PMC10288866_01
PMC10288866_02
The clinical course of the patient. Periods of hospitalizations are shown at the top of the figure, below the charts of medication. Bottom: number of items satisfying the diagnostic criteria and/or scores on diagnostic scales for the childhood autoimmune encephalitis, autoimmune psychosis, and the NMDA receptor encephalitis, and for the catatonia, based on references. The patient's status was assessed at periods of (1) nonspecific complaints, reduced speech and unsteady gait, (2) on admission due to the catatonia syndrome, (3) on discharge after recovery from catatonic symptoms, (4) before administration of methylprednisolone, (5) after the third discharge, and (6) patient at age 14 years and 3 months. Psychosocial stressors preceding the first and second stage of illness are show in the red-flamed boxes. AE, autoimmune encephalitis; APZ, aripiprazole; BFCRS, Bush-Francis catatonia rating scale; ESC, escitalopram; IRDA, intermittent delta activity; mPSL, methylprednisolone; LOR, lorazepam; N, normal; NMDARE, anti-N-methyl-D-aspartate receptor encephalitis; RMT, ramelteon; WISC-V, Wechsler intelligence scores for children, fifth edition; WM, cerebral white matter.
fneur-14-1200541-g0001.jpg
PMC10288866_04_fneur-14-1200541-g0001.jpg
F1
However, following points were rather atypical for NMDARE (Figure 1, Supplementary Tables S1, S2); (1) the presence of psychosocial stressors triggering each phase of illness, (2) the first phase of nonspecific complaints as long as 12 months, (3) the order of predominant movement disorder (catatonia) phase and late-evolving psychiatric phase, (4) negative CSF results, and (5) hypoperfusion on SPECT imaging not involving the limbic areas.
Neuroimaging and electroencephalography of the patient. (A) T2-weighted MR imaging at age 12 years and 5 months, during the first hospitalization. (B, C) MR images at age 13 years and 5 months, on the second admission owing to catatonic mutism. (B) Several high-intensity dots (arrows) are observed. (C) The hippocampus appears unremarkable on the para-midline sagittal slice. (D) MR image at age 14 years and 1 month, which demonstrated vague high signal areas (arrows) in the bilateral deep parietal white matter. (E)
99m Tc-ECD SPECT at age 13 years and 6 months, colored by the easy Z-score imaging system. Hypoperfusion is observed in the bilateral parietal and left occipital areas. (F) Electroencephalogram on the first day of admission at 13 years and 5 months. Widespread high-amplitude slow-wave activity is detected.
fneur-14-1200541-g0002.jpg
PMC10288866_04_fneur-14-1200541-g0002.jpg
F2
A SPECT examination found hypoperfusion in the bilateral parietal and left occipital lobes (Figure 2E), contradicting the pathophysiology of primary psychiatric illness to explain the catatonia and subsequent psychosis. However, following points were rather atypical for NMDARE (Figure 1, Supplementary Tables S1, S2); (1) the presence of psychosocial stressors triggering each phase of illness, (2) the first phase of nonspecific complaints as long as 12 months, (3) the order of predominant movement disorder (catatonia) phase and late-evolving psychiatric phase, (4) negative CSF results, and (5) hypoperfusion on SPECT imaging not involving the limbic areas. Follow-up MRI revealed nonspecific high signal regions (arrows) in the bilateral deep parietal white matter (Figure 2D).
PMC10288866_03
The clinical course of the patient. Periods of hospitalizations are shown at the top of the figure, below the charts of medication. Bottom: number of items satisfying the diagnostic criteria and/or scores on diagnostic scales for the childhood autoimmune encephalitis, autoimmune psychosis, and the NMDA receptor encephalitis, and for the catatonia, based on references. The patient's status was assessed at periods of (1) nonspecific complaints, reduced speech and unsteady gait, (2) on admission due to the catatonia syndrome, (3) on discharge after recovery from catatonic symptoms, (4) before administration of methylprednisolone, (5) after the third discharge, and (6) patient at age 14 years and 3 months. Psychosocial stressors preceding the first and second stage of illness are show in the red-flamed boxes. AE, autoimmune encephalitis; APZ, aripiprazole; BFCRS, Bush-Francis catatonia rating scale; ESC, escitalopram; IRDA, intermittent delta activity; mPSL, methylprednisolone; LOR, lorazepam; N, normal; NMDARE, anti-N-methyl-D-aspartate receptor encephalitis; RMT, ramelteon; WISC-V, Wechsler intelligence scores for children, fifth edition; WM, cerebral white matter.
fneur-14-1200541-g0001.jpg
PMC10288866_04_fneur-14-1200541-g0001.jpg
F1
However, following points were rather atypical for NMDARE (Figure 1, Supplementary Tables S1, S2); (1) the presence of psychosocial stressors triggering each phase of illness, (2) the first phase of nonspecific complaints as long as 12 months, (3) the order of predominant movement disorder (catatonia) phase and late-evolving psychiatric phase, (4) negative CSF results, and (5) hypoperfusion on SPECT imaging not involving the limbic areas.
