Anti-N-methyl-D-aspartate receptor-associated encephalitis: A review of clinicopathologic hallmarks and multimodal imaging manifestations

Anti-N-methyl-D-aspartate receptor-associated encephalitis(NMDARE)is a rare immune-mediated neuroinflammatory condition characterized by the rapid onset of neuropsychiatric symptoms and autonomic dysfunction.The mechanism of pathogenesis remains incompletely understood,but is thought to be related to antibodies targeting the GluN1 subunit of the NMDA receptor with resultant downstream dysregulation of dopaminergic pathways.Young adults are most frequently affected;the median age at diagnosis is 21 years.There is a strong female predilection with a female sex predominance of 4:1.NMDARE often develops as a paraneoplastic process and is most commonly associated with ovarian teratoma.However,NMDARE has also been described in patients with small cell lung cancer,clear cell renal carcinoma,and other benign and malignant neoplasms.Diagnosis is based on correlation of the clinical presentation,electro-encephalography,laboratory studies,and imaging.Computed tomography,positron emission tomography,and magnetic resonance imaging are essential to identify an underlying tumor,exclude clinicopathologic mimics,and predict the likelihood of long-term functional impairment.Nuclear imaging may be of value for prognostication and to assess the response to therapy.Treatment may involve high-dose corticosteroids,intravenous immunoglobulin,and plasma exchange.Herein,we review the hallmark clinicopathologic features and imaging findings of this rare but potentially devastating condition and summarize diagnostic criteria,treatment regimens,and proposed pathogenetic mechanisms.

Laryngospasm as an uncommon presentation in a patient with anti-N-methyl-D-aspartate receptor encephalitis:A case report

BACKGROUND Anti-N-methyl-D-aspartate receptor(anti-NMDAR)encephalitis is a rare autoimmune disorder.The symptoms of anti-NMDAR encephalitis include behavioral problems,speech problems,psychosis,seizures,and memory deficits,among others.However,laryngospasm is rare.We present the case of a patient with anti-NMDAR antibodies and severe laryngospasms.CASE SUMMARY The patient was a 15-year-old female with normal psychomotor development.She was initially admitted to our neurological intensive care unit with seizures.She received anti-epilepsy treatment,and the seizures disappeared.However,2 wk later,she developed behavioral problems and speech impairment.Then,she developed severe laryngospasms,which were treated with intubation and a tracheotomy.Antibodies against the NMDAR were detected in the patient’s cerebrospinal fluid.Therefore,she was diagnosed with anti-NMDAR encephalitis.In addition,she received intravenously administered immunoglobulins,and methylprednisolone was administered.The patient’s symptoms gradually improved,and she was discharged from our hospital.Approximately 9 mo later,the patient could speak sentences,walk independently,and carry out activities of daily living independently.Through our case report,we highlighted laryngospasm as an uncommon presentation in patients with anti-NMDAR encephalitis.CONCLUSION Laryngospasm may be an uncommon clinical manifestation of anti-NMDAR encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis that aggravates after acinetobacter baumannii pneumonia:A case report

We report an atypical case of anti-N-methyl-D-aspartate receptor encephalitis(ANMDARE). A 27-year-old man diagnosed with ANMDARE received immunotherapy and had a good recovery. However, within one month, he developed severe status epilepticus and decreased level of conscience with new hyperpyrexia and dyspnea, and was admitted to the emergency intensive care unit. Acinetobacter baumanii were found in the sputum culture; and anti-NMDAR antibodies were positive(titer: 1/80) in the cerebrospinal fluid. Repeated immunotherapy was administered with antibacterial agents, and the patient recovered except for mild psychiatric sequelae. This is the first report of ANMDARE that aggravates after acinetobacter baumannii pneumonia. Awareness and knowledge of this disorder should be extended, especially in the emergency medicine community.

