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Arch Pediatr Crit Care > Volume 2(1); 2024 > Article
Song and Park: Anti‑N-methyl-D-aspartate receptor encephalitis in a 15-year-old girl: a case report

Abstract

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially fatal autoimmune disorder characterized by the production of antibodies against NMDAR. This condition leads to significant dysregulation of neurotransmission, resulting in a wide range of neuropsychiatric symptoms, including seizures, hallucinations, abnormal movements, and autonomic disturbances. Due to its diverse presenting manifestations, anti-NMDAR encephalitis is often underdiagnosed and can be misdiagnosed as viral or other types of encephalitis. Therefore, when clinical suspicion arises, testing for anti-NMDA receptor antibodies in cerebrospinal fluid or serum is crucial for an accurate diagnosis. Here, we report the case of a 15-year-old girl who initially presented with psychiatric symptoms and progressive mental changes, and was diagnosed with anti-NMDAR encephalitis. During the evaluation for paraneoplastic syndrome, a mature ovarian teratoma was discovered, and tumor resection was subsequently performed. She was treated sequentially with methylprednisolone, intravenous immunoglobulin, plasmapheresis, and rituximab. However, her altered mentality and intractable dyskinesia persisted. These symptoms were ultimately successfully managed with a combination of diazepam, dantrolene sodium hydrate, and olanzapine. An accurate early diagnosis and prompt intervention are crucial for improving the clinical outcomes of patients with anti-NMDAR receptor encephalitis. Dyskinesia is often present and can be quite intractable, indicating a need for evidence-based management guidelines.

INTRODUCTION

Since the novel detection of specific autoantibodies to the N-methyl-D-aspartate receptor (NMDAR) associated with paraneoplastic encephalitis, anti-NMDAR encephalitis has been recognized as a relatively common neuroinflammatory syndrome [1]. This condition disproportionately affects children and young women, with approximately 50% of the affected female patients having tumors, most commonly ovarian teratomas [2]. The presentation of the disease often involves multistage progression of symptoms or a variety of overlapping manifestations, making early recognition challenging [3-7].
Herein, we report the case of a young female adolescent who initially presented with a mild headache, which progressed to psychiatric symptoms. She was subsequently diagnosed with anti-NMDAR encephalitis in conjunction with an ovarian teratoma. The requirements for approval of the Institutional Review Board of Asan Medical Center (No. 2024-0736) and informed consent were waived.