Neuroimaging and electroencephalography of the patient. (A) T2-weighted MR imaging at age 12 years and 5 months, during the first hospitalization. (B, C) MR images at age 13 years and 5 months, on the second admission owing to catatonic mutism. (B) Several high-intensity dots (arrows) are observed. (C) The hippocampus appears unremarkable on the para-midline sagittal slice. (D) MR image at age 14 years and 1 month, which demonstrated vague high signal areas (arrows) in the bilateral deep parietal white matter. (E)
99m Tc-ECD SPECT at age 13 years and 6 months, colored by the easy Z-score imaging system. Hypoperfusion is observed in the bilateral parietal and left occipital areas. (F) Electroencephalogram on the first day of admission at 13 years and 5 months. Widespread high-amplitude slow-wave activity is detected.
fneur-14-1200541-g0002.jpg
PMC10288866_04_fneur-14-1200541-g0002.jpg
F2
A SPECT examination found hypoperfusion in the bilateral parietal and left occipital lobes (Figure 2E), contradicting the pathophysiology of primary psychiatric illness to explain the catatonia and subsequent psychosis. However, following points were rather atypical for NMDARE (Figure 1, Supplementary Tables S1, S2); (1) the presence of psychosocial stressors triggering each phase of illness, (2) the first phase of nonspecific complaints as long as 12 months, (3) the order of predominant movement disorder (catatonia) phase and late-evolving psychiatric phase, (4) negative CSF results, and (5) hypoperfusion on SPECT imaging not involving the limbic areas. Follow-up MRI revealed nonspecific high signal regions (arrows) in the bilateral deep parietal white matter (Figure 2D).
PMC10288866_04
The clinical course of the patient. Periods of hospitalizations are shown at the top of the figure, below the charts of medication. Bottom: number of items satisfying the diagnostic criteria and/or scores on diagnostic scales for the childhood autoimmune encephalitis, autoimmune psychosis, and the NMDA receptor encephalitis, and for the catatonia, based on references. The patient's status was assessed at periods of (1) nonspecific complaints, reduced speech and unsteady gait, (2) on admission due to the catatonia syndrome, (3) on discharge after recovery from catatonic symptoms, (4) before administration of methylprednisolone, (5) after the third discharge, and (6) patient at age 14 years and 3 months. Psychosocial stressors preceding the first and second stage of illness are show in the red-flamed boxes. AE, autoimmune encephalitis; APZ, aripiprazole; BFCRS, Bush-Francis catatonia rating scale; ESC, escitalopram; IRDA, intermittent delta activity; mPSL, methylprednisolone; LOR, lorazepam; N, normal; NMDARE, anti-N-methyl-D-aspartate receptor encephalitis; RMT, ramelteon; WISC-V, Wechsler intelligence scores for children, fifth edition; WM, cerebral white matter.
fneur-14-1200541-g0001.jpg
PMC10288866_04_fneur-14-1200541-g0001.jpg
F1
However, following points were rather atypical for NMDARE (Figure 1, Supplementary Tables S1, S2); (1) the presence of psychosocial stressors triggering each phase of illness, (2) the first phase of nonspecific complaints as long as 12 months, (3) the order of predominant movement disorder (catatonia) phase and late-evolving psychiatric phase, (4) negative CSF results, and (5) hypoperfusion on SPECT imaging not involving the limbic areas.
Neuroimaging and electroencephalography of the patient. (A) T2-weighted MR imaging at age 12 years and 5 months, during the first hospitalization. (B, C) MR images at age 13 years and 5 months, on the second admission owing to catatonic mutism. (B) Several high-intensity dots (arrows) are observed. (C) The hippocampus appears unremarkable on the para-midline sagittal slice. (D) MR image at age 14 years and 1 month, which demonstrated vague high signal areas (arrows) in the bilateral deep parietal white matter. (E)
99m Tc-ECD SPECT at age 13 years and 6 months, colored by the easy Z-score imaging system. Hypoperfusion is observed in the bilateral parietal and left occipital areas. (F) Electroencephalogram on the first day of admission at 13 years and 5 months. Widespread high-amplitude slow-wave activity is detected.
fneur-14-1200541-g0002.jpg
PMC10288866_04_fneur-14-1200541-g0002.jpg
F2
A SPECT examination found hypoperfusion in the bilateral parietal and left occipital lobes (Figure 2E), contradicting the pathophysiology of primary psychiatric illness to explain the catatonia and subsequent psychosis. However, following points were rather atypical for NMDARE (Figure 1, Supplementary Tables S1, S2); (1) the presence of psychosocial stressors triggering each phase of illness, (2) the first phase of nonspecific complaints as long as 12 months, (3) the order of predominant movement disorder (catatonia) phase and late-evolving psychiatric phase, (4) negative CSF results, and (5) hypoperfusion on SPECT imaging not involving the limbic areas. Follow-up MRI revealed nonspecific high signal regions (arrows) in the bilateral deep parietal white matter (Figure 2D).
