABA+/Cr, Glx/Cr, NAA/Cr, and GABA+/Glx ratios. There was no correlation with tremor severity. Our results are in line with previously published studies; however, additional studies on a larger number of patients are warranted to confirm these findings. Furthermore medication-subgroups did not exhibit differences with respect to GABA+/Cr, Glx/Cr, NAA/Cr, and GABA+/Glx ratios. A recent study, of similar size, found an inverse association between tremor severity and the GABA+/Glx ratio in the cerebellum of essential tremor patients. We were unable to replicate these findings. The field of tremor research is plagued by heterogeneous results, and we would caution against drawing firm conclusions based on pilot studies.
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http://dx.doi.org/10.3389/fneur.2021.664735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136412PMC
May 2021

SSEP amplitudes add information for prognostication in postanoxic coma.

Resuscitation 2021 06 10;163:172-175. Epub 2021 Apr 10.

Department of Intensive Care, Amsterdam UMC and University of Amsterdam, The Netherlands; Amsterdam Neuroscience, Amsterdam, The Netherlands.

Objective: To investigate whether somatosensory evoked potential (SSEP) amplitude adds information for prediction of poor outcome in postanoxic coma.

Methods: In this retrospective cohort study we included adult patients admitted after cardiac arrest between January 2010 and June 2018 who remained in coma and had SSEP recorded for prognostication. Outcome was dichotomized in poor (Cerebral Performance Category (CPC) 4-5) and good (CPC 1-3) at ICU discharge. Sensitivity of bilaterally absent N20 potential was calculated. In case the N20 potential was not bilaterally absent, the amplitude contralateral to stimulation side (baseline-N20, N20-P25, and maximum) was determined. At a specificity of 100%, SEPP amplitude sensitivities were determined for poor outcome.

Results: SSEP recordings were performed in 197 patients of whom 57 had bilaterally absent N20 potentials. From 140 patients, 16 (11%) had a good outcome. The sensitivity for poor outcome of bilaterally absent N20 was 31%. At a specificity of 100%, contralateral amplitude thresholds were 0.34 μV (baseline-N20), 0.99 μV (N20-P25) and 1.0 μV (maximum), corresponding to a sensitivity for poor outcome of 38%, 44% and 40%. Combination of bilaterally absent N20 and a N20-P25 threshold below 0.99 μV yielded a sensitivity of 62%.

Conclusions: Our results confirm that very low cortical SSEP amplitudes are highly predictive of poor outcome in patients with postanoxic coma. Adding 'N20-P25 threshold amplitude' to the 'bilaterally absent N20' criterion, increased sensitivity substantially.
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http://dx.doi.org/10.1016/j.resuscitation.2021.03.033DOI Listing
June 2021

Structural and functional correlates of subthalamic deep brain stimulation-induced apathy in Parkinson's disease.

Brain Stimul 2021 Jan-Feb;14(1):192-201. Epub 2020 Dec 30.

Amsterdam UMC, Vrije Universiteit Amsterdam, Neurology, Amsterdam Neuroscience, De Boelelaan, 1117, Amsterdam, the Netherlands.

Background: Notwithstanding the large improvement in motor function in Parkinson's disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase. Postoperative apathy cannot always be related to a dose reduction of dopaminergic medication and stimulation itself may play a role.

Objective: We studied whether apathy in DBS-treated PD patients could be a stimulation effect.

Methods: In 26 PD patients we acquired apathy scores before and >6 months after DBS of the subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation) were performed ≥6 months after DBS placement. Change in apathy severity was correlated with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii) stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in functional connectivity of brain regions that have an alleged role in apathy.

Results: Average apathy severity significantly increased after DBS (p < 0.001) and the number of patients considered apathetic increased from two to nine. Change in apathy severity did not correlate with improvement in motor function or dose reduction of dopaminergic medication. For the left hemisphere, increase in apathy was associated with a more dorsolateral stimulation location (p = 0.010). The increase in apathy severity correlated with a decrease in alpha1 functional connectivity of the dorsolateral prefrontal cortex (p = 0.006), but not with changes of the medial orbitofrontal or the anterior cingulate cortex.

Conclusions: The present observations suggest that apathy after STN-DBS is not necessarily related to dose reductions of dopaminergic medication, but may be an effect of the stimulation itself. This highlights the importance of determining optimal DBS settings based on both motor and non-motor symptoms.
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http://dx.doi.org/10.1016/j.brs.2020.12.008DOI Listing
October 2021

Pentameric repeat expansions: cortical myoclonus or cortical tremor?

Brain 2020 10;143(10):e86

Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1093/brain/awaa259DOI Listing
October 2020

Awakening after a sleeping pill: Restoring functional brain networks after severe brain injury.

Cortex 2020 11 3;132:135-146. Epub 2020 Sep 3.

Amsterdam UMC, University of Amsterdam, Department of Neurosurgery, Amsterdam Neuroscience, Amsterdam, the Netherlands.

