Random forest regression model presented that the overall prediction power of severity reached 0.806, among which the number of polynucleated cells in cerebrospinal fluid contributed the most. Potential pathogenic causes exhibited that the proportion of mycoplasma was the highest, followed by Epstein-Barr virus. Conclusion: Our findings provided evidence for early identification of autoimmune encephalitis in children, especially in severe cases.

The first case of a study describing a child who recovered from severe neurological sequelae due to anti-NMDA receptors after three infusions of allogeneic.

This case report suggests thatumbilical cord–derived mesenchymal stem/stromal cells (UC-MSCs) therapy may ameliorate severe neurological sequelae due to anti-NMDA receptor encephalitis. A study with a larger sample size should be performed to evaluate the efficacy of UC-MSCs for AE as well as severe neurological sequelae due to AE.

NMDARe may occur simultaneously or sequentially with different demyelinating diseases. Compared with the age of patients with classical NMDARe, patients with overlapping MS or AQP4-positive NMOSD tended to be slightly older. They also had lower incidence of ovarian teratoma. Overlapping syndrome patients frequently presented atypical symptoms and/or MRI abnormalities when compared with classical NMDARe. MRI scans and detection of OB, AQP4, and MOG antibodies are helpful for identifying overlapping syndromes. Favorable outcome was observed in patients overlapping with MOGAD, but no robust comparison can be drawn with the patients overlapping with AQP4-Ab-positive NMOSD and MS regarding the small number of available data. Long-term follow-up investigation is needed because of the long interval between NMDARe and demyelinating diseases.

The six patients enrolled for this study presented with typical symptoms resulting in a diagnosis of ovarian teratoma induced anti-NMDAR encephalitis. Appropriate interventions led to a positive outcome in all the patients, with five of six patients reporting full recovery and the sixth patient recovering with a few deficits. No death was recorded. The literature survey comprising of 155 patients cases across 130 case reports of anti-NMDAR encephalitis clearly indicated an upward trend in the reports/diagnosis in China, particularly in the surveyed time from 2014 through 2019. The majority of patients (150/155) underwent surgical intervention resulting in positive outcome. No treatment intervention was mentioned for one case while the four patients who were not surgically operated succumbed to the disease.

This case report presents the clinical vignette of a 30-year-old male patient, who presented with altered sensorium, disorganized behavior, and perceptual disturbance. Initially, he was put on standard psychotropic medications that did not help. After a careful review, the patient was diagnosed with anti-NMDA receptor encephalitis endorsed by the identification of CSF antibodies. There are several points to be highlighted within this case study. Initially, clinical suspicion and keeping a broad differential, despite what may appear as exclusively psychiatric symptoms, are important to prevent any delay in the appropriate testing or procedures that can hone in on the diagnosis. Successful treatment hinges on prompt induction of first-line treatment with steroids, and potentially second-line therapy with adjunct IVIG or immunosuppressants. Communication within the multidisciplinary approach, often combining clinicians from a myriad of subspecialties, is paramount to positive patient outcomes. Clinicians should remain alert and suspicious regarding the possibility of anti-NMDA receptor encephalitis in a patient with predominantly disorganized or psychotic symptoms who may not be responding to conventional antipsychotic therapy.

Background

A variety of psychiatric syndromes are associated with NMDAR autoantibodies; however, their clinical relevance when only present in the serum is unclear. We explored whether patients with CSF NMDAR autoantibodies could be distinguished from patients with serum-only NMDAR autoantibodies.

Conclusion

Patients with an isolated psychiatric syndrome with CSF NMDAR autoantibodies can potentially be distinguished from those with serum-only NMDAR autoantibodies based on clinicodemographic and investigation findings.

The patient was treated with an escalating immunotherapy regimen from 11 to 15 weeks of gestation, including steroids, plasma exchange, IV immunoglobulins, and rituximab, with no clinical response. At 16 weeks of gestation, she received cyclophosphamide with clinical improvement after 4 weeks. She subsequently gave birth to a healthy, term baby boy, who continued to do well at the follow-up.