(A) Autoantibody to glutamate receptors and levels of cytokines, chemokines, and other factors in the cerebrospinal fluid (CSF) specimens, taken at three distinct phases of illness. Antibodies to GluN2B-NT2, GluN2B-CT, GluN1-NT, and GluD2-NT were measured by ELISA. Cytokines, chemokines, and other factors in CSF were measured by multiplex fluorescent immunoassays utilizing the Bio-Plex Pro Human Cytokine 27-plex Assay (Bio-Plex, Hercules, CA). The panel comprises interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin/CCL11, fibroblast growth factor-2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), IFN-gamma-induced protein 10 (IP-10)/CXCL10, monocyte chemotactic protein-1 (MCP-1)/CCL2, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4, platelet-derived growth factor BB (PDGF-BB), regulated on activation, normal T cell expressed and secreted (RANTES)/CCL5, tumor necrosis factor-alpha (TNF-alpha), and vascular endothelial growth factor (VEGF). Levels of granzyme B in CSF were measured by the Human Granzyme B ELISA Kit (Cat. No. KT-078, Kamiya Biomedical Company, Seattle, WA, USA). (B-D) Results on the cell-based assay using CSF at age 12 y 9 m (B), 13 y 5 m (C), and 13 y 9 m (D). (B, C) Cell bodies of cultured HEK cells, transfected with a cDNA coding GluN1/2B, are positively stained (green) by an antibody against the GuN1 epitope but are immunonegative by CSF staining. (D) Alongside the immunostaining of GluN1, the cell body is positively stained (red) by the CSF, taken just before the intravenous methylprednisolone therapy. Colocalization (yellow) of the immunostaining by the GluN1 antibody and the CSF is determined.
fneur-14-1200541-g0003.jpg
PMC10288866_05_fneur-14-1200541-g0003.jpg
F3
Such an extended course of hallucinations and delusions prompted us to examine the CSF specimen with cell based assay (CBA), which qualified a positive result of anti-NMDA receptor antibodies for the specimen taken just before the intravenous methylprednisolone (Figure 3).
PMC10288866_05
(A) Autoantibody to glutamate receptors and levels of cytokines, chemokines, and other factors in the cerebrospinal fluid (CSF) specimens, taken at three distinct phases of illness. Antibodies to GluN2B-NT2, GluN2B-CT, GluN1-NT, and GluD2-NT were measured by ELISA. Cytokines, chemokines, and other factors in CSF were measured by multiplex fluorescent immunoassays utilizing the Bio-Plex Pro Human Cytokine 27-plex Assay (Bio-Plex, Hercules, CA). The panel comprises interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin/CCL11, fibroblast growth factor-2 (FGF-2), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), IFN-gamma-induced protein 10 (IP-10)/CXCL10, monocyte chemotactic protein-1 (MCP-1)/CCL2, macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4, platelet-derived growth factor BB (PDGF-BB), regulated on activation, normal T cell expressed and secreted (RANTES)/CCL5, tumor necrosis factor-alpha (TNF-alpha), and vascular endothelial growth factor (VEGF). Levels of granzyme B in CSF were measured by the Human Granzyme B ELISA Kit (Cat. No. KT-078, Kamiya Biomedical Company, Seattle, WA, USA). (B-D) Results on the cell-based assay using CSF at age 12 y 9 m (B), 13 y 5 m (C), and 13 y 9 m (D). (B, C) Cell bodies of cultured HEK cells, transfected with a cDNA coding GluN1/2B, are positively stained (green) by an antibody against the GuN1 epitope but are immunonegative by CSF staining. (D) Alongside the immunostaining of GluN1, the cell body is positively stained (red) by the CSF, taken just before the intravenous methylprednisolone therapy. Colocalization (yellow) of the immunostaining by the GluN1 antibody and the CSF is determined.
fneur-14-1200541-g0003.jpg
PMC10288866_05_fneur-14-1200541-g0003.jpg
F3
Such an extended course of hallucinations and delusions prompted us to examine the CSF specimen with cell based assay (CBA), which qualified a positive result of anti-NMDA receptor antibodies for the specimen taken just before the intravenous methylprednisolone (Figure 3).