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Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Open accessAbstract
Summary Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients’ antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.
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TL;DR
This case series characterizes 100 patients with anti-NMDA-receptor encephalitis and shows that antibodies target the extracellular N-terminal domain of NR1, reduce cell-surface NMDA receptors and postsynaptic receptor clusters, and that early tumour treatment is associated with better outcome and fewer relapses. The disorder is severe but often reversible, with 75 patients recovering or having mild deficits and 25 having severe deficits or dying.
Key findings
- Among 100 patients, median age was 23 years (range 5–76) and 91 were women; all presented with psychiatric symptoms or memory problems, 76 had seizures, 88 unresponsiveness, 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation.
- 58 (59%) of 98 assessed patients had tumours, most commonly ovarian teratoma; early tumour treatment was associated with better outcome (p=0.004) and fewer neurological relapses (p=0.009) than in other patients.
- 75 patients recovered or had mild deficits and 25 had severe deficits or died; improvement was associated with a decrease in serum antibody titres.
- Patients’ antibodies mainly targeted the extracellular N-terminal domain of NR1 and decreased cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect reversed by antibody removal.
Methods
- Observational case series of 100 patients with encephalitis and NR1–NR2 antibodies; clinical information was obtained by authors or referring physicians, with control samples from 20 healthy individuals and 230 patients with suspected autoimmune or paraneoplastic encephalitis or tumours without encephalitis.
- HEK293 cells expressing single or assembled NR1–NR2 subunits were used to map the antibody epitope; antibody titres were measured by ELISA, and effects on neuronal cultures were assessed by quantitative confocal analysis of NMDA-receptor clusters and by biotinylation/immunoblot of cell-surface NR1.
- Statistical analyses used Fisher’s two-sided exact test, Kruskal-Wallis and Wilcoxon rank-sum tests with Bonferroni correction, and Kruskal-Wallis non-parametric ANOVA with Dunn’s pairwise comparison.
Limitations
- The paper states that follow-up CSF titres were not obtained in most patients after improvement, and that future studies should clarify the best type and duration of immunotherapy, the role of prodromal events, and the molecular mechanisms decreasing NMDA receptors.
- Evident from the text: this is an observational case series without randomized treatment allocation, so associations between early tumour treatment and outcome may be confounded; some clinical and laboratory data are reported as “data not shown.”
- Evident from the text: the pathogenic evidence relies partly on in-vitro rat hippocampal neuronal cultures and HEK293 assays, which may not fully capture human disease mechanisms.
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70 Own result · 15 Not checked yet · 13 Own interpretation · 1 Own method
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In the paper
“All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation.”
- Also stated in: § Results · plain
“During the first 3 weeks of symptom presentation, 76 patients had seizures.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Abstract > Findings
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- Also stated in: § Results · plain
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In the paper
“Median age of patients was 23 years (range 5–76 years); 91 were women.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Abstract > Findings
plainn = 100- Asserted: passes — The authors put it forward as true.
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In the paper
“Median age of patients was 23 years (range 5–76 years); 91 were women.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Abstract > Findings
plainn = 100- Asserted: passes — The authors put it forward as true.
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In the paper
“All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Abstract > Findings
plainn = 100- Asserted: passes — The authors put it forward as true.
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In the paper
“92 patients had extensive EEG monitoring, 77% had generalised or predominantly frontotemporal slow or disorganised activity (delta-theta) without epileptic discharges.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 92- Asserted: passes — The authors put it forward as true.
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“20 (27%) had prominent sleep dysfunction, including hypersomnia and inversion of sleep patterns.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 75- Asserted: passes — The authors put it forward as true.
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In the paper
“23 presented with short-term memory loss or seizures alone or associated with psychiatric manifestations.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plaincorrelationaln = 23- Asserted: passes — The authors put it forward as true.
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In the paper
“The median duration of hospitalisation was 2.5 months (range 1–14 months).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In six patients, the tumour was diagnosed after recovery from the encephalitis (56–380 months).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit.”