Ovarian teratoma related anti-N-methyl-D-aspartate receptor encephalitis:A case series and review of the literature

BACKGROUND Anti-N-methyl-D-aspartate receptor(NMDAR)encephalitis is a rare but important complication of ovarian teratoma.Between July 2012 and December 2019,six patients with ovarian teratoma-associated anti-NMDAR encephalitis were enrolled in our hospital and their clinical characteristics,treatment,and follow-up were reviewed.We also conducted a systematic literature review of ovarian teratoma related anti-NMDAR encephalitis reports between January 2014 and December 2019.AIM To better understand anti-NMDAR encephalitis through literature review and patients enrolled in our hospital.METHODS The six patients enrolled in the study were those diagnosed with anti-NMDAR encephalitis.Their history,clinical manifestations,and medications were recorded and optimum treatment provided in addition to maintaining a record of the follow-ups.In addition,we also extensively surveyed the literature and provide summarized data from 155 published cases of anti-NMDAR encephalitis from 130 case reports.PubMed and Scopus were the sources of these publications and the time period covered was 6 years ranging from January 2014 through December 2019.RESULTS 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.CONCLUSION Suspected anti-NMDAR encephalitis should be quickly evaluated for anti-NMDAR antibodies since early diagnosis is important.In case of a tumor,its earliest and complete removal is recommended.Finally,early use of corticosteroids and IgG-depleting strategies(intravenous immunoglobulin or plasma exchange)may improve outcome.

Anti-N-methyl-D-aspartate-receptor antibody encephalitis combined with syphilis:A case report

BACKGROUND Anti-N-methyl-D-aspartate-receptor(NMDAR)encephalitis is a common type of autoimmune encephalitis characterized by complex clinical signs and variable imaging manifestations.The pathogenesis of the disease is unclear.Syphilis is an infectious disease caused by Treponema pallidum that can invade the nervous and immune systems and cause systemic symptoms.There are few reports of anti-NMDAR encephalitis with syphilis,and the association between them is unknown;both diseases are related to immune system damage.We report a case of anti-NMDAR encephalitis with syphilis.CASE SUMMARY A 32-year-old man was admitted to our hospital with complaints of cognitive decline,diplopia,and walking instability during the previous 6 mo.He developed dysarthria,difficulty swallowing,and involuntary shaking of his head,neck,and limbs during the month prior to presentation.Cranial magnetic resonance imaging showed symmetrical abnormal signals in the pons,midbrain,and bilateral basal ganglia,and inflammatory demyelination was considered.The diagnosis of syphilis was confirmed based on the syphilis diagnosis test and the syphilis rapid test.He was given anti-syphilis treatment,but the above symptoms gradually worsened.Anti-NMDAR antibody was positive in cerebrospinal fluid but was negative in serum.Due to the cerebrospinal fluid findings,anti-NMDAR encephalitis was a consideration.According to the patient’s weight,he was treated with intravenous methylprednisolone 1 g QD for 5 d,with the dose gradually decreased for 6 mo,and immunoglobulin 25 g QD for 5 d;his symptoms improved after treatment.CONCLUSION This case shows that anti-NMDAR encephalitis may be combined with syphilis,which should be recognized to avoid misdiagnosis and treatment delay.

Anesthetic Management of Patients with Anti-N-methyl-D-aspartate Receptor Encephalitis:A Report of Two Cases

ANTI-N-METHYL-D-ASPARTATE (NMDA) receptorencephalitis is a newly recognized autoimmunedisease. It is predominantly described in youngwomen with a series of symptoms, includingpersonality change, memory loss, seizures, involuntarymovements, autonomic dysfunction et al.1 It is commonlyassociated with mature ovarian teratomas.2 Since its firstdenomination by Dalmau et al,1 many scientific publicationshave emerged on anti-NMDA receptor encephalitis, butonly a few focused on the anesthetic management ofpatients with this disease.3-5 Herein we reported two caseswith anti-NMDA receptor encephalitis in association withovarian teratoma and discussed the anesthetic managementand the outcomes of these patients.

