Understanding Anti-NMDA Receptor Encephalitis: A Young Woman's Medical Mystery

Table of Contents

• Case Presentation: A Sudden Onset of Symptoms
• Initial Hospital Course and Testing
• Differential Diagnosis: Considering All Possibilities
• Final Diagnosis and Treatment Approach
• Pathology Findings: Confirming the Cause
• Clinical Implications for Patients
• Limitations and Diagnostic Challenges
• Patient Recommendations and Key Takeaways
• Source Information

Case Presentation: A Sudden Onset of Symptoms

A previously healthy 19-year-old woman was admitted to Massachusetts General Hospital after experiencing 10 days of concerning symptoms. Her problems began with slowed speech and intermittent shaking and numbness in her right arm. Seven days before admission, bystanders witnessed her collapse on a subway platform with full-body shaking.

When emergency services arrived, she was confused, drooling, and had bitten her tongue. During ambulance transport to another hospital's emergency department, she gradually became more alert but had no memory of the subway incident. Her initial vital signs and physical examination were normal, but blood tests showed elevated lactate levels at 13.9 mmol/L (normal range: 0.7-2.1 mmol/L) and creatine kinase at 84 U/L (normal range: 30-135 U/L).

Other blood tests including electrolytes, glucose, liver enzymes, kidney function, and complete blood count were all normal. Imaging studies of her brain - both computed tomography (CT) and magnetic resonance imaging (MRI) performed without contrast - showed no abnormalities. Despite these normal findings, she was admitted to the hospital for further observation.

Initial Hospital Course and Testing

During her first hospital day at the outside facility, the patient experienced three episodes of sudden, intense fear and dread, each followed by full-body shaking lasting 60-90 seconds. During the third episode, she stopped breathing and her oxygen saturation dropped to 50% while breathing room air. Medical staff administered supplemental oxygen and started treatment with intravenous lorazepam and levetiracetam (anti-seizure medications).

On the second hospital day, doctors added lamotrigine (another anti-seizure medication) to her treatment regimen. She continued having episodes of stuttering speech. An electroencephalogram (EEG) performed on the third hospital day showed no evidence of electrical seizures or epileptic patterns in her brain. She was discharged on the fifth day with plans to continue levetiracetam and lamotrigine and follow up with neurology.

On the way home from the hospital, her parents noticed rhythmic mouth movements and right arm shaking. When they spoke to her, she would stare blankly without responding. They returned to the emergency department where she couldn't speak but could communicate by typing on her phone. She was readmitted to the outside hospital where she continued having intermittent muteness and right-sided twitching. Another EEG was reportedly normal, and she was discharged again after three days.

One day after this second discharge, her symptoms persisted with right arm numbness, twitching, and intermittent muteness. Her parents brought her to Massachusetts General Hospital's emergency department for further evaluation.

Differential Diagnosis: Considering All Possibilities

The medical team approached her complex presentation by grouping her symptoms into three categories: seizure-like activity, catatonia (a neuropsychiatric condition affecting movement and behavior), and psychotic symptoms. Her initial collapse with shaking, confusion, and elevated lactate levels suggested generalized seizures. The right-sided symptoms and feeling of dread were consistent with focal seizures originating from the left parietal lobe of the brain.

However, several factors didn't fit typical seizure disorders: the symptoms continued despite anti-seizure medications, and EEG tests repeatedly showed no epileptic activity. Her developing bizarre behaviors, variable speech patterns, and occasional muteness suggested possible catatonia. Her disorganized thinking and sense of mental fragmentation pointed toward psychotic symptoms.

The medical team systematically considered and ruled out numerous possibilities:

• Substance-induced psychosis: Unlikely given symptom persistence in a controlled hospital setting
• Infections: Herpes simplex virus (HSV), Lyme disease, tuberculosis, and neurocysticercosis were considered but ruled out through testing
• Autoimmune conditions: Multiple sclerosis, lupus, and vasculitis were unlikely given normal imaging and absence of characteristic symptoms
• Metabolic/endocrine disorders: Normal blood tests ruled out most possibilities
• Genetic conditions: Wilson's disease was unlikely without liver symptoms

The team ultimately focused on autoimmune encephalitis, particularly anti-NMDA receptor encephalitis, which commonly presents with psychiatric symptoms, seizures, and movement disorders in young women. This condition often associates with ovarian teratomas and frequently shows normal brain MRI results (in up to 50% of cases).

Final Diagnosis and Treatment Approach

The medical team reached a presumptive diagnosis of anti-NMDA receptor encephalitis while awaiting confirmatory antibody testing. They performed a lumbar puncture (spinal tap) which showed 19 white blood cells per microliter (normal: 0-5) with 89% lymphocytes, suggesting inflammation in the central nervous system. Cerebrospinal fluid (CSF) glucose and protein levels were normal.

