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

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Experiments where patients' antibodies were added to cultures of hippocampal neurons or infused into the hippocampus of rodents showed specific antibody-mediated internalization of NMDAR and alteration of the mechanisms of synaptic plasticity.

“Experiments where patients’ antibodies were added to cultures of hippocampal neurons or infused into the hippocampus of rodents showed specific antibody-mediated internalization of NMDAR and alteration of the mechanisms of synaptic plasticity.9, 10”

• cites [9] Hughes, 2010, Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis, J Neurosci sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [10] Mikasova, 2012, Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis, Brain sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The disorder has been recognized in patients of all ages, but more frequently in young adults and children with or without teratoma.

“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”

• cites [3] Dalmau, 2008, Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies, Lancet Neurol sourceSupported
• cites [4] Florance, 2009, Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents, Ann Neurol sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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.

“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”

• cites [3] Dalmau, 2008, Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies, Lancet Neurol sourcePartly supported

  The Results (page not supplied) report that most patients presented with psychiatric symptoms and later developed seizures, dyskinesias, autonomic instability, and hypoventilation; some also had speech disturbances. The claimed sequence is not fully supported: the paper describes a catatonic-like state developing after decreased consciousness, while some patients had memory loss at presentation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

In a center focused on the study of encephalitis of unclear etiology, the frequency of anti-NMDAR encephalitis surpassed that of any specific viral etiologies in young individuals.

“In a center focused in the study of encephalitis of unclear etiology the frequency of anti-NMDAR encephalitis surpassed that of any specific viral etiologies in young individuals.6”

• cites [6] Gable, 2012, The Frequency of autoimmune N-Methyl-D-Aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project, Clin Infect Dis sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Despite the severity of the disease, patients often improve after intensive care support, immunotherapy, and prolonged hospitalizations that require multidisciplinary care.

“Despite the severity of the disease, patients often improve after intensive care support, immunotherapy, and prolonged hospitalizations that require multidisciplinary care.3, 11”

• cites [3] Dalmau, 2008, Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies, Lancet Neurol sourceSupported
• cites [11] Irani, 2010, N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes, Brain sourcePartly supported

  The Results (Clinical outcomes and serial estimations of antibodies; page unavailable) document severe disability, an average hospital stay of 160 days, immunotherapy, and improvement associated with earlier treatment. The Discussion (page unavailable) describes prolonged ventilation and intensive-care admissions. The paper does not establish that multidisciplinary care was required or that intensive-care support itself led to improvement. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Epidemiological studies suggest that anti-NMDAR encephalitis is the most common cause of autoimmune encephalitis after acute demyelinating encephalomyelitis (ADEM).

“Epidemiological studies suggest that this disorder is the most common cause of autoimmune encephalitis after acute demyelinating encephalomyelitis (ADEM).5”

• cites [5] Granerod, 2010, Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study, Lancet Infect Dis sourcePartly supported

  The Discussion (page unavailable) says that about a fifth of patients had immune-mediated encephalitis, mostly ADEM, and reports 16 antibody-associated cases. The Results (page unavailable) identify NMDA receptor antibodies among the causes, but the passages do not establish that anti-NMDAR encephalitis was more common than the other antibody-associated cause after ADEM. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

Follow-up information was obtained at regular intervals (4, 8, 12, 18, and 24 months) after symptom onset; neurological status was assessed with the modified Rankin scale (mRS).

“Follow-up information was obtained at regular intervals (4, 8, 12, 18, and 24 months) after symptom onset; neurological status was assessed with the modified Rankin scale (mRS).12”

• cites [12] van Swieten, 1988, Interobserver agreement for the assessment of handicap in stroke patients, Stroke sourcePartly supported

  The Subjects and Methods section says the researchers used the modified Rankin scale to assess handicap in stroke patients. It does not report follow-up at 4, 8, 12, 18, and 24 months; its patients were assessed within the first week or within five months after stroke. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Studies suggest that the syndrome and response to treatment may differ between children and adults.