In conclusion, anti-NMDA receptor encephalitis is a rare disease underdiagnosed due to the variability of the initial symptoms. In general, emergency physicians are not familiar with this disease. In case of patient with suggestive clinical picture of anti NMDAR encephalitis presenting to the emergency room, lumbar puncture should be performed as soon as possible to look for CSF pleocytosis and oligoclonal bands. Abnormal EEG findings and brain MRI can help to not delay the initiation of immunosuppressive treatment. The diagnosis is confirmed by the detection of antibodies anti-NMDAR in the CSF. The possibility of this pathology should be taken into account as a differential diagnosis for patients presenting with acute psychosis or encephalitis before diagnosing a psychiatric illness.

INTERPRETATION: In NMDAR encephalitis, cerebellar volume reduction was progressive once developed. Cerebellar volume reduction might reflect disease burden and extent of progression and be associated with poor outcomes in multiple functional domains.

Cotard’s syndrome is uncommon psychopathology among patients with psychotic illnesses. Limited cases had been reported regarding the occurrence of this syndrome in anti-NMDAR encephalitis which itself is a relatively new disease that often presents with florid psychotic symptoms. This poses difficulties in differentiating it from a primary psychiatric illness. Late recognition of anti-NMDAR encephalitis can lead to death as it can progress to autonomic instability in its natural course of illness

This case report sheds some useful insights on the relatively rare co-occurrence of Cotard’s syndrome and anti-NMDAR encephalitis. Even though experiencing treatment-related complications and receiving only a week of antipsychotic therapy, the patient managed to make a full recovery. She did not require long-term antipsychotic medication to remain well. The main good prognostic factor in this patient is the early suspicion of this condition. 

there are very few reports that has linked a varicella zoster virus (VZV) reactivation with anti-NMDAR encephalitis. In this report, we describe a case of a 57-year-old man presented with atypical clinical presentation of anti-NMDAR encephalitis with gait ataxia, complete ophtalmoplegia, and abolished reflexes followed by drowsiness and confusion. Favorable outcome with combined antiviral treatment and immunomodulatory therapy was observed. Concomitant VZV reactivation with autoimmune encephalitis is possible. Prognosis and therapeutic options in this rare condition remain to be clarified.

Conclusion: Anti-NMDAR encephalitis secondary to CNS infection has its imaging features-extensive lesion distribution, leptomeningeal enhancement, early atrophy, and necrosis-that could deepen the understanding of the pathophysiology and manifestation of the autoimmune encephalitis besides the classic type.

Study supports the notion of a neurobehavioral phenotype of ANMDARE characterized by a fluctuating course with psychotic and affective symptoms, catatonic signs, and global cognitive dysfunction, often accompanied by seizures and dyskinesia. The catatonia-delirium comorbidity could be a distinctive neurobehavioral phenotype of ANMDARE.

We update the infants with anti-NMDAR encephalitis in the literature. Clinical outcomes suggest that patients with anti-NMDAR encephalitis are mostly poor in the infants, excluding our case. We propose that early and appropriate treatments are critical for timely diagnosis and rapid improvement.

Conclusions: From the results, it is suggested that the phenomenological features understood as indicative of anti-NMDA receptor encephalitis include: (1) antecedent common cold-like symptoms (31.9%) in the prodromal phase, (2) delirium or acute confusional state (65.9%), (3) symptoms considered to be sudden personality changes (40.4%) in the psychotic phase, (4) central hypoventilation (14.9%) in the unresponsive phase, (5) motor disturbances (57.4%), and (6) autonomic symptoms, mainly without fluctuations (48.9%), in the hyperkinetic phase. These features were found to be similar to “primary mental confusion” (confusion mentale primitive) in French psychiatry in the late 19th century. We believe that classical psychiatry can contribute considerably to the interpretation of biological research results.

