A rare case of anti–NMDA receptor encephalitis presenting with subacute neuropsychiatric symptoms in an older patient

Abstract

Anti–NMDA receptor encephalitis is a rare autoimmune condition that often presents with delirium and seizures. While classically associated with younger women and ovarian teratomas, it can occur across a broader demographic and mimic a psychotic disorder or metabolic conditions. This case describes a 59-year-old woman with a history of fibromyalgia and depressive disorder who presented with subacute delirium, behavioral disturbances, and incontinence. Initial evaluations were unrevealing, and early diagnostic considerations attributed her presentation to a psychotic disorder. However, further workup, including cerebrospinal fluid antibody testing, confirmed anti–NMDA receptor encephalitis. This case underscores the diagnostic challenges posed by autoimmune encephalitis and highlights the importance of maintaining a broad differential. Anchoring bias and premature diagnostic closure can delay life-saving treatment; clinicians must remain vigilant when evaluating unexplained subacute neuropsychiatric decline.

KEY POINTS

• Anti-NMDA receptor encephalitis is a rare autoimmune encephalitis that may present with delirium, seizures, and symptoms attributable to a psychotic disorder.

• Viral infections, including herpes simplex virus and COVID-19, are potential postinfectious triggers.

• Diagnosis relies on cerebrospinal fluid testing for anti-NMDA receptor antibodies.

• Early recognition and immunosuppression are associated with improved outcomes in all psychiatric domains and reduced disease severity.

CME

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CASE SUMMARY

A 59-year-old woman with hypothyroidism, hypertension, type 2 diabetes mellitus, fibromyalgia, and recent COVID-19 infection presented with delirium and urinary and fecal incontinence. Initial evaluation in the emergency department, including neuroimaging, laboratory studies, and lumbar puncture, was unrevealing. She was referred to psychiatry for presumed depressive disorder without inpatient psychiatric admission, but progressive neurological decline, including worsening delirium, incontinence, behavioral changes, and repetitive nonsensical speech, led to hospital admission. Repeat cerebrospinal fluid (CSF) analysis showed elevated mononuclear cells without evidence of infection or malignancy. Brain magnetic resonance imaging (MRI) and electroencephalogram demonstrated no acute intracranial abnormalities. She received empiric treatment with antivirals, high-dose intravenous corticosteroids (methylprednisolone 1 g daily for 5 days), and five sessions of plasmapheresis without clinical improvement. A CSF autoimmune panel later returned positive for anti-NMDA receptor antibodies (titer 1:320), establishing the diagnosis. She was treated with intravenous immunoglobulin (2 g/kg), followed by rituximab (2 doses).

Her hospital course was complicated by aspiration pneumonia, status epilepticus, and methicillin-sensitive Staphylococcus aureus bacteremia. She required intubation, antibiotic therapy, tracheostomy, and percutaneous endoscopic gastrostomy (PEG) tube placement. A comprehensive malignancy evaluation, including outpatient pelvic imaging, was recommended.

Over the months following discharge to long-term acute care, the patient was subsequently transferred to an inpatient neurology service for continued management and rehabilitation. She has shown gradual neurologic improvement, though recovery has been slow, and she later underwent decannulation and PEG tube removal prior to discharge home near her premorbid functional baseline. She required relearning of activities of daily living, remains on antiseizure medication, and will likely require ongoing intensive rehabilitation with potential for residual neurologic deficits.

CLINICAL QUESTIONS

1. Anti-NMDA receptor encephalitis is classically associated with which underlying condition in women?

   1. Breast carcinoma

   2. Ovarian teratoma

   3. Endometrial carcinoma

   4. Cervical dysplasia

2. A 59-year-old woman presents with subacute onset of delirium following a recent viral illness. Initial evaluation, including brain MRI and routine CSF studies, is unrevealing. Given continued neurologic decline, autoimmune encephalitis is suspected, including anti-NMDA receptor encephalitis. What is the most appropriate next diagnostic step to confirm the diagnosis?

   1. Repeat brain MRI with contrast at regular intervals

   2. Serum autoimmune antibody testing alone

   3. CSF autoimmune encephalitis antibody testing

   4. Long-term electroencephalographic monitoring

Answers are provided at the end of the article.

DISCUSSION

Anti-NMDA receptor encephalitis is a rare but increasingly recognized cause of autoimmune encephalitis, with an estimated incidence of 1.5 per million people per year.¹ It is mediated by IgG antibodies targeting the GluN1 (NR1) subunit of the NMDA receptor and is classically associated with young women and ovarian teratomas, although it can occur across all age groups and in the absence of neoplasm.^2,3 The clinical presentation typically involves a subacute onset of psychiatric symptoms, speech disturbance, seizures, movement disorders, and autonomic instability.⁴ Infectious triggers, most notably herpes simplex virus, are well documented; more recent studies suggest that COVID-19 may act as a potential trigger through molecular mimicry mechanisms.^5–7 Anti-NMDA receptor encephalitis should be considered in patients with rapidly evolving neuropsychiatric symptoms, particularly when initial infectious, metabolic, or psychiatric workups are unrevealing.⁴ Early diagnosis and treatment are associated with improved outcomes, although the ideal window for immunosuppression has not been clearly established.⁴

ANSWERS TO CLINICAL QUESTIONS

Question 1, b. Anti-NMDA receptor encephalitis is strongly associated with ovarian teratomas due to ectopic expression of NMDA receptor subunits within neural tissue present in the tumor. Although most commonly observed in younger women, this association can occur at any age. Identification and removal of an associated teratoma is linked to improved neurologic outcomes and reduced relapse risk.³

Question 2, c. NMDA receptor encephalitis may present with normal neuroimaging and nonspecific CSF findings early in the disease course. CSF antibody testing is the most sensitive and specific diagnostic modality and is essential for timely diagnosis. Early confirmation facilitates prompt initiation of immunotherapy and improves outcomes.³

Disclosure statement/Funding

The planners and faculty for this activity have no relevant financial relationships to disclose. The authors report no funding. The patient consented to publication of this case report.