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  • 1
    Online Resource
    Online Resource
    Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2
    Wiley ; 2021
    In:  Annals of Neurology Vol. 90, No. 1 ( 2021-07), p. 101-117
    Details
    In: Annals of Neurology, Wiley, Vol. 90, No. 1 ( 2021-07), p. 101-117
    Abstract: The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2‐abs) in patients with autoimmune encephalitis, and describe the clinical‐immunological features and antibody effects. Methods Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell‐based assay (CBA) with GluK2‐expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2‐ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2‐expressing HEK293 cells. Results Patients’ antibodies precipitated GluK2. GluK2 antibody‐specificity was confirmed by CBA, immunoprecipitation, GluK2‐immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno‐absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non‐kainate receptors (alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors [AMPAR] and N‐methyl‐D‐aspartate receptors [NMDAR] ) leading to identify 6 additional cases with GluK2‐abs among patients with anti‐AMPAR (5/71) or anti‐NMDAR encephalitis (1/73). GluK2‐abs internalized GluK2 in HEK293 cells and neurons; these antibody‐effects were reversible in neurons. A significant reduction of GluK2‐mediated currents was observed in cells treated with patients’ GluK2 serum following the time frame of antibody‐mediated GluK2 internalization. Interpretation GluK2‐abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021;90:107–123
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v90.1
    DOI: 10.1002/ana.26098
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2037912-2
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  • 2
    Online Resource
    Online Resource
    Seizure-related 6 homolog like 2 autoimmunity : Neurologic syndrome and antibody effects
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Neurology - Neuroimmunology Neuroinflammation Vol. 8, No. 1 ( 2021-01), p. e916-
    Details
    In: Neurology - Neuroimmunology Neuroinflammation, Ovid Technologies (Wolters Kluwer Health), Vol. 8, No. 1 ( 2021-01), p. e916-
    Abstract: To describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures. Methods SEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with SEZ6L2 to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons. Results In addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54–69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons. Conclusions SEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.
    Type of Medium: Online Resource
    ISSN: 2332-7812
    URL: Article
    DOI: 10.1212/NXI.0000000000000916
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2767740-0
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  • 3
    Online Resource
    Online Resource
    Table_1.docx
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-6-29)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-6-29)
    Abstract: Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE). Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience suggests diagnostic limitations. Here, we assessed the performance of the commercial IIFA in serum and CSF samples of patients with suspected AE previously examined by rat brain immunohistochemistry (Cohort A). Of 6213 samples, 404 (6.5%) showed brain immunostaining suggestive of NSAb: 163 (40%) were positive by commercial IIFA and 241 (60%) were negative. When these 241 samples were re-assessed with in-house IIFA, 42 (18%) were positive: 21 (9%) had NSAb against antigens not included in the commercial IIFA and the other 21 (9%) had NSAb against antigens included in the commercial kit (false negative results). False negative results occurred more frequently with CSF (29% vs 10% in serum) and predominantly affected GABA B R (39%), LGI1 (17%) and AMPAR (11%) antibodies. Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABA B R or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA. Patients with discordant GABA B R antibody results (positive in-house but negative commercial IIFA) were less likely to develop full-blown clinical syndrome; no significant clinical differences were noted for the other antibodies. Overall, NSAb testing by commercial IIFA led to false negative results in a substantial number of patients, mainly those affected by anti-LG1, GABA B R or AMPAR encephalitis. If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommended.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.691536
    DOI: 10.3389/fimmu.2021.691536.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 4
    Online Resource
    Online Resource
    Thymoma-associated neuronal surface antibodies and clinical manifestations (4620)
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Neurology Vol. 96, No. 15_supplement ( 2021-04-13)
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 96, No. 15_supplement ( 2021-04-13)
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.96.15_supplement.4620