- Also stated in: § Results · plain
“Hence the main epitope region recognised by all patients’ antibodies lies within the extracellular region of the NR1 subunit (webtable 3).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Abstract > Findings
plainn = 92- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Results · plain
- It may state two separate claims as one. 30
- Probably not a substantial claim. 8
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In the paper
“One boy (11 years old, without tumour) and 21 women and girls were younger than 19 years (median 15 years, range 5–18 years); 12 had an ovarian teratoma (five with immature features), and nine had no tumour.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 21- Asserted: passes — The authors put it forward as true.
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In the paper
“14 patients had brain biopsy: findings for two were normal, 12 showed mild perivascular lymphocytic cuffng, and ten microglial activation.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 14- Asserted: passes — The authors put it forward as true.
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“The median time from symptom presentation to initial signs of improvement was 8 weeks (range 2–24 weeks) for the group of patients with early tumour treatment, 11 weeks (4–40 weeks) for the group whose tumour was treated late or not treated, and 10 weeks (2–50 weeks) for the group without tumour (Kruskal-Wallis, p=0.10)”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
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“All had negative results for neuronophagic nodules and viral assays.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 14- Asserted: passes — The authors put it forward as true.
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“37 patients had cardiac dysrhythmias, including tachycardia or bradycardia, with prolonged pauses in seven patients; four needed pacemakers.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 37- Asserted: passes — The authors put it forward as true.
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“While hospitalised, seven patients had high levels of serum creatine kinase, six developed pulmonary embolism, six transient aphasia, four hemiparesis, and four tetraparesis.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
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“Median follow-up was 17 months (1–194 months): 47 patients had full recovery, 28 mild stable deficits, 18 severe deficits, and seven died as a result of the neurological disorder.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 47- Asserted: passes — The authors put it forward as true.
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“52 patients had dyskinesias, autonomic instability, and hypoventilation, 27 patients had two of these symptoms, and 14 had just one; the remaining seven patients developed a milder syndrome of seizures and psychiatric symptoms.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 52- Asserted: passes — The authors put it forward as true.
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“All teratomas contained nervous tissue; 25 were examined for expression of NMDA receptors, and all were positive (data not shown).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
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“Eight patients had bilateral teratomas; four were synchronous, two had history of a contralateral teratoma, and two developed contralateral teratomas before recurrence of the encephalitis.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
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In the paper
“These findings were limited to a single area of the brain in 19 patients: 16 had abnormalities in medial temporal lobes, two in the corpus callosum, and one in the brainstem.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plainn = 19- Asserted: passes — The authors put it forward as true.
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In the paper
“Patients who improved had a parallel decrease of serum titres, whereas those who did not improve maintained high titres in CSF and serum (figure 3).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
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In the paper
“Relapses were less common in patients with early tumour treatment (1 of 36) than in other patients (14 of 64; p=0.009), including patients whose tumour was treated late (six of 22; p=0.009) and patients without tumour (eight of 42; p=0.03).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Our study indicates that 41% of patients with anti-NMDA-receptor encephalitis do not have a clinically detectable tumour, and that men and children can also be affected.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Discussion
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In the paper
“Four patients who died and whose CSF was available were among the group with the highest titres, whereas the seven patients with milder syndromes had the lowest titres (data not shown).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plaincorrelationaln = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“The use of these heteromers abrogated the reactivity of sera or CSF from 92 patients’, and substantially decreased the reactivity of the samples of the remaining eight cases.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plaindirectn = 92- Asserted: passes — The authors put it forward as true.
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In the paper
“While poorly responsive or in a catatonic-like state, 93 patients developed hypoventilation, autonomic imbalance, or abnormal movements, all overlapping in 52 patients.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Discussion
plaincorrelationaln = 93- Asserted: passes — The authors put it forward as true.
