Long-term memory dysfunction constitutes a dynamic and frequent condition in limbic encephalitis
- 1Neurophysiology, University of Bonn, Germany
Limbic encephalitis (LE) is an autoimmune disease defined by clinical criteria such as seizures, psychiatric and in particular working memory abnormalities in conjunction with apparative criteria underlying structural or functional changes in the temporal lobe according to autoimmune encephalitis guidelines (Graus et al., 2016). Working memory encompasses a transient encoding of information in readiness for further processing within a time window of seconds during cognitive task operations based on neurophysiological mechanisms such as short-term synaptic facilitation (Barak and Tsodyks, 2014). On the contrary, long-term memory (LTM) serves to encode, consolidate, and finally store information for long intervals ranging from minutes to months or even life (Dudai et al., 2015) through cellular mechanisms such as long-term potentiation (LTP) (Lynch et al., 1979).
In translational transfer experiments of autoimmune encephalitis from humans to the mouse, critical impairment of synaptic LTP in the hippocampus was proved by autoantibodies against the N-methyl-D-aspartate receptor (NMDAR) (Planaguma et al., 2016) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA2 (Haselmann et al., 2018). Synaptic LTP in the hippocampus is considered to be a mechanism of synaptic consolidation (Bramham, 2007) serving to enable LTM storage within the hippocampus. Not only antibodies against glutamatergic receptors cause LTM dysfunction probably due to altered synaptic transmission and plasticity - LGI1-LE is also assumed to be based on a synaptic mechanism, as hippocampal AMPA 2 receptors are reduced via neutralization of LGI1-ADAM22 interaction by LGI1-antibodies (Ohkawa et al., 2013). AMPA receptor reduction is functionally partially equivalent to enhanced AMPAR endocytosis as fewer AMPARs become available for synaptic transmission. LTP might in turn be impaired (Dong et al., 2015) and LTM formation as well consequently via this suggested process.
On the contrary, the pathophysiology of accelerated long-term forgetting (ALF) is still not well understood. It occurs often in temporal lobe epilepsy patients (Butler and Zeman, 2008), has been reported recently in LE, and is even more predominant in LE not associated with autoantibodies (Helmstaedter et al., 2018) (Table 1). ALF can be assessed by neuropsychological tests assessing long-term free recall entailing a one-week time period with not derogated free recall after half an hour (Helmstaedter et al., 2018). ALF is believed to be based on a shortage of memory consolidation (Blake et al., 2000), so that ALF in LE clearly depicts LTM dysfunction. Persistent deficits in memory retrieval (Finke et al., 2017) and recognition (Nascimento-Alves et al., 2017), anterograde (Butler et al., 2014) and retrograde (Kartsounis and de Silva, 2011; Bataller et al., 2010), autobiographic (Joubert et al., 2016), visuospatial, verbal and episodic LTM deficits have been reported in LE patients (Frisch et al., 2013; Kanazawa et al., 2014; Malter et al., 2014; Dodich et al., 2016; Finke et al., 2017; Heine et al., 2018) ) (for reports on LTM dysfunction in adult LE patients see Table 1, n≥6). These distinct facets of LTM deficits often occurred in LE patients in association with antibodies against membrane surface antigens such as voltage-gated potassium channels (VGKC) with its subgroups of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), AMPARs as well as antibodies against intracellular antigens such as glutamic acid decarboxylase 65 (GAD65) and Ma/Ta2. The time frame of LTM decline ranged from a month to years (Frisch et al., 2013; Malter et al., 2014; Finke et al., 2017; Witt et al., 2015; Hansen et al., 2016) and even decades, with dynamic fluctuations in memory capacity over time (Hansen et al., 2018) (Table 1).
