Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood-Brain Barrier Disruption and Neuronal Damage.

The disruption of the blood-brain barrier (BBB) is hypothesized to be involved in the progression of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but its mechanism is still unclear. Recently, the phosphatidylinositol 3-kinase (PI3K)/threonine kinase (Akt) pathway is involved in the regulation of the BBB in various diseases. This study is aimed to investigate the mechanism of BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. Female C57BL/6J mice were actively immunized to establish an anti-NMDAR encephalitis mouse model and evaluate the neurobehavior changes of mice. To study its potential mechanism, LY294002 (PI3K inhibitor, 8 mg/kg) and Recilisib (PI3K agonist, 10 mg/kg) were treated by intraperitoneal injection, respectively. Anti-NMDAR encephalitis mice showed neurological deficits, increased BBB permeability, open endothelial tight junctions (TJs), and decreased expression of TJ-related proteins zonula occludens (ZO)-1 and Claudin-5. However, administration of PI3K inhibitor significantly reduced the expression of p-PI3K and p-Akt, improved neurobehavior function, decreased BBB permeability, and upregulated the expressions of ZO-1 and Claudin-5. Furthermore, PI3K inhibition reversed the decline of NMDAR NR1 in the membranes of hippocampal neurons, which reduced the loss of neuron-specific nucleoprotein (NeuN) and microtubule-associated protein 2 (MAP2). In contrast, administration of the PI3K agonist Recilisib showed a tendency to exacerbate BBB breakdown and neurological deficits. Our results showed that the activation of PI3K/Akt, along with the changes in TJ-related proteins ZO-1 and Claudin-5, may be closely related to BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. PI3K inhibition attenuates BBB disruption and neuronal damage in mice, thereby improving neurobehavior.

Single-nucleus RNA sequencing unveils critical regulators in various hippocampal neurons for anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease with variable clinical manifestations caused by NMDAR autoantibody. The underlying molecular underpinnings of this disease are rarely characterized on a genomic scale. Anti-NMDAR encephalitis mainly affects the hippocampus, however, its effect on gene expression in hippocampal neurons is unclear at present. Here, we construct the active and passive immunization mouse models of anti-NMDAR encephalitis, and use single-nucleus RNA sequencing to investigate the diverse expression profile of neuronal populations isolated from different hippocampal regions. Dramatic changes in cell proportions and differentially expressed genes were observed in excitatory neurons of the dentate gyrus (DG) subregion. In addition, we found that ATP metabolism and biosynthetic regulators related genes in excitatory neurons of DG subregion were significantly affected. Kcnq1ot1 in inhibitory neurons and Meg3 in interneurons also changed. Notably, the latter two molecules exhibited opposite changes in different models. Therefore, the above genes were used as potential targets for further research on the pathological process of anti-NMDAR encephalitis. These data involve various hippocampal neurons, which delineate a framework for understanding the hippocampal neuronal circuit and the potential molecular mechanisms of anti-NMDAR encephalitis.

Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and anti-leucine-rich glioma-inactivated 1 encephalitis (anti-LGI1E) are the two most common types of antibody-mediated autoimmune encephalitis. We performed a comprehensive analysis of the B-cell immune repertoire in patients with anti-NMDARE (n = 7) and anti-LGI1E (n = 10) and healthy controls (n = 4). The results revealed the presence of many common clones between patients with these two types of autoimmune encephalitis, which were mostly class-switched. Additionally, many differences were found among the anti-NMDARE, anti-LGI1E, and healthy control groups, including the diversity of the B-cell immune repertoire and gene usage preference. These findings suggest that the same adaptive immune responses occur in patients with anti-NMDARE and anti-LGI1E, which deserves further exploration.

The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review.

Ovarian teratomas are by far the most common ovarian germ cell tumor. Most teratomas are benign unless a somatic transformation occurs. The designation of teratoma refers to a neoplasm that differentiates toward somatic-type cell populations. Recent research shows a striking association between ovarian teratomas and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, a rare and understudied paraneoplastic neurological syndrome (PNS). Among teratomas, mature teratomas are thought to have a greater relevance with those neurological impairments. PNS is described as a neurologic deficit triggered by an underlying remote tumor, whereas anti-NMDAR encephalitis is characterized by a complex neuropsychiatric syndrome and the presence of autoantibodies in cerebral spinal fluid against the GluN1 subunit of the NMDAR. This review aims to summarize recent reports on the association between anti-NMDAR encephalitis and ovarian teratoma. In particular, the molecular pathway of pathogenesis and the updated mechanism and disease models would be discussed. We hope to provide an in-depth review of this issue and, therefore, to better understand its epidemiology, diagnostic approach, and treatment strategies.

