Clinical Neurophysiology 126 (2015) 1069–1070
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Ion channel dysfunction and peripheral nerve hyperexcitability See Article, pages 1246–1254
Ectopic motor and sensory symptoms are a part of everyday life. Most people have at some stage experienced occasional nocturnal muscle cramps, fasciculations without weakness or paraesthesiae on leg crossing, and in the main, these symptoms do not signify neurological dysfunction. Clinicians however would be only too aware of patients who present for clinical evaluation due to increasing frequency and severity of these kinds of symptoms. From a mechanistic perspective, the development of disabling ectopic motor and sensory symptoms has been viewed as a clinical manifestation of peripheral nerve hyperexcitability (PNH). A number of varied clinical phenotypes have been described in the PNH spectrum (Liewluck et al., 2014), including acquired neuromyotonia with hyperhidrosis (Isaacs Syndrome), acquired neuromyotonia with autonomic features and encephalopathy (Morvan Syndrome) and cramp fasciculation syndrome (CFS). The term ‘cramp-fasciculation syndrome’ was put forward by Tahmoush and colleagues to describe a syndrome of muscle pain, cramps and exercise intolerance Tahmoush et al. (1991). Needle electromyography (EMG) in their original cohort demonstrated variable changes, ranging from occasional fasciculations through to frequent grouped discharges, which persisted after nerve block but which were terminated by regional curare, suggesting a distal motor origin. While there remains no clear distinction between the various syndromes in the PNH spectrum, the EMG abnormalities in CFS have generally been regarded as less severe, less persistent and often provoked by exercise. In contrast, needle EMG in acquired neuromyotonia may disclose severe continuous spontaneous activity that may take the form of fibrillation potentials, frequent fasciculations and persistent grouped discharges. Diagnostic investigations in patients with all forms of PNH are aimed at detecting an underlying cause such as motor neuropathy, anterior horn cell disease or an immune mechanism, specifically antibodies directed against voltage-gated fast potassium channels. However in a large proportion of patients, extensive diagnostic testing fails to reveal an underlying cause. Previous work has also demonstrated that the clinical and immunological features do not differ significantly between those patients who have EMG evidence of muscle hyperexcitability compared to those who do not (Hart et al., 2002). Due to these inconsistencies, the relationship between aetiological factors and the development of clinical symptoms remains poorly understood and there has been little consensus regarding the most effective means of treating patients with this condition. Nerve excitability testing is a clinical technique that provides information on the behaviour of the various voltage-gated ion
channels, energy-dependent pumps and exchangers that are involved in impulse transmission in peripheral nerve axons (Krishnan et al., 2009). Clinical studies of excitability have spanned a wide range of peripheral nerve disorders, including metabolic (Krishnan et al., 2006), toxic (Park et al., 2009), demyelinating (Lin et al., 2011) and degenerative disorders (Kanai et al., 2006) and have provided important pathophysiological insights that will in the future enable novel diagnostic and treatment approaches for peripheral nerve disease. While PNH and nerve excitability assessment may appear like an ideal match, previous studies of excitability in PNH have been underwhelming, with only subtle changes in excitability measures (Kiernan et al., 2001; Park et al., 2014). Possible causes for this include the vast clinical and electrophysiological heterogeneity of PNH presentations and the potential distal site of generation of ectopic motor discharges, an area of the peripheral nervous system that is difficult to assess using standard excitability techniques. In this issue of Clinical Neurophysiology, Shimatani and colleagues revisit nerve excitability testing in PNH, with studies undertaken in four patients with idiopathic PNH (Shimatani et al., 2015). In contrast to previous studies, the authors demonstrated striking changes in excitability parameters. Specifically, their studies showed prominent changes in accommodative properties of the nerve, with reduced accommodation to prolonged depolarising currents. Assessment of recovery cycle parameters demonstrated reduced refractoriness and late subexcitability with increased superexcitability. The authors also undertook mathematical modelling of the data using the Bostock model of the human motor axon to investigate the potential cause for these findings. Modelling of the data suggested that a loss of voltage dependence of a slow K+ current may explain the findings. The most compelling feature of this study is the tight clustering of excitability values, with a very clear distinction between patient and control data, particularly for superexcitability and in the accommodative response to prolonged hyperpolarization. The study also raises some interesting questions for future research. Firstly, what underlies the functional change noted in the patient data? The authors excluded a genetic mutation in KCNQ2, a voltage-gated ion channel that mediates a slow K+ current in human peripheral nerve axons, but antibody-mediated block of this channel remains a possibility. Secondly, what are the specific clinical and electrophysiological characteristics that led to such prominent changes in these patients? This will require studies in much larger cohorts, with concurrent studies in disease control groups. These studies will help establish a basis for whether excitability testing