They initiated empirical treatment with intravenous methylprednisolone (a steroid) on hospital day 3, followed by intravenous immune globulin (IVIG) on hospital day 6. These immunosuppressive treatments aim to reduce the antibodies attacking NMDA receptors in the brain. Imaging studies revealed a 17-centimeter ovarian mass containing fat, calcifications, and soft tissue, consistent with an immature teratoma.

On hospital day 7, the patient underwent surgery to remove the left ovary and fallopian tube (salpingo-oophorectomy) and a cyst removal from the right ovary (cystectomy). The pathological examination confirmed the diagnosis, showing immature teratoma tissue with primitive neuroepithelial components.

Pathology Findings: Confirming the Cause

The surgical specimens revealed significant findings. The left ovary measured 16.5 centimeters and contained mature tissue from all three germ layers (ectoderm, mesoderm, and endoderm), characteristic of teratomas. Critically, it also showed immature neuroepithelial tissue comprising approximately 70% of the tumor volume, with primitive cells showing brisk mitotic activity.

Additionally, the pathology showed components consistent with yolk-sac tumor, representing approximately 30% of the tumor volume. Immunohistochemical staining was positive for glypican-3 in both the immature teratoma and yolk-sac tumor components. On hospital day 11, serum testing confirmed the presence of antibodies targeting the glutamate NR1 subunit of NMDA receptors, definitively confirming the diagnosis of anti-NMDA receptor encephalitis.

Clinical Implications for Patients

This case illustrates several important clinical points for patients and families facing similar symptoms. Anti-NMDA receptor encephalitis typically affects young women and often presents with psychiatric symptoms, seizures, movement disorders, and cognitive changes. The condition can be mistaken for primary psychiatric illness, but the presence of neurological symptoms should prompt consideration of autoimmune causes.

Early diagnosis and treatment are critical for better outcomes. The condition is frequently associated with ovarian teratomas (in approximately 50% of young women with this diagnosis), making pelvic imaging an essential part of the diagnostic workup. Treatment involves immunotherapy (steroids and IVIG) and removal of any associated tumor, which often leads to significant improvement in symptoms.

Patients and families should know that recovery can be prolonged, often taking months to years, and may require extensive rehabilitation. However, with appropriate treatment, approximately 80% of patients achieve good functional recovery, though some may have residual cognitive or behavioral issues.

Limitations and Diagnostic Challenges

This case highlights several diagnostic challenges. The initial normal EEG and MRI findings delayed the diagnosis, as these tests are often normal in early anti-NMDA receptor encephalitis. The psychiatric symptoms initially overshadowed the neurological aspects, demonstrating how complex these cases can be.

Antibody testing for NMDA receptors takes 7-10 days, creating a diagnostic gap where clinicians must make treatment decisions based on clinical suspicion alone. In this case, CSF testing for antibodies couldn't be completed due to limited sample availability, though serum testing proved sufficient for diagnosis.

The case also shows how symptoms can evolve over time, beginning with seizure-like activity and progressing to include movement disorders and psychiatric symptoms. This progression pattern is characteristic but can be misinterpreted as separate conditions rather than different manifestations of the same disease process.

Patient Recommendations and Key Takeaways

For patients and families experiencing similar symptoms, this case offers several important recommendations:

1. Seek comprehensive evaluation when neurological and psychiatric symptoms occur together, especially in young women
2. Persist in seeking answers when initial tests are normal but symptoms continue or worsen despite treatment
3. Ask about autoimmune encephalitis as a possible cause when facing complex neuropsychiatric symptoms
4. Ensure complete testing including pelvic imaging in young women with suspected autoimmune encephalitis
5. Understand that recovery takes time and may involve multiple specialists including neurologists, psychiatrists, and rehabilitation therapists

This case demonstrates the importance of considering autoimmune causes for neuropsychiatric symptoms and the critical relationship between ovarian teratomas and anti-NMDA receptor encephalitis in young women. Early tumor removal combined with immunotherapy offers the best chance for recovery.

Source Information

Original Article Title: Case 22-2025: A 19-Year-Old Woman with Seizurelike Activity and Odd Behaviors

Authors: Judith A. Restrepo, M.D., Amirkasra Mojtahed, M.D., Leah W. Morelli, M.D., Nagagopal Venna, M.D., Gulisa Turashvili, M.D., Ph.D.

Publication: The New England Journal of Medicine, July 31, 2025, Volume 393, Pages 488-496

DOI: 10.1056/NEJMcpc2412531

This patient-friendly article is based on peer-reviewed research from the Case Records of the Massachusetts General Hospital.