E Maneta

H Kawano

HM Braakman

J Dalmau

MJ Titulaer

MS Kayser

MS Zandi

T Iizuka

Yuichiro Shimoyama

Osamu Umegaki

Tomoyuki Agui

Noriko Kadono

Toshiaki Minami

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CASE REPORT Open AccessAnti-NMDA receptor encephalitispresenting as an acute psychotic episodemisdiagnosed as dissociative disorder:a case reportYuichiro Shimoyama1*, Osamu Umegaki1, Tomoyuki Agui2, Noriko Kadono1 and Toshiaki Minami1AbstractBackground: In 2005, “anti-N-methyl-D-aspartate (NMDA) receptor encephalitis,” a syndrome with prominentpsychiatric symptoms, memory loss, decrease in level of consciousness, and central hypoventilation, was describedin young women with ovarian teratomas and antibodies against an antigen highly expressed in the hippocampus.This report highlights the growing need for increased awareness among psychiatrists and other relevant medicalprofessionals about this under-diagnosed disorder, which should be considered in differential diagnoses.Case presentation: A 19-year-old female with no psychiatric history presented to a district general hospital withacute psychosis, emotional lability, memory deficit, fluctuating behavioral changes such as wandering and babbling,and seizure. She was admitted to the hospital with a provisional diagnosis of dissociative disorder. Soon afteradmission, she developed aspiration pneumonia and was intubated for mechanical ventilation. She was transferredto our hospital for further assessment and admitted to the intensive care unit for ventilation. Laboratory test resultswere unremarkable, but her EEG showed non-specific slowing with no epileptiform activity, and brain computedtomography (CT) and MRI also showed no remarkable findings. Cerebrospinal fluid (CSF) analysis showed anelevated white blood cell count (15 cells/hpf; 70 % lymphocytes), and blood serum and CSF samples tested positivefor NMDA receptor antibodies. Abdominal contrast-enhanced CT revealed an ovarian teratoma, which wassubsequently removed laparoscopically. Postoperative immunotherapy (steroids, intravenous immunoglobulin, andplasmapheresis) led to gradual improvement. On day 25 of hospitalization, neuropsychological assessmentdemonstrated that overall, she had returned to her premorbid level of functioning. Her condition substantiallyimproved over several months of cognitive rehabilitation, and she was eventually discharged on day 75.Conclusions: Anti-NMDA receptor encephalitis, a form of autoimmune encephalitis, is commonly associated withtumors and often misdiagnosed. Diagnosis can be confirmed by detecting NMDA receptor antibodies in thepatient’s serum or CSF. Management can be achieved with immunosuppressive therapy and tumor resection.Keywords: Limbic encephalitis, N-Methyl-D-aspartate (NMDA) receptor encephalitis, Paraneoplastic, MisdiagnosisAbbreviations: NMDA, N-Methyl-D-aspartate; MRI, Magnetic resonance imaging; CSF, Cerebrospinal fluid;ICU, Intensive care unit; CT, Computed tomography* Correspondence: shimocchiliebesfreud512@yahoo.co.jp1Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi,Takatsuki, Osaka 569-8686, JapanFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made.Shimoyama et al. JA Clinical Reports  (2016) 2:22 DOI 10.1186/s40981-016-0048-3BackgroundIn 2005, “anti-N-methyl-D-aspartate (NMDA) receptorencephalitis,” a syndrome with prominent psychiatricsymptoms, memory loss, decrease in level of conscious-ness, and central hypoventilation, was described inyoung women with ovarian teratomas and antibodiesagainst an antigen highly expressed in the hippocampus.When severe, this disorder can be life-threatening, re-quiring intensive care treatment [1]. Here, we presentthe case of a 19-year-old female with anti-NMDA recep-tor encephalitis who was first diagnosed with dissociativedisorder. The present case is noteworthy because of thedramatic and rapid recovery from surgery she made be-fore returning to her premorbid level of functioning.Anti-NMDA receptor encephalitis is often misdiagnosedas viral encephalitis, neuroleptic malignant syndrome, oracute psychotic disorder, but treatment is specific anddelays are associated with poor outcomes. As such, thisreport highlights the growing need for increased aware-ness among psychiatrists and other relevant medicalprofessionals about this under-diagnosed disorder, whichshould be considered in differential diagnoses.Case presentationA 19-year-old female with no psychiatric history pre-sented to a district general hospital with a history ofacute psychosis, emotionally