“Moreover, studies suggest that the syndrome and response to treatment may differ between children and adults.4”

• cites [4] Florance, 2009, Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents, Ann Neurol sourcePartly supported

  The Discussion describes differences between children and adults in symptom frequency and presentation, supporting the syndrome portion. It reports mixed responses to immunotherapy in children and suggests this could relate to their lower rate of tumors, but it does not establish a difference in treatment response between children and adults. Page numbers were not available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

If a tumor is found, removal is important because it expedites improvement and decreases relapses.

“If a tumor is found, removal is important because it expedites improvement and decreases relapses.3, 17”

• cites [3] Dalmau, 2008, Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies, Lancet Neurol sourcePartly supported

  The Results report fewer relapses after early tumour treatment (1 of 36 versus 14 of 64) and better outcomes when tumours were removed within four months. Initial improvement occurred sooner in the early-treatment group (median 8 versus 11 weeks), but that difference was not statistically significant (p=0.10). The claim overstates the evidence by saying removal itself expedites improvement and decreases relapses; early treatment usually also included immunotherapy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [17] Sabin, 2008, Case records of the Massachusetts General Hospital. Case 26-2008. A 26-year-old woman with headache and behavioral changes, N Engl J Med sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Samples were considered positive if they fulfilled previously reported criteria including a characteristic pattern of immunostaining of the neuropil of rat brain and specific reactivity with HEK293 cells expressing GluN1 subunits of the NMDAR.

“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.”

• cites [3] Dalmau, 2008, Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies, Lancet Neurol sourcePartly supported

  The Methods (Patients and procedures; page unavailable) say samples were considered positive when three immunohistochemical criteria were met, and describe testing sera and CSF against NR1-expressing HEK293 cells. Our copy does not specify that rat-brain neuropil immunostaining was one of those positivity criteria, so that part of the attributed description remains unsupported. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The discovery of anti-NMDAR encephalitis has changed the diagnostic and treatment approach to several neurologic and psychiatric disorders, and has led to the identification of an expanding group of autoimmune encephalitis related to antibodies against synaptic proteins.

“The discovery of anti-NMDAR encephalitis has changed the diagnostic and treatment approach to several neurologic and psychiatric disorders, and has led to the identification of an expanding group of autoimmune encephalitis related to antibodies against synaptic proteins.19”

• cites [19] Lancaster, 2012, Neuronal autoantigens—pathogenesis, associated disorders and antibody testing, Nat Rev Neurol sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Rapidly progressive alterations of memory, behavior, cognition, and psychosis previously thought to be idiopathic or viral-induced are now known to be autoimmune.

“Rapidly progressive alterations of memory, behavior, cognition, and psychosis previously thought to be idiopathic or viral-induced are now known to be autoimmune.20-23”

• cites [20] Chapman, 2011, Anti-NMDA receptor encephalitis: diagnosis, psychiatric presentation, and treatment, Am J Psychiatry sourceNot checked — no full text of the source
• cites [21] Kayser, 2011, The emerging link between autoimmune disorders and neuropsychiatric disease, J Neuropsychiatry Clin Neurosci sourcePartly supported

  The “Autoimmune Synaptic Encephalitis” section says limbic encephalitides once thought viral or paraneoplastic commonly have an autoimmune cause and can develop over days to weeks with memory and psychiatric symptoms. The claim overgeneralizes this finding: the paper does not say that rapidly progressive changes of these kinds are all now known to be autoimmune, and it describes some cases as idiopathic autoimmune processes rather than formerly thought idiopathic. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [22] Pruss, 2012, IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment, Neurology sourcePartly supported

  The Discussion says synaptic autoimmunity can cause acute, severe changes in memory, behavior, and cognition, and the Index patient section describes delusions and hallucinations. But this paper primarily studies slowly progressive impairment; the Clinical course section says none of its seven patients had acute symptoms resembling classic anti-NMDAR encephalitis. Our copy does not establish that these conditions were previously thought to be viral-induced. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [23] Pruss, 2012, NMDA receptor antibodies in herpes simplex encephalitis, Ann Neurol sourcePartly supported

  The Abstract’s Interpretation and the Discussion report NMDAR autoantibodies in some patients with herpes simplex encephalitis and suggest that autoimmunity may contribute to their symptoms. They do not establish that the listed memory, behavioral, cognitive, and psychotic symptoms—previously considered idiopathic or viral-induced—are now known to be autoimmune; the Discussion says clinical differences between antibody-positive and antibody-negative patients were not established. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

45 patients had one or multiple relapses, representing a 12% risk within 2 years.

