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Purpose/Aim: Acquired neuromyotonia or Isaacs syndrome is a type of peripheral nerve hyperexcitability of autoimmune origin. It may occur as an isolated, paraneoplastic or accompanied with some aut...

Autoimmunity mediated by IgG4 subclass autoantibodies is an expanding field of research. Due to their structural characteristics a key feature of IgG4 antibodies is the ability to exchange Fab-arms with other, unrelated, IgG4 molecules, making the IgG4 molecule potentially monovalent for the specific antigen. However, whether those disease-associated antigen-specific IgG4 are mono- or divalent for their antigens is unknown. Myasthenia gravis (MG) with antibodies to muscle specific kinase (MuSK-MG) is a well-recognized disease in which the predominant pathogenic IgG4 antibody binds to extracellular epitopes on MuSK at the neuromuscular junction; this inhibits a pathway that clusters the acetylcholine (neurotransmitter) receptors and leads to failure of neuromuscular transmission. In vitro Fab-arm exchange-inducing conditions were applied to MuSK antibodies in sera, purified IgG4 and IgG1-3 sub-fractions. Solid-phase cross-linking assays were established to determine the extent of pre-existing and inducible Fab-arm exchange. Functional effects of the resulting populations of IgG4 antibodies were determined by measuring inhibition of agrin-induced AChR clustering in C2C12 cells. To confirm the results, κ/κ, λ/λ and hybrid κ/λ IgG4s were isolated and tested for MuSK antibodies. At least fifty percent of patients had IgG4, but not IgG1-3, MuSK antibodies that could undergo Fab-arm exchange in vitro under reducing conditions. Also MuSK antibodies were found in vivo that were divalent (monospecific for MuSK). Fab-arm exchange with normal human IgG4 did not prevent the inhibitory effect of serum derived MuSK antibodies on AChR clustering in C2C12 mouse myotubes. The results suggest that a considerable proportion of MuSK IgG4 could already be Fab-arm exchanged in vivo. This was confirmed by isolating endogenous IgG4 MuSK antibodies containing both κ and λ light chains, i.e. hybrid IgG4 molecules. These new findings demonstrate that Fab-arm exchanged antibodies are pathogenic. publisher: Elsevier articletitle: IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients journaltitle: Journal of Autoimmunity articlelink: http://dx.doi.org/10.1016/j.jaut.2016.11.005 content_type: article copyright: © 2016 The Authors. Published by Elsevier Ltd. ispartof: Journal of Autoimmunity vol:77 pages:104-115 ispartof: location:England status: published

Item does not contain fulltext OBJECTIVE: To assess the clinical relevance of a positive voltage-gated potassium channel (VGKC) test in patients lacking antibodies to LGI1 and Caspr2. METHODS: VGKC-positive patients were tested for LGI1 and Caspr2 antibodies. Patients lacking both antibodies were matched (1:2) to VGKC-negative patients. Clinical and paraclinical criteria were used to blindly determine evidence for autoimmune inflammation in both groups. Patients with an inconclusive VGKC titer were analyzed in the same way. RESULTS: A total of 1,455 patients were tested by VGKC radioimmunoassay. Fifty-six patients tested positive, 50 of whom were available to be included. Twenty-five patients had antibodies to LGI1 (n = 19) or Caspr2 (n = 6) and 25 patients lacked both antibodies. Evidence for autoimmune inflammation was present in 7 (28%) of the VGKC-positive patients lacking LGI1 and Caspr2, compared to 9 (18%) of the VGKC-negative controls (p = 0.38). Evidence for autoimmune inflammation was mainly found in patients with limbic encephalitis/encephalomyelitis (57%), but not in other clinical phenotypes (5%, p < 0.01). VGKC titers were significantly higher in patients with antibodies to LGI1 or Caspr2 (p < 0.001). However, antibodies to Caspr2 could also be detected in patients with inconclusive low VGKC titer, while many VGKC-positive patients had no evidence for autoimmune inflammation. CONCLUSIONS: VGKC positivity in the absence of antibodies to LGI1 and Caspr2 is not a clear marker for autoimmune inflammation and seems not to contribute in clinical practice. No cutoff value for the VGKC titer was appropriate to discriminate between patients with and without autoimmune inflammation. 8 p.

