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FV 10 Automated motor unit counting (MSCAN) in amyotrophic lateral sclerosis
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Abstracts / Clinical Neurophysiology 128 (2017) e305–e412
Free Lecture FV 8 An update on neurophysiological diagnostic in pediatric neurology—P. Broser 1,2,*, O. Maier 1 (1 Stiftung OstSwitzerlander Kinderspital, Neuro-Pädiatrie, St. Gallen, Switzerland, 2 Stiftung OstSwitzerlander Kinderspital, KER-Zentrum, St. Gallen, Switzerland) ⇑ Corresponding author at: Charité Universitätsmedizin Berlin, Centrum für Schlaganfallforschung, Berlin, Germany.
Evoked potentials are an important neurophysiological method in pediatrics. Most commonly used are brainstem auditory evoked potentials (BAEP), visual evoked potentials (VEP) and somatosensory evoked potentials (SEP). BAEPs are useful in screening for hearing disorders and for evaluating brain stem function. VEPs are performed to evaluate visual functioning and for diagnosis of demyelinating diseases. SEPs allow evaluation of the functional integrity of the somatosensory system from the peripheral nerve to the cerebral cortex and can be a useful additional prognostic tool in determining coma and asphyxia outcome. In pediatrics, motor evoked potentials (MEP) are mainly used in scientific studies. During this presentation we will show recent developments in the use of neurophysiological diagnostic in pediatric neurology. Given that the spectrum of indication differs from that in adult neurology, maturation processes and age-related effects in focus of these techniques.
Conclusion: In clinically pure LMND patients, the involvement of corticoefferent tracts was demonstrated, in particular along the CST, supporting the hypothesis that LMND is a phenotypical variant of ALS. This finding suggests to treat these patients like ALS, including the opportunity to participate in clinical trials. References Kassubek J, Müller HP, Del Tredici K, et al. Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology. Brain 2014;137:1733–40. Müller HP, Turner MR, Grosskreutz J, et al. A large-scale multicentre cerebral diffusion tensor imaging study in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. doi:10.1016/j.clinph.2017.06.051
Free Lecture FV 10 Automated motor unit counting (MSCAN) in amyotrophic lateral sclerosis—M. Hohmann *, M. Appelfeller, A. Gunkel, B. Ilse, B. Stubendorff, O.W. Witte, J. Grosskreutz (Universitätsklinikum Jena, Hans-Berger-Klinik für Neurologie, Jena, Germany) ⇑ Corresponding author at: Ludwig-Maximilians-Universität, Deutsches Schwindel-und Gleichgewichtszentrum, München, Germany.
doi:10.1016/j.clinph.2017.06.050
Free Lecture FV 9 Diffusion tensor imaging in pure lower motor neuron disease—J. Kassubek *, A. Rosenbohm, H.P. Müller, A. Hübers, A.C. Ludolph (Uniklinik Ulm, Neurologie, Ulm, Germany) ⇑ Corresponding author at: Uniklinik Köln, Klinik für Neurologie, Köln, Germany.
Introduction: Criteria for assessing upper motor neuron pathology in lower motor neuron disease (LMND) still remain a major issue in clinical diagnosis. This study was designed to investigate patients with the clinical diagnosis of adult pure LMND by use of wholebrain based diffusion tensor imaging (DTI) in order to delineate alterations of corticoefferent pathways in vivo. Methods: Comparison of fractional anisotropy (FA) maps was performed by whole brain-based spatial statistics for 37 LMND patients vs. 53 matched controls to detect white matter structural alterations. LMND patients were clinically differentiated in fast and slow progressors. Tract specific alterations were investigated by fiber tracking techniques according to the staging hypothesis for amyotrophic lateral sclerosis (ALS). Results: The analysis of white matter structural connectivity demonstrated widespread and characteristic patterns of alterations in patients with LMND, predominantly along the corticospinal tract (CST), with multiple clusters of regional FA reductions in the motor system at p < 0.05 (corrected for multiple comparisons). Fast progressing LMND showed substantial CST involvement, while slow progressors showed less CST alterations. In the tract-specific analysis according to the ALS-staging pattern (Kassubek et al., 2014), fast progressing LMND showed significant alterations of ALS-related tract systems (Müller et al., xxxx) beyond the CST compared to slow progressors and controls.