Cardiac autonomic dysfunction was the most common subtype (77.8%). Patients with a higher incidence of ovarian teratoma, mechanical ventilation, neurological intensive care unit admission, and elevated glucose and NMDAR antibody titer in the CSF were more likely to exhibit autonomic dysfunction or PSH. Episodes of PSH can be suppressed by monotherapy in patients without prior sedative drug use with an efficacy of 90%.

Paroxysmal sympathetic hyperactivity (PSH) is a common clinical condition in patients with anti-NMDAR encephalitis, especially in severe cases, and can be effectively managed by several drug monotherapies. Despite necessitating longer hospital stay, autonomic dysfunction or PSH do not seem to compromise the neurological recovery of patients.

Our study made several noteworthy contributions to the CSF Ab titers of anti-NMDAR encephalitis. Patients starting with psychiatric symptoms showed a higher titer than those with seizures and memory deficits, especially among youths in the subacute phase. Yet, the level of the titers was unaffected by age, duration, gender or other complications within 15–30 days of onset. Regarding the clinical severity, the titers showed a weak correlation with the mRS, but no correlation with the CASE. Further larger prospective studies are needed to better validate our findings, and related experiments are urgently required to explore their potential mechanisms.

This study of 76 patients made several noteworthy contributions to the CSF Ab titers of anti-NMDAR encephalitis. Patients starting with psychiatric symptoms showed a higher titer than those with seizures and memory deficits, especially among youths in the subacute phase. Yet, the level of the titers was unaffected by age, duration, gender or other complications within 15–30 days of onset. Regarding the clinical severity, the titers showed a weak correlation with the mRS, but no correlation with the CASE.

This case shows that anti-NMDAR encephalitis can present with isolated memory loss. Neural antibody testing in these patients could play a pivotal role in early diagnosis and prompt treatment.

Conclusions: This is the first demonstration of the damage by anti-NMDAR antibodies on early dendritic development in vitro. As a strategy to protect embryonic neurons, our findings may support the efficacy of early immunotherapy for anti-NMDAR encephalitis in pregnancy.

Conclusions: Loss of normal posterior dominant rhythm (PDR), absence of sleep architecture, and epileptiform discharges are associated with worse outcomes at one year which has not been reported before. EEG characteristics may help prognosticate in NMDARE. Larger studies are needed to confirm these findings.

Conclusions: Loss of normal posterior dominant rhythm (PDR), absence of sleep architecture, and epileptiform discharges are associated with worse outcomes at one year which has not been reported before. EEG characteristics may help prognosticate in NMDARE. Larger studies are needed to confirm these findings.

Results

The sample (n=283) had a mean age of 10.8 years with 75.3% females. The most common prodromal and presenting symptom was seizure (29.7% and 63.3%, respectively). Partial and full recovery did not differ for prodromal and presenting symptoms. Multivariate logistic regression analysis found that (1) delusion were significantly associated with higher odds and aggressive behavior was associated with lower odds for abnormal findings on magnetic resonance imaging (MRI); (2) waxing and waning of symptoms were significantly associated with higher odds for abnormal electroencephalograms (EEG), and (3) increased age and psychosis were each significantly associated with increased odds, and sleep disturbance and orofacial dyskinesia with lower odds for tumor presence.

Conclusion

Given the pattern of findings, routinely obtaining MRI and EEG should be considered for anti-NMDAR encephalitis in children and adolescents presenting with delusion and waxing and waning of symptoms, respectively. Investigation of tumors should be considered in patients with anti-NMDAR encephalitis especially when psychosis is present.

Our case report highlights the importance of early diagnosis of AEp, early treatment with immunotherapy, long-term clinical follow-up, and timely escalation and continuation of immunotherapy in achieving a good patient outcome, retaining intellectual development, and quality of life.