lability, memory deficit,fluctuating behavioral changes such as wandering andbabbling, and seizure. Neurological examination did notreveal any focal signs, and routine laboratory workupwas normal. She was admitted to the hospital with aprovisional diagnosis of dissociative disorder. Soon afteradmission, she developed aspiration pneumonia and wasintubated for mechanical ventilation. At the time, re-peated seizures occurred every 10 min. Although ancil-lary tests including magnetic resonance imaging (MRI),electroencephalogram (EEG), and cerebrospinal fluid(CSF) analysis were unremarkable, the presentation ofacute psychosis in combination with recurrent seizuresand a relentless course suggested autoimmune encephal-itis. She was transferred to our hospital for further as-sessment and admitted to the intensive care unit (ICU)for ventilation, where sedation was performed with pro-pofol and dexmedetomidine. Her condition upon arrivalwas as follows: Glasgow Coma Scale score 1-T-1, re-spiratory rate 12 breaths/min on ventilation, pulse rate80 beats/min, blood pressure 110/79 mmHg, and bodytemperature 36.6 °C. There were no notable laboratorytest results, her EEG showed non-specific slowing withno epileptiform activity, CSF analysis showed an elevatedwhite blood cell count (15 cells/hpf; 70 % lymphocytes),and brain computed tomography (CT) and MRI showedno remarkable findings (Figs. 1 and 2). Her blood serumand CSF samples collected at the time of arrival weresent to Dr. Dalmau’s laboratory for the measurement ofanti-NMDA receptor antibody levels. The acute presen-tation of a severe psychotic state, with cognitive impair-ment, fluctuating behavioral changes, and recurrentseizures led to a clinical diagnosis of probable auto-immune encephalitis. However, as the possibility of viralencephalitis remained, intravenous acyclovir was initi-ated and continued until the results of polymerase chainreaction of CSF samples were found negative 1 weeklater. Given the suspicion of anti-NMDA receptorFig. 1 Head CT image with no remarkable findingsFig. 2 Brain MRI image with no remarkable findingsShimoyama et al. JA Clinical Reports  (2016) 2:22 Page 2 of 5encephalitis, abdominal contrast-enhanced CT (Fig. 3)was performed, and a cystic lesion with calcification inthe pelvis was identified. The lesion was determined tobe an ovarian teratoma and was subsequently removedlaparoscopically. Postoperatively, she underwent a totalof seven plasmapheresis treatments (on days 2, 5, 7, 9,14, 16, and 19), as well as betamethasone (first at 32 mgand gradually decreased) and IVIg (0.4 g/kg/day) for5 days, which led to gradual improvement. On postoper-ative day 12, she was extubated, and the administrationof propofol and dexmedetomidine was stopped. Soonafter, the patient experienced a generalized tonic-clonicseizure. She was treated with levetiracetam 500 mg/dayand did not experience a second generalized tonic-clonicseizure. On day 25 of hospitalization, blood serum andCSF samples were found positive for anti-NMDA recep-tor antibodies, leading to a confirmed diagnosis of anti-NMDA receptor encephalitis. Neuropsychological as-sessment performed at that time demonstrated thatoverall, she had returned to her premorbid level of func-tioning. She showed profound improvement over severalmonths of cognitive rehabilitation and was eventuallydischarged on day 75. After discharge, she was referredto a cognitive rehabilitation day service facility. Sincethen, she has not experienced any relapse in generalizedtonic-clonic seizures or other symptoms. The patientreturned to school 2 months after discharge.DiscussionAnti-NMDA receptor encephalitis is a form of auto-immune encephalitis first reported in 2007 by Dalmau etal. of the University of Pennsylvania [2]. In October2008, clinical data from 100 cases, gathered from aroundthe world, were published in Lancet Neurology [3]. Thistype of encephalitis often occurs in young women at amedian age of 23 years, with a male-to-female ratioof 9:91 [3]. Patients with this disease exhibit psychi-atric symptoms, involuntary movement of the faceand limbs, disturbance of consciousness, and centralhypoventilation. In the early phase, patients developmany different psychiatric symptoms, but they followa very similar course—gradually improving after pro-gressing through common cold symptoms, a period ofpsychiatric symptoms, an immobile period, and ahyperactive period [4]. Some cases of anti-NMDA re-ceptor antibodies identified in patients with purelypsychiatric disorders have