Some patients with severe brain injury show short-term neurological improvements, such as recovery of consciousness, motor function, or speech after administering zolpidem, a GABA receptor agonist. The working mechanism of this paradoxical phenomenon remains unknown. In this study, we used electroencephalography and magnetoencephalography to investigate a spectacular zolpidem-induced awakening, including the recovery of functional communication and the ability to walk in a patient with severe hypoxic-ischemic brain injury. We show that cognitive deficits, speech loss, and motor impairments after severe brain injury are associated with stronger beta band connectivity throughout the brain and suggest that neurological recovery after zolpidem occurs with the restoration of beta band connectivity. This exploratory work proposes an essential role for beta rhythms in goal-directed behavior and cognition. It advocates further fundamental and clinical research on the role of increased beta band connectivity in the development of neurological deficits after severe brain injury.
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http://dx.doi.org/10.1016/j.cortex.2020.08.011DOI Listing
November 2020

EEG reactivity testing for prediction of good outcome in patients after cardiac arrest.

Neurology 2020 08 10;95(6):e653-e661. Epub 2020 Jul 10.

From the Departments of Neurology/Clinical Neurophysiology (M.M.A., A.-F.v.R.) and Intensive Care (J. Horn, M.J.S.), Amsterdam Neuroscience, and Laboratory for Experimental Intensive Care and Anesthesiology (J. Horn, M.J.S.), Amsterdam UMC, University of Amsterdam; Department of Neurology (J. Hofmeijer, H.M.K.), Rijnstate Hospital, Arnhem; Clinical Neurophysiology (J. Hofmeijer, M.J.A.M.v.P.), MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede; Department of Intensive Care (C.W.E.H., C.R.v.K.) and Department of Intensive Care Medicine and Neurology, Donders Institute for Brain, Cognition, and Behaviour (H.M.K.), Radboud University Medical Center, Nijmegen; Department of Clinical Neurophysiology (M.J.A.M.v.P.), Medisch Spectrum Twente, Enschede, the Netherlands; Nuffield Department of Medicine (M.J.S.), University of Oxford, UK; and Mahidol-Oxford Tropical Medicine Research Unit (MORU) (M.J.S.), Mahidol University, Bangkok, Thailand.

Objective: To determine the additional value of EEG reactivity (EEG-R) testing to EEG background pattern for prediction of good outcome in adult patients after cardiac arrest (CA).

Methods: In this post hoc analysis of a prospective cohort study, EEG-R was tested twice a day, using a strict protocol. Good outcome was defined as a Cerebral Performance Category score of 1-2 within 6 months. The additional value of EEG-R per EEG background pattern was evaluated using the diagnostic odds ratio (DOR). Prognostic value (sensitivity and specificity) of EEG-R was investigated in relation to time after CA, sedative medication, different stimuli, and repeated testing.

Results: Between 12 and 24 hours after CA, data of 108 patients were available. Patients with a continuous (n = 64) or discontinuous (n = 19) normal voltage background pattern with reactivity were 3 and 8 times more likely to have a good outcome than without reactivity (continuous: DOR, 3.4; 95% confidence interval [CI], 0.97-12.0; = 0.06; discontinuous: DOR, 8.0; 95% CI, 1.0-63.97; = 0.0499). EEG-R was not observed in other background patterns within 24 hours after CA. In 119 patients with a normal voltage EEG background pattern, continuous or discontinuous, any time after CA, prognostic value was highest in sedated patients (sensitivity 81.3%, specificity 59.5%), irrespective of time after CA. EEG-R induced by handclapping and sternal rubbing, especially when combined, had highest prognostic value. Repeated EEG-R testing increased prognostic value.

Conclusion: EEG-R has additional value for prediction of good outcome in patients with discontinuous normal voltage EEG background pattern and possibly with continuous normal voltage. The best stimuli were clapping and sternal rubbing.
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http://dx.doi.org/10.1212/WNL.0000000000009991DOI Listing
August 2020

Distinct cortical activity patterns in Parkinson's disease and essential tremor during a bimanual tapping task.

J Neuroeng Rehabil 2020 03 17;17(1):45. Epub 2020 Mar 17.

Department of Biomedical Signals and Systems, Faculty EEMCS, University of Twente, Postbox 217, 7500 AE, Enschede, The Netherlands.

Background: Parkinson's disease (PD) and essential tremor (ET) are neurodegenerative diseases characterized by movement deficits. Especially in PD, maintaining cyclic movement can be significantly disturbed due to pathological changes in the basal ganglia and the cerebellum. Providing external cues improves timing of these movements in PD and also affects ET. The aim of this study is to determine differences in cortical activation patterns in PD and ET patients during externally and internally cued movements.

Methods: Eleven PD patients, twelve ET patients, OFF tremor suppressing medication, and nineteen age-matched healthy controls (HC) were included and asked to perform a bimanual tapping task at two predefined cue frequencies. The auditory cue, a metronome sound presented at 2 or 4 Hz, was alternately switched on and off every 30 s. Tapping at two different frequencies were used since it is expected that different brain networks are involved at different frequencies as has been shown in previous studies. Cortical activity was recorded using a 64-channel EEG cap. To establish the cortical activation pattern in each group, the task related power (TRP) was calculated for each subject. For inter-groups analysis, EEG electrodes for divided into 5 different areas.

Results: Inter-group analysis revealed significant differences in areas responsible for motor planning, organization and regulation and involved in initiation, maintenance, coordination and planning of complex sequences of movements. Within the area of the primary motor cortex the ET group showed a significantly lower TRP than the HC group. In the area responsible for combining somatosensory, auditory and visual information both patient groups had a higher TRP than the HC group.

