Summary Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. We aimed to assess the presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome. Methods In this multi-institutional observational study, we tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal. Predictors of outcome were determined at the Universities of Pennsylvania (PA, USA) and Barcelona (Spain) by use of a generalised linear mixed model with binary distribution. Results We enrolled 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children ( Interpretation Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months. Funding The Dutch Cancer Society, the National Institutes of Health, the McKnight Neuroscience of Brain Disorders award, The Fondo de Investigaciones Sanitarias, and Fundacio la Marato de TV3.

Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study

Objective
To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis.

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Paraneoplastic anti–N‐methyl‐D‐aspartate receptor encephalitis associated with ovarian teratoma

Since its discovery in 2007, the encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) has entered the mainstream of neurology and other disciplines. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. The disorder predominantly affects children and young adults, occurs with or without tumour association, and responds to treatment but can relapse. The presence of a tumour (usually an ovarian teratoma) is dependent on age, sex, and ethnicity, being more frequent in women older than 18 years, and slightly more predominant in black women than it is in white women. Patients treated with tumour resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) respond faster to treatment and less frequently need second-line immunotherapy (cyclophosphamide or rituximab, or both) than do patients without a tumour who receive similar initial immunotherapy. More than 75% of all patients have substantial recovery that occurs in inverse order of symptom development and is associated with a decline of antibody titres. Patients' antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a mechanism of crosslinking and internalisation. On the basis of models of pharmacological or genetic disruption of NMDAR, these antibody effects reveal a probable pathogenic relation between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(10)70253-2.pdf

Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis

Anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently described disorder with a well defined set of clinical features.1 The associated syndrome has been characterized in adults, frequently young women with teratomas of the ovary who develop changes of mood, behavior, and personality, resembling acute psychosis. The clinical picture usually progresses to include seizures, decreased level of consciousness, dyskinesias, autonomic instability, and hypoventilation.2–5 Despite the severity of the disorder, patients often improve with immunotherapy and removal of the teratoma.1,3,6 These findings and the discovery that all patients have serum and cerebrospinal fluid (CSF) antibodies that react with the cell surface of neurons suggested an immune-mediated pathogenesis.1,7,8 Further studies demonstrated that the target antigen of patients’ antibodies was the NR1 subunit of the NMDAR. Additionally, application of antibodies into cultures of hippocampal neurons resulted in a significant decrease of postsynaptic NMDAR clusters that was reversed after antibody removal.9 A recent series of 100 patients showed that the disorder also occurs in patients without teratoma, and that men and children can be affected. Since then the number of pediatric cases diagnosed at our institution or whose serum and CSF were referred for immunological studies has steadily increased.9 Although this may suggest that in children the phenotype is as characteristic as that of the adults, there are in fact differences in tumor association, neurological presentation, and frequency of symptoms. To facilitate the recognition of this disorder in children, we report eight patients diagnosed over an 8-month period at the Children's Hospital of Philadelphia (CHOP) and review the general clinical features of 24 pediatric cases from other institutions.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/ana.21756

Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents

Objective: To report the definitive diagnosis of anti-NMDA receptor (NMDAR) encephalitis in four Japanese women previously diagnosed with “juvenile acute nonherpetic encephalitis” of unclear etiology, and to describe their long-term follow-up in the absence of tumor resection. Methods: We extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to NR1/NR2 heteromers of the NMDAR in serum/CSF available from the time of symptom onset (4 to 7 years ago) and the present. Results: All patients sequentially developed prodromal symptoms, psychosis, hypoventilation, severe orofacial dyskinesias, and bizarre immunotherapy-resistant involuntary movements that lasted 1 to 12 months. Two patients required mechanical ventilation for 6 and 9 months. Initial tests were normal or unrevealing, including the presence of nonspecific CSF pleocytosis, and normal or mild changes in brain MRI. Eventually, all patients had dramatic recovery of cognitive functions, although one had bilateral leg amputation due to systemic complications. Antibodies to NR1/NR2 heteromers were found in archived serum or CSF but not in long-term follow-up samples. An ovarian teratoma was subsequently demonstrated in three patients (all confirmed pathologically). Conclusion: 1) These findings indicate that “juvenile acute nonherpetic encephalitis” or a subset of this disorder is mediated by an antibody-associated immune response against NR1/NR2 heteromers of the NMDA receptor (NMDAR). 2) Our patients9 clinical features emphasize that anti-NMDAR encephalitis is severe but potentially reversible and may precede by years the detection of an ovarian teratoma. 3) Although recovery may occur without tumor removal, the severity and extended duration of symptoms support tumor removal. GLOSSARY: AED = antiepileptic drugs; FDG-PET = [F]fluoro-2-deoxy-d-glucose PET; FLAIR = fluid-attenuated inversion recovery; F-T = frontotemporal; GABA = γ-aminobutyric acid; HHV = human herpes virus; HMPAO = 99mTc-d,l-hexamethyl-propyleneamine oxime; HSV = herpes simplex virus; IMP = N-isoprpyl-p-123I iodoamphetamine; mono = mononuclear cells; NMDAR = NMDA receptor; OCB = oligoclonal bands; OTE = ovarian teratoma associated encephalitis; PD = paroxysmal discharges; PMN = polymorphonuclear cells; IVIg = intravenous immunoglobulin; SSP = stereotactic surface projection; WBC = white blood cells.

Anti-NMDA receptor encephalitis in Japan: Long-term outcome without tumor removal

We report four young women who developed acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and central hypoventilation associated with ovarian teratoma (OT) and cerebrospinal fluid (CSF) inflammatory abnormalities. Three patients recovered with treatment of the tumor or immunosuppression and one died of the disorder. Five other OT patients with a similar syndrome and response to treatment have been reported. Our patients' serum or CSF showed immunolabeling of antigens that were expressed at the cytoplasmic membrane of hippocampal neurons and processes and readily accessed by antibodies in live neurons. Immunoprobing of a hippocampal-expression library resulted in the isolation of EFA6A, a protein that interacts with a member of the two-pore-domain potassium channel family and is involved in the regulation of the dendritic development of hippocampal neurons. EFA6A-purified antibodies reproduced the hippocampal immunolabeling of all patients' antibodies and colocalized with them at the plasma membrane. These findings indicate that in a young woman with acute psychiatric symptoms, seizures, and central hypoventilation, a paraneoplastic immune-mediated syndrome should be considered. Recognition of this disorder is important because despite the severity of the symptoms, patients usually recover. The location and function of the isolated antigen suggest that the disorder is directly mediated by antibodies.

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Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma

Soluble signal regulatory protein-alpha (SIRP-alpha) is elevated in bronchoalveolar lavage (BAL) of mice with lipopolysaccharides (LPS)-induced acute lung injury (ALI). To define the role of soluble SIRP-alpha in the pathogenesis of ALI, we established murine ALI in wild-type (WT) and SIRP-alpha knock-out (KO) mice by intratracheal administration of LPS. The results indicated that lack of SIRP-alpha significantly reduced the pathogenesis of ALI, in association with attenuated lung inflammation, infiltration of neutrophils and expression of pro-inflammatory cytokines in mice. In addition, lack of SIRP-alpha reduced the expression of pro-inflammatory cytokines in LPS-treated bone marrow-derived macrophages (BMDMs) from KO mice, accompanied with improved macrophage phagocytosis. Blockade of soluble SIRP-alpha activity in ALI BAL by anti-SIRP-alpha antibody (aSIRP) effectively reduced the expression of TNF-alpha and IL-6 mRNA transcripts and proteins, improved macrophage phagocytosis in vitro. In addition, lack of SIRP-alpha reduced activation of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) and improved activation of signal transducer and activator of transcription-3 (STAT3) and STAT6. Suppression of SHP-1 activity by tyrosine phosphatase inhibitor 1 (TPI-1) increased activation of STAT3 and STAT6, and improved macrophage phagocytosis, that was effectively reversed by STAT3 and STAT6 inhibitors. Thereby, SIRP-alpha suppressed macrophage phagocytosis through activation of SHP-1, subsequently inhibiting downstream STAT3 and STAT6 signaling. Lack of SIRP-alpha attenuated murine ALI possibly through increasing phagocytosis, and improving STAT3 and STAT6 signaling in macrophages. SIRP-alpha would be promising biomarker and molecular target in the treatment of murine ALI and patients with acute respiratory distress syndrome (ARDS).