The diverse and complex modes of action of anti-NMDA receptor autoantibodies.

NMDA receptors are ligand-gated ion channels that are found throughout the brain and are required for both brain development and many higher order functions. A variety of human patients with diverse clinical phenotypes have been identified that carry autoantibodies directed against NMDA receptor subunits. Here we focus on two general classes of autoantibodies, anti-GluN1 antibodies associated with anti-NMDA receptor encephalitis and anti-GluN2 antibodies associated with systemic lupus erythematosus (SLE). These two general classes of anti-NMDA receptor autoantibodies display a wide range of pathophysiological mechanisms from altering synaptic composition to gating of NMDARs. While we have made progress in understanding how these autoantibodies work at the molecular and cellular level, many unanswered questions remain including their long-term actions on brain function, the significance of clonal variations, and their effects on different NMDA receptor-expressing cell types in local circuits. This information will be needed to define fully the transition from anti-NMDA receptor autoantibodies to a clinical phenotype.

Disturbance of Gut Bacteria and Metabolites Are Associated with Disease Severity and Predict Outcome of NMDAR Encephalitis: A Prospective Case-Control Study.

Objective: We aimed to investigate the associations between the intestinal microbiota, metabolites, cytokines, and clinical severity in anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and to further determine the predictive value of the intestinal microbiota or metabolites in clinical prognosis. Methods: In this prospective observational cohort study of 58 NMDAR encephalitis patients and 49 healthy controls, fecal microbiota, metabolites, and cytokines were quantified and characterized by16S rRNA gene sequencing, liquid chromatography-mass spectrometry, and the Luminex assay, respectively. Results: There were marked variations in the gut microbiota composition and metabolites in critically ill patients. We identified 8 metabolite modules (mainly characterized by fatty acid, glycerophosphoethanolamines, and glycerophosphocholines) that were distinctly classified as negatively or positively associated with bacterial co-abundance groups (CAGs). These CAGs were mainly composed of Bacteroides, Eubacterium_hallii_group, Anaerostipes, Ruminococcus, Butyricicoccus, and Faecalibacterium, which were substantially altered in patients. In addition, these fecal and serum metabolic modules were further correlated with the serum cytokines. Additionally, the combination of clinical features, microbial marker (Granulicatella), and a panel of metabolic markers could further enhance the performance of prognosis discrimination significantly, which yielded an area under the receiver operating characteristic curve of (AUC) of 0.94 (95%CI = 0.7-0.9). Patients with low bacterial diversity are more likely to develop relapse than those with higher bacterial diversity (log-rank p = 0.04, HR = 2.7, 95%CI = 1.0-7.0). Interpretation: The associations between the multi-omics data suggested that certain bacteria might affect the pathogenesis of NMDAR encephalitis by modulating the metabolic pathways of the host and affecting the production of pro-inflammatory cytokines. Furthermore, the disturbance of fecal bacteria may predict the long-term outcome and relapse in NMDAR encephalitis.

Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients' NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient's CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients' or controls' CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient's CSF antibodies, but not those infused with controls' CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.

Study of B Cell Repertoire in Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common antibody-mediated encephalitis. There are several studies on B cell repertoire of anti-NMDAR encephalitis in Caucasians. Here, the cerebrospinal fluid (CSF) samples of 12 Chinese patients with first-episode anti-NMDAR encephalitis were collected to investigate the B cell receptor (BCR) binding to NMDAR by single cell amplification of BCR and Sanger sequencing. BCR data of healthy persons, and of patients with anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis, multiple sclerosis (MS), and neuromyelitis optica spectrum disorder (NMOSD) from the public databases were used as control. A heavy chain common clone IGHV1-18*04,IGHD1-26*01/ IGHD2-2*03/IGHD2-8*01, IGHJ3*02_(CDR3) ARVGSKYGFETFDI was found in 11 of 12 enrolled patients but not in the comparison data set. In addition, 4 shared clonotypes were found among these patients, and three of them contained the common clone. This study also revealed that the antibody gene family usage preference between patients and healthy controls were different, while they had similar antibody mutation rate. Our findings may have potential clinical implications for the diagnosis of anti-NMDAR encephalitis.

