Psychosis can be predominantly associated with psychiatric diseases, but a range of rare and insidious infectious (1, 2), metabolic (3), or autoimmune (4) disorders can produce presentations of psychotic symptoms that are challenging to distinguish from primary mental illness. A recently described (5) form of limbic autoimmune encephalitis (AE), caused by autoantibodies against N-methyl-D-aspartate receptors (NMDAR), often presents initially with psychotic symptoms, which then progress to involve neurological manifestations, such as abnormal movements, catatonia, seizures, and autonomic and respiratory dysregulation that can require intensive level care and be lethal if untreated (6). A recent large-scale prospective study among patients admitted for suspected anti-NMDAR AE (7) indicates a wide spectrum of neuropsychiatric manifestations, including psychotic and affective symptoms, catatonia, global cognitive dysfunction, seizures, and dyskinesias. This study further suggests that a fluctuating course of delirium and catatonic features may distinguish cases of anti-NMDA AE from others with similar presentations (7). The treatment of anti-NMDAR AE requires rapid initiation of immunomodulatory therapies, such as intravenous immunoglobulins (IVIG), steroids, rituximab, and cyclophosphamide (4, 8). Anti-NMDAR AE frequently develops as a paraneoplastic syndrome to teratomas of the ovaries, or, more rarely, of the testicles or mediastinum (9–11). It is more prevalent in females, and cases in male patients are rarely associated with tumors (12).

More recent studies indicate that infections with neurotrophic viruses, such as herpes simplex virus, can trigger flares of anti-NMDAR AE (13, 14). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 respiratory disease, has neurotrophic properties (15). A recent series of case reports in adult (16–18) and pediatric patients (19, 20) indicate that infection with SARS-CoV-2 could induce autoimmunity against NMDAR. While most of these cases were observed in patients hospitalized for severe COVID pneumonia with intensive-level care, the patient described here developed NMDAR AE after a mildly symptomatic COVID-19 disease that could have easily been overlooked in the context of a recent traumatic immigration experience. The case warrants caution both about the complex neuropsychiatric sequela of COVID-19 and vigilance about organic causes for psychiatric symptoms in complex psychosocial settings.

The following patient information was de-identified: A 17-year-old male adolescent, who had migrated from Mesoamerica to the United States 6 weeks prior to his initial hospital presentation, was brought to the emergency room after an episode of disorganized and aggressive behavior with delusional thoughts and auditory hallucinations. Multiple collateral sources, including the patient’s mother, with whom he had lived his entire life, confirmed that he had no prior psychiatric or medical history, other than myopia. He had never required or received psychiatric treatment, and there was no pertinent family history of mental illness. Upon entering the United States as an unaccompanied minor in December 2021, he was detained for 4 weeks after crossing the Mexican border. No behavioral abnormalities were noted during this period, but the patient had a fever of 38°C (100.4°F), along with nasal congestion, cough, and headache with positive rapid antigen testing for SARS-CoV-2 and a positive rapid streptococcal antigen test. A chest x-ray presented no abnormalities. He was treated with a five-day course of oral amoxicillin and further received vaccinations against hepatitis A, hepatitis B, human papilloma virus, influenza, meningococcus, measles, mumps, rubella, tetanus, diphtheria, pertussis, polio, and varicella. The patient later reported being held in social isolation for 15 days and experiencing a “change to his mind” along with problems with his memory during this period.

After being released from border detention, the patient went to stay with relatives in the United States. Initially, no behavioral or neurological abnormalities were noted; however, 1 week before his presentation, the patient likely experienced a generalized seizure with symptoms such as tongue biting, loss of consciousness, postictal paresis, and confusion, as later reported by his family. He also started to display intermittent aggression and endorsed auditory hallucinations of voices, which prompted his initial presentation to an outside hospital. The medical workup, including the basic bloodwork, urine toxicology (see Table 1), and a non-contrast computed tomogram (CT) of the head, was unremarkable. He was initially considered to be suffering from a primary psychotic disorder, started on risperidone, and transferred to our care 4 days later.

The present case raises a few points of clinical and academic importance: First, early symptoms of AE are often predominantly psychiatric, while neurological symptoms such as orofacial automatisms, motor anomalies, and seizures may develop only later in the course of the disease (22). This can cause detrimental delays in diagnosis and adequate treatment. In this particular case, psychosocial factors, such as trauma during detainment and separation from the family, can easily distract from the underlying diagnosis. However, the rapid onset of a psychotic syndrome with atypical features, such as visual hallucinations and intermittently altered mental status in a patient without prior psychiatric history, provides valuable guidance toward an underlying organic cause (4). Recent studies indicate that the symptoms displayed by the patient, namely delirium with psychotic features and catatonia, are indeed highly suggestive and characteristic of anti-NMDAR AE (7).

In cases like the present one, there should be no hesitation to assess for autoantibodies in serum and CSF, which was unfortunately delayed in this case. International consensus guidelines for pediatric anti-NMDAR AE suggest that the initiation of immunomodulatory treatment is crucial for clinical improvement and may be initiated even before laboratory confirmation of anti-NMDAR antibodies, especially if clinical symptoms are convincing and alternative diagnoses have been reasonably excluded (8), as was the case here. Recent studies further indicate that allosteric modulation of NMDAR may be a promising complementary treatment approach, particularly in refractory cases (23).

Second, an emerging association between the COVID-19 disease and NMDAR AE, if further substantiated in the future, should prompt differential diagnostic consideration in cases of acutely emerging psychiatric symptoms following after a recent SARS-CoV-2 infection as present in this case. While the association in this case does not imply causality, the temporal association between COVID-19 symptoms and development of anti-NMDAR AE in this and other cases (16–20), along with the known neurotropic properties of the SARS-CoV-2 virus (15, 24), suggests that autoimmunity could develop in response to exposure of neuronal antigens in the setting of acute infection, with a delayed onset of AE symptoms over the following weeks. In contrast to other reported cases of NMDAR AE after COVID-19 infection (17, 18), the patient reported here developed these symptoms in the absence of significant COVID symptoms and after a completely asymptomatic period of 2–3 weeks following full convalescence from COVID.

The key takeaway from the current case is that AE should be considered in cases of sudden-onset psychiatric symptoms in patients, even after mild or asymptomatic COVID-19 infection. This consideration is particularly crucial if there is no prior psychiatric history or if patients present with atypical symptoms such as fluctuating mental status or comorbid neurological symptoms.

“I’m feeling fine now. Before, everything was making me anxious. I cannot remember much about the time in the hospital but now things are normal again.”

The patient’s assessment describes both the psychotic and affective elements of his experience, leading up to hospitalization, as well as his rapid recovery after successful treatment. He reported ‘memory problems’ and exhibited impaired delayed recall early in his hospitalization. His report of amnesia for the hospitalization period is in line with the involvement of the limbic system in anti-NMDA AE.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

TH: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. LL: Conceptualization, Supervision, Writing – review & editing. TF: Conceptualization, Supervision, Writing – review & editing.