Peripheral Nerve Hyperexcitability Syndrome Research Articles

Peripheral nervous system hyperexcitability in VV2 sporadic Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is a fatal, rapidly progressive neurodegenerative disease. Most cases are sporadic (sCJD). The pathogenesis of sCJD is associated with a conformational change in abnormal prion protein causing widespread neuronal degeneration, and clinical manifestations can be quite protean. Peripheral nerve hyperexcitability syndrome (PNHS) is rarely associated with CJD and is more commonly associated with autoimmune/paraneoplastic syndromes associated with antibodies against the voltage-gated potassium channel complex (VGKC-Abs). Reports of PNHS in CJD are rare. We report 2 patients with progressive cognitive decline in the setting of peripheral nerve hyperexcitability on electrodiagnostic testing. In both patients VGKC-Abs were negative, and autopsy confirmed that both had sCJD, VV2 subtype. While uncommon, it is important to consider sCJD in patients presenting with PNHS and rapidly progressive dementia.

Morvan Syndrome: A Case Report With Patient Narrative and Video.

A 74-year-old gentleman was admitted to the regional neurosciences center with encephalopathy, myokymia, and dysautonomia. Chest imaging had previously identified an incidental mass in the anterior mediastinum, consistent with a primary thymic tumor. Antivoltage-gated potassium channel (anti-VGKC) antibodies were positive (titer 1273 pmol/L) and he was hypokalemic. Electromyogram and nerve conduction studies were in keeping with peripheral nerve hyperexcitability syndrome, and an electroencephalogram was consistent with encephalopathy. A diagnosis of Morvan syndrome was made, for which he was initially treated with high-dose steroids, followed by a 5-day course of intravenous immunoglobulin (IVIG) therapy. He also underwent thymectomy, followed by a postexcision flare of his symptoms requiring intensive care management. Further steroids, plasmapheresis, and IVIG achieved stabilization of his clinical condition, enabling transfer for inpatient neurorehabilitation. He was commenced on azathioprine and a prolonged oral steroid taper. A subsequent presumed incipient relapse responded well to further IVIG treatment. This case report documents a thymoma-associated presentation of anti-VGKC-positive Morvan syndrome supplemented by patient and carer narrative and video, both of which provide valuable further insights into this rare disorder. There are a limited number of publications surrounding this rare condition available in the English literature. This, combined with the heterogenous presentation, association with underlying malignancy, response to treatment, and prognosis, provides a diagnostic challenge. However, the association with anti-VGKC antibody-associated complexes and 2 recent case series have provided some scope for both accurate diagnosis and management.

Isaacs syndrome: A review

Isaacs syndrome is a peripheral nerve hyperexcitability (PNH) syndrome that presents as continuous motor activity. Clinical findings include cramps, fasciculations, and myokymia. Electrodiagnosis plays a key role in diagnosis by demonstrating after-discharges on nerve conduction studies, and fasciculation potentials, myokymic discharges, neuromyotonic discharges, and other types of abnormal spontaneous activity on needle examination. Etiopathogenesis involves the interaction of genetic, autoimmune, and paraneoplastic factors, which requires a broad-ranging evaluation for underlying causes. Initial treatment is symptomatic, but immune therapy is often needed and can be effective. The purpose of this review is to describe the syndrome and its pathogenesis, assist the reader in evaluating patients with suspected Isaacs syndrome and distinguishing it from other disorders of PNH, and suggest an approach to management, including both symptomatic and immunomodulating therapy.

Peripheral nerve hyperexcitability syndromes.