John Newsom-Davis was born in 1932 and died, aged 74, in 2007. After national service in the Royal Air Force, he read Natural Sciences at Cambridge. Following clinical studies at the Middlesex Hospital, he began research into respiratory neurophysiology with Tom Sears at the National Hospital, Queen Square, in London, and spent 1 year with Fred Plum at Cornell University in New York. After neurology specialist training at Queen Square, he became the director of the Batten Unit, continuing his interest in respiratory physiology. There he began to work on myasthenia gravis in collaboration with Ricardo Miledi at University College London and in 1978, after performing the first studies on plasma exchange in that disease, he established a myasthenia gravis research group at the Royal Free Hospital. There he investigated the role of the thymus in this disease and demonstrated an autoimmune basis for the Lambert Eaton myasthenic syndrome and ‘seronegative’ myasthenia. He was awarded the first Medical Research Council Clinical Research Professorship in 1979 but moved to Oxford in 1987 when he was elected Action Research Professor of Neurology. While at Oxford, he continued to run a very successful multidisciplinary group, researched further into the thymic abnormalities and cellular immunology of myasthenia, identified antibody-mediated mechanisms in acquired neuromyotonia, and began the molecular work that identified the genetic basis for many forms of congenital myasthenic syndrome. Meanwhile, he was also involved in university and college governance and contributed widely to the Medical Research Council, government committees, research charities and the Association of British Neurologists. Among many honours, he was elected Fellow of the Royal Society in 1991, appointed Commander of the British Empire in 1996 and made a Foreign Associate Member of the Institute of Medicine of the United States in 2001. Nearing and following retirement from Oxford, where he continued to see patients with myasthenia, he was the President of the Association of British Neurologists and Editor of Brain , and led a National Institutes of Health-funded international trial of thymectomy. * Abbreviations : AChR : acetylcholine receptor ANA : American Neurological Association CMS : congenital myasthenic syndrome HLA : human leukocyte antigen JND : John Newsom-Davis MRC : Medical Research Council

Thymomas and thymic carcinomas are rare epithelial tumors of thymus (TETs) associated with paraneoplastic autoimmune (PN/AI) disorders, including myasthenia gravis (MG), pure red cell aplasia, hypogammaglobulinemia, encephalitis, and acquired neuromyotonia (1,2). Patients affected by these disorders are usually screened for thymoma at diagnosis, and they frequently improve with thymoma treatment (2).

John Newsom-Davis was a key figure in the field of neuroimmunology and combined many outstanding personal qualities with considerable clinical and scientific expertise. His first report of plasma exchange in myasthenia in the late 1970s demonstrated its use both as a treatment and as an experimental tool to establish the pathogenic role of antibodies in neurological disorders. Subsequent investigations into the Lambert Eaton myasthenic syndrome and acquired neuromyotonia showed that these were caused by antibodies to specific ion channels. The field of autoimmune channelopathies is continuing to expand with identification of new antibody-mediated diseases including those affecting the central nervous system. This review will highlight some of his most seminal findings and those that are following on from his work.

Objective To study the generator sites of spontaneous discharges in patients with immune-mediated neuromyotonia. Methods Macro EMGs triggered by both spontaneously and voluntarily activated single action potentials were recorded and the mean peak-to-peak amplitude and area of the macro motor unit potentials were compared in two patients with typical acquired neuromyotonia having positive antibodies against voltage-gated potassium channels. Results Mean peak-to-peak amplitude and area of Macro EMG motor unit potentials (macro MUPs) triggered by spontaneous discharges were significantly smaller than those triggered by voluntary activation in both patients. However, a few macro MUPs triggered by spontaneous discharges resembled those triggered by voluntary activation. Conclusions Spontaneous discharges in two patients with immune-mediated neuromyotonia seem to be mostly generated at sites distal to the terminal axon branching points. Significance This finding may provide a new insight in the understanding of spontaneous discharges in immune-mediated neuromyotonia.

Acquired neuromyotonia, or Isaacs' syndrome, has been described in combination with a variety of other autoimmune disorders; however there has never been a report of seropositive Isaacs' syndrome in a patient with a history of Guillain-Barré syndrome (GBS). Both conditions involve antibody-mediated autoimmune effects on the peripheral nervous system, although the clinical manifestations are quite different. We present a man who experienced an episode of GBS at the age of 21 and subsequently developed Isaacs' syndrome at the age of 24 which was positive for anti-voltage-gated potassium channel (VGKC) antibodies. When treated with intravenous immunoglobulins (IVIg) he developed an eczematous rash that differed markedly in pattern and duration from the usual presentation for this IVIg reaction.