Conclusions: Different neurological networks are involved during cued and non-cued movements in ET, PD and HC. Distinct cortical activation patterns were revealed using task related power calculations. Different activation patterns were revealed during the 2 and 4 Hz tapping task indicating different strategies to execute movements at these rates. The results suggest that a including a cued/non-cued tapping task during clinical decision making could be a valuable tool in an objective diagnostic protocol.
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http://dx.doi.org/10.1186/s12984-020-00670-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079392PMC
March 2020

Motor effects of deep brain stimulation correlate with increased functional connectivity in Parkinson's disease: An MEG study.

Neuroimage Clin 2020 21;26:102225. Epub 2020 Feb 21.

Amsterdam UMC, Vrije Universiteit Amsterdam, Neurology, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established symptomatic treatment in Parkinson's disease, yet its mechanism of action is not fully understood. Locally in the STN, stimulation lowers beta band power, in parallel with symptom relief. Therefore, beta band oscillations are sometimes referred to as "anti-kinetic". However, in recent studies functional interactions have been observed beyond the STN, which we hypothesized to reflect clinical effects of DBS. Resting-state, whole-brain magnetoencephalography (MEG) recordings and assessments on motor function were obtained in 18 Parkinson's disease patients with bilateral STN-DBS, on and off stimulation. For each brain region, we estimated source-space spectral power and functional connectivity with the rest of the brain. Stimulation led to an increase in average peak frequency and a suppression of absolute band power (delta to low-beta band) in the sensorimotor cortices. Significant changes (decreases and increases) in low-beta band functional connectivity were observed upon stimulation. Improvement in bradykinesia/rigidity was significantly related to increases in alpha2 and low-beta band functional connectivity (of sensorimotor regions, the cortex as a whole, and subcortical regions). By contrast, tremor improvement did not correlate with changes in functional connectivity. Our results highlight the distributed effects of DBS on the resting-state brain and suggest that DBS-related improvements in rigidity and bradykinesia, but not tremor, may be mediated by an increase in alpha2 and low-beta functional connectivity. Beyond the local effects of DBS in and around the STN, functional connectivity changes in these frequency bands might therefore be considered as "pro-kinetic".
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http://dx.doi.org/10.1016/j.nicl.2020.102225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049661PMC
February 2021

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.

Nat Commun 2019 10 29;10(1):4919. Epub 2019 Oct 29.

Department of Neurology-centre de référence des epilepsies rares, University Hospital of Strasbourg, 1 Avenue Molière, 67200, Strasbourg, France.

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
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http://dx.doi.org/10.1038/s41467-019-12763-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820781PMC
October 2019

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.

Nat Commun 2019 10 29;10(1):4920. Epub 2019 Oct 29.

Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università, 30, 00185, Rome, Italy.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
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http://dx.doi.org/10.1038/s41467-019-12671-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820779PMC
October 2019

A Power Spectral Density-Based Method to Detect Tremor and Tremor Intermittency in Movement Disorders.

Sensors (Basel) 2019 Oct 4;19(19). Epub 2019 Oct 4.

Department of Biomedical Signals and Systems, University of Twente, 7522 NB Enschede, The Netherlands.

There is no objective gold standard to detect tremors. This concerns not only the choice of the algorithm and sensors, but methods are often designed to detect tremors in one specific group of patients during the performance of a specific task. Therefore, the aim of this study is twofold. First, an objective quantitative method to detect tremor windows (TWs) in accelerometer and electromyography recordings is introduced. Second, the tremor stability index (TSI) is determined to indicate the advantage of detecting TWs prior to analysis. Ten Parkinson's disease (PD) patients, ten essential tremor (ET) patients, and ten healthy controls (HC) performed a resting, postural and movement task. Data was split into 3-s windows, and the power spectral density was calculated for each window. The relative power around the peak frequency with respect to the power in the tremor band was used to classify the windows as either tremor or non-tremor. The method yielded a specificity of 96.45%, sensitivity of 84.84%, and accuracy of 90.80% of tremor detection. During tremors, significant differences were found between groups in all three parameters. The results suggest that the introduced method could be used to determine under which conditions and to which extent undiagnosed patients exhibit tremors.
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http://dx.doi.org/10.3390/s19194301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806079PMC
October 2019

Distance to white matter tracts is associated with deep brain stimulation motor outcome in Parkinson's disease.

J Neurosurg 2019 Jul 26:1-10. Epub 2019 Jul 26.

1Department of Neurology and Clinical Neurophysiology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience.

Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms in patients with Parkinson's disease (PD). However, the underlying mechanism of tremor suppression is not well understood. Stimulation of white matter tracts, such as the dentatorubrothalamic tract (DRT), might be involved. Also, side effects, including dysarthria, might result from (unwanted) stimulation of white matter tracts in proximity to the STN. The aim of this study was to establish an association between stimulation effect on tremor and dysarthria and stimulation location relative to relevant white matter tracts.

Methods: In 35 PD patients in whom a bilateral STN DBS system was implanted, the authors established clinical outcome measures per electrode contact. The distance from each stimulation location to the center of the DRT, corticopontocerebellar tract, pyramidal tract (PT), and medial lemniscus was determined using diffusion-weighted MRI data. Clinical outcome measures were subsequently related to the distances to the white matter tracts.

Results: Patients with activated contacts closer to the DRT showed increased tremor improvement. Proximity of activated contacts to the PT was associated with dysarthria.