Intravenous immunoglobulin accompanied with high-dose methylprednisolone therapy for 17 children with anti-N-methyl-D-aspartate receptor encephalitis:Clinic and nursing

Objective:An increasing number of pediatric patients are being diagnosed with anti-N-methyl-Daspartate receptor(NMDAR)encephalitis,whose treatment requires immunotherapy through nursing interventions.This study aimed to analyze the clinical features and long-term prognosis of pediatric anti-NMDAR encephalitis and to gather nursing experiences of immunotherapy.Methods:Seventeen children diagnosed with anti-NMDAR encephalitis were admitted to the pediatric department.They were subjected to a therapy of intravenous immunoglobulin(IVIG)accompanied with high-dose methylprednisolone(HDMP).Multidisciplinary cooperation and intensive care were used to manage them.The effects of nursing intervention and therapy were repeatedly assessed and analyzed throughout the course of treatment and recovery.Results:None of the patients manifested adverse drug reaction(ADR)during IVIG administration.At the first administration of HDMP,ADRs were promptly and efficiently treated in four patients(24%;i.e.,one case each of hyperglycosemia,hypertension,aggravated symptoms,and gastrointestinal bleed).Two patients underwent rehabilitation,and six patients received hyperbaric oxygenation during hospitalization.Nine patients with indwelling gastric tubes experienced four times of unplanned extubation.Hospital stay ranged from 11 days to 59 days,with the mean duration of 26 days.Discharge evaluation revealed that 16 patients who scored 0e2 on the modified Rankin scale presented obvious remission,and one patient who had a mRS score of 4 exhibited less improvement.The mRS scores of hospitalization,discharge,and six-month follow-up displayed statistically significant differences.Conclusions:Nursing interventions of immunotherapy ensures the security of IVIG administration.Multidisciplinary cooperation promotes remission.Our findings can serve as reference for healthcare teams.

Four-year-old anti-N-methyl-D-aspartate receptor encephalitis patient with ovarian teratoma: A case report

BACKGROUND A population-based comparative study in United States shows that the prevalence and incidence of autoimmune encephalitis are comparable to those of infectious encephalitis and its detection is increasing over time.Some patients are complicated with ovarian teratoma.The younger the patient is,the less likely a tumor will be present.CASE SUMMARY This case report describes the successful treatment of anti-N-methyl-D-aspartatereceptor(NMDAR)encephalitis by early laparoscopic ovarian cystectomy and immunotherapy in a 4-year-old female child.And to the best of our knowledge,this detailed case report describes the youngest patient to date with anti-NMDAR encephalitis who underwent laparoscopic ovarian cystectomy.CONCLUSION Although the younger the patient is,the less likely a tumor will be detected,we still emphasize that all patients with suspected or confirmed anti-NMDAR encephalitis should be screened for ovarian tumors if possible.Prompt initiation of immunotherapy and tumor removal are crucial for good outcomes.

Paroxysmal speech disorder as the initial symptom in a young adult with anti-N-methyl-D-aspartate receptor encephalitis: A case report

BACKGROUND Anti-N-methyl-D-aspartate receptor(anti-NMDAR)encephalitis is a treatable but frequently misdiagnosed autoimmune disease.Speech dysfunction,as one of the common manifestations of anti-NMDAR encephalitis,is usually reported as a symptom secondary to psychiatric symptoms or seizures rather than the initial symptom in a paroxysmal form.We report a case of anti-NMDAR encephalitis with paroxysmal speech disorder as a rare initial manifestation,and hope that it will contribute to the literature.CASE SUMMARY A 39-year-old man with anti-NMDAR encephalitis initially presented with paroxysmal nonfluent aphasia and was misdiagnosed with a transient ischemic attack and cerebral infarction successively.The patient subsequently presented with seizures,but no abnormalities were found on brain magnetic resonance imaging or electroencephalogram.Cerebrospinal fluid(CSF)analysis revealed mild pleocytosis and increased protein levels.Anti-NMDAR antibodies in serum and CSF were detected for a conclusive diagnosis.After immunotherapy,the patient made a full recovery.CONCLUSION This case suggests that paroxysmal speech disorder may be the presenting symptom of anti-NMDAR encephalitis in a young patient.