http://dx.doi.org/10.1016/j.clinph.2014.09.012 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1070
Editorial / Clinical Neurophysiology 126 (2015) 1069–1070
has a potential diagnostic role in this context. Finally, what do these findings mean for the treatment of PNH? While excitability testing is a highly specialised technique available at only selected centres internationally, its greatest accomplishment to date has been its ability to drive the development of new treatment paradigms for peripheral nerve disease. For patients with PNH, treatments are currently administered using a hit-and-miss approach, with Na+ channel blockers the most frequently used class of drug. These drugs are not always effective and other drugs, such as K+ channel agonists may play a role in PNH treatment in the future. Studies such as the Shimatani paper will hopefully be the start of research into more directed treatment approaches for PNH in the years ahead. Conflict of interest None. References Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 2002;125:1887–95. Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain 2006;129:953–62. Kiernan MC, Hart IK, Bostock H. Excitability properties of motor axons in patients with spontaneous motor unit activity. J Neurol Neurosurg Psychiatry 2001;70:56–64. Krishnan AV, Lin CSY, Park SB, Kiernan MC. Axonal ion channels from bench to bedside: a translational neuroscience perspective. Prog Neurobiol 2009;89:288–313. Krishnan AV, Phoon RK, Pussell BA, Charlesworth JA, Bostock H, Kiernan MC. Neuropathy, axonal Na+ /K+ pump function and activity-dependent
excitability changes in end-stage kidney disease. Clin Neurophysiol 2006;117:992–7. Liewluck T, Klein CJ, Jones Jr LK. Cramp-fasciculation syndrome in patients with and without neural autoantibodies. Muscle Nerve 2014;49:351–6. Lin CS, Krishnan AV, Park SB, Kiernan MC. Modulatory effects on axonal function following intravenous immunoglobulin therapy in CIDP. Arch Neurol 2011;68:862–9. Park SB, Lin CS, Krishnan AV, Simon NG, Bostock H, Vincent A, et al. Axonal dysfunction with voltage gated potassium channel complex antibodies. Exp Neurol 2014;261c:337–42. Park SB, Lin CSY, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC. Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy. Brain 2009;132:2712–23. Shimatani Y, Nodera H, Shibuta Y, Miyazaki Y, Misawa S, Kuwabara S, et al. Abnormal gating of axonal slow potassium current in cramp-fasciculation syndrome. Clin Neurophysiol 2015;126:1246–1254. Tahmoush AJ, Alonso RJ, Tahmoush GP, Heiman-Patterson TD. Cramp-fasciculation syndrome: a treatable hyperexcitable peripheral nerve disorder. Neurology 1991;41:1021–4.
⇑
Arun V. Krishnan Prince of Wales Clinical School, University of New South Wales, Sydney, Australia ⇑ Address: Department of Neurology, Prince of Wales Hospital, Randwick, NSW 2031, Australia. Tel.: +61 2 9382 2414; fax: +61 2 9382 2428. E-mail address: [email protected] Available online 28 September 2014
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Ion channel dysfunction and peripheral nerve hyperexcitability See Article, pages 1246–1254
Ectopic motor and sensory symptoms are a part of everyday life. Most people have at some stage experienced occasional nocturnal muscle cramps, fasciculations without weakness or paraesthesiae on leg crossing, and in the main, these symptoms do not signify neurological dysfunction. Clinicians however would be only too aware of patients who present for clinical evaluation due to increasing frequency and severity of these kinds of symptoms. From a mechanistic perspective, the development of disabling ectopic motor and sensory symptoms has been viewed as a clinical manifestation of peripheral nerve hyperexcitability (PNH). A number of varied clinical phenotypes have been described in the PNH spectrum (Liewluck et al., 2014), including acquired neuromyotonia with hyperhidrosis (Isaacs Syndrome), acquired neuromyotonia with autonomic features and encephalopathy (Morvan Syndrome) and cramp fasciculation syndrome (CFS). The term ‘cramp-fasciculation syndrome’ was put forward by Tahmoush and colleagues to describe a syndrome of muscle pain, cramps and exercise intolerance Tahmoush et al. (1991). Needle electromyography (EMG) in their original cohort demonstrated variable changes, ranging from occasional fasciculations through to frequent grouped discharges, which persisted after nerve block but which were terminated by regional curare, suggesting a distal motor origin. While there remains no clear distinction between the various syndromes in the PNH spectrum, the EMG abnormalities in CFS have generally been regarded as less severe, less persistent and often provoked by exercise. In contrast, needle EMG in acquired neuromyotonia may disclose severe continuous spontaneous activity that may take the form of fibrillation potentials, frequent fasciculations and persistent grouped discharges. Diagnostic investigations in patients with all forms of PNH are aimed at detecting an underlying cause such as motor neuropathy, anterior horn cell disease or an immune mechanism, specifically antibodies directed against voltage-gated fast potassium channels. However in a large proportion of patients, extensive diagnostic testing fails to reveal an underlying cause. Previous work has also demonstrated that the clinical and immunological features do not differ significantly between those patients who have EMG evidence of muscle hyperexcitability compared to those who do not (Hart et al., 2002). Due to these inconsistencies, the relationship between aetiological factors and the development of clinical symptoms remains poorly understood and there has been little consensus regarding the most effective means of treating patients with this condition. Nerve excitability testing is a clinical technique that provides information on the behaviour of the various voltage-gated ion
