Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut

Abstract

Knut the polar bear of the Berlin Zoological Garden drowned in 2011 following seizures and was diagnosed as having suffered encephalitis of unknown etiology after exhaustive pathogen screening. Using the diagnostic criteria applied to human patients, we demonstrate that Knut’s encephalitis is almost identical to anti-NMDA receptor encephalitis which is a severe autoimmune disease representing the most common non-infectious encephalitis in humans. High concentrations of antibodies specific against the NR1 subunit of the NMDA receptor were detected in Knut’s cerebrospinal fluid. Histological examination demonstrated very similar patterns of plasma cell infiltration and minimal neuronal loss in affected brain areas. We conclude that Knut suffered anti-NMDA receptor encephalitis making his the first reported non-human case of this treatable disease. The results suggest that anti-NMDA receptor encephalitis may be a disease of broad relevance to mammals that until now has remained undiagnosed.

Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model

“…As an exception, a recent report described "anti-NMDAR1 encephalitis" in the young polar bear Knut [27]. Based on the present findings, Knut may have belonged to those nondomesticated species in captivity- Fig.…”

“…SP signal peptide, S1, S2 segments of the ligand-binding domain, TMD A transmembrane domain A, TMD B transmembrane domain B, TMD C transmembrane domain C comparable to monkey species investigated here-that are affected by chronic early-life stress, inducing NMDAR1-AB seropositivity. Pre-existing NMDAR1-AB of this bear may have ultimately shaped the clinical picture of an encephalitis of unexplained origin (likely infectious according to the zoo's pathology reports) where an epileptic seizure led to drowning [27].…”

“…Plasma (50 μl) and 25 μg of FITC-conjugated protein-A (Sigma-Aldrich) were incubated for 2 h in the dark at room temperature (RT). The mixture was then diluted to 250 μl (PBS) and unbound FITC-Protein-A was removed using 100-kDa Amicon filter units (Sartorius, Göttingen, Germany), reconcentrating tõ 50 μl [27]. NMDAR1-AB seropositivity was determined using Euroimmun assay combined with commercial monoclonal mouse NMDAR1-AB (114011; M68, SYSY, Göttingen, Germany).…”

All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class

“…Broader significance of NMDAR1-AB is underscored by their presence in mammalians other than humans. 27 This is less surprising in view of the substantial seroprevalence also of other brain-directed AB in species like rabbits, pigs and cows. 28 While irrespective of the epitope, all 14 NMDAR1-AB-positive sera investigated here (IgM, IgG, IgA) revealed similar AB functionality (internalization, electrophysiology), the AB-inducing factors may have determined the epitopes via mechanisms like molecular mimicry.…”

Persistence of parenchymal and perivascular T-cells in treatment-refractory anti-N-methyl-D-aspartate receptor encephalitis

“…Histopathologic examination of post-mortem brain samples of NMDAR-AE cases have revealed microglial activation and perivascular B-cell and plasma cell infiltrates 14 . Rare perivascular and intra-parenchymal T-cells have also been reported, however, the role of T-cells in the pathogenesis of this condition has not been investigated to date, particularly in cases that are refractory to treatment 13,15 .…”