also been reported [5, 6].The complication rate for teratomas is reported to be59, and 95 % of all teratomas are ovarian teratomas;additionally, mediastinal teratoma, orchioncus, smallcell lung carcinoma, and other tumors have been re-ported [7]. Definitive diagnosis is possible when anti-NMDA receptor antibodies are detected in the CSFand blood serum.We present a case of successful treatment of paraneo-plastic anti-NMDA receptor encephalitis. In this case, a19-year-old woman was admitted following an abrupt-onset episode of emotional lability, memory deficit,fluctuating behavioral changes such as wandering andbabbling, and seizure. Although routine physical andlaboratory tests were normal, the appearance of fluctua-tions in mental status combined with repeated general-ized seizures, results of spinal fluid examination with anelevated number of lymphoid cells, and slow activity inEEG initially led to a diagnosis of suspected limbic en-cephalitis. The current management guidelines for thisdisorder advocate early detection and removal of theteratoma [1]. In our case, the discovery of a teratoma byabdominal CT suggested a diagnosis of anti-NMDA re-ceptor encephalitis, and the teratoma was urgently re-moved even before the results of anti-NMDA receptorantibodies in CSF were obtained.In general, the majority of patients present with acombination of behavioral, cognitive, and motor symp-toms, as well as speech disorder, seizures, and decreasedlevel of consciousness, with psychiatric symptoms oftenpredominating in the early phase. Such a presentationoften leads patients to first seek psychiatric evaluationand treatment, leading to a crucial delay in diagnosisand immunotherapy [8]. Moreover, a recent largecohort-based study revealed that 4 % of patients pre-sented with isolated psychiatric episodes (pure psychi-atric symptoms without neurological involvement) [9].In this cohort, brain MRI, EEG, and CSF studies wereabnormal in 33, 90, and 79 % of patients, respectively.Fig. 3 Abdominal CT image showing a right cystic adnexal masswith an internal focus of fat and high-attenuation material, suggestingan ovarian teratoma (red circle)Shimoyama et al. JA Clinical Reports  (2016) 2:22 Page 3 of 5Moreover, results of these ancillary tests in patients withisolated psychiatric episodes were similar to the cohortpopulation at large. As early recognition of these epi-sodes and initiation of appropriate therapy was shown tobe an important prognostic factor, the authors recom-mended that, in patients with new-onset psychosis, his-tory of encephalitis, subtle neurological symptoms, andabnormal, albeit non-specific, CSF, EEG, or MRI find-ings, prompt screening should be performed for NMDAreceptor antibodies and ovarian teratomas when applic-able [9]. In the present case, although the patient wasfirst diagnosed with dissociative disorder at a districtgeneral hospital, prompt screening for NMDA receptorantibodies, early detection and removal of the ovarianteratoma, and immunotherapy following surgery wereadequately performed at our hospital after transfer.Recent data suggest that over half of patients respondto first-line immunotherapy (steroids, intravenous im-munoglobulin, and plasmapheresis, alone or in combin-ation) within 4 weeks. Moreover, second-line treatment(rituximab and/or cyclophosphamide) is usually effectivewhen first-line therapies fail. When relevant, rapid re-moval of an associated neoplasm is warranted and pos-sibly reduces the future risk of relapse, which mayexceed 10 % during the first 2 years. Despite optimaltreatment, the recovery process can continue for over18 months [1]. A prolonged hospital stay is to be ex-pected with a reported median hospitalization period of2.5 months (range, 2 to 14 months) [4]. These interven-tions resulted in marked improvements over the courseof several months in this case. Notably, neuropsycho-logical assessment performed on day 25 of hospitalizationdemonstrated that overall, she had returned to her pre-morbid level of functioning. The present case represents arelatively short time to recovery relative to that of previousreports [2].This patient underwent general anesthesia for her sur-gery. In general, preoperative measures to prevent deepvein thrombosis are required because the duration ofsedation under mechanical ventilation can sometimes bequite long in these patients. In addition, during surgery,the use of ketamine and nitrous oxide should be avoided,as they inhibit NMDA receptors (NMDAR) [10] andvolatile anesthetics exhibit a wide