NMDAR Antibodies Alter Dopamine Receptors and Cause Psychotic Behavior in Mice.

OBJECTIVE: The aim was to demonstrate that antibodies from patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis alter the levels of dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) and cause psychotic-like features in mice. METHODS: Cultured rat hippocampal neurons were treated with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, and the effects on clusters of D1R and D2R were quantified. In vivo studies included 71 C57BL/6J mice that were chronically infused with CSF from patients or controls through ventricular catheters connected to subcutaneous osmotic pumps. Prepulse inhibition of the acoustic startling reflex (PPI; a marker of psychotic-like behavior), memory, locomotor activity, and the density of cell-surface and synaptic D1R, D2R, and NMDAR clusters were examined at different time points using reported techniques. RESULTS: In cultured neurons, CSF from patients, but not from controls, caused a significant decrease of cell-surface D1R and an increase of D2R clusters. In mice, CSF from patients caused a significant decrease of synaptic and total cell-surface D1R clusters and an increase of D2R clusters associated with a decrease of PPI. These effects were accompanied by memory impairment and a reduction of surface NMDARs, as reported in this model. The psychotic-like features, memory impairment, and changes in levels of D1R, D2R, and NMDAR progressively improved several days after the infusion of CSF from patients stopped. INTERPRETATION: In addition to memory deficits and reduction of NMDARs, CSF antibodies from patients with anti-NMDAR encephalitis cause reversible psychotic-like features accompanied by changes (D1R decrease, D2R increase) in cell-surface dopamine receptor clusters. ANN NEUROL 2020 ANN NEUROL 2020;88:603-613.

N-Methyl-D-Aspartate Receptor Antibodies in Autoimmune Encephalopathy Alter Oligodendrocyte Function.

OBJECTIVE: Antibodies against neuronal N-methyl-D-aspartate receptors (NMDARs) in patients with anti-NMDAR encephalitis alter neuronal synaptic function and plasticity, but the effects on other cells of the nervous system are unknown. METHODS: Cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis (preabsorbed or not with GluN1) and a human NMDAR-specific monoclonal antibody (SSM5) derived from plasma cells of a patient, along the corresponding controls, were used in the studies. To evaluate the activity of oligodendrocyte NMDARs and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in vitro after exposure to patients' CSF antibodies or SSM5, we used a functional assay based on cytosolic Ca2+ imaging. Expression of the glucose transporter (GLUT1) in oligodendrocytes was assessed by immunocytochemistry. RESULTS: NMDAR agonist responses were robustly reduced after preincubation of oligodendrocytes with patients' CSF or SSM5 but remained largely unaltered with the corresponding controls. These effects were NMDAR specific, as patients' CSF did not alter responses to AMPA receptor agonists and was abrogated by preabsorption of CSF with HEK cells expressing GluN1 subunit. Patients' CSF also reduced oligodendrocyte expression of glucose transporter GLUT1 induced by NMDAR activity. INTERPRETATION: Antibodies from patients with anti-NMDAR encephalitis specifically alter the function of NMDARs in oligodendrocytes, causing a decrease of expression of GLUT1. Considering that normal GLUT1 expression in oligodendrocytes and myelin is needed to metabolically support axonal function, the findings suggest a link between antibody-mediated dysfunction of NMDARs in oligodendrocytes and the white matter alterations reported in patients with this disorder. ANN NEUROL 2020;87:670-676.

Different FDG-PET metabolic patterns of anti-AMPAR and anti-NMDAR encephalitis: Case report and literature review.

