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Angela Vincent - One of the best experts on this subject based on the ideXlab platform.
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high sensitivity and specificity in proposed clinical diagnostic criteria for anti n methyl d Aspartate Receptor encephalitis
Developmental Medicine & Child Neurology, 2017Co-Authors: Shekeeb S Mohammad, Yael Hacohen, Sekhar Pillai, Angela Vincent, Russell C Dale, Esther M Tantsis, Hannah F Jones, Ming K LimAbstract:Aim To determine the validity of the proposed clinical diagnostic criteria for anti-N-methyl-d-Aspartate Receptor (NMDAR) encephalitis in paediatric patients. Method The diagnostic criteria for anti-NMDAR encephalitis proposed by Graus et al. (2016) use clinical features and conventional investigations to facilitate early immunotherapy before antibody status is available. The criteria are satisfied if patients develop four out of six symptom groups within 3 months, together with at least one abnormal investigation (electroencephalography/cerebrospinal fluid) and reasonable exclusion of other disorders. We evaluated the validity of the criteria using a retrospective cohort of paediatric patients with encephalitis. Twenty-nine patients with anti-NMDAR encephalitis and 74 comparison children with encephalitis were included. Results As expected, the percentage of patients with anti-NMDAR encephalitis who fulfilled the clinical criteria increased over time. During the hospital inpatient admission, most patients (26/29, 90%) with anti-NMDAR encephalitis fulfilled the criteria, significantly more than the comparison group (3/74, 4%) (p<0.001). The median time of fulfilling the criteria in patients with anti-NMDAR encephalitis was 2 weeks from first symptom onset (range 1–6). The sensitivity of the criteria was 90% (95% confidence interval 73–98) and the specificity was 96% (95% confidence interval 89–99). Interpretation The proposed diagnostic criteria for anti-NMDAR encephalitis have good sensitivity and specificity. Incomplete criteria do not exclude the diagnosis. What this paper adds The proposed clinical diagnostic criteria for anti-N-methyl-d-Aspartate Receptor (NMDAR) encephalitis by Graus et al. (2016) have high sensitivity and specificity in paediatric patients. The median time of fulfilling the criteria in patients with anti-NMDAR was 2 weeks from first symptom onset.
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anti n methyl d Aspartate Receptor encephalitis in a young child with histological evidence on brain biopsy of coexistent herpes simplex virus type 1 infection
Pediatric Infectious Disease Journal, 2016Co-Authors: Mark Ellul, Angela Vincent, Michael J Griffiths, Anand Iyer, Shivaram Avula, Sylviane Defres, Atik Baborie, Natalie G Martin, Manish Sadarangani, Andrew J PollardAbstract:We report a 3-year-old boy with anti-N-methyl-D-Aspartate Receptor encephalitis with a typical syndrome of movement disorder and encephalopathy and evidence of herpes simplex virus (HSV) type 1 infection on brain biopsy. HSV type 1 infection and anti-N-methyl-D-Aspartate Receptor encephalitis are temporally linked in some cases: this case suggests that prodromal HSV type-1 infection may be clinically subtle and easily missed.
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pediatric herpes simplex virus encephalitis complicated by n methyl d Aspartate Receptor antibody encephalitis
Journal of the Pediatric Infectious Diseases Society, 2015Co-Authors: Alasdair Bamford, Yael Hacohen, Angela Vincent, Belinda H A Crowe, Antonia Clarke, Gareth Tudorwilliams, Vanessa Sanchoshimizu, Sunil PullaperumaAbstract:: N-methyl-D-Aspartate Receptor antibodies (NMDAR-Abs) can contribute to neurological relapse after herpes simplex virus encephalitis (HSE). We describe a child with NMDAR-Ab encephalitis after HSE, which was recognized and treated early. We discuss the case in the context of existing reports, and we propose a modified immunotherapy strategy to minimize risk of viral reactivation.
