Anti N-methyl-D-aspartate receptor encephalitis: a game-changer?

Fischer, Corinne E.; Golas, Angela; Schweizer, Tom A.; Muñoz, David G.; Ismail, Zahinoor; Qian, Winnie; Tang‐Wai, David F.; Rotstein, Dalia; Day, Gregory S.

doi:10.1080/14737175.2016.1184088

Cited by 6 publications

(8 citation statements)

References 119 publications

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“…Two major GluN2 subunits, GluN2A and GluN2B, contribute to hippocampal NMDAR responses. The two classes localize and function differently (Chen et al, 1999;Tovar and Westbrook, 1999;. To determine whether one class is preferentially lost with patient CSF incubation, we used pharmacological isolation with the GluN2B-selective antagonist ifenprodil (10 M).…”

Section: Resultsmentioning

confidence: 99%

“…6A-D). We further evaluated whether the potentiation of NMDA current results from acute drug presence by briefly incubating cells with the steroid scavenger ␥-cyclodextrin (␥-CDX; 500 M, 2 min; Akk et al, 2005;Shu et al, 2007;Paul et al, 2013). Although ␥-CDX incubation alone appeared to have a mild potentiating effect, the scavenger effectively reversed the persisting PAM potentiation (Fig.…”

Section: Effects Of Oxysterol-like Pams On Receptor Function Followinmentioning

confidence: 99%

“…Other results suggest that human NMDAR antibodies may alter surface NMDAR retention at synapses (Mikasova et al, 2012). The combined effects are thought to be responsible for the unique manifestations of signs and symptoms that characterize patients with NMDARE, a hypothesis reinforced by the observation that several clinical features are reproduced with pharmacological blockade of NMDARs (Krystal et al, 2002;Anticevic et al, 2012;. Although loss of surface receptors is key to antibody effects, whether remaining surface receptors exhibit altered function because of antibody binding is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis

Warikoo¹,

Brunwasser

Benz³

et al. 2018

J. Neurosci.

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-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction. Anti--methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.

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Section: Resultsmentioning

confidence: 99%

Section: Effects Of Oxysterol-like Pams On Receptor Function Followinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis

Warikoo¹,

Brunwasser

Benz³

et al. 2018

J. Neurosci.

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“…41,42 Accordingly, screening for serum NMDAR IgG autoantibodies has been performed in individuals with unexplained psychiatric presentations in whom obtaining CSF may present undue challenges. 2,9,34 However, building evidence suggests that the accuracy of serum testing alone is inadequate. 7 Indeed, at least 1 of 13 patients with definite anti-NMDAR encephalitis included in our meta-analyses may have been misdiagnosed if relying on serum testing alone.…”

Section: Discussionmentioning

confidence: 99%

“…Since its description in 2007, 1 anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is increasingly recognized as a common, potentially reversible cause of psychiatric and neurologic morbidity. 2 Early diagnosis and treatment is key to optimizing outcomes, 3,4 exemplifying the need for rapid and reliable antibody testing in patients with suspected anti-NMDAR encephalitis. The detection of IgG autoantibodies against the GluN1 subunit of central nervous system NMDARs establishes the diagnosis in symptomatic patients.…”

Section: Introductionmentioning

confidence: 99%

Testing for N-methyl-d-aspartate Receptor Autoantibodies in Clinical Practice

Brooks

Yarbrough

Bucelli

et al. 2019

Can. J. Neurol. Sci.

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Abstract:Background:The diagnosis of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis relies on the detection of NMDAR IgG autoantibodies in the serum or cerebrospinal fluid (CSF) of symptomatic patients. Commercial kits are available that allow NMDAR IgG autoantibodies to be measured in local laboratories. However, the performance of these tests outside of reference laboratories is unknown.Objectives:To report an unexpectedly low rate of NMDAR autoantibody detection in serum from patients with anti-NMDAR encephalitis tested using a commercially available diagnostic kit in an exemplar clinical laboratory.Methods:Paired CSF and serum samples from seven patients with definite anti-NMDAR encephalitis were tested for NMDAR IgG autoantibodies using commercially available cell-based assays run according to manufacturer’s recommendations. Rates of autoantibody detection in serum tested at our center were compared with those derived from systematic review and meta-analyses incorporating studies published during or before March 2019.Results:NMDAR IgG autoantibodies were detected in the CSF of all patients tested at our clinical laboratory but not in paired serum samples. Rates of the detection were lower than those previously reported. A similar association was recognized through meta-analyses, with lower odds of NMDAR IgG autoantibody detection associated with serum testing performed in nonreference laboratories.Conclusions:Commercial kits may yield lower-than-expected rates of NMDAR IgG autoantibody detection in serum when run in exemplar clinical (nonreference) laboratories. Additional studies are needed to decipher the factors that contribute to lower-than-expected rates of serum positivity. CSF testing is recommended in patients with suspected anti-NMDAR encephalitis.

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First report of concomitant cryptococcal meningitis and anti-NMDAR encephalitis

Valdoleiros

Calejo

Marinho

et al. 2020

Brain, Behavior, & Immunity - Health

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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder, seen most often in young adults and children, triggered by tumors or infections. We report a case of cryptococcal meningitis in a patient with sarcoidosis, presenting prominent neuropsychiatric symptoms, electroencephalographic features of autoimmune encephalitis and positive anti-NMDAR antibodies in the cerebrospinal fluid, raising the hypothesis of an infectious immune-mediated mechanism triggering the production of anti-NMDAR antibodies. Since anti-NMDAR encephalitis is potentially fatal and has significant morbidity, further descriptions of its etiological associations are essential to early identification and prompt treatment.

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Anti N-methyl-D-aspartate receptor encephalitis: a game-changer?

Cited by 6 publications

References 119 publications

Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis

Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis

Testing for N-methyl-d-aspartate Receptor Autoantibodies in Clinical Practice

First report of concomitant cryptococcal meningitis and anti-NMDAR encephalitis

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