Peripheral nerve hyperexcitability (PNH) syndromes can be subclassified as primary and secondary. The main primary PNH syndromes are neuromyotonia, cramp-fasciculation syndrome (CFS), and Morvan's syndrome, which cause widespread symptoms and signs without the association of an evident peripheral nerve disease. Their major symptoms are muscle twitching and stiffness, which differ only in severity between neuromyotonia and CFS. Cramps, pseudomyotonia, hyperhidrosis, and some other autonomic abnormalities, as well as mild positive sensory phenomena, can be seen in several patients. Symptoms reflecting the involvement of the central nervous system occur in Morvan's syndrome. Secondary PNH syndromes are generally seen in patients with focal or diffuse diseases affecting the peripheral nervous system. The PNH-related symptoms and signs are generally found incidentally during clinical or electrodiagnostic examinations. The electrophysiological findings that are very useful in the diagnosis of PNH are myokymic and neuromyotonic discharges in needle electromyography along with some additional indicators of increased nerve fiber excitability. Based on clinicopathological and etiological associations, PNH syndromes can also be classified as immune mediated, genetic, and those caused by other miscellaneous factors. There has been an increasing awareness on the role of voltage-gated potassium channel complex autoimmunity in primary PNH pathogenesis. Then again, a long list of toxic compounds and genetic factors has also been implicated in development of PNH. The management of primary PNH syndromes comprises symptomatic treatment with anticonvulsant drugs, immune modulation if necessary, and treatment of possible associated dysimmune and/or malignant conditions.

Fasciculations in human hereditary disease.

Fasciculations are a manifestation of peripheral nerve hyperexcitability in addition to myokymia, neuromyotonia, cramps, or tetany. Fasciculations occur in hereditary and non-hereditary diseases. Among the hereditary diseases, fasciculations are most frequently reported in familial amyotrophic lateral sclerosis (FALS), and spinal muscular atrophy (SMA). Among the non-hereditary diseases, fasciculations occur most frequently in peripheral nerve hyperexcitability syndromes (Isaac's syndrome, voltage-gated potassium channelopathy, cramp fasciculation syndrome, Morvan syndrome). If the cause of fasciculations remains unknown, they are called benign. Systematically reviewing the literature about fasciculations in hereditary disease shows that fasciculations can be a phenotypic feature in bulbospinal muscular atrophy (BSMA), GM2-gangliosidosis, triple-A syndrome, or hereditary neuropathy. Additionally, fasciculations have been reported in familial amyloidosis, spinocerebellar ataxias, Huntington's disease, Rett syndrome, central nervous system disease due to L1-cell adhesion molecule (L1CAM) mutations, Fabry's disease, or Gerstmann-Sträussler disease. Rarely, fasciculations may be a phenotypic feature in patients with mitochondrial disorders or other myopathies. Fasciculations are part of the phenotype in much more genetic disorders than commonly assumed. Fasciculations not only occur in motor neuron disease, but also in hereditary neuropathy, spinocerebellar ataxia, GM2-gangliosidosis, Huntington's disease, Rett syndrome, Fabry's disease, Gerstmann-Sträussler disease, mitochondrial disorders, or muscular dystrophies.

Myasthenia in Acquired Neuromyotonia

BackgroundAcquired neuromyotonia (NMT) forms part of the spectrum of acquired peripheral nerve hyperexcitability syndrome, and is thought to be caused by antibodies to voltage-gated potassium channels (VGKC). Exertional weakness is unusual unless autoimmune myasthenia gravis (MG) is superimposed.Case ReportA case of acquired NMT accompanied by exertional weakness without coexistence of seropositive MG is reported herein.ConclusionsClinical and electrophysiological observations suggest that the cholinergic overactivity in NMT can compromise the safety factor sufficiently to cause a defect in neuromuscular junction transmission.

Experimental validation of in silico predicted KCNA1, KCNA2, KCNA6 and KCNQ2 genes for association studies of peripheral nerve hyperexcitability syndrome in Jack Russell Terriers

KCNA1, KCNA2, KCNA6 and KCNQ2 are associated with peripheral nerve hyperexcitability in humans. In order to determine if these genes are also involved in Jack Russell Terriers with a similar syndrome characterized by myokymia and neuromyotonia, their predicted canine orthologs were first validated experimentally. They were found either incompletely or even incorrectly annotated, mainly due to gaps in the canine genomic sequence and insufficient transcript data. Canine KCNQ2 was found to contain 20 coding exons, of which three are not described in humans. It encodes for at least 14 different transcript variants in the frontal cortex of a single dog, of which only four are also described in humans. Mutation detection in Jack Russell Terriers diagnosed with peripheral nerve hyperexcitability revealed no pathogenetic relevant structural mutations. However, the four missense sequence variations and the 14 transcript variants of KCNQ2 will contribute to the study of the functional diversity of voltage-gated potassium channels.

