Neurofilament Light Chain Levels in Anti-NMDAR Encephalitis and Primary Psychiatric Psychosis.

BACKGROUND AND OBJECTIVES: 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.

Allosteric Modulation of NMDARs Reverses Patients' Autoantibody Effects in Mice.

BACKGROUND AND OBJECTIVES: To demonstrate that an analog (SGE-301) of a brain-derived cholesterol metabolite, 24(S)-hydroxycholesterol, which is a selective positive allosteric modulator (PAM) of NMDA receptors (NMDARs), is able to reverse the memory and synaptic alterations caused by CSF from patients with anti-NMDAR encephalitis in an animal model of passive transfer of antibodies. METHODS: Four groups of mice received (days 1-14) patients' or controls' CSF via osmotic pumps connected to the cerebroventricular system and from day 11 were treated with daily subcutaneous injections of SGE-301 or vehicle (no drug). Visuospatial memory, locomotor activity (LA), synaptic NMDAR cluster density, hippocampal long-term potentiation (LTP), and paired-pulse facilitation (PPF) were assessed on days 10, 13, 18, and 26 using reported techniques. RESULTS: On day 10, mice infused with patients' CSF, but not controls' CSF, presented a significant visuospatial memory deficit, reduction of NMDAR clusters, and impairment of LTP, whereas LA and PPF were unaffected. These alterations persisted until day 18, the time of maximal deficits in this model. In contrast, mice that received patients' CSF but from day 11 were treated with SGE-301 showed memory recovery (day 13), and on day 18, all paradigms (memory, NMDAR clusters, and LTP) had reversed to values similar to those of controls. On day 26, no differences were observed among experimental groups. DISCUSSION: An oxysterol biology-based PAM of NMDARs is able to reverse the synaptic and memory deficits caused by CSF from patients with anti-NMDAR encephalitis. These findings suggest a novel adjuvant treatment approach that deserves future clinical evaluation.

Blocking Placental Class G Immunoglobulin Transfer Prevents NMDA Receptor Antibody Effects in Newborn Mice.

BACKGROUND AND OBJECTIVES: To determine in a mouse model whether neonatal Fc receptor (FcRn) blockade prevents the placental transfer of class G immunoglobulin (IgG) derived from patients with anti-NMDA receptor (NMDAR) encephalitis and their pathogenic effects on the fetuses and offspring. METHODS: Pregnant C57BL/6J mice were administered via tail vein FcRn antibody (FcRn-ab) or saline solution 6 hours before administration of patients' or controls' IgG on days 14, 15, and 16 of gestation. Three experimental groups were established: mice receiving controls' IgG, patients' IgG, or patients' IgG along with pretreatment with FcRn-ab. Immunohistochemical staining, confocal microscopy, hippocampal long-term potentiation, and standardized developmental and behavioral tasks were used to assess the efficacy of treatment with FcRn-ab. RESULTS: In pregnant mice that received patients' IgG, treatment with FcRn-ab prevented the IgG from reaching the fetal brain, abrogating the decrease of NMDAR clusters and the reduction of cortical plate thickness that were observed in fetuses from untreated pregnant mice. Moreover, among the offspring of mothers that received patients' IgG, those whose mothers were treated with FcRn-ab did not develop the alterations that occurred in offspring of untreated mothers, including impairment in hippocampal plasticity, delay in innate reflexes, and visuospatial memory deficits. DISCUSSION: FcRn blockade prevents placental transfer of IgG from patients with anti-NMDAR encephalitis and abrogates the synaptic and neurodevelopmental alterations caused by patients' antibodies. This model has potential therapeutic implications for other antibody-mediated diseases of the CNS during pregnancy.

Thymoma and Autoimmune Encephalitis: Clinical Manifestations and Antibodies.

OBJECTIVE: 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 (GABAAR) (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 GABAAR, 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-GABAAR 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-GABAAR encephalitis was the most frequent AE and occurred more frequently in Japanese patients.