Conclusions: Proximity to specific white matter tracts is associated with tremor outcome and side effects in DBS. This knowledge can help to optimize both electrode placement and postsurgical electrode contact selection. Presurgical white matter tract visualization may improve targeting and DBS outcome. These findings are of interest not only for treatment in PD, but potentially also for other (movement) disorders.
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http://dx.doi.org/10.3171/2019.5.JNS1952DOI Listing
July 2019

Electroencephalographic reactivity as predictor of neurological outcome in postanoxic coma: A multicenter prospective cohort study.

Ann Neurol 2019 07 8;86(1):17-27. Epub 2019 Jun 8.

Amsterdam University Medical Centers, University of Amsterdam, Department of Intensive Care, Amsterdam Neuroscience, Amsterdam, the Netherlands.

Objective: Outcome prediction in patients after cardiac arrest (CA) is challenging. Electroencephalographic reactivity (EEG-R) might be a reliable predictor. We aimed to determine the prognostic value of EEG-R using a standardized assessment.

Methods: In a prospective cohort study, a strictly defined EEG-R assessment protocol was executed twice per day in adult patients after CA. EEG-R was classified as present or absent by 3 EEG readers, blinded to patient characteristics. Uncertain reactivity was classified as present. Primary outcome was best Cerebral Performance Category score (CPC) in 6 months after CA, dichotomized as good (CPC = 1-2) or poor (CPC = 3-5). EEG-R was considered reliable for predicting poor outcome if specificity was ≥95%. For good outcome prediction, a specificity of ≥80% was used. Added value of EEG-R was the increase in specificity when combined with EEG background, neurological examination, and somatosensory evoked potentials (SSEPs).

Results: Of 160 patients enrolled, 149 were available for analyses. Absence of EEG-R for poor outcome prediction had a specificity of 82% and a sensitivity of 73%. For good outcome prediction, specificity was 73% and sensitivity 82%. Specificity for poor outcome prediction increased from 98% to 99% when EEG-R was added to a multimodal model. For good outcome prediction, specificity increased from 70% to 89%.

Interpretation: EEG-R testing in itself is not sufficiently reliable for outcome prediction in patients after CA. For poor outcome prediction, it has no substantial added value to EEG background, neurological examination, and SSEPs. For prediction of good outcome, EEG-R seems to have added value. ANN NEUROL 2019.
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http://dx.doi.org/10.1002/ana.25507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618107PMC
July 2019

Deficits in tapping accuracy and variability in tremor patients.

J Neuroeng Rehabil 2019 05 7;16(1):54. Epub 2019 May 7.

Department of Biomedical Signals and Systems, University of Twente, Enschede, The Netherlands.

Background: The basal ganglia and cerebellum are brain structures involved in movement initiation, execution and termination. They are thought to be involved in the tremor generation and movement deficits in Parkinson's disease (PD) and essential tremor (ET). Especially in PD, maintaining cyclic movement, such as walking or tapping can be significantly disturbed. Providing external cues improves timing of these movements in PD but its effect on ET has not yet been studied in depth. The aim of this study is to evaluate the usefulness of a bimanual tapping task as a tool during clinical decision making.

Method: Hand movements and tremor was recorded using accelerometers and EMG (m. extensor carpi ulnaris) from PD and ET patients and healthy controls during a bimanual tapping task as a way to distinguish PD from ET. All subjects performed the tapping task at two different frequencies, 2 Hz and 4 Hz, with and without the presence of auditory cues.

Results: No significant intra-group differences were found in the patient groups. Acceleration data revealed significantly less accurate tapping and more variable tapping in PD than in ET and healthy controls. ET subjects tapped less accurate and with a greater variability than healthy controls during the 4 Hz tapping task. Most interestingly the tapping accuracy improved in PD patients when kinetic tremor was recorded with EMG during the task.

Conclusion: Providing ET and PD patients with an external cue results in different tapping performances between patient groups and healthy controls. Furthermore, the findings suggest that kinetic tremor in PD enables patients to perform the task with a greater accuracy. So far this has not been shown in other studies.
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http://dx.doi.org/10.1186/s12984-019-0528-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505201PMC
May 2019

An Unusual Dystonic Manifestation in Wilson's Disease.

Mov Disord Clin Pract 2018 Sep-Oct;5(5):546-547. Epub 2018 Jul 31.

Department of Neurology/Clinical Neurophysiology Academic Medical Center Amsterdam Netherlands.

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http://dx.doi.org/10.1002/mdc3.12639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207128PMC
July 2018

Distinctive tics suppression network in Gilles de la Tourette syndrome distinguished from suppression of natural urges using multimodal imaging.

Neuroimage Clin 2018 19;20:783-792. Epub 2018 Sep 19.

Department of Neurology, University Medical Centre Groningen, University of Groningen, the Netherlands. Electronic address:

Background And Objectives: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by tics. A hallmark of GTS is the ability to voluntarily suppress tics. Our aim was to distinguish the neural circuits involved in the voluntary suppression of ocular tics in GTS patients from blink suppression in healthy subjects.

Methods: Fifteen GTS patients and 22 healthy control subjects were included in a multimodal study using eye-tracker recordings during functional MRI (fMRI). The ability to suppress tics/blinks was compared both on subjective (self-rating) and objective (eye-tracker) performance. For fMRI analysis we used a novel designed performance-adapted block design analysis of tic/blink suppression and release based on eye-tracker monitoring.

