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T37. Electrodiagnostic criteria for neuromuscular transmission disorders suggested by a European consensus group
Abstracts / Clinical Neurophysiology 129 (2018) e1–e65
mechanisms is essential for the development of treatments aimed at prevention of irreversible nerve damage. The present study is a first step in the development of a complex forward mathematical model of the human peripheral myelinated axon which should incorporate all available functional knowledge on higher mammalian or human myelinated axons obtained, for instance, by patch-clamp studies. Here we assessed activation threshold for electrical stimulation and conduction behavior by focussing on segmental demyelination and sodium channel dysfunction in human motor and sensory axons. Methods: We applied an established peripheral myelinated axon model consisting of 40 nodes. To simulate human motor axons, we modified the nodal membrane dynamics to those used in human peripheral motor nerve excitability tests in the median nerve. Sensory axons were simulated by doubling the percentage of persistent sodium channels. Focal segmental demyelination was simultaneously applied on the paranodal, juxtaparanodal, and internodal regions surrounding the three middle nodes by gradually increasing myelin capacitance and conductance until conduction failure occurred. Subsequently, impaired nodal sodium channel function on the three middle nodes was simulated by gradually decreasing the nodal transient and persistent sodium conductance. Results: Normal motor and sensory conduction velocity was approximately 53 m/s and 54 m/s. The activation threshold in the motor axon model was 2% higher than for the sensory axon model. At 70% demyelination, the motor and sensory conduction velocity dropped to 37 m/s. Conduction block occurred for both at 97% of segmental demyelination. With decreasing sodium channel conductance motor axons showed conduction block at a decrease of 94% and sensory axons at 95%. At the site of demyelination the activation threshold increased up to approximately 4-fold in motor and sensory axon model before conduction block occurred. For impaired sodium channel conductance the activation threshold increase was approximately a factor of 3. Conclusion: Using the longitudinal myelinated axon model, we successfully explored the increase in activation threshold and conduction slowing and block due to demyelination and decrease in sodium channel conductance. doi:10.1016/j.clinph.2018.04.036
T36. Motor axonal abnormalities in anti-MAG neuropathy— Kazuaki Kanai *, Tomoko Nakazato, Yasushi Shimo, Genko Oyama, Nobutaka Hattori (Japan) ⇑
Presenting author.
Introduction: Anti-MAG antibody was known to be associated with polyneuropathy associated with immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance, as we call antiMAG neuropathy. Anti-MAG neuropathy is pathologically characterized by the presence of widely spaced myelin (WSM), which affects the structure of nodes of Ranvier. To help understand the physiological actions of anti-MAG antibody and WSM, we examined the effects on the excitability properties of peripheral motor axons. Methods: Four patients with anti-MAG neuropathy were studied. Multiple excitability measurements were made in the median nerve at the wrist, using computerized threshold-tracking (QTRACS with TRONDNF excitability protocol), and compared with normal control data. Subsequently we performed mathematical modeling of the excitability data, using the Bostock model of the human motor axon to simulate axonal excitability measurements (QTRACP with MEMFIT). Results: Nerve excitability studies showed significantly smaller supernormality in recovery cycle and greater changes in excitability with depolarizing currents in threshold electrotonus. Mathematical
e15
modeling suggested that the results could be partially explained by abnormal fast K+ current and/or Na+ current at nodes of Ranvier. Conclusion: This study showed that patients with anti-MAG neuropathy exhibit abnormalities in their motor axons attributable to ion channel dysfunction at nodes. This suggests that anti-MAG antibody causes physiological dysfunction of nodes via changes caused by WSM in peripheral nerve. doi:10.1016/j.clinph.2018.04.037
T37. Electrodiagnostic criteria for neuromuscular transmission disorders suggested by a European consensus group—Kirsten Pugdahl 1,*, Birger Johnsen 1, Hatice Tankisi 1, Jean-Philippe Camdessanché 2, Mamede Carvalho de 3, Peter Fawcett 4, Annick Labarre-Vila 2, Rocco Liguori 5, Wilfred Nix 6, Ian Schofield 4, Anders Fuglsang-Frederiksen 1 (1 Denmark, 2 France, 3 Portugal, 4 United Kingdom, 5 Italy, 6 Germany) ⇑
Presenting author.