range of NMDAR in-hibitory potencies and immobilizing activities. By con-trast, propofol is less likely to produce anesthetic effectsthrough an NMDAR-dependent mechanism. This is be-cause propofol anesthetizes via enhancing GABA-ergictransmission. Therefore, propofol may be a more appro-priate anesthetic for such patients [10]. Postoperatively,many patients require mechanical ventilation to addressrespiratory depression and seizures.In summary, the present case illustrates that, whileanti-NMDA receptor encephalitis is an unfamiliarcondition to many physicians, the inclusion of thisdisorder in differential diagnoses is critical, as promptinitiation of immunotherapy and tumor removal, if ap-propriate, could dramatically improve outcomes.ConclusionsAnti-NMDA receptor encephalitis is an often misdiag-nosed form of autoimmune encephalitis commonlyassociated with tumors. Detection of NMDA receptorantibodies in the patient’s serum or CSF is necessary fora confirmed diagnosis, and management is achieved withearly immunotherapy and tumor removal.AcknowledgementsNoneFundingNoneAvailability of data and materialsNot applicableAuthors’ contributionsYS collected the data and drafted the manuscript. OU, TA, NK, and TMrevised the manuscript. All authors read and approved the final manuscriptfor submission.Authors’ informationNoneCompeting interestsThe authors declare that they have no competing interests.Consent for publicationWritten informed consent was obtained from the patient for publication ofthis case report and any accompanying images. A copy of the writtenconsent is available for review by the Editor-in-Chief of this journal.Author details1Department of Anesthesiology, Osaka Medical College, 2-7 Daigaku-machi,Takatsuki, Osaka 569-8686, Japan. 2Department of Surgery, Osaka MedicalCollege, Takatsuki, Japan.Received: 17 June 2016 Accepted: 26 August 2016References1. Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al.Treatment and prognostic factors for long-term outcome in patients withanti-NMDA receptor encephalitis: an observational cohort study. LancetNeurol. 2013;12:157–65.2. Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al.Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associatedwith ovarian teratoma. Ann Neurol. 2007;61:25–36.3. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects ofantibodies. Lancet Neurol. 2008;7:1091–8.4. Iizuka T, Sakai F, Ide T, Monzen T, Yoshii S, Iigaya M, et al. Anti-NMDAreceptor encephalitis in Japan: long-term outcome without tumor removal.Neurology. 2008;70:504–11.5. Braakman HM, Moers-Hornikx VM, Arts BM, Hupperts RM, Nicolai J. Pearls &oy-sters: electroconvulsive therapy in anti-NMDA receptor encephalitis.Neurology. 2010;75:e44–6.6. Zandi MS, Irani SR, Lang B, Waters P, Jones PB, McKenna P, et al.Disease-relevant autoantibodies in first episode schizophrenia. J Neurol.2011;258:686–8.Shimoyama et al. JA Clinical Reports  (2016) 2:22 Page 4 of 57. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R.Clinical experience and laboratory investigations in patients with anti-NMDARencephalitis. Lancet Neurol. 2011;10:63–74.8. Maneta E, Garcia G. Psychiatric manifestations of Anti-NMDA receptorencephalitis: neurobiological underpinnings and differential diagnosticimplications. Psychosomatics. 2014;55:37–44.9. Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency andcharacteristics of isolated psychiatric episodes in anti-N-methyl-D-aspartate receptor encephalitis. JAMA Neurol. 2013;70:1133–9.10. Kawano H, Hamaguchi E, Kawahito S, Tsutsumi YM, Tanaka K, Kitahata H,et al. Anaesthesia for a patient with paraneoplastic limbic encephalitis withovarian teratoma: relationship to anti-N-methyl-D-aspartate receptorantibodies. Anaesthesia. 2011;66:515–8.Submit your manuscript to a journal and beneﬁ t from:7 Convenient online submission7 Rigorous peer review7 Immediate publication on acceptance7 Open access: articles freely available online7 High visibility within the ﬁ eld7 Retaining the copyright to your article    Submit your next manuscript at 7 springeropen.comShimoyama et al. JA Clinical Reports  (2016) 2:22 Page 5 of 5

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Anti-NMDA receptor encephalitis presenting as an acute psychotic episode misdiagnosed as dissociative disorder: a case report

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Anti-NMDA receptor encephalitis presenting as an acute psychotic episode misdiagnosed as dissociative disorder: a case report

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