INTRODUCTION: 18 F-fluorodeoxyglucose (FDG)-PET metabolic patterns of brain differ among autoimmune encephalitis with different neuronal surface antigens. In this case report, we compared the topographical relationship of cerebral glucose metabolism and antigen distribution in the patients with anti-NMDAR and anti-AMPAR encephalitis. Literature review summarized the common features of brain metabolism of autoimmune encephalitis. METHODS: The cerebral glucose metabolism was evaluated by FDG-PET/CT during acute-to-subacute stage of autoimmune encephalitis and after treatment. The stereo and quantitative analysis of cerebral metabolism used standardized z-score and visualized on three-dimensional stereotactic surface projection. To map NMDAR and AMPAR in human brain, we adopted genetic atlases from the Allen Institute and protein atlases from Zilles's receptor densities. RESULTS: The three-dimensional stereotactic surface projection displayed frontal-dominant hypometabolism in a 66-year-old female patient with anti-AMPAR encephalitis and occipital-dominant hypometabolism in a 29-year-old female patient with anti-NMDAR encephalitis. Receptor density maps revealed opposite frontal-occipital gradients of AMPAR and NMDAR, which reflect reduced metabolism in the correspondent encephalitis. FDG-PET hypometabolic areas possibly represent receptor hypofunction with spatial correspondence to receptor distributions of the autoimmune encephalitis. The reversibility of hypometabolism was in line with patients' cognitive improvement. The literature review summarized six features of metabolic anomalies of autoimmune encephalitis: (a) temporal hypermetabolism, (b) frontal hypermetabolism and (c) occipital hypometabolism in anti-NMDAR encephalitis, (d) hypometabolism in association cortices, (e) sparing of unimodal primary motor cortex, and (e) reversibility in recovery. CONCLUSIONS: The distinct cerebral hypometabolic patterns of autoimmune encephalitis were representative for receptor hypofunction and topographical distribution of antigenic receptors. The reversibility of hypometabolism marked the clinical recovery of autoimmune encephalitis and made FDG-PET of brain a valuable diagnostic tool.

A Metabolic Brain Pattern Associated With Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis causes substantial neurological disability. Autoantibodies causing encephalitis directed against the neuronal cell surface or synapse are of diagnostic importance giving the possibility of successful immunotherapy. OBJECTIVE: In this study, we aim to provide supporting evidence that brain 18F-FDG-PET may be helpful in identifying likely patterns of regional brain glucose metabolism. METHODS: Thirty-three patients (18 men and 15 women; age range of 17-55 y) with positive NMDA receptor antibody encephalitis that underwent an 18F-FDG-PET imaging examination were prospectively selected and compared with a reference group of 14 brain 18F-FDG-PET scans from healthy volunteers using voxel-based statistical analysis. Clusters of hyper- and hypo-metabolism were reported for the whole sample of patients (FWE-corrected P < 0.05), and uncorrected at P < 0.005 for a group of relapsed patients. RESULTS: Mixed metabolic patterns (focal/bilateral hypermetabolism in the temporal lobe, insula, and cerebellum; associated with severe bilateral hypometabolism in the occipital and parietal lobes) were found. CONCLUSIONS: Our findings suggest that 18F-FDG-PET should be included as an imaging tool when assessing affected patients in the clinical workup to rule out anti-NMDA encephalitis and help determine the most effective treatment.

Hyperammonemia in a case of herpes simplex and anti-N-methyl-d-aspartate receptor encephalitis.

Herpes simplex encephalitis (HSE) is a widely accepted risk factor for anti N-methyl-d-aspartate receptor (NMDAR) encephalitis. Association of inherited metabolic disease has never been reported in a patient with HSE and anti-NMDAR encephalitis. Herein, we report a case of pediatric HSE complicated by development of anti-NMDAR encephalitis; this patient showed subsequent recurrent, unexplained episodes of encephalopathy associated with hyperammonemia. The patient was diagnosed with lysinuric protein intolerance (LPI), a rare inborn metabolic disorder. Although it would be difficult to make conclusions regarding the casual link of HSE and anti-NMDAR encephalitis with LPI from a single case, there have been many reports that autoimmune diseases and immunologic abnormalities are frequently associated with LPI. Thus, we speculate that LPI may contribute to the development of anti-NMDAR encephalitis following HSE.

N-Methyl-d-aspartate Receptor Antibody Encephalitis: A Concise Review of the Disorder, Diagnosis, and Management.