Introduction: Despite advances in antibody testing, electrodiagnostic testing still plays a crucial role in diagnosing disorders of the neuromuscular transmission (NMT). Existing criteria for NMT disorders are derived from consensus, while no evidence-based criteria have been published. The aim of this study was to derive evidence-based criteria for the electrodiagnosis of NMT disorders, supported on clinical diagnosis as agreed by consensus (gold standard) in an expert group. Methods: A group of experienced physicians in the European multicentre project ESTEEM representing six different European countries reviewed samples of their patients diagnosed with NMT disorder. A total of 164 examinations obtained a consensus diagnosis of definite (105), probable (44), or possible (15) NMT disorder. In these examinations 405 repetitive nerve stimulation (RNS) and 116 single fibre electromyography (SFEMG) studies were performed. The average numbers of abnormal RNS and SFEMG studies in the patients with a probable consensus diagnosis of NMT disorder served as basis for recommendation of minimal electrodiagnostic criteria. Results: The average number of performed RNS studies per patient from each of eight physicians ranged from 1.9 to 5.2, while the average number of abnormal RNS studies ranged from 0.7 to 3.2. For SFEMG the average number ranged from 0.09 to 1.6 for performed studies and from 0.09 to 1.5 for abnormal studies. In the 99 patients diagnosed with generalised myasthenia, the sensitivity of RNS varied from 43% (abductor digiti minimi muscle) to 78% (nasalis muscle), while the sensitivity of SFEMG ranged from 80% (orbicularis oculi muscle) to 100% (anconeus and frontalis muscles). As minimal electrodiagnostic criteria, the ESTEEM group recommends that either (a) 2 abnormal RNS studies, or (b) 1 abnormal RNS study and 1 abnormal SFEMG study, or (c) 2 abnormal SFEMG should be required to diagnose a NMT disorder. To evaluate the electrodiagnostic tests, the routinely used limits for decrement at the different centres should be applied. Conclusion: Electrodiagnostic consensus recommendations for the minimum number of RNS and SFEMG studies to diagnose disorders of the neuromuscular junction are suggested. The recommendations encourage use of different limits according to the muscle examined and the relevant age group (e.g. children vs. adults), preferably obtained locally at each diagnostic centre. These are the first electrodiagnostic criteria for NMT based on clinical evidence of diagnosis as agreed by consensus. doi:10.1016/j.clinph.2018.04.038
mechanisms is essential for the development of treatments aimed at prevention of irreversible nerve damage. The present study is a first step in the development of a complex forward mathematical model of the human peripheral myelinated axon which should incorporate all available functional knowledge on higher mammalian or human myelinated axons obtained, for instance, by patch-clamp studies. Here we assessed activation threshold for electrical stimulation and conduction behavior by focussing on segmental demyelination and sodium channel dysfunction in human motor and sensory axons. Methods: We applied an established peripheral myelinated axon model consisting of 40 nodes. To simulate human motor axons, we modified the nodal membrane dynamics to those used in human peripheral motor nerve excitability tests in the median nerve. Sensory axons were simulated by doubling the percentage of persistent sodium channels. Focal segmental demyelination was simultaneously applied on the paranodal, juxtaparanodal, and internodal regions surrounding the three middle nodes by gradually increasing myelin capacitance and conductance until conduction failure occurred. Subsequently, impaired nodal sodium channel function on the three middle nodes was simulated by gradually decreasing the nodal transient and persistent sodium conductance. Results: Normal motor and sensory conduction velocity was approximately 53 m/s and 54 m/s. The activation threshold in the motor axon model was 2% higher than for the sensory axon model. At 70% demyelination, the motor and sensory conduction velocity dropped to 37 m/s. Conduction block occurred for both at 97% of segmental demyelination. With decreasing sodium channel conductance motor axons showed conduction block at a decrease of 94% and sensory axons at 95%. At the site of demyelination the activation threshold increased up to approximately 4-fold in motor and sensory axon model before conduction block occurred. For impaired sodium channel conductance the activation threshold increase was approximately a factor of 3. Conclusion: Using the longitudinal myelinated axon model, we successfully explored the increase in activation threshold and conduction slowing and block due to demyelination and decrease in sodium channel conductance. doi:10.1016/j.clinph.2018.04.036
T36. Motor axonal abnormalities in anti-MAG neuropathy— Kazuaki Kanai *, Tomoko Nakazato, Yasushi Shimo, Genko Oyama, Nobutaka Hattori (Japan) ⇑
Presenting author.