NMDAR- and LGI1-E are the 2 most common AE subtypes. Each is representative of 1 of 2 clusters of AE subtypes: NMDAR-E for those with prominent CSF inflammation and LGI1-E for those with little or no CSF inflammation. Beyond the expected quantitative differences, our detailed analysis of CSF findings in therapy-naive acute NMDAR- and LGI1-E shows that each of the 2 AE subtype exhibits a distinct pattern of CSF changes. These are characterized by differences in the interdependencies of CSF parameters and their association with age, disease duration, and disease severity.

NMDAR- and LGI1-E are the 2 most common AE subtypes. Each is representative of 1 of 2 clusters of AE subtypes: NMDAR-E for those with prominent CSF inflammation and LGI1-E for those with little or no CSF inflammation. Beyond the expected quantitative differences, our detailed analysis of CSF findings in therapy-naive acute NMDAR- and LGI1-E shows that each of the 2 AE subtype exhibits a distinct pattern of CSF changes. These are characterized by differences in the interdependencies of CSF parameters and their association with age, disease duration, and disease severity.

This article reviewed studies from 2007 to 2020 and concluded some information regarding clinicopathological characteristics, such as age distribution, histological property, symptoms at presentation, and relapse rate. Though this entity’s incidence varies in different studies, we have concluded that the overall incidence of ovarian teratoma among anti-NMDAR encephalitis patients is 37.4%. However, little data shows the incidence rate of anti-NMDAR encephalitis in ovarian teratoma patients and, therefore, needs more future study.

We have emphasized the cellular and molecular pathways of the disease foundation and thus proposed a hypothetical mechanism of the pathogenesis in ovarian teratoma-related anti-NMDAR encephalitis. The pathological process involves an eccentric cellular composition of the teratoma, patients’ usual immune response, and the interfered interaction of receptors and proteins, which lead to autoantibody-induced encephalitis.

The etiology of the EDB remains essentially unknown. However, it has been postulated that in ANMDAR encephalitis, there is a disruption of the rhythmic neuronal activity. When antibodies block/target NMDAR, the rhythmic neuronal activity is disrupted, leading to the unique EDB pattern. Another theory suggests that delta activity is caused because of focal abnormalities in the brain, and the superimposition of the beta waves is related to the alterations of the NMDA receptors.

There was wide variability in the prevalence of EDB (6%-58%) in our sample which could be related to the timing of the EEG recording. The pooled prevalence was 30.89% (55/178) in patients with seizures. Overall, two studies concluded worse short-term outcomes in patients with EDB but the other two studies displayed a lack of such evidence. Some patients with EDB had prolonged hospital stays, increased ICU admission, and a higher frequency of status epilepticus. These findings suggest that the EDB pattern may be a marker of more severe disease and worse short-term outcomes, while long-term outcomes are not affected. Since treatment with Therapeutic Plasma Exchange (TPE)  in severe anti-NMDAR encephalitis can improve short-term clinical outcomes including epilepsy, we suggest that every patient with EDB pattern may benefit from this treatment.

 Case report the appearance of clinical symptoms and signs of N-methyl-d-Aspartate (NMDA) receptor encephalitis in a patient presenting just days after contraction of influenza B. The offending mature ovarian teratoma was identified and removed on the 10th day after the appearance of symptoms, with subsequent nearly complete resolution of symptoms over the subsequent 6 months. We provide a focused literature review of the clinical and pathophysiologic literature of anti-NMDA receptor encephalitis pertaining to influenza B virus and the pediatric population. Taken together, this study contributes to the pathophysiological understanding of anti-NMDA receptor encephalitis and aids clinicians in its early recognition and management.