Voltage-gated potassium channel autoimmunity and indolent cognitive impairment: a consecutive case series from the University Hospitals Leuven memory clinic

Event Abstract Back to Event Voltage-gated potassium channel autoimmunity and indolent cognitive impairment: a consecutive case series from the University Hospitals Leuven memory clinic Veerle Neyens1* and Rik Vandenberghe1 1 KU Leuven, Belgium Introduction VGKC-Ab (voltage-gated potassium channel antibodies) are an emerging topic in current neurology. They are typically associated with limbic encephalitis, peripheral nerve hyperexcitability and Morvan syndrome. Recent publications however point to a broader clinical spectrum, e.g. psychosis, epileptic syndromes and many others. Here we explore the potential of VGKC-Ab to induce chronic cognitive impairment characterized by episodic memory loss and a more indolent course. Patients and Methods We retrospectively evaluated a series of 70 cases (mean age 60 years, range 42-83) presented at the University Hospitals Leuven memory clinic in whom anti-VGKC antibodies had been tested (October 2009 till February 2012). The indication for the test was the presence of an objective episodic memory deficit in the absence of any other causal explanation. VGKC-Ab titers were assessed by a radioimmunassay performed by the University of Oxford Churchill Hospital. Results Eight patients (6 males, 2 females; age range 45-77 years) tested positive. They had a history of cognitive complaints of 6 months till 6 years. A formal neuropsychological investigation performed in 7 patients could demonstrate a cognitive deficit in all but one. One case showed a classical course starting with an amnestic syndrome followed within three months by epileptic seizures and fluctuating alertness but in the remaining cases the deficit was relatively stable. Titers ranged from 143pM till 5377pM (normal: 0-100pM). In 3 patients titers were beneath 400pM, 4 patients had a titer of more than 400pM. In one the titer was not known. Liquor investigation was normal in one and showed an isolated protein elevation in 4. In 3 cases there were additional abnormalities in cell count (5,6 - 7,2/µl; n = 2), glucose (n=2), IgG-index (n=1) or oligoclonal bands (n=2). VGKC-Ab in CSF were tested in two cases and negative. All patients underwent a brain MRI, which revealed hippocampal atrophy in 1 patient en more widespread volume loss in 2 patients. Onco-PET was performed in all patients, in one a tumor was discovered. Conclusion VGKC-Ab may be of clinical relevance in the diagnosis of cognitive impairment with a more indolent course than typically reported. However, because of the retrospective nature of this case series, we stress the importance of future prospective study. Given the uncertainty about the significance of titers between 100-400 pM, test reports should also include titers and not only a binary distinction between positive versus negative.

025 Guest Lecture

025 Guest Lecture

Clinical and Electrophysiological Characterization of Myokymia and Neuromyotonia in Jack Russell Terriers

Generalized myokymia and neuromyotonia (M/NM) in Jack Russell Terriers (JRTs) is related to peripheral nerve hyperexcitability syndrome in humans, a symptom complex resulting from diverse etiologies. Clinical and electrodiagnostic evaluation is used to narrow the list of possible etiological diagnoses in JRTs with M/NM. Nine healthy JRTs and 8 affected JRTs. A prospective study was conducted comparing clinical and electrophysiological characteristics in 8 JRTs affected by M/NM with 9 healthy JRT controls. All affected dogs except 1 had clinical signs typical of hereditary ataxia (HA). In 6 dogs, neuromyotonic discharges were recorded during electromyogram. Motor nerve conduction studies showed an axonal neuropathy in only 1 affected dog. Compared with controls, brainstem auditory-evoked potentials (BAEP) showed prolonged latencies (P<.05) accompanied by the disappearance of wave components in 3 dogs. Onset latencies of tibial sensory-evoked potentials (SEP) recorded at the lumbar intervertebral level were delayed in the affected group (P<.001). The BAEP and SEP results of the only neuromyotonic dog without ataxia were normal. The BAEP and spinal SEP abnormalities observed in JRTs with M/NM were associated with the presence of HA. Therefore, these electrophysiological findings presumably arise from the neurodegenerative changes characterizing HA and do not directly elucidate the pathogenesis of M/NM. An underlying neuronal ion channel dysfunction is thought to be the cause of M/NM in JRTs.

