In 2007, Dalmau et al. [1] identified autoantibodies to anti-NMDA receptors as a cause of encephalitis, establishing the concept of “anti-NMDA receptor encephalitis”. Since then, various other autoantibodies have been found to be involved in the development of encephalitis and encephalopathy, and the disease concept of “autoimmune encephalitis” has been proposed [2]. The diagnostic criteria for autoimmune encephalitis were also outlined by Glaus et al. in 2016 [3]. Although the clinical picture may vary depending on the type of antibody, psychiatric symptoms are the primary symptoms of many autoimmune encephalitides and are often first examined by psychiatrists [4]. However, anti-NMDA receptor encephalitis differs significantly from common psychiatric disorders, as seizures and central hypoventilation occur in its the clinical course [5]. Immunosuppressive therapy should be the first choice in treatment because early immunosuppressive therapy produces good outcomes [6]. Therefore, psychiatrists should diagnose autoimmune encephalitis as early as possible and provide appropriate treatment.

However, it is not practical to perform invasive tests, particularly lumbar puncture, to confirm the diagnosis in all patients with acute psychiatric symptoms who visit a psychiatric clinic. Furthermore, during periods of severe psychiatric symptoms, tests such as lumbar puncture and electroencephalography, which require the patient to remain at rest, are often difficult to perform. Therefore, it is important to first suspect autoimmune encephalitis based on medical history and symptom evaluation in the psychiatric examination, and then decide whether to proceed with a more invasive examination.

The symptomatology of anti-NMDA receptor encephalitis has already been studied several times [7, 8, 9, 10] and referenced in an excellent review by Dalmau et al. [11]. These studies are important in identifying the psychiatric symptoms associated with this encephalitis because they include a systematic review of numerous cases. However, for practical use in clinical practice, case reports should be read more thoroughly to determine not only what symptoms were seen but also when and in what order they were seen. The clinical course of anti-NMDA receptor encephalitis was studied by Iizuka et al. [5] shortly after its discovery. In particular, their study considers what symptoms appear and in what order they appear in the clinical course of this type of encephalitis. According to Iizuka et al. [5], in all four patients examined, the clinical course progressed through five phases: a prodromal phase, psychotic phase, unresponsive phase, hyperkinetic phase, and gradual recovery phase.

According to Iizuka et al. [5], in the “prodromal phase”, nonspecific cold-like symptoms (e.g., fever, headache, and malaise) associated with the activation of the immune system occur. Subsequently, in the “psychotic phase”, the autoantibody related to the tumor acts on the central nervous system, causing psychiatric symptoms—mainly those characteristic of mood disorders and cognitive-behavioral disorders. As for psychiatric symptoms, all four cases they examined showed significant schizophrenia-like or “atypical psychosis”-like [12] symptoms (e.g., disorganized thinking, delusions, hallucinations, and loss of self-awareness). Additionally, symptoms of emotional disturbance (e.g., apathy, lack of emotion, depression, loneliness, and fear) and cognitive decline (e.g., difficulty in using a cellular phone or passing through an automatic ticket gate) were observed in these cases, and all four patients were initially diagnosed with psychiatric disorders. In this psychotic phase, after psychotic symptoms such as hallucinations and delusions occur, generalized convulsions and marked disturbances of consciousness appear, and the patients enter the next phase. In the “unresponsive phase”, mutism, akinesia, catalepsy, and muscle rigidity are observed. In the following “hyperkinetic phase”, various movement abnormalities—mainly involuntary movements (dyskinesias) of the oral cavity and face—are observed. Various autonomic symptoms also often appear during this period. In the “gradual recovery phase”, slow recovery of disturbances of consciousness and involuntary movement are observed [5].

This detailed, clinical-course-focused description of the phenomenology of anti-NMDA receptor encephalitis appears to have not been fully updated. Thus, we analyzed case reports of anti-NMDA receptor encephalitis in which the order of appearance of the symptoms was well described and examined clues to aid in differential diagnosis (especially for differential diagnosis from schizophrenia) by phase.

In the Discussion section, we discuss the phenomenological understanding of anti-NMDA receptor encephalitis. Because this encephalitis is, of course, an organic disease, the psychiatric symptoms that occur in the course of this encephalitis can be considered those of organic psychosis. In classical psychiatry, there have been discussions that attempt to distinguish between the phenomenology of organic and functional psychoses (e.g., schizophrenia) [13]. In fact, the similarity of anti-NMDA receptor encephalitis to Stauder’s “lethal catatonia” (tödliche Katatonie) syndrome [14] and Mitsuda’s “atypical psychosis” [15] has already been noted [12]. In this section, however, we want to focus on the similarity between anti-NMDA receptor encephalitis and “primary mental confusion” (confusion mentale primitive) [16, 17] in late 19th century French psychiatry.