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In the paper
“Analysis of the reactivity of patients’ sera or CSF against the indicated NMDA-receptor subunits or heteromers showed that antibody reactivity was not modified by changing the NR2 subunit (A, B, C, or D) and was retained by homomers of NR1 (webtable 3).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The receptors are heteromers of NR1 subunits that bind glycine and NR2 (A, B, C, or D) subunits that bind glutamate.1”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Introduction
What the sources say
- Not checked yetcites [1] Lynch, 1994, N-methyl-D-aspartate receptors: different subunit requirements for binding of glutamate antagonists, glycine antagonists, and channel-blocking agents, Mol Pharmacol source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Preliminary studies suggested the target epitopes were located in extracellular regions of NR1–NR2B NMDA receptors.5”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Introduction
What the sources say
- Not checked yetcites [5] Dalmau, 2007, Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma, Ann Neurol source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Despite the severity of the disorder, patients often recovered after tumour removal and immunotherapy, suggesting an immune-mediated pathogenesis.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Introduction
What the sources say
- Not checked yetcites [5] Dalmau, 2007, Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma, Ann Neurol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“NMDA receptors are ligand-gated cation channels with crucial roles in synaptic transmission and plasticity.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Introduction
What the sources say
- Not checked yetcites [1] Lynch, 1994, N-methyl-D-aspartate receptors: different subunit requirements for binding of glutamate antagonists, glycine antagonists, and channel-blocking agents, Mol Pharmacol source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All patients had brain MRI, radiological screening for a systemic neoplasm, and serological or CSF studies that ruled out other disorders (webappendix).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Methods > Patients and procedures
plainn = 21- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Introduction
What the sources say
- Not checked yetcites [2] Coyle, 2006, Glutamate and schizophrenia: beyond the dopamine hypothesis, Cell Mol Neurobiol source
- Not checked yetcites [3] Waxman, 2005, N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease, Neuroscientist source
- Not checked yetcites [4] Lau, 2007, NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders, Nat Rev Neurosci source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Serum and CSF were tested for antibodies against the NMDA receptor,5 and considered positive if three immunohistochemical criteria were fulfilled (figure 1).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Methods > Patients and procedures
What the sources say
- Not checked yetcites [5] Dalmau, 2007, Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma, Ann Neurol source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Introduction
What the sources say
- Not checked yetcites [2] Coyle, 2006, Glutamate and schizophrenia: beyond the dopamine hypothesis, Cell Mol Neurobiol source
- Not checked yetcites [3] Waxman, 2005, N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease, Neuroscientist source
- Not checked yetcites [4] Lau, 2007, NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders, Nat Rev Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The first patients identified were young women with ovarian teratoma who presented with psychosis or memory problems, rapidly progressing to multiple neurological deficits requiring prolonged intensive care support.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Introduction
What the sources say
- Not checked yetcites [5] Dalmau, 2007, Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma, Ann Neurol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“We recently identified a disorder, designated anti-NMDA-receptor encephalitis, that associates with antibodies against NR1–NR2 heteromers and results in a characteristic neuropsychiatric syndrome.5”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Introduction
What the sources say
- Not checked yetcites [5] Dalmau, 2007, Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma, Ann Neurol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Neurological outcome was assessed with the modified Rankin scale (MRS)10 and mini-mental state examination (MMSE).11”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Methods > Patients and procedures
What the sources say
- Not checked yetcites [10] van Swieten, 1988, Interobserver agreement for the assessment of handicap in stroke patients, Stroke source
- Not checked yetcites [11] Folstein, 1975, “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician, J Psychiatr Res source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The latter effect was reversed by removing the antibodies from the cultures, explaining the potential reversibility of patients’ symptoms.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Anti-NMDA-receptor encephalitis represents a new category of immune-mediated disorder that is often paraneoplastic, treatable, and can be diagnosed serologically.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, although the presence of a tumour that expresses NMDA receptors likely contributes to breaking immune tolerance, other unknown immunological triggers seem to be involved.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Recovery from this disorder is typically slow, and symptoms may relapse, especially in patients with undetected or recurrent tumours and patients with no associated tumours.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A pathogenic role of patients’ antibodies is suggested by the correlation between antibody titres and neurological outcome and by the decrease in number of postsynaptic clusters of NMDA receptors caused by patients’ antibodies.”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The effects of patients’ antibodies on rat hippocampal neuronal cultures reflect the effects of those antibodies on human neurons in anti-NMDA-receptor encephalitis.