Overlapping syndrome of recurrent anti-N-methyl-D-aspartate receptor encephalitis and anti-myelin oligodendrocyte glycoprotein demyelinating diseases:A case report

BACKGROUND Anti-N-methyl-D-aspartate receptor encephalitis(NMDARe)is capable of presenting a relapsing course and coexisting with myelin oligodendrocyte glycoprotein antibody disease,whereas it has been relatively rare.We describe a man with no history of tumor who successively developed anti-NMDARe and anti-myelin oligodendrocyte glycoprotein antibody disease.CASE SUMMARY A 29-year-old man was initially admitted with headache,fever,intermittent abnormal behavior,decreased intelligence,limb twitching and loss of consciousness on July 16,2018.On admission,examination reported no abnormality.During his presentation,he experienced aggravated symptoms,and the reexamination of cranial magnetic resonance imaging(MRI)indicated punctate abnormal signals in the left parietal lobe.External examination of cerebrospinal fluid and serum results revealed serum NMDAR antibody(Ab)(-),cerebrospinal fluid NMDAR-Ab(+)1:10 and Epstein-Barr virus capsid antigen antibody Ig G(+).Due to the imaging findings,anti-NMDARe was our primary consideration.The patient was treated with methylprednisolone and gamma globulin pulse therapy,mannitol injection dehydration to reduce intracranial pressure,sodium valproate sustained-release tablets for anti-epilepsy and olanzapine and risperidone to mitigate psychiatric symptoms.The patient was admitted to the hospital for the second time for“abnormal mental behavior and increased limb movements”on December 14,2018.Re-examination of electroencephalography and cranial MRI showed no abnormality.The results of autoimmune encephalitis antibody revealed that serum NMDAR-Ab was weakly positive and cerebrospinal fluid NMDAR-Ab was positive.Considering comprehensive recurrent anti-NMDARe,the patient was treated with propylene-hormone pulse combined with immunosuppressive agents(mycophenolate mofetil),and the symptoms were relieved.The patient was admitted for“hoarseness and double vision”for the third time on August 23,2019.Re-examination of cranial MRI showed abnormal signals in the medulla oblongata and right frontal lobe,and synoptophore examination indicated concomitant esotropia.The patient’s visual acuity further decreased,and the reexamination of cranial MRI+enhancement reported multiple scattered speckled and patchy abnormal signals in the medulla oblongata,left pons arm,left cerebellum and right midbrain,thalamus.The patient was diagnosed with an accompanying demyelinating disease.Serum antimyelin oligodendrocyte glycoprotein 1:10 and NMDAR antibody 1:10 were both positive.The patient was diagnosed with myelin oligodendrocyte glycoprotein antibody-related inflammatory demyelinating disease of the central nervous system complicated with anti-NMDARe overlap syndrome.The patient was successfully treated with methylprednisolone,gamma globulin pulse therapy and rituximab treatment.The patient remained asymptomatic and follow-up MRI scan 6 mo later showed complete removal of the lesion.CONCLUSION We emphasize the rarity of this antibody combination and suggest that these patients may require longer follow-up due to the risk of recurrence of two autoimmune disorders.

抗N-甲基-D-天冬氨酸受体脑炎患者血清orexin-A水平的变化及其临床意义

目的观察抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎患者血清增食欲素-A(orexin-A)水平的变化,并分析其临床意义。方法选择2010年1月至2014年12月在本科治疗的14例抗NMDAR脑炎患者病例组,另外选取14例同期体检健康成人设置对照。比较病例组患者于对照组血清健康orexin-A水平的差异。采用二分类Logistic回归分析法评估血清健康orexin-A水平对抗NMDAR脑炎的影响,采用ROC曲线法评估血清orexin-A用于抗NMDAR脑炎诊断准确性。采用改良的RANKIN量表(m RS)评估患者预后情况。结果病例组患者血清orexin-A水平明显低于对照组(P=0.02)。二分类Logistic回归分析结果显示血清orexin-A是抗NMDAR脑炎的保护因素(OR=2.01;95%CI,1.16-3.17;P<0.01)。根据ROC曲线,orexin-A诊断抗NMDAR脑炎的最佳界限值为384.7ng·L-1,其特异性为85.7%,敏感度为71.4%。AUC为0.806(95%CI,0.639-0.973)。预后良好组与预后不良组比较,两组血清orexin-A水平差异无统计学意义(P=0.61)。结论抗NMDAR脑炎患者血清orexin-A显著降低,但血清orexin-A水平与患者预后情况无明显关系。

