Exploring the Complexities of Anti-NMDAR Encephalitis: A Discussion on Psychiatric Presentations, COVID-19 Associations and Timely Diagnosis and Treatment


Psychosis is a complex and multifaceted condition that, while commonly associated with psychiatric diseases, can also be a manifestation of various infectious, metabolic, and autoimmune disorders. A notable example is the autoimmune disorder known as limbic autoimmune encephalitis (AE), which can be induced by autoantibodies targeting N-methyl-D-aspartate receptors (NMDAR).

This condition often begins with psychotic symptoms before progressing to more severe neurological complications, such as abnormal movements, catatonia, seizures, and autonomic and respiratory dysregulation. These symptoms can be severe and potentially lethal if not properly treated.

The treatment for anti-NMDAR AE involves prompt initiation of immunomodulatory therapies like intravenous immunoglobulins, steroids, rituximab, and cyclophosphamide.

Interestingly, anti-NMDAR AE often develops as a paraneoplastic syndrome, particularly in association with ovarian teratomas. It is more prevalent in females, though rare cases in males have been documented. Recent research has also highlighted the potential role of infections, including herpes simplex virus and SARS-CoV-2 (the virus responsible for COVID-19), in triggering anti-NMDAR AE.

These findings underscore the complexity of the condition and the importance of considering organic causes in the differential diagnosis of psychotic symptoms, especially in patients with a history of recent infection or other medical conditions.

A striking case that illustrates these complexities involved a 17-year-old male adolescent who migrated from Mesoamerica to the United States. Six weeks after his arrival, he presented with disorganized and aggressive behavior, delusional thoughts, and auditory hallucinations. This presentation was particularly challenging as he had no prior psychiatric or medical history. Upon further evaluation, it was revealed that the patient had experienced a mild case of COVID-19, which might have been overlooked due to his traumatic immigration experience.

The patient’s journey through the healthcare system highlights the difficulties in diagnosing such complex cases. Initially, his symptoms were thought to be primarily psychiatric, but further evaluation revealed a fluctuating course of symptoms, including delirium and catatonic features, which suggested the possibility of anti-NMDAR AE. This diagnosis was eventually confirmed through cerebrospinal fluid testing.

Treatment for this patient involved a combination of antipsychotic medications and antiepileptic drugs, but significant improvement was only seen after the initiation of immunomodulatory therapy. This case underscores the need for a high index of suspicion for autoimmune encephalitis in patients presenting with new-onset psychosis, particularly when accompanied by a recent history of infection or other atypical features.

The patient’s eventual recovery also highlights the effectiveness of appropriate treatment for anti-NMDAR AE. However, it raises questions about the long-term management of such patients, especially in the context of discontinuing medication and monitoring for relapse.


The presented case highlights several critical clinical and academic considerations, shedding light on the complexities of diagnosing and treating Anti-NMDAR Encephalitis (AE), particularly in the context of psychiatric symptoms and their potential link to COVID-19.

Psychiatric Predominance and Delayed Neurological Symptoms in AE

One noteworthy aspect of this case is the prominence of psychiatric symptoms in the early stages of AE. AE often begins with psychiatric manifestations, which can make it challenging to differentiate from primary psychiatric disorders. In this case, the patient initially exhibited psychiatric symptoms, including a rapid onset of a psychotic syndrome marked by visual hallucinations and intermittently altered mental status.

Notably, the absence of prior psychiatric history provided a crucial clue pointing towards an underlying organic cause. This observation emphasizes the importance of considering AE in patients with psychiatric symptoms, especially when atypical features are present, as they can guide clinicians toward a more accurate diagnosis (4).

Early recognition of these clues is essential to prevent delays in diagnosis and treatment, which can be detrimental to patient outcomes (22).

Timely Assessment for Autoantibodies in Serum and CSF

In this case, there was a regrettable delay in assessing for autoantibodies in both serum and cerebrospinal fluid (CSF). Prompt detection and diagnosis are essential for initiating appropriate immunomodulatory treatment, even in the absence of laboratory confirmation of anti-NMDAR antibodies.

This aligns with international consensus guidelines for pediatric anti-NMDAR AE, which stress the importance of early treatment initiation based on clinical symptoms when alternative diagnoses have been reasonably ruled out (8). In this instance, the patient’s clinical presentation was highly suggestive of anti-NMDAR AE, warranting a swift intervention. Recent studies also suggest that allosteric modulation of NMDAR may hold promise as a complementary treatment approach, particularly in refractory cases (23). Therefore, this case underscores the significance of a multidisciplinary approach and the need for rapid assessment of autoantibodies to ensure timely and effective treatment.

The Emerging Link Between COVID-19 and NMDAR AE

An intriguing aspect of this case is the temporal association between COVID-19 and the subsequent development of anti-NMDAR AE. While this association does not imply causality, it does raise important questions about the relationship between these two conditions. Recent evidence suggests a potential link between COVID-19 and the development of AE, particularly in cases where psychiatric symptoms emerge after a recent SARS-CoV-2 infection (16–20).

Given the known neurotropic properties of the SARS-CoV-2 virus (15, 24), it is plausible that autoimmunity could arise as a response to neuronal antigen exposure during acute infection, leading to a delayed onset of AE symptoms over the following weeks. Importantly, this case is distinct from other reported instances of NMDAR AE following COVID-19, as the patient developed these symptoms after a completely asymptomatic period of 2–3 weeks following full convalescence from COVID.

Implications for Clinical Practice

This case serves as a crucial reminder that AE should be considered in cases of abrupt-onset psychiatric symptoms, especially in patients with no prior psychiatric history. This consideration becomes even more imperative when patients exhibit atypical symptoms, such as fluctuating mental status or concomitant neurological manifestations.

Given the potential link between COVID-19 and AE, clinicians should maintain a high index of suspicion for AE, even in individuals who have recently recovered from mild or asymptomatic COVID-19. Rapid diagnosis and treatment initiation are pivotal to optimize outcomes in AE cases, underscoring the need for close collaboration among various medical specialties and the timely assessment of autoantibodies.

In conclusion, this case exemplifies the complexity of diagnosing and managing AE, particularly when it presents with psychiatric symptoms and when there is a temporal association with COVID-19. It underscores the importance of early recognition, multidisciplinary collaboration, and timely intervention in optimizing patient outcomes in such challenging cases. Further research is warranted to better understand the relationship between COVID-19 and AE, paving the way for improved diagnostic and treatment strategies in the future.

reference link : https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1270572/full



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