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

Prüss H, Leubner J, Wenke NK, Czirják GÁ, Szentiks CA, Greenwood AD - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Knut’s antibodies demonstrate the characteristic labeling of neurons known from NMDAR encephalitis.Knut’s antibodies strongly bind to the granule cell layer of rat cerebellum (A), a pattern that is characteristic for the staining of CSF from human patients with anti-NMDAR encephalitis (B). Also, the typical neuropil staining can be found on hippocampus sections (C), while it is absent when testing CSF from a control polar bear without encephalitis (D). The immunohistochemistry pattern of Knut’s CSF is very similar to patient CSF staining on rat brain (E) or mouse brain sections (E, insert). Alexa-594-coupled CSF antibodies further show specific immunostaining on cerebellar sections of Knut’s brain (F), which is identical to the pattern when using commercial mouse (G) or rabbit anti-NMDAR antibodies (H) on polar bear brain, but not with control polar bear CSF (I). Bar in A represents 100 μm (A,B), in D 500 μm (C–E), in F 200 μm (F–I).
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f4: Knut’s antibodies demonstrate the characteristic labeling of neurons known from NMDAR encephalitis.Knut’s antibodies strongly bind to the granule cell layer of rat cerebellum (A), a pattern that is characteristic for the staining of CSF from human patients with anti-NMDAR encephalitis (B). Also, the typical neuropil staining can be found on hippocampus sections (C), while it is absent when testing CSF from a control polar bear without encephalitis (D). The immunohistochemistry pattern of Knut’s CSF is very similar to patient CSF staining on rat brain (E) or mouse brain sections (E, insert). Alexa-594-coupled CSF antibodies further show specific immunostaining on cerebellar sections of Knut’s brain (F), which is identical to the pattern when using commercial mouse (G) or rabbit anti-NMDAR antibodies (H) on polar bear brain, but not with control polar bear CSF (I). Bar in A represents 100 μm (A,B), in D 500 μm (C–E), in F 200 μm (F–I).

Mentions: Antibodies from patients with anti-NMDAR encephalitis are known to strongly bind to rat brain sections, particularly in cortical, hippocampal and cerebellar areas6. Knut’s antibodies exhibited an identical labeling pattern as human patients (Fig. 4B) showing intense labeling of rat hippocampus and cerebellum, such as in the cerebellar granule cell layer (Fig. 4A) or hippocampal neuropil (Fig. 4C). CSF from the male polar bear (which died of foreign body ingestion) for which histology was compared to Knut was not available. However, CSF from a second polar bear, Nancy, which died of gastric torsion, did not react at all with rat hippocampus (Fig. 4D) and cerebellum demonstrating reactivity was unique to Knut. As observed in human patients, NMDAR antibodies stain broadly in the hippocampus. Knut’s pattern was very similar to previously reported anti-NMDAR encephalitis cases6 or to experimental staining performed in the current study (Fig. 4E, insert shows staining on mouse brain). However, we did observe a difference in staining in the hilum of hippocampus which exhibited reduced staining with Knut’s CSF but staining nonetheless. Human CSF produced less staining in our experiments and has been reported not to bind to this brain region in humans15. One possible explanation is that in addition to NMDAR antibodies, another anti-receptor antibody is present in Knut’s CSF. However, if this is the case, it would represent a minor component as NMDAR antibody concentrations were very high, staining was reduced in hilum and it would not represent one of the common human encephalitis antibodies as we excluded antibodies against AMPA receptors, Caspr2, LGI1, and GABAb receptor (Fig. 3). Another likely explanation for the observed pattern is species-specific differences in NMDAR binding by polar bears antibodies. Further molecular immunological studies on polar bears will be needed to clarify this point. We further tested whether Knut’s antibodies bind to his own cerebellum. Indeed, strong staining was detectable in the large fiber tracts of the cerebellum with an axonal distribution (Fig. 4F). As the binding pattern is slightly different to rat brain, we confirmed the specificity by using a monoclonal mouse anti-NR1 (Fig. 4G) and a polyclonal rabbit anti-NR1 antibody (Fig. 4H) which gave identical results on the polar bear brain section. CSF from polar bear Nancy showed no reaction with the tissues (Fig. 4I).