Episodic hyperhidrosis as the only clinical manifestation of neuromyotonia

Hyperhidrosis and other autonomic symptoms are frequent in patients with peripheral nerve hyperexcitability syndromes, particularly when they are associated with involvement of the CNS (Morvan syndrome). In this clinical setting, hyperhidrosis is usually associated with prominent muscle hyperactivity, insomnia, or episodes of confusion and visual hallucinations.1 Around 5% of patients with peripheral nerve hyperexcitability and Morvan syndromes are associated with thymoma and more rarely other tumor types.2,3 Up to 35% of patients with these syndromes present raised titers of serum voltage-gated potassium channels (VGKC) antibodies3 and preliminary evidence suggests that the antibodies could be responsible for the clinical features.4 We report a patient with episodes of profuse sweating in absence of clinical neuromyotonia. A 66-year-old man was evaluated for episodes of profuse sweating and malaise. Eighteen months earlier, the patient had received the diagnosis of polymyositis after a clinical picture of progressive anorexia, dysphagia, weight loss, and neck extensor weakness, with a …

Autoimmune disorders of neuronal potassium channels.

Antibodies to voltage-gated potassium channels (VGKCs) appear likely to be the effector mechanisms in many patients with acquired peripheral nerve hyperexcitability (APNH) syndromes, a group of disorders that include neuromyotonia, cramp-fasciculation syndrome, and Isaacs' syndrome. They may contribute to the associated autonomic changes. Through a central action, they may also be the effector mechanism in those with Morvan's syndrome and in some patients with limbic encephalitis. Evidence supporting this hypothesis includes the increased association of APNH with autoimmune diseases (in particular, myasthenia gravis and thymoma), the response to plasmapheresis, passive transfer of APNH to experimental animals by patients' plasma or immunoglobulins, the action of their serum on VGKC currents studied in vitro, and the presence in many patients of IgG antibodies to VGKCs.

Phenotypic variants of autoimmune peripheral nerve hyperexcitability.

Clinicians use many terms including undulating myokymia, neuromyotonia, Isaacs' syndrome and Cramp-Fasciculation Syndrome to describe the motor manifestations of generalized peripheral nerve hyperexcitability (PNH). Our previous findings in a selected group of patients with undulating myokymia or neuromyotonia, and EMG doublet or multiplet ('myokymic') motor unit discharges, indicated that an autoantibody-mediated potassium channelopathy was likely to be the cause of their disorder. This prompted us to search for a common pathogenesis in a wider spectrum of PNH syndromes. We studied the clinical, autoimmune and electrophysiological features of 60 patients presenting with acquired PNH. Patients were grouped according to an EMG criterion: the presence (group A, n = 42) or absence (group B, n = 18) of doublet or multiplet myokymic motor unit discharges. The average ages of onset in the two groups were 45 and 48 years respectively. The relative frequency and topography of the clinical features were similar in both groups. Serum voltage-gated potassium channel (VGKC) antibodies were detected using a (125)I-alpha-dendrotoxin immunoprecipitation assay in 38% of group A and in 28% of group B. Autoimmune disease and other autoantibodies were present in both groups more frequently than would be expected by chance (59 and 28%, respectively)-particularly myasthenia gravis and acetylcholine receptor (AChR) antibodies. The neurological disorder in both groups could occur as a paraneoplastic condition. Thymoma was detected in 19 and 11%, respectively, and lung cancer in 10 and 6%, respectively. An axonal neuropathy was present in six (14%) of group A and in one (6%) of group B patients. Thus, despite the discrete EMG distinction, both groups share clinical features often associated with autoimmune-related diseases, which can occur as paraneoplastic disorders and, importantly, have an increased frequency of VGKC antibodies. We conclude that autoimmunity, and specifically VGKC antibodies in many cases, are strongly implicated in the pathogenesis of both groups, and that the EMG features reflect quantitative rather than qualitative differences between the diverse clinical syndromes. These findings also have relevance for disease management. A classification is proposed that distinguishes immune-mediated PNH (irrespective of whether VGKC antibodies are detectable by standard assays) from non-immune forms of PNH that include toxins, anterior horn cell degeneration in motor neurone disease and genetic disorders.