Cognitive Impairment in Neuromyelitis Optica Spectrum Disorders: A Review of Clinical and Neuroradiological Features

MINI REVIEW published: 12 June 2019 doi: 10.3389/fneur.2019.00608 Cognitive Impairment in Neuromyelitis Optica Spectrum Disorders: A Review of Clinical and Neuroradiological Features Frederike Cosima Oertel 1,2† , Jana Schließeit 1,2,3† , Alexander U. Brandt 1,2,4 and Friedemann Paul 1,2,5* 1 NeuroCure Clinical Research Center, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany, 2 Experimental and Clinical Research Center, Max-Delbrück-Centrum für Molekulare Medizin and Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, 3 Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands, 4 Department of Neurology, University of California, Irvine, Irvine, CA, United States, 5 Department of Neurology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany Edited by: Tjalf Ziemssen, Zentrum für Klinische Neurowissenschaften (ZKN), Germany Reviewed by: Edgar Carnero Contentti, Hospital Alemán, Argentina Ralf Lürding, University of Regensburg, Germany *Correspondence: Friedemann Paul † These authors have contributed Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing autoimmune inflammatory disorders of the central nervous system (CNS) with optic neuritis, myelitis, and brainstem syndromes as clinical hallmarks. With a reported prevalence of up to 70%, cognitive impairment is frequent, but often unrecognized and an insufficiently treated burden of the disease. The most common cognitive dysfunctions are decline in attention and memory performance. Magnetic resonance imaging can be used to access structural correlates of neuropsychological disorders. Cognitive impairment is not only a highly underestimated symptom in patients with NMOSD, but potentially also a clinical correlate of attack-independent changes in NMOSD, which are currently under debate. This article reviews cognitive impairment in NMOSD and discusses associations between structural changes of the CNS and cognitive deficits. Keywords: neuromyelitis optica spectrum disorders, cognition, neuroinflammation, advanced imaging, MRI equally to this work Specialty section: This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology Received: 08 February 2019 Accepted: 22 May 2019 Published: 12 June 2019 Citation: Oertel FC, Schließeit J, Brandt AU and Paul F (2019) Cognitive Impairment in Neuromyelitis Optica Spectrum Disorders: A Review of Clinical and Neuroradiological Features. Front. Neurol. 10:608. doi: 10.3389/fneur.2019.00608 Frontiers in Neurology | www.frontiersin.org INTRODUCTION Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory autoimmune conditions of the central nervous system (CNS) with a typically relapsing course and a strong female preponderance (1–6). Key clinical features comprise optic neuritis, myelitis, and brainstem syndromes (7–13). Approximately 80% of the patients with NMOSD have pathogenic serum autoantibodies against aquaporin-4 (AQP4), a bidirectional water channel protein predominantly expressed by astrocytes, which is present all over the CNS (7, 14–21). AQP4 appears to not only be important for the internal water balance but its downstream mechanisms also seem to be essential for synaptic plasticity and neuronal functioning due to the involvement of astrocytes, although the exact mechanism of action is still unclear (22). In a subgroup of AQP4 antibody (AQP4-IgG) seronegative NMOSD patients as well as in patients with recurrent optic neuritis and a few patients with multiple sclerosis (MS) an antibody against myelin oligodendrocyte glycoprotein (MOG-IgG) can be detected (23–33). Nowadays, MOG-IgG seropositive patients are mostly assigned to a separate disease entity called MOG-IgG autoimmunity [or MOG encephalomyelitis (MOG-EM)], although they are formally still part of the NMO spectrum (5, 34–36). 1 June 2019 | Volume 10 | Article 608 Oertel et al. Cognitive Impairment in Neuromyelitis Optica cognition for example verbal memory, short and long term memory, processing speed, attention, concentration, and verbal fluency (65). Studies investigating which aspects of cognition are most dysfunctional in patients with NMOSD depict ambiguous results: One of the first studies was conducted by Blanc et al. (79). They found alterations in attention, information processing and verbal fluency (79). The meta-analysis of Meng et al. concluded that patients with NMOSD perform generally worse than healthy controls and that patients are significantly worse in the areas of attention, language, memory, processing speed and executive function (75). Similar findings were made by Saji et al., who found that 57% of patients performed significantly worse in at least three cognitive tests compared to healthy controls (65). Furthermore, they found that deficits are predominantly overt in sustained attention, concentration, verbal memory, and speed of information processing (65). However, verbal fluency on semantic stimulation and spatial reasoning were intact (65). Opposed to these results, Vanotti et al. demonstrated a more pronounced dysfunction in the areas of attention and verbal fluencies (76). The variations across results are not only due to heterogeneity of samples including ethnic background, heterogeneity with regards to antibody status, and other interindividual differences, but also due to differences in assessment, the definition and percentage of CI in samples, correction for depression, as well as analysis of magnetic resonance imaging (MRI) and overall differences in study design (72). In particular, the heterogeneous antibody status and MOGIgG could be a major confounder, as many studies had mixed samples for example Blanc et al. (17 AQP4-IgG seropositive patients/13 AQP4-IgG seronegative patients who were not tested for MOG-IgG) (79). Other studies for example Vanotti et al. or Liu et al. have not reported antibody status, and hence may have missed a possible association between antibody status and CI (76, 80). Further constraints entail that most of the studies recruited rather small sample sizes, ranging from 12 to 91 patients, and cover only a limited spectrum of ethnic backgrounds, with most studies being from Asian countries (71). Thus, while CI seems to be commonly present in a high percentage of NMOSD patients the specific domain of dysfunctional performance varies greatly between studies and samples. It appears that the most common cognitive dysfunction across all studies is decline in attention and memory performance. Moreover, the question as to the whether NMOSD pathobiology is causative for CI has not been clarified. In clinical routine, (...truncated)