Anti-N-methyl-D-aspartate receptor encephalitis in a 17-year-old female patient with 3 years of follow-up

To the Editor:Anti-N-methyl-D-aspartate receptor(NMDAR)encephalitis is a potentially lethal autoimmune disease characterized by prominent psychiatric symptoms and seizures.It usually occurs in young female patients with ovarian teratomas.[1] Here,we describe a severe case of anti-NMDAR encephalitis.The patient was originally misdiagnosed as psychosis and did not improve within the first 4 weeks of first-line immunotherapy.Although she did not continue to receive second-line immunotherapy,the patient still recovered well and had no recurrence or tumor observed during 3 years of follow-up.

A Woman with Psychogenic Non-epileptic Seizures and Pelvic Mass

MOST cases of encephalitis are caused by viruses but a few have an immunological basis, such as paraneoplastic encephalitis, with specific antibodies identified. One recently characterized encephalitis caused by antibodies is anti-N- methyl-D-aspartate （NMDA） receptor encephalitis. It is a form of paraneoplastic limbic encephalitis associated with ovarian teratoma and has recently been described.The NMDA receptor mediates excitatory neurotransmission. It is important for synaptic plasticity, and thus for higher function such as learning and memory. This disorder results in prominent psychiatric symptoms followed by a rapid decline of the level of consciousness, central hypoventilation, seizures, involuntary movements and dysautonomia.

Encephalitis associated with autoantibody binding to the anti-N-methyl-D-aspartate receptor:immunopathogenesis,mechanisms,and clinical characteristics

Anti-N-methyl-D-aspartate receptor(NMDAR)encephalitis has been increasingly recognized in recent years.This condition may be the most common cause of antibody-mediated encephalitis worldwide.The majority of patients are young at the time of onset,female,and present with an acute-to-subacute onset of behavioral changes followed by seizure,abnormal movement,autonomic dysfunction,and finally hypoventilation with coma if left untreated.The immunopathogenesis of this disease may be due to antibody-mediated internalization of NMDARs from synapses,which results in the dysfunction of particular brain regions(especially the hippocampus and frontostriatal area).Compared to serum,the cerebrospinal fluid permits the more sensitive detection of anti-NMDAR antibody.Ovarian teratoma may be present in up to 40%of patients but is less frequent in children or late-onset disease(>45 years old).The severity at the time of disease onset and time to appropriate immunotherapy(high-dose steroid plus plasmapheresis or intravenous immunoglobulin)are independent factors that are associated with good outcomes.

Development from recurrent anti‑N‑methyl‑D‑aspartate receptor encephalitis with seizures as the first symptom to autoimmune‑associated epilepsy: a case report

Background Anti-N-methyl-D-aspartate receptor(anti-NMDAR)encephalitis is a novel autoimmune encephalitis(AE)first identified in 2007.It provides a new direction for clinicians when encountering unexplained symptoms such as seizures,psychotic behavioral abnormalities,speech disorders,and involuntary movements.Most patients have a good prognosis after immunotherapy,but some may experience relapses.Case presentation We report a Chinese female patient diagnosed with anti-NMDAR encephalitis.Over the past 30 years,the patient had experienced eight episodes with seizures as the first symptom,which eventually progressed to autoimmune-associated epilepsy.In the last two episodes,both serum and cerebrospinal fluid of the patient were negative for AE-related antibodies,and brain magnetic resonance imaging(MRI)revealed abnormal hyperintensity in the bilateral hippocampi.The patient’s symptoms were poorly controlled by immunotherapy but well controlled by anti-seizure medicines.Conclusions Patients with a long history of AE and multiple relapses that start with seizures may display alterations of brain structure.Physicians should pay attention to autoimmune-associated epilepsy.

