Abstract
PurposeWe present a case of voltage-gated potassium channel (VGKC) complex antibody-positive limbic encephalitis (LE) harboring autoantibodies against Kv1.2. Since the patient responded well to immunotherapy, the autoantibodies were regarded as pathogenic. We aimed to characterize the pathophysiological role of this antibody in comparison to an antibody against the VGKC-associated protein contactin-associated protein-2 (CASPR2).MethodsStereotactic injection of patient sera (anti-Kv1.2-associated LE or anti-CASPR2 encephalopathy) and a control subject was performed into the hippocampus of the anesthetized rat in vivo, and hippocampal slices were prepared for electrophysiological purposes. Using extra- and intracellular techniques, synaptic transmission, long-term potentiation (LTP) and vulnerability to pro-epileptic conditions were analyzed.ResultsWe observed that the slope of the field excitatory postsynaptic potential (fEPSP) was significantly increased at Schaffer collateral-CA1 synapses in anti-Kv1.2-treated and anti-CASPR2-treated rats, but not at medial perforant path-dentate gyrus synapses. The increase of the fEPSP slope in CA1 was accompanied by a decrease of the paired-pulse ratio in anti-Kv1.2, but not in anti-CASPR2 tissue, indicating presynaptic site of anti-Kv1.2. In addition, anti-Kv1.2 tissue showed enhanced LTP in CA1, but dentate gyrus LTP remained unaltered. Importantly, LTP in slices from anti-CASPR2-treated animals did not differ from control values. Intracellular recordings from CA1 neurons revealed that the resting membrane potential and a single action potential were not different between anti-Kv1.2 and control tissue. However, when the depolarization was prolonged, the number of action potentials elicited was reduced in anti-Kv1.2-treated tissue compared to both control and anti-CASPR2 tissue. In contrast, polyspike discharges induced by removal of Mg2+ occurred earlier and more frequently in both patient sera compared to control.ConclusionPatient serum containing anti-Kv1.2 facilitates presynaptic transmitter release as well as postsynaptic depolarization at the Schaffer-collateral-CA1 synapse, but not in the dentate gyrus. As a consequence, both synaptic transmission and LTP in CA1 are facilitated and action potential firing is altered. In contrast, anti-CASPR2 leads to increased postsynaptic potentials, but without changing LTP or firing properties suggesting that anti-Kv1.2 and anti-CASPR2 differ in their cellular effects. Both patient sera alter susceptibility to epileptic conditions, but presumably by different mechanisms.
Highlights
Limbic encephalitis (LE) associated with antibodies against voltage-gated potassium channels (VGKC) was described as a potentially reversible autoimmune encephalitis responding to immunotherapies which was in striking contrast to the formerly known forms of paraneoplastic encephalitis associated with antibodies against intracellular antigens (Buckley et al, 2001)
Kv1.2 channels are present in the middle molecular layer of the dentate gyrus, the CA1 stratum radiatum, and the CA1 stratum lacunosum-moleculare with the most striking immunoreactivity observed on axons and presynaptic terminals (Wang et al, 1993, 1994; Sheng et al, 1994; Monaghan et al, 2001; Gu et al, 2003; Wenzel et al, 2007; Lorincz and Nusser, 2008)
We present a case with status epilepticus due to anti-Kv1.2associated limbic encephalitis (LE), presenting with lateralized delta activity as well as sharp transients, predominantly over right posterior hemispheric leads (Figure 1A, left panel)
Summary
Limbic encephalitis (LE) associated with antibodies against voltage-gated potassium channels (VGKC) was described as a potentially reversible autoimmune encephalitis responding to immunotherapies which was in striking contrast to the formerly known forms of paraneoplastic encephalitis associated with antibodies against intracellular antigens (Buckley et al, 2001). Almost all of the remaining sera, called double-negative VGKC complex antibody-positive samples, had cytosolic targets, but one serum bound to live hippocampal neurons, suggesting a possible novel surface antigen (Lang et al, 2017). Dentate granule cells appeared to be immunonegative (Sheng et al, 1994), and mossy fibers as well as CA3 pyramidal neurons seem to express Kv1.2 only during ontogenesis at immature stages (Prüss et al, 2010)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
