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 Table of Contents  
Year : 2019  |  Volume : 5  |  Issue : 4  |  Page : 213-216

An autopsy case of suspected anti-N-methyl-D-aspartate receptor encephalitis

1 Tokyo Medical Examiner's Office, Tokyo, Japan
2 Tokyo Medical Examiner's Office; Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan
3 National Hospital Organization Shimofusa Psychiatric Medical Center, Chiba, Japan

Date of Submission26-Dec-2018
Date of Decision28-Feb-2019
Date of Acceptance09-Sep-2019
Date of Web Publication11-Dec-2019

Correspondence Address:
Kino Hayashi
Tokyo Medical Examiner's Office, 4-21-18, Otsuka, Bunkyo-ku, Tokyo 112-0012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jfsm.jfsm_59_18

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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.

Keywords: Anti-N-methyl-D-aspartate receptor encephalitis, drowning, epilepsy, forensic autopsy case, hippocampal sclerosis

How to cite this article:
Hayashi K, Hikiji W, Makino Y, Suzuki H. An autopsy case of suspected anti-N-methyl-D-aspartate receptor encephalitis. J Forensic Sci Med 2019;5:213-6

How to cite this URL:
Hayashi K, Hikiji W, Makino Y, Suzuki H. An autopsy case of suspected anti-N-methyl-D-aspartate receptor encephalitis. J Forensic Sci Med [serial online] 2019 [cited 2023 Feb 6];5:213-6. Available from: https://www.jfsmonline.com/text.asp?2019/5/4/213/272725

  Introduction Top

N-methyl-D-aspartate receptors (NMDARs) are a type of glutamate receptor and ion channel protein found in nerve cells, including those within the hippocampus. NMDARs are critical for brain development, generation of rhythms for breathing and locomotion, functioning of learning–memory processes, and neuroplasticity.[1] Anti-NMDAR encephalitis is a type of limbic encephalitis (LE) associated with anti-NMDAR antibodies. It often presents as an acute psychosis and is associated with paraneoplastic syndrome of ovarian teratomas in adult women.[2] Acute autoimmune LE typically starts with a prodromal viral illness before the onset of psychiatric symptoms, seizures, and autonomic failure.[3] Here, 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.

  Case Report Top

A 51-year-old woman who lived with her parents was found dead in her bathtub. She had been diagnosed with schizophrenia and had been undergoing relevant treatment for the past 3 years. According to her parents' statement, on the day of her sudden death, she appeared to be in her usual mental state. She went for a bath at 11 p.m. However, after 30 min, she was found in an unconscious state and had drowned in the water in the bathtub. She did not respond to resuscitation. Brain computed tomography (CT) during resuscitation was unremarkable. To determine the cause of death, an autopsy was performed 12 h after death.

Autopsy findings

The deceased individual was 154 cm tall and weighed 56 kg (body mass index = 23.6 kg/m2). There were no remarkable findings on the external body. During the autopsy, macroscopic examination revealed water aspiration in the lungs (710 g and 600 g in the left and right lungs, respectively) and a 2.5-cm right ovarian cyst. The brain weighed 1170 g. Microscopic examination revealed a mature cystic teratoma of the right ovary [Figure 1]a, [Figure 1]b, [Figure 1]c and severe bilateral hippocampal sclerosis [Figure 2]a, [Figure 2]b, [Figure 2]c. Because of the autopsy findings, the diagnosis of schizophrenia was questioned, and the patient's past medical history was reviewed.
Figure 1: Mature cystic teratoma of the right ovary. (a) The diameter of the right ovary was 2.5 cm. (b) The tumor had foci of mature cartilage tissues. (c) The most common elements were components of stratified squamous epithelium

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Figure 2: Left hippocampus. The location of hippocampal gliosis in the left was CA1 to CA4. (a) Gliosis of left CA3. (b) The left hippocampal dentate granule cells were partially absent. (c) Gliosis of the left CA1. The subiculum (*) was spared from the gliosis

