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  • Autoimmune disorders of the neuromuscular junction.

    24 October 2018

    The neuromuscular junction lies beyond the protection of the blood-brain barrier and is particularly vulnerable to antibody-mediated attack. In myasthenia gravis, the expression of acetylcholine receptors (AChRs) in the thymus is under the control of the autoimmune regulator protein (AIRE), and polymorphisms in the AChR correlate with early onset of disease. In some 'AChR seronegative' patients, thymic abnormalities associated with complement-activating antibodies binding only clustered AChRs have been demonstrated, and in others anti-muscle-specific kinase (MuSK) antibodies that show pathogenic effects in vivo. In Guillain-Barré syndrome, newly described antibodies bind to complex gangliosides. General immunosuppression is still the main treatment, but novel treatments that reduce complement-mediated damage or inhibit the binding of pathogenic antibodies are beginning to look promising.

  • Neuromyotonia and limbic encephalitis sera target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations.

    24 October 2018

    Autoantibodies to Shaker-type (Kv1) K+ channels are now known to be associated with three syndromes. Peripheral nerve hyperexcitability is the chief manifestation of acquired neuromyotonia; the combination of neuromyotonia with autonomic and CNS involvement is called Morvan's syndrome (MoS); and CNS manifestations without peripheral involvement is called limbic encephalitis (LE). To determine the cellular basis of these clinical manifestations, we immunostained mouse neural tissues with sera from patients with neuromyotonia (n = 10), MoS (n = 2) or LE (n = 5), comparing with specific antibodies to relevant K+ channel subunits. Fourteen of 17 patients' sera were positive for Kv1.1, Kv1.2 or Kv1.6 antibodies by immunoprecipitation of 125I-alpha-dendrotoxin-labelled rabbit brain K+ channels. Most sera (11 out of 17) labelled juxtaparanodes of peripheral myelinated axons, co-localizing with Kv1.1 and Kv1.2. In the CNS, all sera tested (n = 12) co-localized with one or more areas of high Kv1.1, Kv1.2 or Kv1.6 channel expression: 10 out of 12 sera co-localized with Kv1.1 and Kv1.2 at spinal cord juxtaparanodes or cerebellar layers, while 3 out of 12 sera co-localized additionally (n = 2) or exclusively (n = 1) with Kv1.6 subunits in Purkinje cells, motor and hippocampal neurons. However, only sera from LE patients labelled the hippocampal areas that are enriched in excitatory, Kv1.1-positive axon terminals. All sera (17 out of 17) labelled one or more of these Kv1 subunits when expressed at the cell membrane of transfected HeLa cells, but not when they were retained in the endoplasmic reticulum. Again, LE sera labelled Kv1.1 subunits more prominently than did MoS or neuromyotonia sera, suggesting an association between higher Kv1.1 specificity and limbic manifestations. In contrast, neuromyotonia sera bound more strongly to Kv1.2 subunits than to Kv1.1 or Kv1.6. These studies support the hypothesis that antibodies to mature surface membrane-expressed Shaker-type K+ channels cause acquired neuromyotonia, MoS and LE, and suggest that future assays based on immunofluorescence of cells expressing individual Kv1 subunits will prove more sensitive than the immunoprecipitation assay. Although more than one type of antibody is often detectable in individual sera, higher affinity for certain subunits or subunit combinations may determine the range of clinical manifestations.

  • New autoantibody mediated disorders of the central nervous system.

    24 October 2018

    PURPOSE OF REVIEW: Recently, central nervous system disorders have been shown to be associated with autoantibodies. This review summarizes the recent findings and assesses the evidence that these conditions are caused by the antibodies, using the criteria established for peripheral nervous system autoimmune diseases. RECENT FINDINGS: Over the last few years, antibodies to voltage-gated calcium and potassium channels, and to glutamate receptors, have been detected in the serum and cerebrospinal fluid of patients with ataxia, limbic encephalitis and certain forms of epilepsy. Some of these patients respond to immunotherapies, suggesting that the antibodies are pathogenic, but there are few demonstrations using the passive transfer approach that antibodies present in the serum can penetrate the blood-brain barrier and affect central nervous system function. Some patients have antibodies to intracellular proteins such as glutamic acid decarboxylase or specific ribonuclear proteins. The pathogenicity of these antibodies must be in some doubt, although intravenous immunoglobulin therapy has been shown to be beneficial in stiff man syndrome, consistent with an autoimmune aetiology for the disease. In only a few conditions, has IgG derived from patients been shown to produce pathogenic effects in vivo or in vitro. SUMMARY: There is much that needs to be done to define the role of these antibodies and to determine how they affect central nervous system function in vivo. These studies must be carried out so that appropriate treatments can be provided for the growing number of patients with possible antibody-mediated conditions.

  • Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.

    24 October 2018

    OBJECTIVE: To describe a distinctive seizure semiology that closely associates with voltage-gated potassium channel (VGKC)-complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE). METHODS: Twenty-nine patients were identified by the authors (n = 15) or referring clinicians (n = 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC-complex antibodies was studied. RESULTS: Videos and still images showed a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency. INTERPRETATION: Recognition of FBDS should prompt testing for VGKC-complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment.

  • Antibodies to neuronal targets in neurological and psychiatric diseases.

    24 October 2018

    The role of antibodies to specific neuronal and muscle ion channels in the etiology of neuromuscular transmission disorders is now well accepted. In addition, maternal antibodies can cross the placenta and cause neonatal disease or even alter the development of the infant, raising the possibility that some neurodevelopmental conditions could be caused by maternal antibodies. Voltage-gated ion channels are expressed in the brain as well as at the neuromuscular junction, and in recent years it has become clear that antibodies to some central nervous system (CNS) channels can be associated with CNS disease. This review highlights features of these conditions, preliminary investigations into neurodevelopmental disorders, and areas for further study.