Introduction: Motor unit number estimations methods have been used to quantify the loss of motor units underlying ALS, a deadly neurodegenerative disease. MUNIX relies on surface interference patterns (SIP) recorded during voluntary isometric contractions. In contrast, the recently developed MSCAN techniques is based on threshold tracking and uses natural threshold oscillations of single axons to identify the number of motor units present. MSCAN allows to estimate the composition of the CMAP from single units and allows to simulate the composition of single motor units. Both studies require approximately 5 min per muscle and an optimal CMAP as starting point. Objective: Our goal was to show a loss of motor units and a decrease of CMAP in ALS patients over time with MSCAN under realistic medical care conditions. Using MSCAN records and ALSFRS-R, we wanted to show disease progression. Methods: MSCAN measurements were performed in 47 ALS patients in up to three muscles in the less affected side (APB, ADM, TA) by threshold-tracking experienced staff. Follow-up measurements were performed after six months in 21 patients. To minimize movement artifacts, limbs were fixed using vacuum cushions. Disease duration, ALSFRS-R, progression rate, ALSFRS-R subscores, diagnostic certainty and clinical stage were extracted from our local database which is an integral part of patient care and reports patient status continuously. Measurements were correlated with model based parameters of ALS progression. Also we calculated ALSFRS-R at the time of the MSCAN measurement taking into account the duration of the disease and D50, which is the number of months after which ALSFRS is reduced to 50% and therefore reflects disease progression. Results: MSCAN values and CMAP amplitudes showed a linear correlation in all muscles in base measurement as well as in follow-up measurement. In the follow-up measurements, a decrease compared with base values could be shown in all three muscles. Concerning motor units, this effect could also be detected in the two hand muscles, but not in TA. The quality and stability of the measurements were greatly improved by fixation of the limbs and using bipolar
Abstracts / Clinical Neurophysiology 128 (2017) e305–e412
stimulation. MSCAN values did not correlate with total ALSFRS-R, cervical respectively lumbal ALSFRS-subscores nor disease duration in our cohort. A trend was seen in MSCAN units respectively CMAP and calculated ALSFRS and D50. Conclusion: MSCAN measurements in clinical routine are feasible and show a reduction of motor units and CMAP in ALS patients over time. The correlation with functional measures was limited, likely due to the focal nature of the measurement. Further longitudinal studies are required to estimate MSCANs value as a prognostic and disease monitoring marker. Acknowledgment: This research is supported by BMBF (Bundesministerium für Bildung and Forschung) in the framework of the E-RARE programme (PYRAMID) and JPND (OnWebDUALS) of the European Union.
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Free Lecture FV 12 Longitudinal study on hippocampal volume and neuropsychological outcome in IgM-NMDAR-antibody-associated encephalopathy—I. Schulze 1,*, C.M. Stoppel 2, D. Bittner 1,3, V. Bittner 1, G. von Hartrott 1, H.J. Heinze 1,3, D. Reinhold 4, J. Kaufmann 1, P. Körtvelyessy 1,3 (1 Universitätsklinikum Magdeburg, Klinik für Neurologie, Magdeburg, Germany, 2 Charité Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie, Berlin, Germany, 3 Deutsches Zentrum für Neurodegenerative Erkrankungen, Magdeburg, Germany, 4 Institut für molekulare und klinische Immunologie, Magdeburg, Germany) ⇑
Corresponding author at: LMU, Neurology, München, Germany.
doi:10.1016/j.clinph.2017.06.052
Free Lecture FV 11 Patterns of abnormal functional connectivity in progressive supranuclear palsy are associated with impaired behavioral performance—J. Rosskopf *, M. Gorges, H.P. Müller, D. Lule, I. Uttner, E.H. Pinkhardt, A.C. Ludolph, J. Kassubek (Uniklinik Ulm, Neurologie, Ulm, Germany) ⇑ Corresponding author at: Max-Planck-Institut für Kognitions- und Neurowissenschaften, Neurologie, Leipzig, Germany.