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autoantibodies to the n methyl d Aspartate Receptor and seizure susceptibility in mice
The Lancet, 2014Co-Authors: Sukhvir Wright, Angela Vincent, Bethan Lang, Kevan Hashemi, Philippa Pettingill, Louise UptonAbstract:Abstract Background Autoantibodies to neuronal surface proteins are found in adult seizure-related disorders such as anti-N-methyl-D-Aspartate Receptor antibody (NMDAR-Ab) encephalitis and limbic encephalitis. We have previously shown, in new-onset childhood epilepsy, that CNS autoantibodies are also found in a proportion of these patients. We aimed to determine whether these antibodies are pathogenic and epileptogenic in vivo. Methods IgG from three patients with NMDAR-Ab encephalitis and two healthy controls was purified for passive transfer. Wireless electroencephalogram (EEG) transmitters were implanted into 15 mice. Nine of these mice were injected intracerebroventricularly with IgG from NMDAR-Ab positive patients and six mice with IgG from controls. 5 days of continuous electrophysiology recordings were used to detect spontaneous and induced epileptiform activity. A library of signature events was created to analyse the EEG recordings of all mice. Seizure susceptibility was tested 48 h after injection with a subthreshold dose of the proconvulsant pentylenetetrazole. Seizures were scored according to a modified Racine scale: 1 non-epileptic behavioural change, 2 partial clonus, 3 generalised clonus, and 4 lethal seizure. Findings Mice injected with NMDAR-Ab positive IgG had increased seizure susceptibility, with all having stage 3 seizures compared with only half of the control-IgG injected group (p=0·04). The number of stage 3 seizures was also significantly higher (mean 7·7 [SD 8·4] vs 0·8 [1·0], p=0·003), as was the total seizure score calculated at the end of 60 min of observation (38 [29·5] vs 7·5 [4·1], p=0·003). Preliminary analysis of the post-mortem tissue showed human IgG in the hippocampi of NMDAR-Ab injected but not in control-IgG injected mice. Interpretation Successful passive transfer of NMDAR-Ab positive IgG shows the epileptogenic potential of these antibodies. EEG analysis and investigation of the underlying pathogenic mechanism in ex-vivo slices is in progress. Funding Wellcome Trust.
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n methyl d Aspartate Receptor antibodies in post herpes simplex virus encephalitis neurological relapse
Movement Disorders, 2014Co-Authors: Yael Hacohen, Kumaran Deiva, Phillipa Pettingill, Esse Menson, Pascale Chretien, Patrick Waters, Ata Siddiqui, Marc Tardieu, Angela VincentAbstract:Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-Aspartate Receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relaps- ing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial. V C 2013 International Parkinson and Move- ment Disorder Society. Key W ords: herpes simplex virus; encephalitis; N-methyl-D-Aspartate (NMDA) Receptor; choreoatheto- sis; movement disorder; relapsing
Josep Dalmau - One of the best experts on this subject based on the ideXlab platform.
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acute mechanisms underlying antibody effects in anti n methyl d Aspartate Receptor encephalitis
Annals of Neurology, 2014Co-Authors: Emilia H Moscato, Josep Dalmau, Ankit Jain, Xiaoyu Peng, Thomas D Parsons, Rita J BalicegordonAbstract:Objective: A severe but treatable form of immune-mediated encephalitis is associated with antibodies in serum and cerebrospinal fluid (CSF) against the GluN1 subunit of the N-methyl-D-Aspartate Receptor (NMDAR). Prolonged exposure of hippocampal neurons to antibodies from patients with anti-NMDAR encephalitis caused a reversible decrease in the synaptic localization and function of NMDARs. However, acute effects of the antibodies, fate of the internalized Receptors, type of neurons affected, and whether neurons develop compensatory homeostatic mechanisms were unknown and are the focus of this study. Methods: Dissociated hippocampal neuron cultures and rodent brain sections were used for immunocytochemical, physiological, and molecular studies. Results: Patient antibodies bind to NMDARs throughout the rodent brain, and decrease NMDAR cluster density in both excitatory and inhibitory hippocampal neurons. They rapidly increase the internalization rate of surface NMDAR clusters, independent of Receptor activity. This internalization likely accounts for the observed decrease in NMDARmediated currents, as no evidence of direct blockade was detected. Once internalized, antibody-bound NMDARs traffic through both recycling endosomes and lysosomes, similar to pharmacologically induced NMDAR endocytosis. The antibodies are responsible for Receptor internalization, as their depletion from CSF abrogates these effects in hippocampal neurons. We find that although anti-NMDAR antibodies do not induce compensatory changes in glutamate Receptor gene expression, they cause a decrease in inhibitory synapse density onto excitatory hippocampal neurons. Interpretation: Our data support an antibody-mediated mechanism of disease pathogenesis driven by immunoglobulin-induced Receptor internalization. Antibody-mediated downregulation of surface NMDARs engages homeostatic synaptic plasticity mechanisms, which may inadvertently contribute to disease progression. ANN NEUROL 2014;76:108–119
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anti n methyl d Aspartate Receptor encephalitis a newly recognized inflammatory brain disease in children
Pediatric Rheumatology, 2012Co-Authors: Nadia Luca, Josep Dalmau, Tassalapa Daengsuwan, Kevin C Jones, Gabrielle Deveber, Jeff Kobayashi, Ronald M Laxer, Susanne M BenselerAbstract:Purpose Inflammatory brain disease causes severe psychiatric and neurological deficits in previously healthy children. The aim of this study was to report characteristic clinical features and outcomes of children diagnosed with AntiN-methyl-D-Aspartate Receptor (NMDAR) encephalitis, a newly recognized anti-neuronal antibody-mediated inflammatory brain disease, seen by the Rheumatology service over an 18 month period.