“To assess the effect of patients’ antibodies on neuronal cultures, we first determined the extent of immunolabelling of NR1 (or NMDA receptor) clusters in postsynaptic dendrites.”
The paper relies on this without support.
HEK293 cells ectopically expressing recombinant NR1 or NR1–NR2B subunits present the same epitopes as native NMDA receptors for patients’ antibodies.
“Antibody titres were measured with ELISA on HEK293 cell lysates ectopically expressing NR1 or NR1–NR2B heteromers (webappendix).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Psychotomimetic models (eg, models that mimic the symptoms of psychosis), especially those based on ketamine (an antagonistic agent of NMDA-R), also support the E/I imbalance hypothesis.”
From Are hallucinations due to an imbalance between excitatory and inhibitory influences on the brain? (2016) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Patients usually present with acute behavioral change, psychosis and catatonia that evolve to include seizures, memory deficit, dyskinesias, speech problems, and autonomic and breathing dysregulation.3”
From Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study (2013) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“If a tumor is found, removal is important because it expedites improvement and decreases relapses.3, 17”
From Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study (2013) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Samples were considered positive if they fulfilled previously reported criteria3 including (1) a characteristic pattern of immunostaining of the neuropil of rat brain, and (2) specific reactivity with HEK293 cells expressing GluN1 (also known as NR1) subunits of the NMDAR.”
From Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study (2013) · cites this paper as [3]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The disorder, named “anti-NMDAR encephalitis”, has since been recognized in patients of all ages, but more frequently in young adults and children with or without teratoma.3, 4”
From Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study (2013) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“Despite the severity of the disease, patients often improve after intensive care support, immunotherapy, and prolonged hospitalizations that require multidisciplinary care.3, 11”
From Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study (2013) · cites this paper as [3]
In the citing paper
“Recently, autoimmune diseases associated with anti-NMDAR antibodies were reported to be associated with severe psychosis 14 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [14]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
“All but one of these patients developed neurological symptoms before the tumour diagnosis (median 8 weeks, range 1–380 weeks).”
§ Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies > Results
“In six patients, the tumour was diagnosed after recovery from the encephalitis (56–380 months).”
Citations
Cites
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975) · Journal of Psychiatric Research · doi:10.1016/0022-3956(75)90026-6 · Cited by 88,282
Hirono, N., Mori, E., Ikejiri, Y., Imamura, T., Shimomura, T., Hashimoto, M., Yamashita, H., & Ikeda, M. (1997) · PubMed · Cited by 21,012
Kok, J. S., Berg, I. J., & Scherder, E. J. A. (2013) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000353441 · Cited by 20,589
Older Adults' Reasons for Using Technology while Aging in Place
Peek, S. T. M., Luijkx, K. G., Rijnaard, M. D., Nieboer, M. E., van der Voort, C. S., Aarts, S., van Hoof, J., Vrijhoef, H. J., & Wouters, E. (2015) · Gerontology · doi:10.1159/000430949 · Cited by 19,852
Sensitivity and False Alarm Rate of a Fall Sensor in Long-Term Fall Detection in the Elderly
Kangas, M., Korpelainen, R., Vikman, I., Nyberg, L., & Jämsä, T. J. (2014) · Gerontology · doi:10.1159/000362720 · Cited by 19,007
Interobserver agreement for the assessment of handicap in stroke patients