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

Prüss H, Leubner J, Wenke NK, Czirják GÁ, Szentiks CA, Greenwood AD - Sci Rep (2015)

Knut’s antibodies demonstrate the characteristic labeling of neurons known from NMDAR encephalitis.Knut’s antibodies strongly bind to the granule cell layer of rat cerebellum (A), a pattern that is characteristic for the staining of CSF from human patients with anti-NMDAR encephalitis (B). Also, the typical neuropil staining can be found on hippocampus sections (C), while it is absent when testing CSF from a control polar bear without encephalitis (D). The immunohistochemistry pattern of Knut’s CSF is very similar to patient CSF staining on rat brain (E) or mouse brain sections (E, insert). Alexa-594-coupled CSF antibodies further show specific immunostaining on cerebellar sections of Knut’s brain (F), which is identical to the pattern when using commercial mouse (G) or rabbit anti-NMDAR antibodies (H) on polar bear brain, but not with control polar bear CSF (I). Bar in A represents 100 μm (A,B), in D 500 μm (C–E), in F 200 μm (F–I).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4551079&req=5

f4: Knut’s antibodies demonstrate the characteristic labeling of neurons known from NMDAR encephalitis.Knut’s antibodies strongly bind to the granule cell layer of rat cerebellum (A), a pattern that is characteristic for the staining of CSF from human patients with anti-NMDAR encephalitis (B). Also, the typical neuropil staining can be found on hippocampus sections (C), while it is absent when testing CSF from a control polar bear without encephalitis (D). The immunohistochemistry pattern of Knut’s CSF is very similar to patient CSF staining on rat brain (E) or mouse brain sections (E, insert). Alexa-594-coupled CSF antibodies further show specific immunostaining on cerebellar sections of Knut’s brain (F), which is identical to the pattern when using commercial mouse (G) or rabbit anti-NMDAR antibodies (H) on polar bear brain, but not with control polar bear CSF (I). Bar in A represents 100 μm (A,B), in D 500 μm (C–E), in F 200 μm (F–I).
Mentions: Antibodies from patients with anti-NMDAR encephalitis are known to strongly bind to rat brain sections, particularly in cortical, hippocampal and cerebellar areas6. Knut’s antibodies exhibited an identical labeling pattern as human patients (Fig. 4B) showing intense labeling of rat hippocampus and cerebellum, such as in the cerebellar granule cell layer (Fig. 4A) or hippocampal neuropil (Fig. 4C). CSF from the male polar bear (which died of foreign body ingestion) for which histology was compared to Knut was not available. However, CSF from a second polar bear, Nancy, which died of gastric torsion, did not react at all with rat hippocampus (Fig. 4D) and cerebellum demonstrating reactivity was unique to Knut. As observed in human patients, NMDAR antibodies stain broadly in the hippocampus. Knut’s pattern was very similar to previously reported anti-NMDAR encephalitis cases6 or to experimental staining performed in the current study (Fig. 4E, insert shows staining on mouse brain). However, we did observe a difference in staining in the hilum of hippocampus which exhibited reduced staining with Knut’s CSF but staining nonetheless. Human CSF produced less staining in our experiments and has been reported not to bind to this brain region in humans15. One possible explanation is that in addition to NMDAR antibodies, another anti-receptor antibody is present in Knut’s CSF. However, if this is the case, it would represent a minor component as NMDAR antibody concentrations were very high, staining was reduced in hilum and it would not represent one of the common human encephalitis antibodies as we excluded antibodies against AMPA receptors, Caspr2, LGI1, and GABAb receptor (Fig. 3). Another likely explanation for the observed pattern is species-specific differences in NMDAR binding by polar bears antibodies. Further molecular immunological studies on polar bears will be needed to clarify this point. We further tested whether Knut’s antibodies bind to his own cerebellum. Indeed, strong staining was detectable in the large fiber tracts of the cerebellum with an axonal distribution (Fig. 4F). As the binding pattern is slightly different to rat brain, we confirmed the specificity by using a monoclonal mouse anti-NR1 (Fig. 4G) and a polyclonal rabbit anti-NR1 antibody (Fig. 4H) which gave identical results on the polar bear brain section. CSF from polar bear Nancy showed no reaction with the tissues (Fig. 4I).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.

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.

No MeSH data available.


Related in: MedlinePlus