channels, energy-dependent pumps and exchangers that are involved in impulse transmission in peripheral nerve axons (Krishnan et al., 2009). Clinical studies of excitability have spanned a wide range of peripheral nerve disorders, including metabolic (Krishnan et al., 2006), toxic (Park et al., 2009), demyelinating (Lin et al., 2011) and degenerative disorders (Kanai et al., 2006) and have provided important pathophysiological insights that will in the future enable novel diagnostic and treatment approaches for peripheral nerve disease. While PNH and nerve excitability assessment may appear like an ideal match, previous studies of excitability in PNH have been underwhelming, with only subtle changes in excitability measures (Kiernan et al., 2001; Park et al., 2014). Possible causes for this include the vast clinical and electrophysiological heterogeneity of PNH presentations and the potential distal site of generation of ectopic motor discharges, an area of the peripheral nervous system that is difficult to assess using standard excitability techniques. In this issue of Clinical Neurophysiology, Shimatani and colleagues revisit nerve excitability testing in PNH, with studies undertaken in four patients with idiopathic PNH (Shimatani et al., 2015). In contrast to previous studies, the authors demonstrated striking changes in excitability parameters. Specifically, their studies showed prominent changes in accommodative properties of the nerve, with reduced accommodation to prolonged depolarising currents. Assessment of recovery cycle parameters demonstrated reduced refractoriness and late subexcitability with increased superexcitability. The authors also undertook mathematical modelling of the data using the Bostock model of the human motor axon to investigate the potential cause for these findings. Modelling of the data suggested that a loss of voltage dependence of a slow K+ current may explain the findings. The most compelling feature of this study is the tight clustering of excitability values, with a very clear distinction between patient and control data, particularly for superexcitability and in the accommodative response to prolonged hyperpolarization. The study also raises some interesting questions for future research. Firstly, what underlies the functional change noted in the patient data? The authors excluded a genetic mutation in KCNQ2, a voltage-gated ion channel that mediates a slow K+ current in human peripheral nerve axons, but antibody-mediated block of this channel remains a possibility. Secondly, what are the specific clinical and electrophysiological characteristics that led to such prominent changes in these patients? This will require studies in much larger cohorts, with concurrent studies in disease control groups. These studies will help establish a basis for whether excitability testing
http://dx.doi.org/10.1016/j.clinph.2014.09.012 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1070
Editorial / Clinical Neurophysiology 126 (2015) 1069–1070
has a potential diagnostic role in this context. Finally, what do these findings mean for the treatment of PNH? While excitability testing is a highly specialised technique available at only selected centres internationally, its greatest accomplishment to date has been its ability to drive the development of new treatment paradigms for peripheral nerve disease. For patients with PNH, treatments are currently administered using a hit-and-miss approach, with Na+ channel blockers the most frequently used class of drug. These drugs are not always effective and other drugs, such as K+ channel agonists may play a role in PNH treatment in the future. Studies such as the Shimatani paper will hopefully be the start of research into more directed treatment approaches for PNH in the years ahead. Conflict of interest None. References Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 2002;125:1887–95. Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain 2006;129:953–62. Kiernan MC, Hart IK, Bostock H. Excitability properties of motor axons in patients with spontaneous motor unit activity. J Neurol Neurosurg Psychiatry 2001;70:56–64. Krishnan AV, Lin CSY, Park SB, Kiernan MC. Axonal ion channels from bench to bedside: a translational neuroscience perspective. Prog Neurobiol 2009;89:288–313. Krishnan AV, Phoon RK, Pussell BA, Charlesworth JA, Bostock H, Kiernan MC. Neuropathy, axonal Na+ /K+ pump function and activity-dependent
excitability changes in end-stage kidney disease. Clin Neurophysiol 2006;117:992–7. Liewluck T, Klein CJ, Jones Jr LK. Cramp-fasciculation syndrome in patients with and without neural autoantibodies. Muscle Nerve 2014;49:351–6. Lin CS, Krishnan AV, Park SB, Kiernan MC. Modulatory effects on axonal function following intravenous immunoglobulin therapy in CIDP. Arch Neurol 2011;68:862–9. Park SB, Lin CS, Krishnan AV, Simon NG, Bostock H, Vincent A, et al. Axonal dysfunction with voltage gated potassium channel complex antibodies. Exp Neurol 2014;261c:337–42. Park SB, Lin CSY, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC. Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy. Brain 2009;132:2712–23. Shimatani Y, Nodera H, Shibuta Y, Miyazaki Y, Misawa S, Kuwabara S, et al. Abnormal gating of axonal slow potassium current in cramp-fasciculation syndrome. Clin Neurophysiol 2015;126:1246–1254. Tahmoush AJ, Alonso RJ, Tahmoush GP, Heiman-Patterson TD. Cramp-fasciculation syndrome: a treatable hyperexcitable peripheral nerve disorder. Neurology 1991;41:1021–4.
⇑
Arun V. Krishnan Prince of Wales Clinical School, University of New South Wales, Sydney, Australia ⇑ Address: Department of Neurology, Prince of Wales Hospital, Randwick, NSW 2031, Australia. Tel.: +61 2 9382 2414; fax: +61 2 9382 2428. E-mail address: [email protected] Available online 28 September 2014