van Swieten, J. C., Koudstaal, P. J., Visser, M. C., Schouten, H. J., & van Gijn, J. (1988) · Stroke · doi:10.1161/01.str.19.5.604 · Cited by 6,512
Paraneoplastic anti– N ‐methyl‐ D ‐aspartate receptor encephalitis associated with ovarian teratoma
Dalmau, J., Tüzün, E., Wu, H., Masjuan, J., Rossi, J. E., Voloschin, A., Baehring, J. M., Shimazaki, H., Koide, R., King, D., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21050 · Cited by 2,492
Self-citationB-cell depletion with rituximab in relapsing-remitting multiple sclerosis
Hauser, S. L., Waubant, E., Arnold, D. L., Vollmer, T., Antel, J., Fox, R. J., Bar-Or, A., Panzara, M., Sarkar, N., Agarwal, S., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0706383 · Cited by 2,439
NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders
Lau, C. G., & Zukin, R. S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2153 · Cited by 1,159
Tibbling, G., Link, H., & Ohman, S. (1977) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365517709091496 · Cited by 971
Cited by
Sorted by citations
A clinical approach to diagnosis of autoimmune encephalitis
Graus, F., Titulaer, M. J., Balu, R., Benseler, S. M., Bien, C. G., Cellucci, T., Cortese, I. C. M., Dale, R. C., Gelfand, J. M., Geschwind, M. D., et al. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00401-9 · Cited by 4,580
Self-citationTitulaer, M. J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L. S., Benseler, S. M., Kawachi, I., Martinez-Hernandez, E., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70310-1 · Cited by 3,165
Self-citationNMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease
Paoletti, P., Bellone, C., & Zhou, Q. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3504 · Cited by 2,523
Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis
Dalmau, J. O., Lancaster, E., Martínez‐Hernández, E., Rosenfeld, M. R., & Balice‐Gordon, R. J. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70253-2 · Cited by 2,428
Self-citationThe role of inflammation in epilepsy
Vezzani, A., French, J., Bartfai, T., & Baram, T. Z. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.178 · Cited by 1,876
Metadata
- Authors
- Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M., Dessain, S. K., Rosenfeld, M. R., Balice-Gordon, R., & Lynch, D. R.
- Affiliations
- University of Pennsylvania (US)
- Lankenau Institute for Medical Research (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Dalmau, Josep
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 7
- Issue
- 12
- Pages
- 1091-1098
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC2607118
- OpenAlex
- W2146199022
- Semantic Scholar
- dd855374110d7c7789974ad4472f335d53b94cd9
- Cited by
- 3,488
- References
- 35
- Citations by year
- 2026: 117 · 2025: 130 · 2024: 170 · 2023: 140 · 2022: 198 · 2021: 239 · 2020: 233 · 2019: 525 · 2018: 213 · 2017: 207 · 2016: 227 · 2015: 196 · 2014: 182 · 2013: 196 · 2012: 169
- FWCI
- 72.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (F31MH083395, R56MH057683, R01MH057683, R21 MH057683)
- National Cancer Institute (R01CA089054, R56CA089054, R01CA107192)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Autoimmune Neurological Disorders and Treatments
- Health Sciences › Medicine › Clinical Neurology › Peripheral Neuropathies and Disorders
- Health Sciences › Medicine › Clinical Neurology › Myasthenia Gravis and Thymoma
- Keywords
- anti-NMDA receptor encephalitis, NMDA receptor antibodies, autoimmune encephalitis, ovarian teratoma, psychiatric symptoms, seizures, dyskinesia, autonomic instability, hypoventilation, antibody epitopes, cancer immunotherapy
- MeSH terms
- Adolescent, Adult, Aged, Animals, Epitopes, Autoantibodies, Autoantigens, Brain, Cell Line, Cells, Cultured, Child, Child, Preschool, Encephalitis, Epilepsy, Female, Humans, Male, Middle Aged, Ovarian Neoplasms, Teratoma, Receptors, N-Methyl-D-Aspartate, Neurocognitive Disorders, Autoimmune Diseases of the Nervous System, Paraneoplastic Syndromes, Nervous System, Protein Subunits, Rats, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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