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 5
    Online Resource
    Online Resource
    Table_1.docx
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-12-15)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-12-15)
    Abstract: Detection of Leucine-rich glioma inactivated 1 (LGI1) antibodies in patients with suspected autoimmune encephalitis is important for diagnostic confirmation and prompt implementation of immunomodulatory treatment. However, the clinical laboratory diagnosis can be challenging. Previous reports have suggested that the type of test and patient’s sample (serum or CSF) have different clinical performances, however, there are no studies comparing different diagnostic tests on paired serum/CSF samples of patients with anti-LGI1 encephalitis. Here, we assessed the clinical performance of a commercial and an in house indirect immunofluorescent cell based assays (IIF-CBA) using paired serum/CSF of 70 patients with suspected anti-LGI1 encephalitis and positive rat brain indirect immunohistochemistry (IIHC). We found that all (100%) patients had CSF antibodies when the in house IIF-CBA was used, but only 88 (83%) were positive if the commercial test was used. In contrast, sera positivity rate was higher with the commercial test (94%) than with the in house assay (86%). If both serum and CSF were examined with the commercial IIFA-CBA, 69/70 (98.5%) patients were positive in at least one of the samples. These findings are clinically important for centers in which rat brain IIHC and in house IIFA-CBA are not available. Moreover, the observation that all patients with anti-LGI1 encephalitis have antibodies in CSF is in line with the concept that these antibodies are pathogenic.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.1069368
    DOI: 10.3389/fimmu.2022.1069368.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 6
    Online Resource
    Online Resource
    Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Neurology Vol. 97, No. 1 ( 2021-07-6), p. e61-e75
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 97, No. 1 ( 2021-07-6), p. e61-e75
    Abstract: To report the neuropsychiatric features and frequency of NMDA receptor (NMDAR) and other neuronal immunoglobulin G antibodies in patients with first episode psychosis (FEP) and to assess the performance of reported warning signs and criteria for autoimmune psychosis (AP). Methods This was a prospective observational study of patients with FEP assessed for neuropsychiatric symptoms, serum and CSF neuronal antibodies (brain immunohistochemistry, cell-based assays, live neurons), and warning signs and criteria of AP. Previous autoimmune FEP series were reviewed. Results One hundred five patients were included; their median age was 30 (range 14–75) years, and 44 (42%) were female. None had neuronal antibodies. Two of 105 (2%) had CSF pleocytosis, 4 of 100 (4%) had brain MRI abnormalities, and 3 of 73 (4%) EEG alterations. Thirty-four (32%) and 39 (37%) patients fulfilled 2 sets of warning signs of AP, and 21 (20%) fulfilled criteria of possible or probable AP, yet none developed AP. The cause of FEP was psychiatric in 101 (96%) and nonpsychiatric in 4 (4%). During this study, 3 patients with psychosis caused by anti-NMDAR encephalitis were transferred to our center; 2 did not meet criteria for possible AP. Of 1,159 reported patients with FEP, only 7 (1%) had CSF studies; 36 (3%) had serum NMDAR antibodies (without definite diagnosis of AP), and 4 had CSF NMDAR antibodies (3 classic anti-NMDAR encephalitis and 1 with isolated psychiatric features). Conclusions NMDAR antibodies were not found in patients with FEP unless they had anti-NMDAR encephalitis. Warning signs and criteria for AP have limited utility when neurologic symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000012191
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 7
    Online Resource
    Online Resource
    Neurofilament Light Chain Levels in Anti-NMDAR Encephalitis and Primary Psychiatric Psychosis
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Neurology Vol. 98, No. 14 ( 2022-04-5), p. e1489-e1498
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 98, No. 14 ( 2022-04-5), p. e1489-e1498
    Abstract: An important challenge in diagnosing anti–NMDA receptor (NMDAR) encephalitis (NMDARe) is differentiating it from a first episode of psychosis (FEP) caused by a psychiatric disease (pFEP). CSF antibody testing distinguishes these diseases, but spinal taps are difficult to obtain in psychiatric facilities. A separate problem is the lack of biomarkers of NMDARe severity and outcome. Here we assessed the performance of neurofilament light chain (NfL) testing in these settings. Methods In this observational study, NfL levels were determined with single-molecule array in patients with NMDARe, pFEP, herpes simplex encephalitis (HSE), and healthy participants (HC), with the last 2 groups used as controls. Receiver operating characteristic (ROC) analyses were performed to assess the prediction accuracy of serum NfL (sNfL) levels for NMDARe and pFEP and to obtain clinically useful cutoffs. Results One hundred eighteen patients with NMDARe (33 with isolated psychosis at presentation), 45 with pFEP, 36 with HSE, and 36 HC were studied. Patients with NMDARe with seizures/status epilepticus, intensive care unit admission, and CSF pleocytosis ( 〉 20 white blood cells/µL) and without early immunotherapy were more likely to have higher NfL (mainly in CSF) than individuals with NMDARe without these features. NfL levels at diagnosis of NMDARe did not correlate with outcome at 1-year follow-up assessed with the modified Rankin Scale. Patients with NMDARe had significantly higher sNfL than individuals with pFEP and HC and lower sNfL than patients with HSE. ROC analysis of sNfL between NMDARe with isolated psychosis and pFEP provided an area under the curve of 0.93 (95% CI 0.87–0.99) and an sNfL cutoff ≥15 pg/mL to distinguish these disorders (sensitivity 85%, specificity 96%, positive likelihood ratio 19.3). Forty-three of 45 (96%) patients with pFEP had sNfL 〈 15 pg/mL, whereas only 5 of 33 (15%) with NMDARe with isolated psychosis were below this cutoff (risk estimation NMDARe vs pFEP: odds ratio 120.4 [95% CI 21.8–664], p 〈 0.001). None of the patients with HSE and 35 of 36 (97%) HC had sNfL 〈 15 pg/mL. Discussion NfL measured at diagnosis of NMDARe associated with features of disease severity but not with long-term outcome. Young patients with FEP and sNfL ≥15 pg/mL had a 120 times higher chance of having NMDARe than those with pFEP. This cutoff correctly classified 96% of patients with pFEP and 85% of patients with NMDARe with isolated psychosis. Patients with FEP of unclear etiology and sNfL ≥15 pg/mL should undergo CSF NMDAR antibody testing.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000200021
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 8
    Online Resource
    Online Resource
    Thymoma and Autoimmune Encephalitis : Clinical Manifestations and Antibodies
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Neurology - Neuroimmunology Neuroinflammation Vol. 8, No. 5 ( 2021-09), p. e1053-
    Details
    In: Neurology - Neuroimmunology Neuroinflammation, Ovid Technologies (Wolters Kluwer Health), Vol. 8, No. 5 ( 2021-09), p. e1053-
    Abstract: To report the clinical, neuroimaging, and antibody associations in patients with autoimmune encephalitis (AE) and thymoma. Methods A retrospective cohort study of 43 patients was conducted. Antibody determination and immunoprecipitation to characterize novel antigens were performed using reported techniques. Results Patients' median age was 52 years (range: 23–88 years). Forty (93%) had neuronal surface antibodies: gamma-aminobutyric acid receptor A (GABA A R) (15), amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) (13), contactin-associated protein-like 2 (CASPR2) (4), leucine-rich, glioma inactivated 1 (LGI1) (3), glycine receptor (GlyR) (3), and unknown antigens (2). Concurrent antibodies against intracellular antigens occurred in 13 (30%; 9 anti–collapsin response mediator protein 5 [CRMP5]) and were more frequent in anti-AMPAR encephalitis (54% vs 20%; p = 0.037). The most common clinical presentation was encephalitis with multiple T2/fluid-attenuated inversion recovery hyperintense lesions in 23 (53%) patients (15 GABA A R, 5 AMPAR, and 1 unknown neuropil antibody), followed by encephalitis with peripheral nerve hyperexcitability in 7 (16%; 4 CASPR2, 2 LGI1, and 1 unknown antibody), limbic encephalitis in 6 (14%; 4 AMPAR, 1 LGI1, and 1 antibody negative), progressive encephalomyelitis with rigidity and myoclonus in 4 (9%; 3 GlyR and 1 AMPAR antibodies), and encephalitis with normal MRI in 3 (7%; AMPAR antibodies). Anti-GABA A R encephalitis was more prevalent in Japanese patients compared with Caucasians and other ethnicities (61% vs 16%; p = 0.003). In anti-AMPAR encephalitis, 3/4 patients with poor and 0/6 with good outcome had concurrent CRMP5 antibodies ( p = 0.033). Immunoprecipitation studies identified metabotropic glutamate receptor 3 antibodies that were additionally found in 5 patients (3 with and 2 without encephalitis). Conclusions AE in patients with thymoma include several clinical-radiologic syndromes that vary according to the associated antibodies. Anti-GABA A R encephalitis was the most frequent AE and occurred more frequently in Japanese patients.
    Type of Medium: Online Resource
    ISSN: 2332-7812
    URL: Article
    DOI: 10.1212/NXI.0000000000001053
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 9
    Online Resource
    Online Resource
    Seizure-related 6 homolog like 2 (SEZ6L2) autoimmunity: Neurologic syndrome and antibody effects (1802)
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Neurology Vol. 96, No. 15_supplement ( 2021-04-13)
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 96, No. 15_supplement ( 2021-04-13)
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.96.15_supplement.1802
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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