No abstract

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.

Antibody-mediated autoimmunity underlies a diverse range of disorders, particularly in the nervous system where the extracellular domains of ion channels and receptors are especially vulnerable targets. We present here a novel means of detecting autoantibodies where the genes of the suspected target proteins are known, and use it to detect specific autoantibodies in acquired neuromyotonia (Isaacs' syndrome), a disorder characterized by hyperexcitable motor nerves and sometimes by central abnormalities. We expressed different human brain voltage-gated potassium channels in Xenopus oocytes by injecting the relevant alpha-subunit complementary RNA, and detected antibody binding by immunohistochemistry on frozen sections. Antibodies were detected to one or more human brain voltage-gated potassium channel in 12 of 12 neuromyotonia patients and none of 18 control subjects. The results establish neuromyotonia as a new antibody-mediated channelopathy and indicate the investigative potential of this molecular immunohistochemical assay.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.