Phenotypic variants of autoimmune peripheral nerve hyperexcitability

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.

Autoimmune disorders of the neuromuscular junction

“…Although no HLA association has yet been demonstrated, other autoimmune diseases are commonly present, and about 20% of patients have a thymoma which can predate the symptoms or be identified after presentation of the neurological disease. Some patients also have MG. [80] However, in contrast to MG and LEMS, some patients appear to have a monophasic illness that recovers spontaneously within a few months or years. There is circumstantial evidence that these forms of the disease occur following an infection or other immune response; one patient developed the disease after multiple wasp stings.…”

“…[89] Central Nervous System Disease with Voltage-gated Potassium channel Antibodies Although the typical neuromyotonia patient does not have central symptoms, some have sensory nerve involvement and sleep problems or anxiety are not infrequent. [80] Some patients have severe neuromyotonia with additional autonomic and marked central symptoms. This is usually called Morvan's syndrome.…”

Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2

“…has been reported as a selective activator of SK2 and SK3 channels (Hougaard et al, 2007), and several selective small molecule channel blockers have been developed (Chen et al, 2000;Faber & Sah, 2002). Neuron hyper-excitability is an essential component of many disorders of the central nervous system (Curatolo et al, 2001), and also plays a role in the molecular basis of addiction (Koob & Le Moal, 2001) and autoimmune disorders (Hart et al, 2002). In particular, it produces enhanced pain transmission in the spinal dorsal horn after spinal cord injury (Gwak & Hulsebosch, 2011).…”

Autoimmune diseases involving nicotinic receptors

“…Discoveries of the pathological mechanisms underlying AChR-based forms of myasthenia helped to distinguish the pathological mechanisms causing other forms of myasthenia. For example, discovery that myasthenia gravis (MG) is caused by an antibody-mediated autoimmune response to muscle AChRs (Drachman, 1994;Lindstrom, 2000aLindstrom, , 2002a laid the conceptual and methodological groundwork for discoveries that: first, Lambert-Eaton myasthenic syndrome (LEMS) is caused by an antibody-mediated autoimmune response to presynaptic active zone voltage-gated calcium channels (Newsom-Davis, 1998;Lang and Vincent, 2002); second, that autoimmune myasthenia lacking antibodies to AChRs or calcium channels have autoantibodies to a receptor tyrosine kinase (Hoch et al, 2001); and, most recently, that autoantibodies to potassium channels can cause peripheral nerve hyperactivity syndromes (Hart et al, 2002). Similarly, studies of the genetic bases of congenital myasthenic syndromes (CMSs) have revealed not only more than 60 mutations in AChR subunits, but also mutations in the collagen tail of the muscle form of acetylcholinesterase, the muscle AChR binding protein rapsyn, choline acetyltransferase, plectin, and other synaptic proteins yet to be identified (Engel et al, 1999(Engel et al, , 2002a.…”