Recently characterized as an immune-mediated channelopaty, Isaacs' syndrome (also known as acquired neuromyotonia) was first described in 1961 in two men with persistent, generalized muscle stiffness, in addition to spontaneous, rapid discharges of motor-unit potentials on electromyography. In the peripheral nervous system, antibodies targeted to voltage-gated potassium channels induce hyperexcitability of motor axons, resulting in signs of muscle stiffness or of pseudomyotonia. A spontaneous burst of single motor-unit activity, and myokymic and neuromyotonic discharges, are the most characteristic features found in electromyography studies. This report describes Isaacs' syndrome in a child, in whom the diagnosis was made by clinical features of acquired, spontaneous muscle overactivity and typical electromyographic findings.

Background Acquired 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 Report A case of acquired NMT accompanied by exertional weakness without coexistence of seropositive MG is reported herein. Conclusions Clinical and electrophysiological observations suggest that the cholinergic overactivity in NMT can compromise the safety factor sufficiently to cause a defect in neuromuscular junction transmission.

We report a 70-year-old woman with Isaacs' syndrome (acquired neuromyotonia) who showed a marked improvement after immunoadsorption plasmapheresis (IAP). She developed hyperhidrosis in her teens, and slowly progressive symptoms of neuromyotonia for over 50 years. An in vitro investigation of her serum with patch-clamp technique suggested the presence of antibodies against potassium channels. She was treated with IAP, which brought disappearance of her symptoms. Though the symptoms started to recur in 3 weeks, moderate improvement has been maintained by immunosuppressive drug treatment.

Acquired neuromyotonia (NMT) is a rare condition resulting from a dysfunction of motor nerves. Current literature suggests acquired NMT is an antibody-mediated channelopathy. We present a case of acquired NMT in a patient with systemic lupus erythematosus. This association has not been previously reported.

Acquired neuromyotonia (ANM) is associated with antibodies to voltage-gated K+ channels (VGKCs). ANM sera reduce the number of K+ currents in neuronal cell lines, but it is not clear how the antibodies act. Here, we show by using the NB-1 cell line that the reduction in K+ currents by IgG is independent of added complement. IgG Fc and Fab fragments from ANM sera had no effect, but three of four ANM F(ab′)2 fragments significantly reduced K+ currents. Thus, cross-linking of the channels by divalent antibodies is likely to be an important mechanism in reducing K+ currents. Ann Neurol 2004;56:440–444

nerves SNAPs were absent. Sural sensory responses are low in amplitude. She walked home unaided after three weeks stay in the hospital. Follow up EMGs were done nine weeks and 17 months later. Motor NCS were consistently normal in all four tests. SNAPs remained unobtainable from all upper limbs sensory nerves and peroneal nerves even after 17 months later. Sural sensory potentials remained low in amplitude. Clinically she feels back to normal however reflexes remained hyporeflexic. Conclusion: Ganglionopathy is a rare condition. Idiopathic, acute onset and monophasic course is presented. NCS obtained during acute illness revealed a different length dependent nature of neuropathy. Clinical recovery is not matched by routine NCS findings.

Acquired neuromyotonia is characterized by hyperexcitability of motor nerves resulting in continuous muscle fiber activity. It occurs most often as a paraneoplastic syndrome in patients with cancers of the immune system. Antibodies against voltage-gated potassium channels (VGKCs) have been detected in some patients. Peripheral neuropathy is sometimes present. We report on a patient with Hodgkin's lymphoma in complete remission who developed paresthesias followed by neuromyotonia with bulbar involvement. Peripheral sensorimotor neuropathy was diagnosed electrophysiologically and evidence of axonal degeneration and demyelination was detected by sural nerve biopsy. The patient's complaints, including dysarthria, improved after carbamazepine treatment. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 834–838, 2001

Thymoma is a diagnosis most often made in adults, and is exceedingly rare in children. The diagnosis of a thymoma is often times linked to an autoimmune process, and the association of thymoma and myasthenia gravis in children has been previously reported. We present the first description of a child of a parent with Isaacs syndrome (congenital or acquired neuromyotonia) presenting with a thymoma. In our patient, an evaluation of underlying disease led to a presumptive diagnosis of congenital Isaacs syndrome. This case demonstrates that for the rare child diagnosed with thymoma, evaluation for an underlying neurologic disorder should be considered.

This is a scientific and clinical review of myasthenia gravis (MG) with chapters on Lambert-Eaton syndrome, congenital myasthenic syndromes, acquired neuromyotonia, and toxin-induced neuromuscular junction disorders. Neuromuscular junction physiology, acetylcholine receptor structure, and immunology are well reviewed in the first three chapters. The clinical chapters on ocular and generalised myasthenia are uniformly strong, although I have some disagreements. The edrophonium (Tensilon) test can …