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fluorodeoxyglucose positron emission tomography in anti n methyl d Aspartate Receptor encephalitis distinct pattern of disease
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Frank Leypoldt, Josep Dalmau, Ralph Buchert, Ingo Kleiter, Jorg Marienhagen, Mathias Gelderblom, Tim Magnus, Christian Gerloff, Jan LewerenzAbstract:Background Patients with encephalitis associated with antibodies against N-methyl-D-Aspartate-Receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose(FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported. Methods The authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease. Results Groupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery. Conclusions A characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.
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fluorodeoxyglucose positron emission tomography in anti n methyl d Aspartate Receptor encephalitis distinct pattern of disease
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Frank Leypoldt, Josep Dalmau, Ralph Buchert, Ingo Kleiter, Jorg Marienhagen, Mathias Gelderblom, Tim Magnus, Christian Gerloff, Jan LewerenzAbstract:Background Patients with encephalitis associated with antibodies against N-methyl-D-Aspartate-Receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose(FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported. Methods The authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease. Results Groupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery. Conclusions A characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.
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anti n methyl d Aspartate Receptor encephalitis a newly recognized inflammatory brain disease in children
Arthritis & Rheumatism, 2011Co-Authors: Nadia Luca, Josep Dalmau, Tassalapa Daengsuwan, Kevin C Jones, Gabrielle Deveber, Jeff Kobayashi, Ronald M Laxer, Susanne M BenselerAbstract:Objective Anti-N-methyl-D-Aspartate Receptor (NMDAR) encephalitis is a newly recognized anti-neuronal antibody-mediated inflammatory brain disease causing severe psychiatric and neurological deficits in previously healthy children. The aim of this study was to report characteristic clinical features and outcomes of children diagnosed with anti-NMDAR encephalitis.
Yael Hacohen - One of the best experts on this subject based on the ideXlab platform.
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high sensitivity and specificity in proposed clinical diagnostic criteria for anti n methyl d Aspartate Receptor encephalitis
Developmental Medicine & Child Neurology, 2017Co-Authors: Shekeeb S Mohammad, Yael Hacohen, Sekhar Pillai, Angela Vincent, Russell C Dale, Esther M Tantsis, Hannah F Jones, Ming K LimAbstract:Aim To determine the validity of the proposed clinical diagnostic criteria for anti-N-methyl-d-Aspartate Receptor (NMDAR) encephalitis in paediatric patients. Method The diagnostic criteria for anti-NMDAR encephalitis proposed by Graus et al. (2016) use clinical features and conventional investigations to facilitate early immunotherapy before antibody status is available. The criteria are satisfied if patients develop four out of six symptom groups within 3 months, together with at least one abnormal investigation (electroencephalography/cerebrospinal fluid) and reasonable exclusion of other disorders. We evaluated the validity of the criteria using a retrospective cohort of paediatric patients with encephalitis. Twenty-nine patients with anti-NMDAR encephalitis and 74 comparison children with encephalitis were included. Results As expected, the percentage of patients with anti-NMDAR encephalitis who fulfilled the clinical criteria increased over time. During the hospital inpatient admission, most patients (26/29, 90%) with anti-NMDAR encephalitis fulfilled the criteria, significantly more than the comparison group (3/74, 4%) (p<0.001). The median time of fulfilling the criteria in patients with anti-NMDAR encephalitis was 2 weeks from first symptom onset (range 1–6). The sensitivity of the criteria was 90% (95% confidence interval 73–98) and the specificity was 96% (95% confidence interval 89–99). Interpretation The proposed diagnostic criteria for anti-NMDAR encephalitis have good sensitivity and specificity. Incomplete criteria do not exclude the diagnosis. What this paper adds The proposed clinical diagnostic criteria for anti-N-methyl-d-Aspartate Receptor (NMDAR) encephalitis by Graus et al. (2016) have high sensitivity and specificity in paediatric patients. The median time of fulfilling the criteria in patients with anti-NMDAR was 2 weeks from first symptom onset.