Anti-NMDA ( N-methyl-d-aspartate) receptor (anti-NMDAR) encephalitis is one of the most common paraneoplastic encephalitides. It occurs in both sexes, across all age ranges, and may occur in the presence or absence of an associated tumor. Its pathogenesis and clinical presentation relate to the presence of IgG1 or IgG3 antibodies targeting the NR1 subunit of the NMDA receptor, leading to a disinhibition of neuronal excitatory pathways. Initial clinical manifestations may be nonspecific, resembling a viral-like illness; however, with disease progression, symptoms can become quite severe, including prominent psychiatric features, cognitive problems, motor dysfunction, and autonomic instability. Anti-NMDAR encephalitis may even result in death in severe untreated cases. Diagnosis can be challenging, given that initial laboratory and radiographic results are typically nonspecific. The majority of patients respond to first or second-line treatments, although therapeutic options remain limited, usually consisting of tumor removal (if there is confirmation of an underlying malignancy) in conjunction with prompt initiation of immunosuppressive medications along with intravenous immunoglobulins and/or plasma exchange. Although the clinical presentation of anti-NMDAR encephalitis overlaps with several other more common neurological and psychiatric disorders, early diagnosis and treatment is essential for a positive prognosis. Here, we concisely review the pathogenesis, diagnosis, and clinical management of this disease.

A Case of Severe Anti-N-Methyl D-Aspartate (Anti-NMDA) Receptor Encephalitis with Refractory Autonomic Instability and Elevated Intracranial Pressure.

BACKGROUND Anti-N-methyl D-Aspartate (anti-NMDA) receptor encephalitis is a rare autoimmune panencephalitis that typically presents with acute psychiatric disturbances and neurological deficits. Anti-NMDA receptor encephalitis is associated with certain tumors, most commonly ovarian teratomas. First-line therapy typically involves immunotherapy and tumor resection, if present, with up to 53% of patients experiencing improvement within 4 weeks. Cardiac arrhythmias and increased intracranial pressure have been reported in anti-NMDA receptor encephalitis, but these complications have usually been self-limited. CASE REPORT We report the case of a previously healthy, obese 21-year-old female who presented with acute encephalopathy. Her psychiatric and neurological function rapidly deteriorated, warranting intubation and mechanical ventilation. Lumbar puncture was performed. Cerebrospinal fluid (CSF) opening pressure was elevated and a lumbar drain was placed. Infectious disease work-up was negative and anti-NMDA receptor antibodies were present in the CSF and serum. Initial treatment included intravenous immunoglobulin (IVIG) therapy, plasmapheresis, methylprednisolone, and bilateral salpingoophorectomy, without clinical improvement. Second-line immunotherapy with cyclophosphamide and rituximab was then administered. The patient also developed intermittent episodes of severe bradycardia and asystole that remained refractory to treatment and required placement of a permanent cardiac pacemaker. CONCLUSIONS Anti-NMDA receptor encephalitis presents with rapidly progressive psychiatric and neurologic dysfunction and can develop a severe and prolonged course with limited response to treatment. Patients can develop severe autonomic dysfunction with bradycardia and asystole that may require placement of permanent cardiac pacemakers. Elevated intracranial pressure may also be associated with anti-NMDA receptor encephalitis, and might contribute to the autonomic instability.

Detection of NMDARs Antibodies in Encephalitis.

There is a range of diseases of the brain that are associated with rapidly developing inflammation. These conditions are called encephalitis, and can be caused by infections, or autoimmune disorders when the subject's immune system reacts against host proteins. The most common form of autoimmune encephalitis is associated with antibodies against the NR1 subunit of the N-Methyl-D-Aspartate Receptor (anti-NMDAR-encephalitis). Antibody detection is important for diagnosis, and can be performed only with techniques that preserve the full tertiary structure (conformation) of the antigen. Here, we describe the methods commonly used to detect NMDAR-antibodies with immunohistochemistry on rat brain slices and on live HEK cells transfected with components of the NMDAR.

FDG-PET hyperactivity pattern in anti-NMDAr encephalitis.

FDG-PET can show anteroposterior glucose metabolism gradient in anti-NMDAr encephalitis, but there are also suggestions that basal ganglia are involved. We examined FDG-PET scans in 5 consecutive episodes of serologically proven anti-NMDAr encephalitis, compared with healthy controls. We confirmed the anteroposterior metabolic gradient and found a significant FDG uptake increase in the caudate nuclei in episodes of varying intensity and delay from the onset of the symptoms. FDG-PET can be useful in the work-up of suspected anti-NMDAr encephalitis disclosing a characteristic cortical and sub-cortical metabolism pattern.

Association of Progressive Cerebellar Atrophy With Long-term Outcome in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis.