 Anti-thyroid antibody positivity, abnormality of FT₃, FT₄, or TSH levels and NTIS are frequent in pediatric anti-NMDAR encephalitis. Thyroid antibody and thyroid hormone abnormalities could be improved through the course of treatment of anti-NMDAR encephalitis. Cases with ATAbs (+) are at older onset ages and more likely to be treated by intravenous immunoglobulin therapy more than once. Unlike adult anti-NMDAR encephalitis, NTIS might not be associated with the clinical characteristics of anti-NMDAR encephalitis in pediatric patients.

120 patients were enrolled in the study. anti-thyroid antibodies (ATAbs) are prevalent in patients with anti-NMDAR encephalitis, especially in severe cases, and correlate with poor prognosis and impaired short-term neurological recovery.

Dual-positivity for anti-NMDAR and anti-MOG antibodies is not commonly encountered in clinical settings. In patients with this disease phenotype, the incidence rate of relapse was very high, but the functional outcome might not be poor. Although overlapping symptoms and imaging changes of NMDARE and MOG-AD were observed in these patients, the overall symptoms seemed to be more similar to NMDARE, rather than MOG-AD.

To evaluate the frequency of anti-NMDAR encephalitis in a secondary mental health service and investigate the challenges of its diagnosis in routine clinical practice.

In 1661 patients assessed for NMDAR-IgG over 12 years, the positivity rate was 3.79%.

In a psychiatric setting, NMDAR-IgG seropositivity rates were low with a positive predictive value for encephalitis around 50% when screened patients had chronic presentations and absence of other diagnostic criteria for encephalitis or psychosis of autoimmune origin. Chronic neuropsychiatric problems in anti-NMDAR encephalitis are not uncommon, so better diagnostic and treatment strategies are still needed.

The incidence of NMDARE in Denmark is currently 0.17/100,000 persons per year, and has increased since 2009. NMDARE patients in Denmark display a higher median age, lower female:male ratio, a less frequent tumor associa-tion and need for ICU admission. Maintenance therapy did not reduce relapse rate. Poor outcome was seen with higher age, likely related to underlying etiology.

Patients with critical anti-NMDAR encephalitis who present with status epilepticus (SE) have a high rate of refractory SE (RSE)/super RSE and recover more slowly than patients without SE, but most of them will eventually achieve good long-term neurological outcomes and live seizure free after the acute phase.

Conclusions: The presence of EDB on EEG in anti-NMDAR encephalitis patients is associated with increased need for ICU admission, worse functional outcomes at 6 months, and risk of death.

In conclusion, for patients with mRS ≥ 4 after first-line immunotherapy and patients with concomitant positive MOG-Ab, we recommend more aggressive treatments like second-line immunotherapy. When second-line immunotherapy is not applicable due to severe adverse effects or other reasons, repetitive first-line immunotherapy can be considered as an option. Both second-line and repetitive first-line immunotherapy are beneficial to reduce relapse rate. The treatment course of sequential oral prednisolone, as a routine maintenance treatment, can be shortened after fully evaluating patients’ conditions.

There is literature to demonstrate a possible connection between anti-NMDAR encephalitis and demyelinating syndromes. As such, autoimmune encephalitis should be considered in patients with multiple sclerosis presenting with atypical symptoms. Determining the correct diagnosis is crucial to inform the appropriate treatment protocol, and to improve prognosis.

Full or substantial recovery occurs in nearly 80% of children with anti-NMDAR encephalitis, and this may be hastened by the use of immunotherapy; one or more relapses can occur in +25%-33% of children. A prompt diagnosis and early treatment should be the aim of therapy if full recovery is to be achieved

Conclusion: By comparison with teratomas in patients without NMDAR-E, teratomas in patients with NMDAR-E are smaller, have few teeth/calcification, and the amount of space occupied by fat components is smaller.

Here we present a case of a 19-year-old female with premorbid psychiatric disease and neuropsychiatric sequelae from HSVE who presented over a year after her initial HSVE with behavioral changes and positive anti-NMDAR antibodies.

Highlights:

Treatment-resistant anti-NMDAR encephalitis patients improve significantly after Bortezomib.