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Past history

Three years previously, she had no previous medical history of seizures or psychiatric illness. She had not used any illegal drugs. Her family history was unremarkable. She got married at the age of 27 years but was divorced at the age of 40 years because her husband faced financial issues, which may have caused her emotional trauma. She lived with her parents following the divorce. According to her parents, before the onset of any symptoms, she had complained of being very tired, but this was attributed to the fact that she worked hard every day to resolve her financial problems. One day, she presented with acute onset of psychiatric symptoms characterized by confusion, memory loss, hallucinations, disorganized thinking, and incoherent speech. An examination performed after 2 days at a local hospital revealed no abnormal findings. The following day, she was referred to a psychiatric hospital for further evaluation. However, during transfer to the psychiatric hospital, she developed a generalized seizure with a high body temperature (38.1°C/100.58°F). Consequently, she was brought to the emergency department of a different hospital. Blood tests revealed leukocytosis (white blood cell count, 19,500/μL) with normal serum C-reactive protein levels. Cerebrospinal fluid (CSF) examination revealed acellular spinal fluid (white blood cell count, 6/μL) with normal protein and glucose levels. Brain CT was normal. The psychiatric symptoms were very severe, and she was referred to a psychiatric hospital the same day. On admission, she had a high body temperature and hypoxia due to pneumonia, for which oxygen and medication were initiated. A few days later, although the patient was able to communicate, she remained disoriented with short-term memory loss and persistent delirium symptoms. Subsequently, she was diagnosed with schizophrenia and discharged. After discharge, she was referred to a local psychiatric clinic and was prescribed hypnotic drugs, including zolpidem and flunitrazepam.

Further examination

The presence of a high body temperature, seizures, and hypoxia strongly suggested acute LE, such as anti-NMDAR encephalitis. Accordingly, we sent her serum to Professor Josep Dalmau at the University of Barcelona for the analysis of anti-NMDAR antibodies. Three years after the potential onset of LE, her serum was negative for anti-NMDAR antibodies, as this has not been absolutely determined.

  Discussion Top

LE refers to an inflammatory disorder involving the hippocampus, amygdala, and insular cortex.[4] Patients with LE usually present with rapidly progressive short-term memory deficits, psychiatric symptoms, and seizures.[5] The causes and frequency of LE in Japan are herpes simplex virus (HSV) (20%), parainfectious syndrome (24%), paraneoplastic syndrome (8%), autoimmune diseases (4%), viral infections other than HSV (2%), and others (40%).[4] Recently, several types of autoimmune encephalitis have been identified, each with its own specific mechanism. In particular, autoimmune LE is associated with certain tumors, and is also an aspect of paraneoplastic syndrome.[5] Currently, the most commonly observed and investigated autoimmune encephalitis is caused by antibodies attacking NMDARs. Anti-NMDAR encephalitis was first described as paraneoplastic LE associated with ovarian teratoma in 2007 by Dalmau and Bataller.[6] To date, there are more than 500 reported cases.[7],[8] Detection of antibodies to the NMDAR subunit in serum or CSF sample is a confirmatory diagnosis.

In neurology and psychiatric clinics, clinicians should be aware that presentation of anti-NMDAR encephalitis includes several characteristic features.[9] Most patients develop viral-like symptoms (e.g., headaches and gastrointestinal symptoms), acute psychiatric symptoms (agitation, bizarre and disinhibited behavior, delusions, and auditory and visual hallucinations), cognitive dysfunction (e.g., memory defects and concentration difficulties), motor dysfunction (e.g., seizures and dyskinetic movements), autonomic instabilities (e.g., central hypoventilation and arrhythmia), and disturbances of consciousness (coma) with ovarian teratoma and CSF inflammatory abnormalities.[2],[10] Anti-NMDAR encephalitis is potentially lethal but also has a high potential for recovery with treatment.[2],[3] Treatment is typically with immunosuppressive medication and surgery to remove the ovarian teratoma. Delay to immunosuppressive treatment results in permanent hippocampal damage.[11] Our case showed sequential development of prodromal symptoms, generalized seizure, schizophrenia-like psychosis, and hypoventilation. The autopsy findings detected an ovarian teratoma and severe bilateral hippocampal sclerosis, which strongly suggest a past history of LE. She did not have another cause of LE such as an autoimmune disease or tumor. The antemortem symptoms in our patient were compatible with anti-NMDAR encephalitis. Nonetheless, her psychiatric symptoms were very severe, and she was referred to a psychiatric hospital. Accordingly, she was diagnosed with schizophrenia and underwent treatment for the previous 3 years. Her postmortem serum was negative for anti-NMDAR antibodies. We were unable to examine her CSF, which was not taken postmortem. Iizuka et al. reported that anti-NMDAR antibodies are found in serum or CSF at onset, but not in long-term follow-up samples.[3] Recovery may occur without ovarian teratoma removal.[3],[8] More than 75% of all patients show substantial recovery in an inverse order of symptom development, which is associated with a decline of antibody titers.[8] Our case was potentially 3 years after the onset of LE. There was no active brain inflammation, which might explain the negative result. Indeed, it may be difficult to accurately diagnose autoimmune encephalitis at postmortem forensic autopsy without a case history and background information. Screening for autoantibodies should be considered by clinicians in any patient who presents with a viral-like illness in the weeks prior to acute psychiatric symptoms with motor dysfunction.[9],[10]