Primary mental confusion, a concept similar to today’s organic psychosis, begins with symptoms like those of the common cold and leads to an acute psychotic state, which includes hallucinations, delusions, and various catatonic symptoms (we will discuss the concept of primary mental confusion in more detail later). Additionally, cases of primary mental confusion were sometimes fatal. In these respects, this concept seems useful in considering the phenomenology of today’s anti-NMDA receptor encephalitis. It also seems important to us that French psychiatrists focused on the clinical course of diseases, describing in detail the course of primary mental confusion and discussing phenomenological features useful for differentiating functional from organic psychoses based on this concept.

At the end of July 2021, we searched for papers on PubMed (https://pubmed.ncbi.nlm.nih.gov/) using the search formula “((“Antibodies” [Mesh]) AND “Anti-N-Methyl-D-Aspartate Receptor Encephalitis” [Mesh]) AND “Receptors, N-Methyl-D-Aspartate” [Mesh]” and found 251 papers. We then examined the idenitifed papers that were fully accessible at the Kyoto University Library Network without any additional costs (105 papers). From those, we found 44 papers in which detailed clinical courses were described. We excluded one paper in Hungarian and another in Chinese because of our linguistic limitations, and we also excluded one paper with an inadequate description of the cases. As a result, 41 papers (including 47 case reports) were obtained [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58]. These 41 case reports included reports in English and Spanish (Fig. 1).

Fig. 1.

Selection of case reports.

Subsequently, two evaluators independently listed the symptoms described in each case and identified the order in which each symptom occurred. In counting symptoms, fever in the prodromal phase was distinguished from hyperthermia as an autonomic symptom in the hyperkinetic phase. Cognitive-behavioral dysfunctions, which can be interpreted as mild disturbances of consciousness, were also distinguished from significant disturbances of consciousness. The symptoms for each phase of the encephalitis are listed and summarized in Tables 1,2. In all cases, we also examined the prevalence of anti-NMDA receptor antibody positivity, EEG abnormalities, and cranial MRI abnormalities.

Additionally, because the recent literature has paid attention to the phenomenological characteristics of anti-NMDA receptor encephalitis in children [59, 60] and the elderly [61], we further divided the study into children and adolescents (0–19 years), adults (20–64 years), and the elderly (65 years and older).

The mean age of the 47 cases was 26.7 ($\pm$ 17.8) years, the minimum age was 17 months [34], and the maximum age was 77 years [50]. Thirty-seven cases (78.7%) were women. In all cases, 47 (100%) were positive for the anti-NMDA receptor antibodies, 26 (55.3%) had EEG abnormalities, and 16 (34.0%) had cranial MRI abnormalities.

Regarding the clinical course, 41 patients (87.2%) had a course that was consistent with the one outlined by Iizuka et al. [5]. Among the other six patients, the hyperkinetic phase preceded the unresponsive phase in four patients [23, 26, 30, 57], and the hyperkinetic phase preceded the psychotic phase in two patients [34, 43]. The symptoms described are listed in Table 1 and summarized in Table 2 according to the clinical course of the disease described above (i.e., the prodromal, psychotic, unresponsive, and hyperkinetic phases).

In terms of phenomenological characteristics by age, there were no major differences in the overall trends. However, in children, adolescents, and the elderly, irritability or aggression was common, and as a result, symptoms considered to be sudden personality changes were often observed. In the elderly, common cold-like symptoms were not seen, and delusions were seen in all cases. In children and adolescents, catatonic symptoms and motor disturbances seemed to be more common (however, please note that, due to the small number of these cases, we did not conduct statistical tests).

In this paper, the phenomenological features and clinical courses of anti-NMDA receptor encephalitis were examined across 47 cases. We also described some features that enable early differential diagnosis, especially between schizophrenia and anti-NMDA receptor encephalitis. We have highlighted that the concept of primary mental confusion in late 19th century French psychiatry is similar to what is known as anti-NMDA receptor encephalitis in our time.

However, because of the limited number of articles used in this paper, we could not examine as many cases as in previous studies; thus, further systematic and non-retrospective studies are necessary. Another limitation of this study is that we were not able to collect a sufficient number of cases involving children and the elderly. In recent years, the clinical features of anti-NMDA receptor encephalitis in children [59, 60] and the elderly [61] have become increasingly well understood. However, since no clear conclusion on the relationship between age and phenomenology has been reached, an exhaustive age-specific phenomelogical evaluation will be needed in the future.

Recently, the viewpoint that emphasizes the involvement of the NMDA receptor in schizophrenia has been taken seriously [74], and anti-NMDA receptor encephalitis may offer many suggestions on the pathology of schizophrenia. In that case, however, the same attention should be paid to the difference between anti-NMDA receptor encephalitis and schizophrenia, as discussed in this paper. In this sense, we believe that classical psychiatry can make a considerable contribution to the interpretation of biological research results.

TM designed the research study. RK and RT performed the research. RK and RT analyzed the data. RK and TM wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

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This research received no external funding.

The authors declare no conflict of interest.