Background: The underlying pathological process in neurodegenerative diseases is associated with altered functional brain organization. Objective: To study functional connectivity and its possible behavioral correlates in specific networks in patients with progressive supranuclear palsy (PSP). Methods: Whole-brain based ‘‘resting-state” fMRI data from 34 PSP patients (Richardson subtype (PSP-RS): n = 22; Parkinsonian subtype (PSP-P): n = 12) and 35 matched healthy controls were subjected to network-based functional connectivity analysis. Results: Group comparison between PSP patients and controls revealed significantly decreased functional connectivity (p < 0.05, corrected) in the prefrontal cortex which was significantly correlated with the cognitive status (p = 0.006). Of note, midbrain network connectivity in PSP patients revealed increased connectivity with the thalamus on the one hand, while regionally decreased functional connectivity within the midbrain was significantly correlated with vertical gaze palsy (p = 0.004) as quantified by videooculographically on the other hand. PSP-RS showed significantly increased functional motor network connectivity with the medial prefrontal gyrus, whereas PSP-P patients presented no significant difference in motor network connectivity. Conclusion: PSP-associated neurodegeneration may be attributed to both, decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (i.e. cognitive decline, gaze palsy), whereas the pattern of increased functional connectivity may be attributed to adaptive changes. doi:10.1016/j.clinph.2017.06.053
Introduction: Anti-NMDAR-IgM-autoantibodies (IgM-NMDARaab) are occurring in approximately 4–5% of the general population (Dahm et al., 2014). IgM-NMDAR-aab are also associated to a rare encephalopathy presenting with symptoms resembling frontotemporal dementia (FTD) but with much faster progression as a neurodegenerative disease (Doss et al., 2014). Treatment with an immunosuppressive therapy is recommend but has not been evaluated with neuroimaging and neuropsychology. Here, we present longitudinal data on two cases. Methods: We identified two patients referred to us presenting memory disturbances and memory loss together with a severe executive dysfunction and alteration in behavior developing within 3– 5 months. CSF did not reveal an Alzheimer’s-disease like constellation. Routine MRI scans were considered normal. Neuropsychological testing showed severe deficits in frontotemporal functioning. Antibody screening via indirect immunofluorescence test (IFT) involved IgM-, IgA- and IgG-NMDAR-ab, Lgi-1-, CASPR2-, DPPX- and AMPA-IgG-ab and also onconeuronal ab via an immunoblot analysis (anti-Hu, -Yo, -Ri, -CV2, -Ma2, -Amphiphysin, -GAD65, -Tr(DNER), -Sox1, -Titin and -Recoverinab; all tests were performed by Euroimmun, Lübeck, Germany). Both patients received multiple methylprednisolone (MP) i.v. therapies (each cycle with 1 g i.v. per day for 3 days for a total of 9 g MP (Pat1) or 15 g MP(Pat2)). MRI scans were conducted during therapy and after therapy. Data were acquired on a 3-Tesla MR scanner (Siemens MAGNETOM Prisma, Erlangen, Germany) equipped with a 20-channel head coil. T1-weighted, high-resolution structural MR-images were obtained using a three dimensional MPRAGE sequence yielding an isotropic resolution of 1 mm3. Hippocampal volume was manually assessed via Multitracer software (free software, UCLA, USA) and double-checked. Neuropsychological assessment was identically performed for each patient during each assessment time point (Rey-Figure, Trail making test A/B, executive and memory test, digit and word-span). Results: Serum titers were highly pathological for path patients, with Pat1 having an IgM-NMDAR-aab titer of 1:160 and Pat2 of 1:320. No other abs were detected via immunoblot or IFT. In addition, results of manual assessment revealed that hippocampal (HC) volume increased bilaterally in Pat1 due to MP-treatment. Accordingly, neuropsychological measures of memory function (digit span, Rey-figure) improved slightly in Pat1. In Pat2, in contrast, only the right HC had a slight volume increase, while the left HC volume showed a slight decrease. Nevertheless, initial memory dysfunctions observed in Pat2 declined remarkably in the course of our treatment. Beyond that, clinical assessment showed an overall
Abstracts / Clinical Neurophysiology 128 (2017) e305–e412
Free Lecture FV 8 An update on neurophysiological diagnostic in pediatric neurology—P. Broser 1,2,*, O. Maier 1 (1 Stiftung OstSwitzerlander Kinderspital, Neuro-Pädiatrie, St. Gallen, Switzerland, 2 Stiftung OstSwitzerlander Kinderspital, KER-Zentrum, St. Gallen, Switzerland) ⇑ Corresponding author at: Charité Universitätsmedizin Berlin, Centrum für Schlaganfallforschung, Berlin, Germany.