“45 patients had one or multiple relapses (representing a 12% risk within 2 years)”

May combine two claims.

Treatment effects and outcome were assessable in 501 patients with median follow-up 24 months.

“Treatment effects and outcome were assessable in 501 (median follow-up 24 months): 472 (94%) underwent first-line immunotherapy or tumor removal, resulting in improvement within four weeks in 251 (53%).”

May combine two claims.

In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were comparable to those of the entire cohort.

“In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were comparable to those of the entire cohort.”

May combine two claims.

During the first 24 months, 394/501 reached good outcome (mRS 0-2; median 6 months).

“During the first 24 months, 394/501 reached good outcome (mRS 0-2; median 6 months), and 30 died.”

May combine two claims.

Among the 501 patients with at least 4 months follow-up, 461 (92%) were treated with first-line immunotherapy, 134 (27%) with second-line immunotherapy, 10 (2%) with tumor removal without immunotherapy, and 29 (6%) were not treated.

“Among the 501 patients with at least 4 months follow-up, 461 (92%) were treated with first-line immunotherapy, 134 (27%) with second-line immunotherapy (Figure 2 and Table 2), 10 (2%) with tumor removal without immunotherapy, and 29 (6%) were not treated (see below).”

May combine two claims.

During the first month of the disease, 498 of 571 (87%) patients developed four or more of the 8 categories of symptoms; only 6 (1%) remained mono-symptomatic.

“During the first month of the disease, 498 of 571 (87%) patients developed four or more of the 8 categories of symptoms; only 6 (1%) remained mono-symptomatic (Table 1).”

May combine two claims.

Of 197 patients with teratoma, 189 (96%) had tumor resection, 20 (11%) of them at neurological relapse or after recovery.

“Of 197 patients with teratoma, 189 (96%) had tumor resection, 20 (11%) of them at neurological relapse or after recovery.”

May combine two claims.

MRI of the brain, EEG and CSF studies were abnormal in 180/540 (33%), 432/482 (90%) and 418/532 (79%) patients, respectively.

“MRI of the brain, EEG and CSF studies were abnormal in 180/540 (33%), 432/482 (90%) and 418/532 (79%) patients, respectively.”

May combine two claims.

The presence of a tumor predominated in patients between 12 and 45 years; only 4 females younger than 12 years (6%) and 7 males (6%, all adults) had a tumor (p<0.0005).

“The presence of a tumor predominated in patients between 12 and 45 years; only 4 females younger than 12 years (6%), and 7 males (6%, all adults) had a tumor (p<0·0005).”

May combine two claims.

Among patients who received second-line immunotherapy, 84/125 reached an mRS 0-2 during the first 24 months, while among those who did not receive second-line immunotherapy 49/96 reached an mRS 0-2 (median 10 and 15 months, respectively).

“Among patients who received second line immunotherapy, 84/125 reached an mRS 0-2 during the first 24 months, while among those who did not receive second line immunotherapy 49/96 reached an mRS 0-2 (median 10 and 15 months, respectively); at 24 month follow-up 43/55 (78%) and 32/58 (55%) had a good outcome (Figure 3C and 3D).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ten studies and one extended review describing at least three patients were identified; five of them included at least twenty-five patients.

“Ten studies and one extended review describing at least three patients were identified; five of them included at least twenty-five patients.”

May combine two claims.

Eighty-two of 177 (46%) children failed first-line immunotherapy; in these patients, the magnitude of the effects of second-line immunotherapy (used in 53 cases, 65%) was comparable to that of the entire cohort although due to the smaller sample size it did not reach significance (OR 3.35, CI 0.86-12.98, p=0.081).