CASE REPORT

A 15-year-old female adolescent with no significant medical history visited a secondary hospital with symptoms of itching, nausea, and headache 5 days prior to hospital admission. Two days before visiting the secondary hospital, she developed fever. An initial lumbar puncture and cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 1,400 cells/µL, protein level of 127 mg/dL, and glucose level of 67 mg/dL, with lymphocytic pleocytosis suggestive of meningitis. Although no organisms were observed on the Gram stain, she was started on antibiotics, including vancomycin and cefotaxime. Subsequently, she developed psychiatric symptoms and exhibited language deficits, dysarthria, and hallucinations. Brain magnetic resonance imaging (MRI) raised suspicions of herpes simplex virus (HSV) encephalitis, prompting the initiation of acyclovir therapy.
Following a CSF analysis that showed improvement (400 cells/µL, protein 127 mg/dL, and glucose 68 mg/dL), but persistent psychiatric symptoms, the patient was transferred to our hospital for further evaluation and management. At the emergency room of our hospital, she presented with short-term memory loss, emotional lability, anxiety, and involuntary twitching, leading to suspicion of focal motor seizures. This prompted the administration of levetiracetam. Based on outside brain MRI readings, her antibiotic regimen and acyclovir for suspected HSV encephalitis were maintained. Due to worsening consciousness and respiratory difficulty, she was transferred to the pediatric intensive care unit for intubation and mechanical ventilatory support. Electroencephalography (EEG) showed non-specific cerebral dysfunction without focal lateralizing or epileptiform discharges. A review of the outside brain MRI demonstrated subtle hyperintensity in the bilateral hippocampi, bilateral temporal lobes, and bilateral insula in T2 weighted images and fluid-attenuated inversion recovery (FLAIR) images (Fig. 1). These findings were highly suspicious for autoimmune encephalitis rather than HSV encephalitis, leading us to start intravenous methylprednisolone therapy (1 g) starting on the third day of hospitalization and lasting for 3 days, followed by intravenous immunoglobulin (400 mg/kg) for 5 days. Despite these treatments, the patient continued to exhibit abnormal movements and agitation, complicating the weaning from mechanical ventilation. Imaging evaluation for paraneoplastic syndrome on the seventh day of hospitalization revealed an ovarian mature cystic teratoma (Fig. 2), which was surgically resected on the ninth hospital day. Positive anti-NMDAR antibodies in the CSF confirmed the diagnosis of anti-NMDAR encephalitis on the 10th hospital day. Despite the surgical resection of teratoma, her symptoms persisted from the 13th hospital day. Plasma exchange was performed 10 times on a daily schedule based on the working days. However, the patient’s neuropsychiatric symptoms and dyskinesia did not improve. Furthermore, her severe orofacial dyskinesia led to the loss of several teeth (the right maxillary middle tooth, lateral tooth, and left middle tooth (#11, 12, 21), and the left lateral tooth (#22), tongue and lip lacerations, and damage to the endotracheal tube. Continuous chewing movements caused leakage in the endotracheal tube, necessitating a tracheostomy. Various medications, including midazolam, ketamine, haloperidol, quetiapine, tetrabenazine, and trihexyphenidyl, were used to manage her symptoms, albeit with limited success. Ultimately, rituximab therapy was initiated, along with continuous symptom monitoring and medication adjustments. Specifically, 500 mg of rituximab was administered once a week starting on the 29th day of hospitalization and lasting for 4 weeks. After 49 days of hospitalization, the patient showed clinical improvement and was transferred to a general ward for rehabilitation.
Follow-up brain MRI performed on the 90th day of hospitalization revealed a significant improvement of the previously noted subtle hyperintensity in FLAIR/T2 images, indicating a nearly resolved state of autoimmune encephalitis (Fig. 3). With gradual improvement, the patient was successfully weaned from mechanical ventilation, and the patient underwent tracheostomy removal. Following ongoing rehabilitation and recovery, she was discharged from the hospital with significant improvement in cognitive and neurological functions.
Over a 5-year follow-up, the patient's anti-NMDAR antibody status became negative 4 years after disease occurrence and remained stable, and no recurrent tumor was identified. The patient achieved near-complete mental recovery, eventually attending university.

