Anti-N-Methyl-D-Aspartate Receptor Encephalitis in a 17-Year-Old Female Patient with 3 Years of Follow-Up

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder characterized by neuropsychiatric manifestations, seizures, and autonomic instability. Predominantly affecting young females, it is often associated with ovarian teratomas. This article details a rare case of a 17-year-old female patient who presented with acute psychiatric symptoms, was initially misdiagnosed, and exhibited incomplete response to first-line immunotherapy. Despite the absence of second-line treatment, the patient achieved significant recovery over three years of follow-up, offering insights into the variable clinical trajectories of this condition.

Clinical Presentation and Initial Misdiagnosis

The patient, a previously healthy adolescent with no history of epilepsy or psychiatric disorders, developed abrupt-onset paranoia and behavioral changes. Within 11 days, her condition deteriorated to include confusion, low-grade fever, and generalized seizures. Initial evaluation at a mental health center led to a misdiagnosis of primary psychiatric illness. This highlights a critical challenge in managing anti-NMDAR encephalitis, as approximately 80% of cases initially manifest with psychiatric symptoms, including agitation, hallucinations, and personality changes.

Upon transfer to a tertiary hospital, the patient exhibited nonverbal status, unresponsiveness to stimuli, and bilateral Babinski signs. Notably, meningeal signs were absent. Laboratory investigations revealed an elevated erythrocyte sedimentation rate (58 mm/h), suggestive of systemic inflammation. Chest computed tomography indicated mild pulmonary infection, while abdominal, pelvic, and cranial imaging showed no structural abnormalities. Cerebrospinal fluid (CSF) analysis demonstrated mild pleocytosis (15 nucleated cells/mL), normal protein (0.40 g/L), glucose (3.81 mmol/L), and chloride (117.5 mmol/L) levels. Electroencephalography (EEG) revealed generalized slow-wave activity without epileptiform discharges, aligning with the non-specific encephalopathic patterns seen in early-stage anti-NMDAR encephalitis.

Diagnostic Challenges and Key Clinical Features

The patient’s clinical course was marked by two distinctive neurological phenomena: oro-lingual-facial dyskinesias and hypersalivation. The former, characterized by involuntary movements of the mouth, tongue, and face, is a recognized feature of anti-NMDAR encephalitis and often mistaken for seizure activity. The latter symptom, described as “bubbles of a crab” covering the nose and mouth due to excessive saliva production, represents an underreported manifestation. Hypersalivation in this context may reflect dysautonomia or direct antibody-mediated disruption of salivary control pathways.

Definitive diagnosis was confirmed via detection of NMDAR antibodies in both CSF and serum, meeting established diagnostic criteria. The absence of ovarian teratoma on imaging and during follow-up distinguishes this case from the 60% of patients with tumor-associated anti-NMDAR encephalitis.

Treatment Response and Immunotherapy Outcomes

Initial management included empiric antiviral therapy (intravenous acyclovir) and antiepileptic drugs. Upon serological confirmation of anti-NMDAR encephalitis, first-line immunotherapy was initiated: two cycles of intravenous immunoglobulin (IVIG; 0.4 g/kg/day for 5 days) and high-dose methylprednisolone (500 mg/day for 5 days). Despite these interventions, the patient’s psychiatric symptoms persisted, with a modified Rankin Scale (mRS) score of 5 (severe disability) at 4 weeks post-treatment.

Notably, second-line therapies such as rituximab or cyclophosphamide were not administered due to concerns over potential adverse effects. Contrary to expectations, the patient demonstrated gradual improvement after transfer to a rehabilitation facility. By 6 months, her mRS score improved to 2 (minimal disability), reflecting near-complete functional recovery. Three-year follow-up revealed no relapses or tumor development, underscoring the possibility of favorable outcomes even in severe, immunotherapy-resistant cases.

Pathophysiological and Therapeutic Considerations

Anti-NMDAR encephalitis arises from antibody-mediated internalization of NMDA receptors, leading to synaptic hypofunction and neuronal excitability changes. The prominence of psychiatric symptoms correlates with receptor density in frontal and limbic regions. While ovarian teratomas are a common trigger, the absence of neoplasia in this case suggests alternative antigenic stimuli, such as viral infections or genetic predispositions.

Current guidelines recommend tumor resection (if identified) combined with first-line immunotherapy. For non-responders, second-line agents targeting B-cell populations or broader immune suppression are advised. This case challenges the imperative for aggressive second-line therapy, as spontaneous recovery occurred despite early treatment resistance. Potential explanations include delayed antibody clearance, endogenous neuroplasticity, or subclinical immunomodulatory effects of initial therapies.

Long-Term Prognosis and Surveillance

The patient’s 3-year remission aligns with studies showing that 75–80% of patients achieve good outcomes with multimodal therapy. However, the risk of late-onset ovarian teratoma necessitates prolonged surveillance. Annual pelvic imaging is recommended for at least a decade post-diagnosis, as tumor emergence has been reported years after initial presentation.

Clinical Implications and Future Directions

This case reinforces several critical lessons:

1. Early Diagnosis: Anti-NMDAR encephalitis must be considered in adolescents presenting with acute psychiatric symptoms, particularly when accompanied by seizures or dyskinesias.
2. Phenotypic Variability: Hypersalivation and oro-lingual-facial dyskinesias are underrecognized features that can aid diagnosis.
3. Therapeutic Patience: Delayed responses to immunotherapy may occur, necessitating extended observation before escalating to riskier therapies.
4. Tumor Vigilance: Even in antibody-positive, tumor-negative cases, long-term oncological monitoring remains essential.

Future research should explore biomarkers predicting immunotherapy resistance and mechanisms underlying spontaneous recovery. Additionally, standardized protocols for rehabilitation in anti-NMDAR encephalitis could optimize functional outcomes.

doi.org/10.1097/CM9.0000000000000190

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