“Eighty-two of 177 (46%) children failed first-line immunotherapy; in these patients, the magnitude of the effects of second-line immunotherapy (used in 53 cases, 65%; Table S5) was comparable to that of the entire cohort although due to the smaller sample size it did not reach significance (Table S6B, OR 3·35, CI 0·86-12·98, p=0·081).”

May combine two claims.

During the 24 month follow-up, 45 patients (representing a 12% risk) had clinical relapses, which in 15 patients (33%) were multiple.

“During the 24 month follow-up, 45 patients (representing a 12% risk) had clinical relapses, which in 15 patients (33%) were multiple (Table S4).”

May combine two claims.

The study confirms the female preponderance, the high frequency of the disease in children, and a higher risk for an underlying teratoma in African-Americans.

“It confirms the female preponderance, the high frequency of the disease in children, and a higher risk for an underlying teratoma in African-Americans.”

May combine two claims.

ICU stay and time from symptom onset until initiation of treatment were identified as significant prognostic factors.

“however, “ICU stay” and “time from symptom onset until initiation of treatment” were identified as significant prognostic factors.”

May combine two claims.

207 tumors (94%) were ovarian teratomas, 4 (2%) extraovarian teratomas, and 9 (4%) other tumors.

“Two hundred and seven tumors (94%) were ovarian teratomas, 4 (2%) extraovarian teratomas, and 9 (4%) other tumors (two of each, lung, breast, testicular; one ovarian carcinoma, one thymic carcinomas, and one pancreatic cancer).”

Probably not a substantial claim: may not pass S3 (load-bearing).

211 (37%) of all 577 patients were younger than 18 years.

“Two hundred and eleven (37%) of all 577 patients were younger than 18 years, and 28 (5%) were 45 or older.”

May combine two claims.

During the first 24 months, 241/251 patients who improved with first-line therapy reached an mRS 0-2 (median 3 months); at 24 month follow-up 111/115 (97%) had a good outcome.

“During the first 24 months 241/251 reached an mRS 0-2 (median 3 months); at 24 month follow-up 111/115 (97%) of these patients had a good outcome (Figure 3B).”

May combine two claims.

In 16 relapses (23%) the severity of symptoms was comparable to that of the initial episode, and in 7 (10%) was worse.

“In 16 relapses (23%) the severity of symptoms was comparable to that of the initial episode, and in 7 (10%) was worse.”

May combine two claims.

495/571 patients (87%) had a maximum mRS of 5, and 435 (77%) were admitted to the ICU.

“The assessment of disease severity showed that 495/571 patients (87%) had a maximum mRS of 5, and 435 (77%) were admitted to the ICU.”

May combine two claims.

Compared with the initial episode, 46/69 (67%) relapses were less severe, more frequently mono-symptomatic (24, 35%), and resulted in fewer admissions (12, 17%) to the ICU (all p<0.0001).

“Compared with the initial episode, 46/69 (67%) relapses were less severe (as reflected by a lower mRS score measured at the stage of maximum severity), more frequently mono-symptomatic (24, 35%), and resulted in fewer admissions (12, 17%) to the ICU (all p<0·0001).”

Probably not a substantial claim: may not pass S3 (load-bearing).

28 (5%) of all 577 patients were 45 or older.

“Two hundred and eleven (37%) of all 577 patients were younger than 18 years, and 28 (5%) were 45 or older.”

Probably not a substantial claim: may not pass S3 (load-bearing).

468 patients were female (81%).

“Four hundred and sixty-eight patients were female (81%; Figure 1A and Table S1).”

May combine two claims.

Movement disorders were more frequent in children, while memory deficits and central hypoventilation occurred more often in adults.

“While movement disorders were more frequent in children, memory deficits and central hypoventilation occurred more often in adults (Figure 1C).”

May combine two claims.

In the current study, the frequency of relapses was somewhat less frequent than in previous reports; in addition, the milder nature of the symptoms compared with the initial episodes was noted in most relapses.