Utility and Safety of Intrathecal Methotrexate Treatment in Severe Anti-N-methyI-D-aspartate Receptor Encephalitis： A Pilot Study

Background： Anti-N-methyl-D-aspartate receptor （anti-NMDAR） encephalitis is a treatable autoimmune neurologic syndrome that occurs with or without tumor association. However, some severe cases are refractory to systemic immunotherapy. This pilot study aimed to evaluate the utility and safety of intrathecal methotrexate injection for severe patients with anti-NMDAR encephalitis who did not respond to first-line immunotherapy. Methods： Intrathecal injections with methotrexate and dexamethasone were performed weekly in four legible patients within consecutive 4 weeks. Cerebrospinal fluid （CSF） was collected at baseline and each time of intrathecal injection lbr identification of anti-NMDAR antibody titers. Results： Significant clinical improvement was observed in three patients associated with a stepwise decrease of CSF anti-NMDAR antibody titers （maximum： 1/320 to minimum： 1/10）. After 2 months of follow-up, they were able to follow simple commands and had appropriate interactions with people （modified Rankin scale [mRS] of 0-2）. At 12 months of follow-up, they all had returned to most activities of daily life （.mRS of 0）, and no relapses were reported. One patient showed no clinical improvement and died of neurologic complications. Conclusions： lntrathecal treatment may be a potentially useful supplementary therapy in severely affected patients with anti-NMDAR encephalitis. Further large cohort study and animal experiment may help us elaborate the utility of intrathecal injection of methotrexate and its mechanism of action.

Anesthesia management for a patient with anti-NMDA receptor encephalitis undergoing ovarian tumor resection

Anti-N-Methyl-D-aspartate （NMDA） receptor （Anti-NMDA-R） encephalitis presents a series of psychiatric syndromes,including confusion,seizures,hypoventilation and autonomic nerve dysfunction.Only a few literatures about the anesthesia management for patients with anti-NMDA receptor encephalitis were reported,1 it is wise to understand the development of disease and the effect of anesthetics on brain function in the presence of NMDA receptors＇ abnormality.Herein we reported a case of the intra-operative anesthesia management and monitoring.

Potential Effect of Preoperative Immunotherapy on Anesthesia of Patients with Anti-N-methyI-D-aspartate Receptor Encephalitis

Anti-N-methyl-D-aspartate receptor （anti-NMDA-R） encephalitis is a newly recognized neuro-autoimmune disease. Patients usually present with a series of neurological and psychiatric syndromes including memory impairment, seizures, dyskinesia, autonomic nervous system dysfunction, etc. Anti-NMDA-R encephalitis usually affects young women with teratoma being a common co-existing condition in nearly 47% of the diagnosed patients. Previous studies have shown that teratoma removal, being the current first-line therapy, may enhance the effectiveness of autoimmune therapy and decrease the incidence of relapse, However, poorly controlled encephalitis poses as a perioperative anesthetic risk. Therefore, timing of the surgery is of great concern and is a question yet to be answered. Due to low incidence of anti-NMDA-R encephalitis in general population, literature of the perioperative management in these group of patients is scarce. Only few case reports were found yet, none has discussed the issue of surgery timing. In this study, 6 patients with anti-NMDA-R encephalitis undergoing teratoma removal were reviewed, and timing of surgery and anesthetic management for these patients were discussed.

An Autopsy Case of Suspected Anti‑N‑Methyl‑D‑Aspartate Receptor Encephalitis

N-methyl-D-aspartate receptor(NMDAR)encephalitis is a rare type of autoimmune limbic encephalitis.Herein,we report an autopsy case of highly suspected anti‑NMDAR encephalitis,based on the patient’s past psychiatric history and autopsy findings of bilateral hippocampal sclerosis and ovarian teratoma.We found that it can be difficult to accurately diagnose autoimmune encephalitis at postmortem forensic autopsy without a case history and background information.