Results: We found that the subjective self-reported ability to suppress tics or blinks showed no significant correlation with objective task performance. In GTS during successful suppression of tics, the dorsal anterior cingulate cortex and associated limbic areas showed increased activation. During successful suppression of eye blinks in healthy subjects, the right ventrolateral prefrontal cortex and supplementary and cingulate motor areas showed increased activation.

Conclusions: These findings demonstrate that GTS patients use a characteristic limbic suppression strategy. In contrast, control subjects use the voluntary sensorimotor circuits and the classical 'stop' network to suppress natural urges. The employment of different neural suppression networks provides support for cognitive behavioral therapy in GTS.
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http://dx.doi.org/10.1016/j.nicl.2018.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169325PMC
January 2019

Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review.

Tremor Other Hyperkinet Mov (N Y) 2018 23;8:503. Epub 2018 Jan 23.

Department of Neurology and Clinical Neurophysiology, Amsterdam Neuroscience, Academic Medical Center, Amsterdam, The Netherlands.

Background: Autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE) is characterized by distal tremulous myoclonus, generalized seizures, and signs of cortical reflex myoclonus. FCMTE has been described in over 100 pedigrees worldwide, under several different names and acronyms. Pathological changes have been located in the cerebellum. This systematic review discusses the clinical spectrum, treatment, pathophysiology, and genetic findings.

Methods: We carried out a PubMed search, using a combination of the following search terms: cortical tremor, myoclonus, epilepsy, benign course, adult onset, familial, and autosomal dominant; this resulted in a total of 77 studies (761 patients; 126 pedigrees) fulfilling the inclusion and exclusion criteria.

Results: Phenotypic differences across pedigrees exist, possibly related to underlying genetic differences. A "benign" phenotype has been described in several Japanese families and pedigrees linked to 8q (FCMTE1). French patients (5p linkage; FCMTE3) exhibit more severe progression, and in Japanese/Chinese pedigrees (with unknown linkage) anticipation has been suggested. Preferred treatment is with valproate (mind teratogenicity), levetiracetam, and/or clonazepam. Several genes have been identified, which differ in potential pathogenicity.

Discussion: Based on the core features (above), the syndrome can be considered a distinct clinical entity. Clinical features may also include proximal myoclonus and mild progression with aging. Valproate or levetiracetam, with or without clonazepam, reduces symptoms. FCMTE is a heterogeneous disorder, and likely to include a variety of different conditions with mutations of different genes. Distinct phenotypic traits might reflect different genetic mutations. Genes involved in Purkinje cell outgrowth or those encoding for ion channels or neurotransmitters seem good candidate genes.
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http://dx.doi.org/10.7916/D85155WJDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801339PMC
November 2018

δ-Catenin () missense mutation in familial cortical myoclonic tremor and epilepsy.

Neurology 2017 Dec 10;89(23):2341-2350. Epub 2017 Nov 10.

From the Departments of Neurology and Clinical Neurophysiology (A.-F.v.R., A.B., M.A.J.T.), Academic Medical Centre, Amsterdam Neuroscience, University of Amsterdam; Departments of Functional Genomics and Clinical Genetics (A.J.G.), CNCR, Neuroscience Campus Amsterdam, VU University and VU Medical Centre; Departments of Human Genetics (B.d.V., S.K., L.S.V., A.M.J.M.v.d.M.), Clinical Genetics (G.W.E.S.), and Neurology (A.M.J.M.v.d.M.), Leiden University Medical Centre; and Department of Neurology (P.M.C.C., M.A.J.T.), University Medical Centre Groningen, University of Groningen, the Netherlands.

Objective: To identify the causative gene in a large Dutch family with familial cortical myoclonic tremor and epilepsy (FCMTE).

Methods: We performed exome sequencing for 3 patients of our FCMTE family. Next, we performed knock-down (shRNA) and rescue experiments by overexpressing wild-type and mutant human δ-catenin (CTNND2) proteins in cortical mouse neurons and compared the results with morphologic abnormalities in the postmortem FCMTE brain.

Results: We identified a missense mutation, p.Glu1044Lys, in the gene that cosegregated with the FCMTE phenotype. The knock-down of in cultured cortical mouse neurons revealed increased neurite outgrowth that was rescued by overexpression of wild-type, but not mutant, CTNND2 and was reminiscent of the morphologic abnormalities observed in cerebellar Purkinje cells from patients with FCMTE.

Conclusions: We propose as the causal gene in FCMTE3. Functional testing of the mutant protein revealed abnormal neuronal sprouting, consistent with the abnormal cerebellar Purkinje cell morphology in patients with FCMTE.
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http://dx.doi.org/10.1212/WNL.0000000000004709DOI Listing
December 2017

Intermittent cortical involvement in the preservation of tremor in essential tremor.

J Neurophysiol 2017 11 12;118(5):2628-2635. Epub 2017 Jul 12.

Department of Neurology and Clinical Neurophysiology, Academic Medical Center, Amsterdam, The Netherlands.