DISCUSSION

This case involved anti-NMDAR encephalitis presenting with typical symptoms that align with established diagnostic criteria. These criteria require the rapid onset of at least four out of six major symptom groups: abnormal psychiatric behavior or cognitive dysfunction; speech dysfunction, including pressured speech, verbal reduction, or mutism; seizures; movement disorders, dyskinesias, or rigidity/abnormal postures; decreased level of consciousness; and autonomic dysfunction or central hypoventilation. Diagnostic confirmation is supported by abnormal EEG and/or CSF findings, which may include pleocytosis or oligoclonal bands, after reasonably excluding other disorders [8,9].
Autoimmune encephalitis is the most common and treatable form of the condition, typically preceded by nonspecific prodromal symptoms such as headaches, low-grade fevers, or symptoms of an upper respiratory infection. These initial signs are followed within 2 weeks by profound neuropsychiatric manifestations, including short-term memory loss, language deficits, delusions, hallucinations, seizures, and disturbed consciousness [4,7,10,11]. Mechanistically, the characteristic psychiatric symptoms are believed to result from NMDA receptor hypo-function, which occurs when autoantibodies bind to the GluN1 subunit of the receptor, leading to its internalization [10,12,13].
NMDAR encephalitis is a rare paraneoplastic neurological syndrome. Notably, there is an association between NMDAR encephalitis and an underlying neoplastic condition, with approximately 38% of cases linked to ovarian teratomas [2,13]. Ovarian teratomas may contain both mature and immature neuronal tissues that express NMDA receptors, potentially contributing to the synthesis of autoantibodies. These antibodies can then cross-react with NMDA receptors in the neuronal system [7,11,13].
The diagnosis of this condition is based on typical clinical manifestations and the progression of symptoms. Brain MRI often reveals subtle T2 or FLAIR sequence hyperintensities in the hippocampal, frontobasal, insular, or basal ganglia regions in approximately 50% of cases. EEG may also show abnormal findings in up to 90% of cases [2,9]. The confirmative test is anti-NMDAR antibodies in the CSF or serum [10,14].
In this case, due to early suspicion and a positive confirmative test for anti-NMDAR antibodies in the CSF, a prompt diagnosis was made, including the detection of an ovarian teratoma. The primary treatment strategies include immunomodulation with high-dose steroids, plasmapheresis, and immunoglobulin. Rituximab and cyclophosphamide are considered as second-line therapies. Tumor removal is recommended as a crucial step for controlling the causal factor, which reportedly leads to rapid clinical improvement [9,14]. However, in this patient, despite aggressive management involving tumor resection and early initiation of immune therapy, the symptoms did not improve rapidly.
As well as psychiatric symptoms, focal motor seizures present at a relatively early period of the disease and sometimes overlap with movement disorders, such as ataxia, catatonia, choreiform movements, and dyskinesia during disease progression [10]. This overlap of abnormal movements and complex seizures can create clinical dilemmas and lead to misinterpretations, potentially resulting in the unnecessary over- or under-dosing of antiepileptic drugs or other medications used to control dyskinesia. Although the mechanisms behind these phenomena are not fully understood, they are thought to be related to receptor hyperfunction [13].
Dyskinesia is one of the most troubling symptoms of the disease, commonly presenting in most patients and often including orofacial dyskinesia [12]. The severe form of dyskinesia can lead to self-injury or rhabdomyolysis [15-17], necessitating the use of anesthetics or neuromuscular blockers in the intensive care unit setting. This patient exhibited a severe form of dyskinesia, particularly orofacial dyskinesia, which resulted in the loss of several teeth, lacerations to the lips and tongue, and significant mouth bleeding. Management was consistent with previous reports, employing sedatives, neuromuscular blockers, botulinum toxin, and immunomodulation [16,18]. Other researchers have suggested tramadol, benzodiazepines, or a mega-dose of diazepam for managing symptoms [14,15,19]. In this case, neuromuscular blockers, antipsychotics, and benzodiazepines were combined for symptom control. Although there is no definitive evidence-based gold standard treatment protocol for recovering from dyskinesia, given its incidence and significance, a consensus-based recommendation is required.
The prognosis is dependent on various factors. Approximately 80% of affected patients recover or continue to experience mild sequelae, while the remaining 20% may encounter severe deficits or die [2,10]. Favorable outcomes are associated with early diagnosis and the prompt initiation of immunomodulatory management, along with tumor elimination if feasible [20].
In conclusion, anti-NMDAR encephalitis is an antibody-mediated autoimmune disorder, often linked with paraneoplastic syndrome. The clinical presentation of this condition can vary significantly, and the overlapping symptoms and progression of the disease make early diagnosis difficult. Therefore, maintaining a high level of suspicion and conducting a thorough evaluation, which includes testing for NMDAR antibodies, is crucial for achieving a timely and accurate diagnosis.
The primary treatment approach involves immunomodulation. Should initial therapy prove unsuccessful, second-line treatments, including rituximab and/or cyclophosphamide, may be considered. Dyskinesia is a common symptom among patients with this condition; however, managing dyskinesia can be challenging. There is a need for evidence-based guidelines to effectively control this difficult aspect of the disease.

ARTICLE INFORMATION

CONFLICT OF INTEREST
Seong Jong Park is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
AUTHOR CONTRIBUTIONS
Conceptualization: all authors. Visualization: HS. Project administration: HS. Writing - original draft: all authors. Writing - review & editing: all authors.

Fig. 1.
Brain magnetic resonance imaging. (A) T2-weighted and (B) fluid-attenuated inversion recovery imaging findings show subtle hyperintensity in the bilateral hippocampi, temporal lobes, and insula (arrows).
apcc-2024-00059f1.jpg
Fig. 2.
Computed tomography of the abdomen and pelvis shows a 2.4-cm cystic mass (arrows) with a possible gross fat component in the left adnexa, suggesting a mature ovarian teratoma, left. (A) Coronal view. (B) Axial view.
apcc-2024-00059f2.jpg
Fig. 3.
Follow-up brain magnetic resonance imaging. (A) T2-weighted and (B) fluid-attenuated inversion recovery (FLAIR) imaging findings show nearly complete resolution of the previously noted subtle FLAIR/T2 hyperintensity in the bilateral hippocampi, bilateral temporal lobes, and bilateral insula, suggesting improvement of presumed autoimmune encephalitis.
apcc-2024-00059f3.jpg