Evoked potentials are an important neurophysiological method in pediatrics. Most commonly used are brainstem auditory evoked potentials (BAEP), visual evoked potentials (VEP) and somatosensory evoked potentials (SEP). BAEPs are useful in screening for hearing disorders and for evaluating brain stem function. VEPs are performed to evaluate visual functioning and for diagnosis of demyelinating diseases. SEPs allow evaluation of the functional integrity of the somatosensory system from the peripheral nerve to the cerebral cortex and can be a useful additional prognostic tool in determining coma and asphyxia outcome. In pediatrics, motor evoked potentials (MEP) are mainly used in scientific studies. During this presentation we will show recent developments in the use of neurophysiological diagnostic in pediatric neurology. Given that the spectrum of indication differs from that in adult neurology, maturation processes and age-related effects in focus of these techniques.
Conclusion: In clinically pure LMND patients, the involvement of corticoefferent tracts was demonstrated, in particular along the CST, supporting the hypothesis that LMND is a phenotypical variant of ALS. This finding suggests to treat these patients like ALS, including the opportunity to participate in clinical trials. References Kassubek J, Müller HP, Del Tredici K, et al. Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology. Brain 2014;137:1733–40. Müller HP, Turner MR, Grosskreutz J, et al. A large-scale multicentre cerebral diffusion tensor imaging study in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. doi:10.1016/j.clinph.2017.06.051
Free Lecture FV 10 Automated motor unit counting (MSCAN) in amyotrophic lateral sclerosis—M. Hohmann *, M. Appelfeller, A. Gunkel, B. Ilse, B. Stubendorff, O.W. Witte, J. Grosskreutz (Universitätsklinikum Jena, Hans-Berger-Klinik für Neurologie, Jena, Germany) ⇑ Corresponding author at: Ludwig-Maximilians-Universität, Deutsches Schwindel-und Gleichgewichtszentrum, München, Germany.
doi:10.1016/j.clinph.2017.06.050
Free Lecture FV 9 Diffusion tensor imaging in pure lower motor neuron disease—J. Kassubek *, A. Rosenbohm, H.P. Müller, A. Hübers, A.C. Ludolph (Uniklinik Ulm, Neurologie, Ulm, Germany) ⇑ Corresponding author at: Uniklinik Köln, Klinik für Neurologie, Köln, Germany.
Introduction: Criteria for assessing upper motor neuron pathology in lower motor neuron disease (LMND) still remain a major issue in clinical diagnosis. This study was designed to investigate patients with the clinical diagnosis of adult pure LMND by use of wholebrain based diffusion tensor imaging (DTI) in order to delineate alterations of corticoefferent pathways in vivo. Methods: Comparison of fractional anisotropy (FA) maps was performed by whole brain-based spatial statistics for 37 LMND patients vs. 53 matched controls to detect white matter structural alterations. LMND patients were clinically differentiated in fast and slow progressors. Tract specific alterations were investigated by fiber tracking techniques according to the staging hypothesis for amyotrophic lateral sclerosis (ALS). Results: The analysis of white matter structural connectivity demonstrated widespread and characteristic patterns of alterations in patients with LMND, predominantly along the corticospinal tract (CST), with multiple clusters of regional FA reductions in the motor system at p < 0.05 (corrected for multiple comparisons). Fast progressing LMND showed substantial CST involvement, while slow progressors showed less CST alterations. In the tract-specific analysis according to the ALS-staging pattern (Kassubek et al., 2014), fast progressing LMND showed significant alterations of ALS-related tract systems (Müller et al., xxxx) beyond the CST compared to slow progressors and controls.