IMPORTANCE: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that occurs with IgG antibodies against the GluN1 subunit of NMDAR. Some patients develop reversible diffuse cerebral atrophy (DCA), but the long-term clinical significance of progressive brain and cerebellar atrophy is unknown. OBJECTIVE: To report the long-term clinical implications of DCA and cerebellar atrophy in anti-NMDAR encephalitis. DESIGN, SETTING, AND PARTICIPANTS: A retrospective observational study and long-term imaging investigation was conducted in the Department of Neurology at Kitasato University. Fifteen patients with anti-NMDAR encephalitis admitted to Kitasato University Hospital between January 1, 1999, and December 31, 2014, were included; data analysis was conducted between July 15, 2015, and January 18, 2016. EXPOSURES: Neurologic examination, immunotherapy, and magnetic resonance imaging (MRI) studies were performed. MAIN OUTCOMES AND MEASURES: Long-term MRI changes in association with disease severity, serious complications (eg, pulmonary embolism, septic shock, and rhabdomyolysis), treatment, and outcome. RESULTS: The clinical outcome of 15 patients (median age, 21 years, [range, 14-46 years]; 10 [67%] female) was evaluated after a median follow-up of 68 months (range, 10-179 months). Thirteen patients (87%) received first-line immunotherapy (intravenous high-dose methylprednisolone, intravenous immunoglobulin, and plasma exchange alone or combined), and 4 individuals (27%) also received cyclophosphamide; 2 patients (13%) did not receive immunotherapy. In 5 patients (33%), ovarian teratoma was found and removed. Serious complications developed in 4 patients (27%). Follow-up MRI revealed DCA in 5 patients (33%) that, in 2 individuals (13%), was associated with progressive cerebellar atrophy. Long-term outcome was good in 13 patients (87%) and poor in the other 2 individuals (13%). Although cerebellar atrophy was associated with poor long-term outcome (2 of 2 vs 0 of 13 patients; P = .01), other features, such as DCA without cerebellar atrophy, serious complications, ventilatory support, or prolonged hospitalization, were not associated with a poor outcome. Five patients with DCA had longer hospitalizations (11.1 vs 2.4 months; P = .002), required ventilatory support more frequently (5 of 5 vs 4 of 10 patients; P = .04), and developed more serious complications (4 of 5 vs 0 of 10 patients; P = .004) compared with those without DCA. Although DCA was reversible, cerebellar atrophy was irreversible. CONCLUSIONS AND RELEVANCE: In anti-NMDAR encephalitis, DCA can be reversible and does not imply a poor clinical outcome. In contrast, cerebellar atrophy was irreversible and associated with a poor outcome. This observation deserves further study to confirm progressive cerebellar atrophy as a prognostic marker of poor outcome.

Changing Brain Metabolism Patterns in Patients With ANMDARE: Serial 18F-FDG PET/CT Findings.

PURPOSE: The aim of this study was to describe brain metabolic changing patterns demonstrated by serial brain FDG PET/CT scans and their relationship with the clinical course in patients with anti-N-methyl-d-aspartate receptor encephalitis (ANMDARE). PATIENTS AND METHODS: Eighteen serial PET scans of 8 patients with ANMDARE were reviewed. All the 18 PET scans were divided into 4 groups according to studies timing in different clinical course: group A, the acute and subacute phase; group B, early recovery phase; group C, recovery phase; and group D, relapsing phase. Antibody levels of ANMDARE of all these patients were tested at the same time. The PET images of each group were analyzed visually and also compared with 10 age- and sex-matched normal controls using voxel-wise statistical parametric mapping analysis (SPM5). RESULTS: Variable brain metabolic patterns and its association with the clinical course and the levels of NMDA antibody were demonstrated by FDG PET images. First, severe hypometabolism in bilateral occipital lobes and relatively mild hypermetabolism in the partial frontal and basal ganglia in acute and subacute phase, the level of antibody was high. Second, in early recovery phase when the symptoms was partially improved, extensive cortical hypometabolism was observed, and the level of antibody was low. Third, the patients in the recovery phase have no obvious neurological and psychiatric symptoms; PET images were nearly normal, and the antibodies tests were all negative, correspondingly. Fourth, 3 scans of relapsing phase presented heterogeneous brain metabolic abnormalities. CONCLUSIONS: There existed a specific serial brain metabolic changing pattern that correlated with the clinical course and antibody level in ANMDARE.