Clinical significance of Kelch-like protein 11 antibodies.

OBJECTIVE: To report the clinical and oncologic associations of antibodies against Kelch-like protein 11 (KLHL11-ab), recently suggested as biomarkers of a paraneoplastic brainstem cerebellar syndrome associated with testicular seminoma, and to determine the value of immunohistochemistry as a screening technique. METHODS: Studies included 432 sera or CSF from 329 patients with paraneoplastic (157) or autoimmune neurologic syndromes (172); 63 with neurologic symptoms and benign teratomas; 28 with small-cell lung cancer, and 12 healthy subjects. KLHL11-abs were examined using a cell-based assay (CBA) with HEK293 cells transfected with a human KLHL11 clone. The CBA specificity was confirmed by immunoprecipitation. All positive samples were examined by immunohistochemistry on rat brain sections. RESULTS: KLHL11-abs were detected in 32 patients by CBA, and patients' antibodies immunoprecipitated KLHL11. Using rat brain immunohistochemistry, only 7 samples (22%) were positive. Patients' median age was 28 years (range 9-76 years), and 16 (50%) were women. Tumors were identified in 23/32 (72%) patients, including 14 teratomas and 7 seminomas or mixed germ cell tumors. Thirteen (41%) patients had cerebellar ataxia (7) or encephalitis with brainstem cerebellar symptoms (6), 7 (22%) anti-NMDA receptor (NMDAR) encephalitis (5 with ovarian teratoma), 5 (16%) opsoclonus-myoclonus, 3 (9%) limbic encephalitis, and 4 (12%) diverse neurologic symptoms (3 with benign teratomas). Concurrent autoantibodies occurred in 14 (44%) patients (7 anti-NMDAR, 6 Ma2, and 1 Hu). CONCLUSIONS: KLHL11-abs associate with a spectrum of syndromes and tumors wider than those previously reported; 44% of patients have concurrent neuronal antibodies, some of them (anti-NMDAR) pathogenically relevant. Brain immunostaining is not useful for routine screening of KLHL11-abs.

JNK Isoforms Are Involved in the Control of Adult Hippocampal Neurogenesis in Mice, Both in Physiological Conditions and in an Experimental Model of Temporal Lobe Epilepsy.

Neurogenesis in the adult dentate gyrus (DG) of the hippocampus allows the continuous generation of new neurons. This cellular process can be disturbed under specific environmental conditions, such as epileptic seizures; however, the underlying mechanisms responsible for their control remain largely unknown. Although different studies have linked the JNK (c-Jun-N-terminal-kinase) activity with the regulation of cell proliferation and differentiation, the specific function of JNK in controlling adult hippocampal neurogenesis is not well known. The purpose of this study was to analyze the role of JNK isoforms (JNK1/JNK2/JNK3) in adult-hippocampal neurogenesis. To achieve this goal, we used JNK-knockout mice (Jnk1-/-, Jnk2-/-, and Jnk3-/-), untreated and treated with intraperitoneal injections of kainic acid (KA), as an experimental model of epilepsy. In each condition, we identified cell subpopulations at different stages of neuronal maturation by immunohistochemical specific markers. In physiological conditions, we evidenced that JNK1 and JNK3 control the levels of one subtype of early progenitor cells (GFAP+/Sox2+) but not the GFAP+/Nestin+ cell subtype. Moreover, the absence of JNK1 induces an increase of immature neurons (Doublecortin+; PSA-NCAM+ cells) compared with wild-type (WT). On the other hand, Jnk1-/- and Jnk3-/- mice showed an increased capacity to maintain hippocampal homeostasis, since calbindin immunoreactivity is higher than in WT. An important fact is that, after KA injection, Jnk1-/- and Jnk3-/- mice show no increase in the different neurogenic cell subpopulation analyzed, in contrast to what occurs in WT and Jnk2-/- mice. All these data support that JNK isoforms are involved in the adult neurogenesis control.