Introduction: Motor unit number estimations methods have been used to quantify the loss of motor units underlying ALS, a deadly neurodegenerative disease. MUNIX relies on surface interference patterns (SIP) recorded during voluntary isometric contractions. In contrast, the recently developed MSCAN techniques is based on threshold tracking and uses natural threshold oscillations of single axons to identify the number of motor units present. MSCAN allows to estimate the composition of the CMAP from single units and allows to simulate the composition of single motor units. Both studies require approximately 5 min per muscle and an optimal CMAP as starting point. Objective: Our goal was to show a loss of motor units and a decrease of CMAP in ALS patients over time with MSCAN under realistic medical care conditions. Using MSCAN records and ALSFRS-R, we wanted to show disease progression. Methods: MSCAN measurements were performed in 47 ALS patients in up to three muscles in the less affected side (APB, ADM, TA) by threshold-tracking experienced staff. Follow-up measurements were performed after six months in 21 patients. To minimize movement artifacts, limbs were fixed using vacuum cushions. Disease duration, ALSFRS-R, progression rate, ALSFRS-R subscores, diagnostic certainty and clinical stage were extracted from our local database which is an integral part of patient care and reports patient status continuously. Measurements were correlated with model based parameters of ALS progression. Also we calculated ALSFRS-R at the time of the MSCAN measurement taking into account the duration of the disease and D50, which is the number of months after which ALSFRS is reduced to 50% and therefore reflects disease progression. Results: MSCAN values and CMAP amplitudes showed a linear correlation in all muscles in base measurement as well as in follow-up measurement. In the follow-up measurements, a decrease compared with base values could be shown in all three muscles. Concerning motor units, this effect could also be detected in the two hand muscles, but not in TA. The quality and stability of the measurements were greatly improved by fixation of the limbs and using bipolar
Abstracts / Clinical Neurophysiology 128 (2017) e305–e412
stimulation. MSCAN values did not correlate with total ALSFRS-R, cervical respectively lumbal ALSFRS-subscores nor disease duration in our cohort. A trend was seen in MSCAN units respectively CMAP and calculated ALSFRS and D50. Conclusion: MSCAN measurements in clinical routine are feasible and show a reduction of motor units and CMAP in ALS patients over time. The correlation with functional measures was limited, likely due to the focal nature of the measurement. Further longitudinal studies are required to estimate MSCANs value as a prognostic and disease monitoring marker. Acknowledgment: This research is supported by BMBF (Bundesministerium für Bildung and Forschung) in the framework of the E-RARE programme (PYRAMID) and JPND (OnWebDUALS) of the European Union.
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Free Lecture FV 12 Longitudinal study on hippocampal volume and neuropsychological outcome in IgM-NMDAR-antibody-associated encephalopathy—I. Schulze 1,*, C.M. Stoppel 2, D. Bittner 1,3, V. Bittner 1, G. von Hartrott 1, H.J. Heinze 1,3, D. Reinhold 4, J. Kaufmann 1, P. Körtvelyessy 1,3 (1 Universitätsklinikum Magdeburg, Klinik für Neurologie, Magdeburg, Germany, 2 Charité Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie, Berlin, Germany, 3 Deutsches Zentrum für Neurodegenerative Erkrankungen, Magdeburg, Germany, 4 Institut für molekulare und klinische Immunologie, Magdeburg, Germany) ⇑
Corresponding author at: LMU, Neurology, München, Germany.
doi:10.1016/j.clinph.2017.06.052
Free Lecture FV 11 Patterns of abnormal functional connectivity in progressive supranuclear palsy are associated with impaired behavioral performance—J. Rosskopf *, M. Gorges, H.P. Müller, D. Lule, I. Uttner, E.H. Pinkhardt, A.C. Ludolph, J. Kassubek (Uniklinik Ulm, Neurologie, Ulm, Germany) ⇑ Corresponding author at: Max-Planck-Institut für Kognitions- und Neurowissenschaften, Neurologie, Leipzig, Germany.