“In the current study, the frequency of relapses was somewhat less frequent than in previous reports; in addition, the milder nature of the symptoms compared with the initial episodes was noted in most relapses.”

May combine two claims.

First-line immunotherapy was often insufficient to control the disease; in this group, the addition of second-line immunotherapy proved to associate significantly with a better outcome compared with those who did not receive second-line immunotherapy.

“First-line immunotherapy was often insufficient to control the disease; in this group of patients the addition of second-line immunotherapy proved to associate significantly with a better outcome compared with those who did not receive second-line immunotherapy.”

May combine two claims.

At 24 month follow-up 43/55 (78%) of those who received second-line immunotherapy and 32/58 (55%) of those who did not had a good outcome.

“at 24 month follow-up 43/55 (78%) and 32/58 (55%) had a good outcome (Figure 3C and 3D).”

May combine two claims.

Second-line immunotherapy was well tolerated; only 4 patients had serious adverse effects, all reversible.

“Second-line immunotherapy was well tolerated; only 4 patients had serious adverse effects, all reversible (Table 2).”

May combine two claims.

220 (38%) patients had an underlying neoplasm; of these, 213 were women (representing 46% of all women).

“Two hundred and twenty (38%) patients had an underlying neoplasm; of these, 213 were women (representing 46% of all women).”

May combine two claims.

In univariable analysis, factors associated with good outcome included no need for ICU (p<0.0001), early treatment (p=0.009), and low severity of disease within four weeks of onset (maximum mRS, p=0.011).

“In univariable analysis, the factors associated with good outcome included, no need for ICU (p<0·0001), early treatment (p=0·009), and low severity of disease within four weeks of onset (maximum mRS, p=0·011).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Six of the nine patients with tumors other than teratomas were older than 45 years.

“Six of the nine patients with tumors other than teratomas were older than 45 years.”

May combine two claims.

238 adults (65%) presented with behavioral problems, while 55 children below 12 years (50%) presented with seizures or movement disorders.

“Two hundred and thirty-eight adults (65%) presented with behavioral problems, while 55 children below 12 years (50%) presented with seizures or movement disorders (Figure 1B).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The frequency of males was higher in age groups below 12 years (43: 39%) and above 45 (12: 43%, p<0.0001).

“The frequency of males was higher in age groups below 12 years (43: 39%) and above 45 (12: 43%, p<0·0001).”

Classified as probably not a substantial claim.

Anti-NMDAR encephalitis is an autoimmune disorder.

“Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined.”

Classified as probably not a substantial claim.

Factors associated with a good outcome (p<0.1) were included in generalized linear mixed models with binary distribution, declaring the subject as random and the other factors as fixed effects.

“Factors associated with a good outcome (p<0·1) were included in generalized linear mixed models with binary distribution, declaring the subject as random and the other factors as fixed effects.13”

• cites [13] Verbeke, 2005Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

After failing first-line immunotherapy, all these patients remained in a similar poor neurological status, enabling the comparison between those who subsequently received second-line immunotherapy with those who did not.

“Indeed, after failing first-line immunotherapy, all these patients remained in a similar poor neurological status, enabling the comparison between those who subsequently received second-line immunotherapy with those who did not.”

Classified as probably not a substantial claim. May combine two claims.

All mRS scores at defined time points were used, and the time point from onset of disease was included as an additional variable.

“All mRS scores at defined time points were used (4, 8, 12, 18, and 24 months; e.g. each patient’s follow-up could provide a maximum of 5 scores). The “time point from onset of disease” was included as an additional variable, allowing us to analyze patients with different duration of follow-up.”

Classified as probably not a substantial claim. May combine two claims.

The study has the limitations of not being randomized but sets the base for future trials to determine the efficacy of each individual treatment and duration of immunotherapy.

“Our study has the limitations of not being randomized but sets the base for future trials to determine the efficacy of each individual treatment (e.g., steroids, IVIg, plasmapheresis, rituximab, and cyclophosphamide) and duration of immunotherapy.”

