A bstract : 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.
Patients presenting with subacute amnesia are frequently seen in acute neurological practice. Amongst the differential diagnoses, herpes simplex encephalitis, Korsakoff's syndrome and limbic encephalitis should be considered. Limbic encephalitis is typically a paraneoplastic syndrome with a poor prognosis; thus, identifying those patients with potentially reversible symptoms is important. Voltage-gated potassium channel antibodies (VGKC-Ab) have recently been reported in three cases of reversible limbic encephalitis. Here we review the clinical, immunological and neuropsychological features of 10 patients (nine male, one female; age range 44-79 years), eight of whom were identified in two centres over a period of 15 months. The patients presented with 1-52 week histories of memory loss, confusion and seizures. Low plasma sodium concentrations, initially resistant to treatment, were present in eight out of 10. Brain MRI at onset showed signal change in the medial temporal lobes in eight out of 10 cases. Paraneoplastic antibodies were negative, but VGKC-Ab ranged from 450 to 5128 pM (neurological and healthy controls <100 pM). CSF oligoclonal bands were found in only one, but bands matched with those in the serum were found in six other patients. VGKC-Abs in the CSF, tested in five individuals, varied between <1 and 10% of serum values. Only one patient had neuromyotonia, which was excluded by electromyography in seven of the others. Formal neuropsychology testing showed severe and global impairment of memory, with sparing of general intellect in all but two patients, and of nominal functions in all but one. Variable regimes of steroids, plasma exchange and intravenous immunoglobulin were associated with variable falls in serum VGKC-Abs, to values between 2 and 88% of the initial values, together with marked improvement of neuropsychological functioning in six patients, slight improvement in three and none in one. The improvement in neuropsychological functioning in seven patients correlated broadly with the fall in antibodies. However, varying degrees of cerebral atrophy and residual cognitive impairment were common. Over the same period, only one paraneoplastic case of limbic encephalitis was identified between the two main centres. Thus, VGKC-Ab-associated encephalopathy is a relatively common form of autoimmune, non-paraneoplastic, potentially treatable encephalitis that can be diagnosed by a serological test. Establishing the frequency of this new syndrome, the full range of clinical presentations and means of early recognition, and optimal immunotherapy, should now be the aim.
A 71-year-old woman presented with severe back pain, limb weakness and cranial nerve dysfunction associated with high cerebrospinal fluid (CSF) protein; we diagnosed Guillain-Barré syndrome and her symptoms completely resolved after intravenous immunoglobulin. Over the next 4 years, she had three further episodes of excruciating back pain accompanied by raised CSF protein, but without weakness, sensory loss, or abnormalities in routine nerve conduction studies. Sensory evoked potentials suggested proximal demyelination and lumbosacral plexus imaging suggested inflammation. We argue that this is a relapsing proximal polyradiculoneuropathy on the spectrum of chronic inflammatory demyelinating polyradiculoneuropathy.
Autoantibodies against the extracellular domains of the voltage-gated potassium channel (VGKC) complex proteins, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (CASPR2), are found in patients with limbic encephalitis, faciobrachial dystonic seizures, Morvan’s syndrome and neuromyotonia. However, in routine testing, VGKC-complex-antibodies without LGI1- or CASPR2-reactivities (‘double-negative’) are commoner than LGI1- or CASPR2-specificities. Therefore, the target (s) and clinical associations of double-negative antibodies need to be determined.
Methods
Sera (n=1131) from several clinically-defined cohorts were tested for IgG-radioimmunoprecipitation of 125I-aDTX-labelled VGKC-complexes, 125I-aDTX and 125I-aDTX-labelled Kv1-subunits, live hippocampal neuron reactivity, and by cell-based assays using Kv1-subunits, LGI1 and CASPR2.
Results
VGKC-complex-antibodies were found in 162 of 1131 (14%) sera. Ninety of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, ten (14%) immunoprecipitated 125I-aDTX itself, and 27 (38%) bound to solubilized co-expressed Kv1.1/1.2/1.6 subunits and/or Kv1.2 subunits alone, at levels proportionate to VGKC-complex-antibody levels (r=0.57, p=0.0017). The Kv1-precipitating samples only bound to permeabilised Kv1-expressing HEK cells. These intracellular Kv1-antibodies mainly associated with non-immune disease aetiologies, poor longitudinal clinical-serological correlations, and a limited immunotherapy-response.
Conclusions
Double-negative VGKC-complex-antibodies are often directed against cytosolic epitopes of Kv1-subunits, and occasionally against non-mammalian aDTX. These are not neuronal-surface antibodies. They consequently lack pathogenic potential, and do not in themselves support use of immunotherapies. VGKC-complex radioimmunoassay testing should cease; antibodies against LGI1 and CASPR2 provide greater specificity and sensitivity.
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