Introduction: Anti-MAG antibody was known to be associated with polyneuropathy associated with immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance, as we call antiMAG neuropathy. Anti-MAG neuropathy is pathologically characterized by the presence of widely spaced myelin (WSM), which affects the structure of nodes of Ranvier. To help understand the physiological actions of anti-MAG antibody and WSM, we examined the effects on the excitability properties of peripheral motor axons. Methods: Four patients with anti-MAG neuropathy were studied. Multiple excitability measurements were made in the median nerve at the wrist, using computerized threshold-tracking (QTRACS with TRONDNF excitability protocol), and compared with normal control data. Subsequently we performed mathematical modeling of the excitability data, using the Bostock model of the human motor axon to simulate axonal excitability measurements (QTRACP with MEMFIT). Results: Nerve excitability studies showed significantly smaller supernormality in recovery cycle and greater changes in excitability with depolarizing currents in threshold electrotonus. Mathematical
e15
modeling suggested that the results could be partially explained by abnormal fast K+ current and/or Na+ current at nodes of Ranvier. Conclusion: This study showed that patients with anti-MAG neuropathy exhibit abnormalities in their motor axons attributable to ion channel dysfunction at nodes. This suggests that anti-MAG antibody causes physiological dysfunction of nodes via changes caused by WSM in peripheral nerve. doi:10.1016/j.clinph.2018.04.037
T37. Electrodiagnostic criteria for neuromuscular transmission disorders suggested by a European consensus group—Kirsten Pugdahl 1,*, Birger Johnsen 1, Hatice Tankisi 1, Jean-Philippe Camdessanché 2, Mamede Carvalho de 3, Peter Fawcett 4, Annick Labarre-Vila 2, Rocco Liguori 5, Wilfred Nix 6, Ian Schofield 4, Anders Fuglsang-Frederiksen 1 (1 Denmark, 2 France, 3 Portugal, 4 United Kingdom, 5 Italy, 6 Germany) ⇑
Presenting author.
Introduction: Despite advances in antibody testing, electrodiagnostic testing still plays a crucial role in diagnosing disorders of the neuromuscular transmission (NMT). Existing criteria for NMT disorders are derived from consensus, while no evidence-based criteria have been published. The aim of this study was to derive evidence-based criteria for the electrodiagnosis of NMT disorders, supported on clinical diagnosis as agreed by consensus (gold standard) in an expert group. Methods: A group of experienced physicians in the European multicentre project ESTEEM representing six different European countries reviewed samples of their patients diagnosed with NMT disorder. A total of 164 examinations obtained a consensus diagnosis of definite (105), probable (44), or possible (15) NMT disorder. In these examinations 405 repetitive nerve stimulation (RNS) and 116 single fibre electromyography (SFEMG) studies were performed. The average numbers of abnormal RNS and SFEMG studies in the patients with a probable consensus diagnosis of NMT disorder served as basis for recommendation of minimal electrodiagnostic criteria. Results: The average number of performed RNS studies per patient from each of eight physicians ranged from 1.9 to 5.2, while the average number of abnormal RNS studies ranged from 0.7 to 3.2. For SFEMG the average number ranged from 0.09 to 1.6 for performed studies and from 0.09 to 1.5 for abnormal studies. In the 99 patients diagnosed with generalised myasthenia, the sensitivity of RNS varied from 43% (abductor digiti minimi muscle) to 78% (nasalis muscle), while the sensitivity of SFEMG ranged from 80% (orbicularis oculi muscle) to 100% (anconeus and frontalis muscles). As minimal electrodiagnostic criteria, the ESTEEM group recommends that either (a) 2 abnormal RNS studies, or (b) 1 abnormal RNS study and 1 abnormal SFEMG study, or (c) 2 abnormal SFEMG should be required to diagnose a NMT disorder. To evaluate the electrodiagnostic tests, the routinely used limits for decrement at the different centres should be applied. Conclusion: Electrodiagnostic consensus recommendations for the minimum number of RNS and SFEMG studies to diagnose disorders of the neuromuscular junction are suggested. The recommendations encourage use of different limits according to the muscle examined and the relevant age group (e.g. children vs. adults), preferably obtained locally at each diagnostic centre. These are the first electrodiagnostic criteria for NMT based on clinical evidence of diagnosis as agreed by consensus. doi:10.1016/j.clinph.2018.04.038