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pediatric herpes simplex virus encephalitis complicated by n methyl d Aspartate Receptor antibody encephalitis
Journal of the Pediatric Infectious Diseases Society, 2015Co-Authors: Alasdair Bamford, Yael Hacohen, Angela Vincent, Belinda H A Crowe, Antonia Clarke, Gareth Tudorwilliams, Vanessa Sanchoshimizu, Sunil PullaperumaAbstract:: N-methyl-D-Aspartate Receptor antibodies (NMDAR-Abs) can contribute to neurological relapse after herpes simplex virus encephalitis (HSE). We describe a child with NMDAR-Ab encephalitis after HSE, which was recognized and treated early. We discuss the case in the context of existing reports, and we propose a modified immunotherapy strategy to minimize risk of viral reactivation.
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n methyl d Aspartate Receptor antibodies in post herpes simplex virus encephalitis neurological relapse
Movement Disorders, 2014Co-Authors: Yael Hacohen, Kumaran Deiva, Phillipa Pettingill, Esse Menson, Pascale Chretien, Patrick Waters, Ata Siddiqui, Marc Tardieu, Angela VincentAbstract:Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-Aspartate Receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relaps- ing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial. V C 2013 International Parkinson and Move- ment Disorder Society. Key W ords: herpes simplex virus; encephalitis; N-methyl-D-Aspartate (NMDA) Receptor; choreoatheto- sis; movement disorder; relapsing
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n methyl d Aspartate Receptor antibodies in post herpes simplex virus encephalitis neurological relapse
Movement Disorders, 2014Co-Authors: Yael Hacohen, Kumaran Deiva, Phillipa Pettingill, Esse Menson, Pascale Chretien, Patrick Waters, Ata Siddiqui, Marc Tardieu, Jeanpierre Lin, Angela VincentAbstract:Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-Aspartate Receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial.
Frank Leypoldt - One of the best experts on this subject based on the ideXlab platform.
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structural hippocampal damage following anti n methyl d Aspartate Receptor encephalitis
Biological Psychiatry, 2016Co-Authors: Frank Leypoldt, Carsten Finke, Ute A Kopp, Anna Pajkert, Janina Behrens, Jens Wuerfel, Christoph J Ploner, Harald PrussAbstract:Abstract Background The majority of patients with anti- N -methyl-D-Aspartate Receptor (NMDAR) encephalitis suffer from persistent memory impairment despite unremarkable routine clinical magnetic resonance imaging. With improved acute care in these patients, neurocognitive impairment represents the major contributor to long-term morbidity and has thus become a focus of attention. Methods Forty patients with anti-NMDAR encephalitis after the acute disease stage and 25 healthy control subjects underwent multimodal structural imaging that combined volumetry of hippocampal subfields with analysis of hippocampal microstructural integrity. Verbal and visuospatial memory performance was assessed in all patients and correlation and mediation analyses were performed to examine associations between hippocampal structural integrity, memory performance, and disease severity. Results Hippocampal volumes were significantly reduced in patients and hippocampal subfield analysis revealed bilateral atrophy of the input and output regions of the hippocampal circuit. Microstructural integrity was impaired in both hippocampi in patients. Importantly, hippocampal volumetric and microstructural integrity measures correlated with memory performance and disease severity and duration. Mediation analysis revealed that hippocampal microstructure mediated the effect of disease severity on memory performance. Conclusions Data from this largest cohort of anti-NMDAR encephalitis patients that underwent extensive multimodal magnetic resonance imaging demonstrate that structural hippocampal damage and associated memory deficits are important long-term sequelae of the encephalitis. Correlation with disease duration and severity highlights the need for rapid diagnosis and adequate immunotherapy to prevent persistent damage to the hippocampus. Advanced imaging protocols may allow a more detailed analysis of structural damage to assess disease progression in clinical routine examinations and for therapy evaluation in prospective trials.