Functional LTM impairment seems to be based on the structural integrity of mesiotemporal brain structures, as LTM function is known to correlate with reduced hippocampal subfield volumes, eg, the CA1-4, dentate gyrus or subiculum in VGKC or paraneoplastic antibody positive-encephalitis (Finke et al., 2017; Miller et al., 2017; Hansen et al., 2016). LE involves frontal lobe structures (Heine et al., 2018) also, but the main underlying brain pathology on the macroscopic (Wagner et al., 2015) and microscopic level (involving infiltrating lymphocytes) affects the amygdalohippocampal complex (Bien et al., 2012) indicating that dysfunctional LTM is more probable than impaired working-memory pathways. In particular, some LE forms are susceptible to LTM dysfunction as their disease-mediating antibodies against membrane receptors such as AMPA- (Dogan Onugoren et al., 2015), NMDA- (Finke et al., 2012), metabotropic glutamate receptor 5 (mGluR5) receptors (Mat et al., 2013) are critically involved in hippocampal synaptic long-term plasticity and LTM formation (Volianskis et al., 2015; Dong et al., 2015; Hagena and Manahan-Vaughan, 2015). It is thus not surprising that some AMPAR-antibodies associated LE patients present with an amnestic syndrome such as the unique clinical manifestation of autoimmunity (Joubert et al., 2015). Antibody-mediated immunopathology involving distinct memory phenotypes fluctuates (Hansen et al., 2018), but its pathogenic antigen-antibody interaction of glutamatergic receptors often take days to develop functional changes in receptor electrophysiology (neuronal incubation with antibody serum requires days: Ohkawa et al., 2013) and antibody-directed epitopes undergo posttranslational changes in protein expression (van Coevorden-Hameete et al., 2014) ,indicating time preconditions to worsen LTM function. LTM dysfunction is not a unique feature of limbic dysfunction induced by autoimmunity, but can also be caused by viral encephalitis such as herpes simplex encephalitis. The clinical features of viral encephalitis affecting the temporal lobe can resemble those of autoimmune-mediated limbic encephalitis, but frequently start with a more fulminant onset, often with fever or aphasia. The diagnosis of viral encephalitis must be ascertained by detecting viral DNA in the cerebrospinal fluid via a polymerase chain reaction. The type of LTM impairment in herpes simplex encephalitis affecting either verbal memory(pattern a) and/or memory of names (pattern b) (Frisch et al., 2015), and/or memory of living things (pattern c) (Noppeney et al., 2007) depends on structural lesions in the temporal lobe [involving the hippocampus (a) (Frisch et al., 2015) or the lateral temporal lobe (b) (Frisch et al., 2015) or antero-medial temporal cortex (c) (Noppeney et al., 2007)].
The occurrence of episodic LTM deficits in LE are often not followed by working memory disturbances (Nascimento-Alves et al., 2017), so that there may be patients suffering from LE who are not registered due to application of the Graus et al. criteria (2016). Redefining the memory criteria in LE has been proposed to consider episodic LTM function in LE patients (Nacimento-Alves et al., 2017). We suggest an even more amplified and elaborated LTM-dysfunction criterion in addition to working memory performance to adapt LE criteria to include several aspects of episodic, semantic and visuospatial LTM and ALF. Thus, to diagnose limbic encephalitis, we suggest incorporating this aforementioned novel memory criterion within the existing criteria from Graus (2016) (Table 1B). Furthermore, we recommend utilizing specific neuropsychological tests (Table 1C) to detect subtle LTM deficits in LE patients.
This suggested framework provides a more realistic imprint of memory impairment in LE and might help us identify and treat LE patients with LTM disabilities. This is particularly important, as early immunosuppressive or other treatment options (e.g. tumor resection) are essential to improve or recover memory performance in LE patients.
No conflict of interest.
Keywords: Autoimmunity, Limbic Encephalitis, Long-term memory, Autoantibodies, Synaptic consolidation
Received: 13 Sep 2018;
Accepted: 18 Mar 2019.
Edited by:Tjalf Ziemssen, Zentrum für Klinische Neurowissenschaften (ZKN), Germany
Reviewed by:Sonja Hochmeister, Medical University of Graz, Austria
Yoshiro Ohara, Kanazawa Medical University, Japan
Copyright: © 2019 Hansen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Niels Hansen, University of Bonn, Neurophysiology, Bonn, Germany, Niels.Hansen@ruhr-uni-bochum.de