Conclusion: Our study indicated that the SCR level was negatively correlated with incidence of psychiatric symptoms in female patients, and a higher SCR level could be a protective factor for psychiatric symptoms in female patients with anti-NMDAR encephalitis.

Highlights

Decreased consciousness, ICU admission, a higher Neutrophil-to-lymphocyte ratio (NLR), and CSF protein are related to the integrity of the BBB in anti-NMDAR encephalitis patients.

This study, NMDAR antibodies did not predict transition to psychosis, as defined by operationalized criteria, or nonremission from the CHR state. NMDAR antibody seropositivity was however associated with a deterioration in disability-associated functioning, short of transition, and indeed greater antibody titre was associated with greater deterioration in function, overall suggesting that NMDAR antibody serostatus should be further evaluated as a predictive marker of functional outcome.

Conclusions

Highlights

We concluded that the early application of combined immunotherapy consisting of tocilizumab (T-SIRT) had better efficacy than was found for delayed or partial application of this combination in anti-NMDAR encephalitis.

There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients’ NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity.

All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301. Additional investigations showed  SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.

Highlights

anti-NMDARE may have long-term negative psychosocial impact on patients.

Over 30% of participants did not resume work/school after illness.

Misdiagnosis was associated with decreased odds of a return to work/school

Psychiatry follow-up was associated with increased odds of return to work/school

Ongoing seizures and neuropsychiatric issues were associated with worse outcomes.

. In this report, patient with anti-NMDAR IgG manifested gait ataxia as the initial symptoms, simultaneously with lesions involving the cerebellum. (Brain magnetic resonance imagery involving cerebellum has not been reported)

We exclude co-existence of multiple auto-antibodies include ataxia (ACA)-related antibodies, classic onconeural auto-antibodies, aquaporin-4 (AQP4) IgG, myelin ligodendrocyte glycoprotein (MOG) IgG,

We used cell based assay and tissue based assay to confirm the the diagnosis of definite anti-NMDAR IgG.

Methods: Patients recovering from anti-NMDARe were invited to participate in a prospective observational single center study including comprehensive clinical, video-polysomnography (V-PSG) sleep assessment and neuropsychological evaluation. Age and sex-matched healthy participants served as controls.

Conclusions: Sleep disturbances are frequent in anti-NMDARe. They show a temporal pattern (predominantly insomnia at onset; hypersomnia during recovery), associate with behavioral and cognitive changes, and can occur with confusional arousals during NREM sleep.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis was first described by Dalmau et al in 2007, describing an illness with predominantly neuropsychiatric symptoms in young women.  An association with paraneoplastic syndromes is recognized, the most common neoplasm being ovarian in origin – usually a teratoma.  However, neoplasms of the mediastinum (extragonadal teratoma), lymphoma, testicular cancer, and pontine glioma have also been described. Recognized early, it is highly responsive to treatment with a favourable outcome; 75% of patients achieving full recovery or having minor neurological deficits at 17 months. However, in most instances, many patients retain cognitive deficits for a long time.

Conclusions- Focal seizures were most common in patients with abnormal MRI lesions. In the acute stage of the disease, the abnormal MRI group was more likely than the normal MRI group to achieve seizure control. Abnormal MRI findings did not affect the overall good prognosis of patients with anti‐NMDAR encephalitis with seizures.

Conclusions: Several features including prodromal cognitive deficits, speech disturbance, antipsychotic sensitivity and catatonia are seen early in the course of anti-NMDAR encephalitis. These key features would not be typical of primary psychiatric disease and clinicians should have a low index of suspicion to proceed to lumbar puncture.

Conclusions: 13% of patients with anti-NMDAR encephalitis are seronegative. These patients are more likely to be male, with milder forms of the disease, and without tumors.

2017 NHS England will commission rituximab for second line treatment for anti-NMDAR autoimmune encephalitis in accordance with the criteria outlined in this document.