Cortical involvement in essential tremor, an involuntary action tremor supposedly of subcortical origin, is uncertain. Conflicting results of corticomuscular coherence studies in essential tremor suggest an intermittent corticomuscular coupling. On the basis of the literature, we hypothesized that corticomuscular coupling is influenced by bilateral motor synchronization and "cognitive states" such as awareness of tremor. In the present study, we investigated ) the existence of intermittent corticomuscular coherence (CMC) in essential tremor and ) factors that influence CMC strength. In 18 essential tremor patients and 18 healthy controls, who mimicked tremor, we simultaneously recorded 64-channel EEG and 6-channel bipolar surface EMG from right and left wrist extensors and flexors. Right-sided (mimicked) hand tremor was recorded with and without a cognitive arithmetic task and with left-sided (mimicked) hand tremor. CMC values per task were compared within and between groups. Changes in CMC strength during tasks were calculated. Our main findings are ) significant CMC around the (mimicked) tremor frequency across all tasks in both groups; ) significant differences in CMC between unilateral tasks, with the highest values during the cognitive task only in the essential tremor group; and ) significant fluctuations of CMC strength over time, independent of the tremor intensity, only in the essential tremor group. Our results suggest a limited role, and certainly not a continuous steering role, of sensorimotor cortical neurons in the generation of tremor. In clinical practice, these findings might help to standardize tremor registration and the interpretation of the analysis. The part of the motor cortex involved in essential tremor is uncertain. The current electrophysiological study is the first to assess corticomuscular coherence systematically. The study shows a dynamic nature of corticomuscular coherence and a possible influence of cognitive states. The results elucidate the involvement of the motor cortex in tremor and help interpret the varying results in the literature. In clinical practice, the findings may guide in standardizing tremor registration and its interpretation.
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http://dx.doi.org/10.1152/jn.00848.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672541PMC
November 2017

Thalamic deep brain stimulation for orthostatic tremor: A multicenter international registry.

Mov Disord 2017 Aug 20;32(8):1240-1244. Epub 2017 Jun 20.

Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.

Background: We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor.

Methods: Data from 17 patients were reviewed, comparing presurgical, short-term (0-48 months), and long-term (≥48 months) follow-up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment-related complications.

Results: There was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long-term follow-up (8 of 17). The latency of symptoms on standing significantly improved, both in the short-term (P = 0.001) and in the long-term (P = 0.018). Three patients obtained no/minimal benefit from the procedure.

Conclusions: Deep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27082DOI Listing
August 2017

Clinician and patient perceptions of free will in movement disorders: mind the gap.

J Neurol Neurosurg Psychiatry 2017 06 11;88(6):532-533. Epub 2017 Mar 11.

Department of Philosophy, Faculty of Humanities, VU University, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1136/jnnp-2016-315152DOI Listing
June 2017

Familial cortical myoclonic tremor and epilepsy: Description of a new South African pedigree with 30 year follow up.

Parkinsonism Relat Disord 2017 May 21;38:35-40. Epub 2017 Feb 21.

Department of Neurology, University of Pretoria, Pretoria, South Africa.

Aim: The aims of this study were to report the index case of a South African family with cortical myoclonic tremor and epilepsy, to describe the pedigree with the clinical findings and results of additional investigations, and to report the unique follow-up evaluation of affected and unaffected family members after 30 years.

Methods: The index case led to evaluation of the clinical files of patients from 1978/1979 and clinical assessment and investigation of patients from this cohort as well as newly identified family members. Patients were examined clinically; cortical myoclonic tremor severity was scored by using the Fahn-Tolosa- Marin-Tremor Rating Scale and the Myoclonus Rating Scale. Cortical origin of myoclonus was proven. Statistical analyses were done to assess the impact of cortical myoclonic tremor on quality of life.

Conclusion: Clinical data was available for 23 patients. Increase in cortical myoclonic tremor and age showed a statistically significant correlation with worsening of the sub-score for Quality of Life (FTMTRS) and myoclonus rating scale. After 30 years eleven of fourteen patients could be followed up. Progression of cortical myoclonic tremor severity was noted but epilepsy control was adequate with all patients reporting less than two seizures per year. No clinical features of neurodegeneration were found.

Discussion: We describe the initial presentation and 30 year follow-up of a four generation South African family with FCMTE. The unique long term follow up of this pedigree supports previous findings that the condition does not cause additional progressive neurological deterioration and quality of life is mostly influenced by worsening of the cortical myoclonic tremor with age.
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http://dx.doi.org/10.1016/j.parkreldis.2017.02.016DOI Listing
May 2017

Clinical decision-making in functional and hyperkinetic movement disorders.

Neurology 2017 Jan 2;88(2):118-123. Epub 2016 Dec 2.

From the Department of Neurology and Clinical Neurophysiology (S.M.A.v.d.S., A.-F.v.R., J.H.T.M.K.) and Clinical Research Unit (R.J.d.H.), Academic Medical Center, Amsterdam; Altrecht Academic Anxiety Center and Department of Clinical & Health Psychology (D.C.C.), University of Utrecht; and Department of Neurology (M.A.J.T.), University Medical Center Groningen, University of Groningen, the Netherlands.

Objective: Functional or psychogenic movement disorders (FMD) present a diagnostic challenge. To diagnose FMD, clinicians must have experience with signs typical of FMD and distinguishing features from other hyperkinetic disorders. The aim of this study was to clarify the decision-making process of expert clinicians while diagnosing FMD, myoclonus, and tics.