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Soluble SIRP-Alpha Promotes Murine Acute Lung Injury Through Suppressing Macrophage Phagocytosis

Abstract Background Signal transducer and activator of transcription 6 (STAT6) is an intracelluar transcriotion factor and NLRP3 (Nod-like receptor containing a pyrin domain 3) is a component of NLRP3 inflammasome in pyroptotic cells. There was increased activation of STAT6 and expression of NLRP3 in mice with murine acute lung injury (ALI). However, it is unknown their roles in the development of murine ALI. We in this study, investigated the effects of STAT6 signaling on murine ALI and pyroptosis in STAT6 knock-out (KO) mice and macrophages. Results STAT6 was activated in the lung tissues of mice 2 days after intratracheal treatmemt with 5 mg/kg LPS. Lack of STAT6 expression in KO mice induced more severe lung inflammation, associated with elevated neutrophil influx and expression of TNF-alpha, IL-6 and IL-1beta in the inflamed lung tissues. In addition, the expression of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), p-p38 MAPK (p38 mitogen-activated protein kinase) and ratio of LC3-II/I (microtubule-associated protein-1 light chain-3) was increased, accompanied with the increased polarization of Siglec-F(−) subtype macrophages in KO mice with ALI. Further studies in bone marrow-derived macrophages (BMDMs) revealed that lack of STAT6 increased the expression of NLRP3 and p-p38 MAPK, in association with elevated expression of TNF-alpha, IL-1beta and Calreticulin in LPS-treated KO BMDMs. Conclusions Lack of STAT6 exacerbated murine ALI through improving the expression of NLRP3 and activation of p38 MAPK in macrophages. STAT6 has an immune suppressive role in the development of ALI and would be a promising therapeutic target in the treatment of ALI and possibly among patients with acute respiratory distress syndrome (ARDS). 

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Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages

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Transitory appearance of immune suppressive polymorphonuclear neutrophils (PMNs) defined as myeloid‐derived suppressor cells (PMNs‐MDSCs) in newborns is important for their protection from inflammation associated with newly established gut microbiota. Here, we report that inhibition of the type I IFN (IFN1) pathway played a major role in regulation of PMNs‐MDSCs‐suppressive activity during first weeks of life. Expression of the IFN1 receptor IFNAR1 was markedly lower in PMNs‐MDSCs. However, in newborn mice, down‐regulation of IFNAR1 was not sufficient to render PMNs immune suppressive. That also required the presence of a positive signal from lactoferrin via its receptor low‐density lipoprotein receptor‐related protein 2. The latter effect was mediated via NF‐κB activation, which was tempered by IFN1 in a manner that involved suppressor of cytokine signaling 3. Thus, we discovered a mechanism of tight regulation of immune suppressive PMNs‐MDSCs in newborns, which may be used in the development of therapies of neonatal pathologies.

Zhilong Jiang

Papers

Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma

Soluble SIRP-Alpha Promotes Murine Acute Lung Injury Through Suppressing Macrophage Phagocytosis

Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages

Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages

Mechanisms regulating transitory suppressive activity of neutrophils in newborns: PMNs‐MDSCs in newborns