Neuroglial tissue within the teratoma may be involved in the pathogenesis of anti-NMDAR encephalitis.[12],[13] Day et al. found clusters of abnormal neurons showing multinucleation or dysmorphia within a teratoma.[13] Iemura et al. found that NMDAR-positive small neuronal clusters with proliferative activity are characteristically present in ovarian teratomas associated with NMDAR encephalitis.[12] These findings may be useful for more accurate diagnosis of anti-NMDAR encephalitis. However, our case had a mature cystic teratoma without immature neuroglial tissue. The mechanism that causes anti-NMDAR encephalitis remains unclear, especially in patients without ovarian teratoma. This encephalitis is not always paraneoplastic.[3],[7],[8],[14] Young females comprise around 80% of all anti-NMDAR encephalitis patients, and 40% of them are reported to have ovarian teratomas.[7],[8]

There are few autopsy reports of acute LE. Pathology findings remain to be fully elucidated. Anti-NMDAR encephalitis accounts for a relevant proportion of unexplained new-onset epilepsies.[14] Moreover, bilateral hippocampal volumes are significantly reduced in anti-NMDAR encephalitis patients who undergo multimodal magnetic resonance imaging.[15] Hippocampal sclerosis is the most common pathological abnormality in temporal lobe epilepsy and an underlying reason for reduced hippocampal volume. Hippocampal sclerosis has certain specific patterns of neuronal loss. Usually, the CA2 region and subiculum are spared from gliosis.[16] Our patient exhibited bilateral hippocampal sclerosis with sparing of the subiculum from gliosis. Furthermore, some reports have shown that hippocampal sclerosis without active inflammation can occur with a long paraneoplastic history[17],[18] [Figure 3]. Our case had not been diagnosed with epilepsy, but we believe that hippocampal sclerosis in our patient was due to anti-NMDAR encephalitis and could be a cause of adult-onset temporal lobe epilepsy.[19],[20]
Figure 3: Classification and differential diagnosis of limbic encephalitis. *NPLE: Nonparaneoplastic limbic encephalitis, **PNLE: Paraneoplastic limbic encephalitis, ***HSV: Herpes simplex virus

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Based on data from the Tokyo medical examiner's office, there were 364 unexpected epileptic deaths during the past 20 years, with 106 patients (29.1%) found in the bathtub.[21] We encounter several cases of unexpected deaths due to drowning in the bathtub because most Japanese individuals enjoy taking a bath with the entire body soaked in the bathtub. In particular, epileptic patients should be careful while taking a bath.

  Conclusions Top

At initial presentation, acute LE was not suspected and the patient was diagnosed with schizophrenia. However, autopsy findings and details of the initial clinical presentation strongly suggest that the patient had an acute form of LE, such as anti-NMDAR encephalitis, rather than schizophrenia.

Clinicians should consider NMDAR encephalitis and check for the presence of an ovarian teratoma if they encounter female patients who show acute psychiatric symptoms after viral-like symptoms.

LE could be associated with hippocampal sclerosis that causes epilepsy. Patients with a LE diagnosis should be careful while taking a bath to avoid drowning.