Methods: Thirty-nine movement disorders experts rated 60 patients using a standardized web-based survey resembling clinical practice. It provided 5 steps of incremental information: (1) visual first impression of the patient, (2) medical history, (3) neurologic examination on video, (4) the Bereitschaftspotential (BP), and (5) psychiatric evaluation. After full evaluation of each case, experts were asked which diagnostic step was decisive. In addition, interim switches in diagnosis after each informational step were calculated.

Results: After full evaluation, the experts annotated the first impression of the patients as decisive in 18.5% of cases. Medical history was considered decisive in 33.3% of cases. Neurologic examination was considered decisive in 39.7%, the BP in 8%, and the psychiatric interview in 0.5% of cases. Most diagnostic switches occurred after addition of the medical history (34.5%). Addition of the neurologic examination led to 13.8% of diagnostic switches. The BP results led to diagnostic switches in 7.2% of cases. Psychiatric evaluation resulted in the lowest number of diagnostic switches (2.7% of cases).

Conclusions: Experts predominantly rely on clinical assessment to diagnose FMD. Importantly, ancillary tests do not determine the final diagnosis of this expert panel. In general, the experts infrequently changed their differential diagnosis.
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http://dx.doi.org/10.1212/WNL.0000000000003479DOI Listing
January 2017

Targeted brain activation using an MR-compatible wrist torque measurement device and isometric motor tasks during functional magnetic resonance imaging.

Magn Reson Imaging 2016 Jul 8;34(6):795-802. Epub 2016 Mar 8.

Department of BioMechanical Engineering, Faculty of Mechanical, Maritime and Materials Engineering, Delft University of Technology, Delft, The Netherlands; Laboratory of Biomechanical Engineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.

Dedicated pairs of isometric wrist flexion tasks, with and without visual feedback of the exerted torque, were designed to target activation of the CBL and BG in healthy subjects during functional magnetic resonance imaging (fMRI). Selective activation of the cerebellum (CBL) and basal ganglia (BG), often implicated in movement disorders such as tremor and dystonia, may help identify pathological changes and expedite diagnosis. A prototyped MR-compatible wrist torque measurement device, free of magnetic and conductive materials, allowed safe execution of tasks during fMRI without causing artifacts. A significant increase of activity in CBL and BG was found in healthy volunteers during a constant torque task with visual feedback compared to a constant torque task without visual feedback. This study shows that specific pairs of motor tasks using MR-compatible equipment at the wrist allow for targeted activation of CBL and BG, paving a new way for research into the pathophysiology of movement disorders.
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http://dx.doi.org/10.1016/j.mri.2016.02.002DOI Listing
July 2016

Bilateral cerebellar activation in unilaterally challenged essential tremor.

Neuroimage Clin 2016 28;11:1-9. Epub 2015 Dec 28.

Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands; Neuroimaging Center, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands. Electronic address:

Background: Essential tremor (ET) is one of the most common hyperkinetic movement disorders. Previous research into the pathophysiology of ET suggested underlying cerebellar abnormalities.

Objective: In this study, we added electromyography as an index of tremor intensity to functional Magnetic Resonance Imaging (EMG-fMRI) to study a group of ET patients selected according to strict criteria to achieve maximal homogeneity. With this approach we expected to improve upon the localization of the bilateral cerebellar abnormalities found in earlier fMRI studies.

Methods: We included 21 propranolol sensitive patients, who were not using other tremor medication, with a definite diagnosis of ET defined by the Tremor Investigation Group. Simultaneous EMG-fMRI recordings were performed while patients were off tremor medication. Patients performed unilateral right hand and arm extension, inducing tremor, alternated with relaxation (rest). Twenty-one healthy, age- and sex-matched participants mimicked tremor during right arm extension. EMG power variability at the individual tremor frequency as a measure of tremor intensity variability was used as a regressor, mathematically independent of the block regressor, in the general linear model used for fMRI analysis, to find specific tremor-related activations.

Results: Block-related activations were found in the classical upper-limb motor network, both for ET patients and healthy participants in motor, premotor and supplementary motor areas. In ET patients, we found tremor-related activations bilaterally in the cerebellum: in left lobules V, VI, VIIb and IX and in right lobules V, VI, VIIIa and b, and in the brainstem. In healthy controls we found simulated tremor-related activations in right cerebellar lobule V.

Conclusions: Our results expand on previous findings of bilateral cerebellar involvement in ET. We have identified specific areas in the bilateral somatomotor regions of the cerebellum: lobules V, VI and VIII.
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http://dx.doi.org/10.1016/j.nicl.2015.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732188PMC
December 2016

Standardized EEG interpretation accurately predicts prognosis after cardiac arrest.

Neurology 2016 Apr 10;86(16):1482-90. Epub 2016 Feb 10.

Authors' affiliations are listed at the end of the article.

Objective: To identify reliable predictors of outcome in comatose patients after cardiac arrest using a single routine EEG and standardized interpretation according to the terminology proposed by the American Clinical Neurophysiology Society.

Methods: In this cohort study, 4 EEG specialists, blinded to outcome, evaluated prospectively recorded EEGs in the Target Temperature Management trial (TTM trial) that randomized patients to 33°C vs 36°C. Routine EEG was performed in patients still comatose after rewarming. EEGs were classified into highly malignant (suppression, suppression with periodic discharges, burst-suppression), malignant (periodic or rhythmic patterns, pathological or nonreactive background), and benign EEG (absence of malignant features). Poor outcome was defined as best Cerebral Performance Category score 3-5 until 180 days.