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overlapping demyelinating syndromes and anti n methyl d Aspartate Receptor encephalitis
Annals of Neurology, 2014Co-Authors: Maarten J Titulaer, Frank Leypoldt, Romana Hoftberger, Takahiro Iizuka, Lindsey Mccracken, Tania Cellucci, Leslie BensonAbstract:Objective To report the clinical, radiological, and immunological association of demyelinating disorders with anti–N-methyl-D-Aspartate Receptor (NMDAR) encephalitis. Methods Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. Results Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p < 0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p = 0.011). Interpretation Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis. Ann Neurol 2014;75:411–428
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functional and structural brain changes in anti n methyl d Aspartate Receptor encephalitis
Annals of Neurology, 2013Co-Authors: Carsten Finke, Frank Leypoldt, Ute A Kopp, Jens Wuerfel, Michael Scheel, Luisamaria Pech, Carina Soemmer, Jeremias Schlichting, Alexander U BrandtAbstract:OBJECTIVE: Anti-N-methyl-D-Aspartate Receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti-NMDAR encephalitis. METHODS: Twenty-four patients with established diagnosis of anti-NMDAR encephalitis and age- and gender-matched controls underwent neuropsychological testing and multimodal MRI, including T1w/T2w structural imaging, analysis of resting state functional connectivity, analysis of white matter using diffusion tensor imaging, and analysis of gray matter using voxel-based morphometry. RESULTS: Patients showed significantly reduced functional connectivity of the left and right hippocampus with the anterior default mode network. Connectivity of both hippocampi predicted memory performance in patients. Diffusion tensor imaging revealed extensive white matter changes, which were most prominent in the cingulum and which correlated with disease severity. In contrast, no differences in T1w/T2w structural imaging and gray matter morphology were observed between patients and controls. INTERPRETATION: Anti-NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinicoradiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis.
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fluorodeoxyglucose positron emission tomography in anti n methyl d Aspartate Receptor encephalitis distinct pattern of disease
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Frank Leypoldt, Josep Dalmau, Ralph Buchert, Ingo Kleiter, Jorg Marienhagen, Mathias Gelderblom, Tim Magnus, Christian Gerloff, Jan LewerenzAbstract:Background Patients with encephalitis associated with antibodies against N-methyl-D-Aspartate-Receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose(FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported. Methods The authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease. Results Groupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery. Conclusions A characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.
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fluorodeoxyglucose positron emission tomography in anti n methyl d Aspartate Receptor encephalitis distinct pattern of disease
Journal of Neurology Neurosurgery and Psychiatry, 2012Co-Authors: Frank Leypoldt, Josep Dalmau, Ralph Buchert, Ingo Kleiter, Jorg Marienhagen, Mathias Gelderblom, Tim Magnus, Christian Gerloff, Jan LewerenzAbstract:Background Patients with encephalitis associated with antibodies against N-methyl-D-Aspartate-Receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose(FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported. Methods The authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease. Results Groupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery. Conclusions A characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.
Betty Jurek - One of the best experts on this subject based on the ideXlab platform.
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human gestational n methyl d Aspartate Receptor autoantibodies impair neonatal murine brain function
Annals of Neurology, 2019Co-Authors: Betty Jurek, Mariya Chayka, Jakob Kreye, Katharina Lang, Larissa Kraus, Pawel FidzinskiAbstract:Objective Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-Aspartate Receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. Methods We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240μg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. Results Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. Interpretation The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. ANN NEUROL 2019;86:656-670.
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human cerebrospinal fluid monoclonal n methyl d Aspartate Receptor autoantibodies are sufficient for encephalitis pathogenesis
Brain, 2016Co-Authors: Mariya Chayka, Jakob Kreye, Nina K Wenke, Jonas Leubner, Rajagopal Murugan, Nikolaus Maier, Betty JurekAbstract:SEE ZEKERIDOU AND LENNON DOI101093/AWW213 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Anti-N-methyl-D-Aspartate Receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Little is known about the cerebrospinal fluid autoantibody repertoire. Antibodies against the NR1 subunit of the NMDAR are thought to be pathogenic; however, direct proof is lacking as previous experiments could not distinguish the contribution of further anti-neuronal antibodies. Using single cell cloning of full-length immunoglobulin heavy and light chain genes, we generated a panel of recombinant monoclonal NR1 antibodies from cerebrospinal fluid memory B cells and antibody secreting cells of NMDAR encephalitis patients. Cells typically carried somatically mutated immunoglobulin genes and had undergone class-switching to immunoglobulin G, clonally expanded cells carried identical somatic hypermutation patterns. A fraction of NR1 antibodies were non-mutated, thus resembling 'naturally occurring antibodies' and indicating that tolerance induction against NMDAR was incomplete and somatic hypermutation not essential for functional antibodies. However, only a small percentage of cerebrospinal fluid-derived antibodies reacted against NR1. Instead, nearly all further antibodies bound specifically to diverse brain-expressed epitopes including neuronal surfaces, suggesting that a broad repertoire of antibody-secreting cells enrich in the central nervous system during encephalitis. Our functional data using primary hippocampal neurons indicate that human cerebrospinal fluid-derived monoclonal NR1 antibodies alone are sufficient to cause neuronal surface Receptor downregulation and subsequent impairment of NMDAR-mediated currents, thus providing ultimate proof of antibody pathogenicity. The observed formation of immunological memory might be relevant for clinical relapses.