The authors are really grateful to Dr. Takahiro Iizuka at Kitasato University, School of Medicine, and Professor Josep Dalmau at the University of Barcelona for the analysis of anti-N-methyl-D-aspartate receptor antibodies. We would like to thank Enago (www.enago.jp) for the English language review.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

VanDongen AM. Biology of the NMDA Receptor. Boca Raton: CRC Press; 2009.  Back to cited text no. 1
Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005;58:594-604.  Back to cited text no. 2
Iizuka T, Sakai F, Ide T, Monzen T, Yoshii S, Iigaya M, et al. Anti-NMDA receptor encephalitis in Japan: Long-term outcome without tumor removal. Neurology 2008;70:504-11.  Back to cited text no. 3
Seki M, Suzuki S, Suzuki N. Limbic encephalitis up to date. Nihon Rinsho 2011;69:442-7.  Back to cited text no. 4
Suzuki S, Seki M, Suzuki N. Recent concept of limbic encephalitis: Progress in anti-NMDA receptor encephalitis. Nihon Rinsho Meneki Gakkai Kaishi 2013;36:86-94.  Back to cited text no. 5
Dalmau J, Bataller L. Limbic encephalitis: The new cell membrane antigens and a proposal of clinical-immunological classification with therapeutic implications. Neurologia 2007;22:526-37.  Back to cited text no. 6
Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study. Lancet Neurol 2013;12:157-65.  Back to cited text no. 7
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63-74.  Back to cited text no. 8
Maneta E, Garcia G. Psychiatric manifestations of anti-NMDA receptor encephalitis: Neurobiological underpinnings and differential diagnostic implications. Psychosomatics 2014;55:37-44.  Back to cited text no. 9
Barry H, Byrne S, Barrett E, Murphy KC, Cotter DR. Anti-N-methyl-d-aspartate receptor encephalitis: Review of clinical presentation, diagnosis and treatment. BJPsych Bull 2015;39:19-23.  Back to cited text no. 10
Finke C, Kopp UA, Prüss H, Dalmau J, Wandinger KP, Ploner CJ. Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry 2012;83:195-8.  Back to cited text no. 11
Iemura Y, Yamada Y, Hirata M, Kataoka TR, Minamiguchi S, Haga H. Histopathological characterization of the neuroglial tissue in ovarian teratoma associated with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. Pathol Int 2018;68:677-84.  Back to cited text no. 12
Day GS, Laiq S, Tang-Wai DF, Munoz DG. Abnormal neurons in teratomas in NMDAR encephalitis. JAMA Neurol 2014;71:717-24.  Back to cited text no. 13
Niehusmann P, Dalmau J, Rudlowski C, Vincent A, Elger CE, Rossi JE, et al. Diagnostic value of N-methyl-D-aspartate receptor antibodies in women with new-onset epilepsy. Arch Neurol 2009;66:458-64.  Back to cited text no. 14
Finke C, Kopp UA, Pajkert A, Behrens JR, Leypoldt F, Wuerfel JT, et al. Structural hippocampal damage following anti-N-methyl-D-aspartate receptor encephalitis. Biol Psychiatry 2016;79:727-34.  Back to cited text no. 15
Omoto S, Fukuda T, Arai N, Suzuki M. An autopsy case of chronic epilepsy with unilateral hippocampal sclerosis and cognitive decline. Brain Nerve 2014;66:1109-18.  Back to cited text no. 16
Okamoto K. Neuropathological findings of acute limbic encephalitis and encephalopathy. J Clin Exp Med (Igaku No Ayumi) 2007;223:291-4.  Back to cited text no. 17
Shinohara T, Kojima H, Nakamura N, Ogata A, Betsuyaku T, Suzuki A, et al. Pathology of pure hippocampal sclerosis in a patient with dementia and Hodgkin's disease: The Ophelia syndrome. Neuropathology 2005;25:353-60.  Back to cited text no. 18
Toyota T, Akamatsu N, Tsuji S, Nishizawa S. Limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies as a cause of adult-onset mesial temporal lobe epilepsy. J UOEH 2014;36:129-33.  Back to cited text no. 19
Popkirov S, Ismail FS, Grönheit W, Kapauer M, Wellmer J, Bien CG. Progressive hippocampal sclerosis after viral encephalitis: Potential role of NMDA receptor antibodies. Seizure 2017;51:6-8.  Back to cited text no. 20
Hayashi K, Harada K, Fukunaga T. Unexpected epileptic deaths, statistical trends of Tokyo medical examiner's office. J Jpn Epil Soc 2017;34:628-36.  Back to cited text no. 21


  [Figure 1], [Figure 2], [Figure 3]


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