Classified as probably not a substantial claim.

After creation of the model, the effect of second-line immunotherapy was determined by adding second-line immunotherapy to the same model applied to only those patients who had failed first-line immunotherapy.

“After creation of this model, the effect of second-line immunotherapy was determined by adding second-line immunotherapy to the same model applied to only those patients who had failed first-line immunotherapy.”

May combine two claims.

Symptom presentation varied between children and adults, but in most cases the progression of symptoms evolved towards a similar syndrome.

“Symptom presentation varied between children and adults (“more neurological in children”, “more psychiatric in adults”), but in most cases the progression of symptoms evolved towards a similar syndrome.”

May combine two claims.

By establishing the last follow-up assessment at 24 months, the study likely underestimates the frequency and level of recovery because some patients had a shorter follow-up, others continued to improve after 24 months, and those with substantial improvement tended to discontinue follow-ups.

“By establishing the last follow-up assessment at 24 months, our study likely underestimates the frequency and level of recovery because some patients had a shorter follow-up, others continued to improve after 24 months, and those with substantial improvement tended to discontinue follow-ups (Figure S5A and B).”

Probably not a substantial claim: may not pass S4 (based).

This is the first study to provide extensive and structured follow-up and prognostic factors determining outcome.

“This is the first study to provide extensive and structured follow-up and prognostic factors determining outcome.”

May combine two claims.

For the same reasons, the frequency of mortality is likely overestimated; imputation analysis estimated 7% mortality at 24 months.

“For the same reasons, the frequency of mortality is likely overestimated; imputation analysis estimated 7% mortality at 24 months (Figure S5C).”

May combine two claims.

Although selection bias cannot be ruled out in observational studies like this, the authors could not identify obvious bias between patients who after failing first-line therapies were treated with second-line therapy and those who did not: severity of symptoms and duration of ICU stay was similar (92% vs 88%, and 88% vs 87%, respectively), and there were no differences in age, gender, ethnicity,和

“Although selection bias cannot be ruled out in observational studies like this, we could not identify obvious bias between patients who after failing first-line therapies were treated with second-line therapy and those who did not: the severity of symptoms and duration of ICU stay was similar (92% vs 88%, and 88% vs 87%, respectively), and there were no differences in age, gender, ethnicity, and”

Probably not a substantial claim: may not pass S2 (checkable).

Our study extends epidemiological and clinical knowledge on anti-NMDAR encephalitis.

“Our study extends epidemiological and clinical knowledge on anti-NMDAR encephalitis.”

Classified as probably not a substantial claim.

All patients tested positive for NMDAR antibodies were included without selection criteria other than availability of clinical information.

“All patients tested positive for NMDAR antibodies were included in the study without selection criteria other than availability of clinical information.”

Classified as probably not a substantial claim.

Factors influencing outcome were assessed by univariable binary logistic regression independently of the treatments given.

“Factors influencing outcome were assessed by univariable binary logistic regression (good outcome defined as mRS 0-2) independently of the treatments given.”

Classified as probably not a substantial claim.

Patients with a follow-up shorter than 4 months were excluded from analysis of effects of treatment and outcome.

“Patients with a follow-up shorter than 4 months were excluded from analysis of effects of treatment and outcome.”

May combine two claims.

Second-line immunotherapy with rituximab, cyclophosphamide or both significantly improved the outcome of those who did not respond to first-line therapy, and decreased the frequency of relapses.

“Moreover, second-line immunotherapy with rituximab, cyclophosphamide or both significantly improved the outcome of those who did not respond to first-line therapy, and decreased the frequency of relapses.”

May combine two claims.

This large observational study demonstrates that immunotherapy and tumor removal if applicable result in substantial neurological improvement in 81% of patients with anti-NMDAR encephalitis after a median follow-up of 24 months.

“This large, observational study demonstrates that immunotherapy and tumor removal if applicable, result in substantial neurological improvement in 81% of patients with anti-NMDAR encephalitis after a median follow-up of 24 months.”