Results: Eight TTM sites randomized 202 patients. EEGs were recorded in 103 patients at a median 77 hours after cardiac arrest; 37% had a highly malignant EEG and all had a poor outcome (specificity 100%, sensitivity 50%). Any malignant EEG feature had a low specificity to predict poor prognosis (48%) but if 2 malignant EEG features were present specificity increased to 96% (p < 0.001). Specificity and sensitivity were not significantly affected by targeted temperature or sedation. A benign EEG was found in 1% of the patients with a poor outcome.

Conclusions: Highly malignant EEG after rewarming reliably predicted poor outcome in half of patients without false predictions. An isolated finding of a single malignant feature did not predict poor outcome whereas a benign EEG was highly predictive of a good outcome.
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http://dx.doi.org/10.1212/WNL.0000000000002462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836886PMC
April 2016

Motor network disruption in essential tremor: a functional and effective connectivity study.

Brain 2015 Oct 5;138(Pt 10):2934-47. Epub 2015 Aug 5.

1 Department of Neurology and Clinical Neurophysiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 2 Brain Imaging Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Although involvement of the cerebello-thalamo-cortical network has often been suggested in essential tremor, the source of oscillatory activity remains largely unknown. To elucidate mechanisms of tremor generation, it is of crucial importance to study the dynamics within the cerebello-thalamo-cortical network. Using a combination of electromyography and functional magnetic resonance imaging, it is possible to record the peripheral manifestation of tremor simultaneously with brain activity related to tremor generation. Our first aim was to study the intrinsic activity of regions within the cerebello-thalamo-cortical network using dynamic causal modelling to estimate effective connectivity driven by the concurrently recorded tremor signal. Our second aim was to objectify how the functional integrity of the cerebello-thalamo-cortical network is affected in essential tremor. We investigated the functional connectivity between cerebellar and cortical motor regions showing activations during a motor task. Twenty-two essential tremor patients and 22 healthy controls were analysed. For the effective connectivity analysis, a network of tremor-signal related regions was constructed, consisting of the left primary motor cortex, premotor cortex, supplementary motor area, left thalamus, and right cerebellar motor regions lobule V and lobule VIII. A measure of variation in tremor severity over time, derived from the electromyogram, was included as modulatory input on intrinsic connections and on the extrinsic cerebello-thalamic connections, giving a total of 128 models. Bayesian model selection and random effects Bayesian model averaging were used. Separate seed-based functional connectivity analyses for the left primary motor cortex, left supplementary motor area and right cerebellar lobules IV, V, VI and VIII were performed. We report two novel findings that support an important role for the cerebellar system in the pathophysiology of essential tremor. First, in the effective connectivity analysis, tremor variation during the motor task has an excitatory effect on both the extrinsic connection from cerebellar lobule V to the thalamus, and the intrinsic activity of cerebellar lobule V and thalamus. Second, the functional integrity of the motor network is affected in essential tremor, with a decrease in functional connectivity between cortical and cerebellar motor regions. This decrease in functional connectivity, related to the motor task, correlates with an increase in clinical tremor severity. Interestingly, increased functional connectivity between right cerebellar lobules I-IV and the left thalamus correlates with an increase in clinical tremor severity. In conclusion, our findings suggest that cerebello-dentato-thalamic activity and cerebello-cortical connectivity is disturbed in essential tremor, supporting previous evidence of functional cerebellar changes in essential tremor.
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http://dx.doi.org/10.1093/brain/awv225DOI Listing
October 2015

Thalamic deep brain stimulation for orthostatic tremor: Clinical and neurophysiological correlates.

Parkinsonism Relat Disord 2015 Aug 9;21(8):1005-7. Epub 2015 Jun 9.

Department of Neurology/Clinical Neurophysiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.parkreldis.2015.06.008DOI Listing
August 2015

Interrater variability of EEG interpretation in comatose cardiac arrest patients.

Clin Neurophysiol 2015 Dec 11;126(12):2397-404. Epub 2015 Apr 11.

Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden. Electronic address:

Objective: EEG is widely used to predict outcome in comatose cardiac arrest patients, but its value has been limited by lack of a uniform classification. We used the EEG terminology proposed by the American Clinical Neurophysiology Society (ACNS) to assess interrater variability in a cohort of cardiac arrest patients included in the Target Temperature Management trial. The main objective was to evaluate if malignant EEG-patterns could reliably be identified.

Methods: Full-length EEGs from 103 comatose cardiac arrest patients were interpreted by four EEG-specialists with different nationalities who were blinded for patient outcome. Percent agreement and kappa (κ) for the categories in the ACNS EEG terminology and for prespecified malignant EEG-patterns were calculated.

Results: There was substantial interrater agreement (κ 0.71) for highly malignant patterns and moderate agreement (κ 0.42) for malignant patterns. Substantial agreement was found for malignant periodic or rhythmic patterns (κ 0.72) while agreement for identifying an unreactive EEG was fair (κ 0.26).

Conclusions: The ACNS EEG terminology can be used to identify highly malignant EEG-patterns in post cardiac arrest patients in an international context with high reliability.

Significance: The establishment of strict criteria with high transferability between interpreters will increase the usefulness of routine EEG to assess neurological prognosis after cardiac arrest.
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http://dx.doi.org/10.1016/j.clinph.2015.03.017DOI Listing
December 2015
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