REFERENCES

1. Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61:25-36.
crossref pmid pmc
2. Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157-65.
crossref pmid pmc
3. Tirado-García LA, Piña-Ballantyne SA, Cienfuegos-Meza J, Tena-Suck ML. Anti-N-methyl-D-aspartate receptor encephalitis with diffuse demyelinating plaques: a case report of an atypical presentation. Cureus 2023;15:e41595.
crossref pmid pmc
4. Steeman A, Andriescu I, Sporcq C, Mathieu D, Meurant V, Mazairac G. Case report of anti-NMDA receptor encephalitis in a 24-year-old female: an uncommon presentation. Egypt J Neurol Psychiatr Neurosurg 2022;58:79.
crossref pmid pmc pdf
5. Bu Y, Zhang T, Guo J. Case report: anti-N-Methyl-D-Aspartate receptor encephalitis and bilateral temporal calcifications. BMC Neurol 2020;20:386.
crossref pmid pmc pdf
6. Pavǎl D, Cîmpan CM, Gherghel N, Damian LO, Tohǎnean N, Micluţia IV. Case report: anti-N-methyl-D-aspartate receptor encephalitis manifesting with an isolated psychiatric episode and normal ancillary tests. Front Psychiatry 2022;13:905088.
crossref pmid pmc
7. Luo Y, Li J, Jiang F, Tan A, Qin X, Xiao X, et al. Autoimmune encephalitis with psychotic manifestations and cognitive impairment presenting as schizophrenia: case report and literature review. Front Psychiatry 2022;13:827138.
crossref pmid pmc
8. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391-404.
crossref pmid pmc
9. Nguyen L, Wang C. Anti-NMDA receptor autoimmune encephalitis: diagnosis and management strategies. Int J Gen Med 2023;16:7-21.
crossref pmid pmc pdf
10. Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol 2019;18:1045-57.
crossref pmid
11. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med 2018;378:840-51.
crossref pmid
12. Masdeu JC, Dalmau J, Berman KF. NMDA receptor internalization by autoantibodies: a reversible mechanism underlying psychosis? Trends Neurosci 2016;39:300-10.
crossref pmid pmc
13. Alzghoul H, Kadri F, Ismail MF, Youssef R, Shamaileh M, Al-Assi AR, et al. Paraneoplastic NMDA encephalitis, a case report and an extensive review of available literature. Radiol Case Rep 2024;19:1371-85.
crossref pmid pmc
14. Barry H, Byrne S, Barrett E, Murphy KC, Cotter DR. Anti-N-methyl-D-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment. BJPsych Bull 2015;39:19-23.
crossref pmid pmc
15. Lee ST. Symptomatic treatments of N-methyl-D-aspartate receptor encephalitis. Encephalitis 2021;1:4-6.
crossref pmid pmc pdf
16. Zheng F, Ye X, Shi X, Poonit ND, Lin Z. Management of refractory orofacial dyskinesia caused by anti-N-methyl-D-aspartate receptor encephalitis using botulinum toxin. Front Neurol 2018;9:81.
crossref pmid pmc
17. Lim JA, Lee ST, Kim TJ, Moon J, Sunwoo JS, Byun JI, et al. Frequent rhabdomyolysis in anti-NMDA receptor encephalitis. J Neuroimmunol 2016;298:178-80.
crossref pmid
18. Haq AU, Nabi D, Alam M, Ullah SA. The spectrum of movement disorders in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis both in children and adults: an experience from a single tertiary care center. Cureus 2021;13:e20376.
crossref pmid pmc
19. Seifi A, Kitchen DL. Management of dyskinesia in anti-NMDAR encephalitis with tramadol. Clin Neurol Neurosurg 2016;147:105-7.
crossref pmid
20. Sühs KW, Wegner F, Skripuletz T, Trebst C, Tayeb SB, Raab P, et al. Heterogeneity of clinical features and corresponding antibodies in seven patients with anti-NMDA receptor encephalitis. Exp Ther Med 2015;10:1283-92.
crossref pmid pmc
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