Background: The underlying pathological process in neurodegenerative diseases is associated with altered functional brain organization. Objective: To study functional connectivity and its possible behavioral correlates in specific networks in patients with progressive supranuclear palsy (PSP). Methods: Whole-brain based ‘‘resting-state” fMRI data from 34 PSP patients (Richardson subtype (PSP-RS): n = 22; Parkinsonian subtype (PSP-P): n = 12) and 35 matched healthy controls were subjected to network-based functional connectivity analysis. Results: Group comparison between PSP patients and controls revealed significantly decreased functional connectivity (p < 0.05, corrected) in the prefrontal cortex which was significantly correlated with the cognitive status (p = 0.006). Of note, midbrain network connectivity in PSP patients revealed increased connectivity with the thalamus on the one hand, while regionally decreased functional connectivity within the midbrain was significantly correlated with vertical gaze palsy (p = 0.004) as quantified by videooculographically on the other hand. PSP-RS showed significantly increased functional motor network connectivity with the medial prefrontal gyrus, whereas PSP-P patients presented no significant difference in motor network connectivity. Conclusion: PSP-associated neurodegeneration may be attributed to both, decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (i.e. cognitive decline, gaze palsy), whereas the pattern of increased functional connectivity may be attributed to adaptive changes. doi:10.1016/j.clinph.2017.06.053
Introduction: Anti-NMDAR-IgM-autoantibodies (IgM-NMDARaab) are occurring in approximately 4–5% of the general population (Dahm et al., 2014). IgM-NMDAR-aab are also associated to a rare encephalopathy presenting with symptoms resembling frontotemporal dementia (FTD) but with much faster progression as a neurodegenerative disease (Doss et al., 2014). Treatment with an immunosuppressive therapy is recommend but has not been evaluated with neuroimaging and neuropsychology. Here, we present longitudinal data on two cases. Methods: We identified two patients referred to us presenting memory disturbances and memory loss together with a severe executive dysfunction and alteration in behavior developing within 3– 5 months. CSF did not reveal an Alzheimer’s-disease like constellation. Routine MRI scans were considered normal. Neuropsychological testing showed severe deficits in frontotemporal functioning. Antibody screening via indirect immunofluorescence test (IFT) involved IgM-, IgA- and IgG-NMDAR-ab, Lgi-1-, CASPR2-, DPPX- and AMPA-IgG-ab and also onconeuronal ab via an immunoblot analysis (anti-Hu, -Yo, -Ri, -CV2, -Ma2, -Amphiphysin, -GAD65, -Tr(DNER), -Sox1, -Titin and -Recoverinab; all tests were performed by Euroimmun, Lübeck, Germany). Both patients received multiple methylprednisolone (MP) i.v. therapies (each cycle with 1 g i.v. per day for 3 days for a total of 9 g MP (Pat1) or 15 g MP(Pat2)). MRI scans were conducted during therapy and after therapy. Data were acquired on a 3-Tesla MR scanner (Siemens MAGNETOM Prisma, Erlangen, Germany) equipped with a 20-channel head coil. T1-weighted, high-resolution structural MR-images were obtained using a three dimensional MPRAGE sequence yielding an isotropic resolution of 1 mm3. Hippocampal volume was manually assessed via Multitracer software (free software, UCLA, USA) and double-checked. Neuropsychological assessment was identically performed for each patient during each assessment time point (Rey-Figure, Trail making test A/B, executive and memory test, digit and word-span). Results: Serum titers were highly pathological for path patients, with Pat1 having an IgM-NMDAR-aab titer of 1:160 and Pat2 of 1:320. No other abs were detected via immunoblot or IFT. In addition, results of manual assessment revealed that hippocampal (HC) volume increased bilaterally in Pat1 due to MP-treatment. Accordingly, neuropsychological measures of memory function (digit span, Rey-figure) improved slightly in Pat1. In Pat2, in contrast, only the right HC had a slight volume increase, while the left HC volume showed a slight decrease. Nevertheless, initial memory dysfunctions observed in Pat2 declined remarkably in the course of our treatment. Beyond that, clinical assessment showed an overall