Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis associated with mature ovarian teratoma: a case report

Abstract

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is an autoimmune condition often characterized by acute neuropsychiatric manifestations, including psychiatric symptoms, seizures, autonomic instability, and cognitive dysfunction. Early diagnosis and treatment are crucial for improving patient outcomes.

This report presents the case of a 27-year-old woman with known anti-NMDA receptor encephalitis who experienced progressive worsening of confusion, memory loss, and agitation. The patient was transferred to a tertiary care center for further evaluation and treatment. A computed tomography scan with contrast showed a 40 mm complex mass in the right adnexa, consistent with ovarian teratoma. The patient was hospitalized for 37 days, requiring immunotherapy, neurologic, psychiatric, cardiovascular, and operative management. The ovarian teratoma was successfully removed via robotic-assisted right salpingo-oophorectomy.

This case underscores the importance of surgical management of ovarian teratoma in a reproductive-aged woman with anti-NMDA receptor encephalitis. A multidisciplinary approach should be employed, and individualized treatment should be tailored to the patient's clinical status. Optimal treatment strategies for anti-NMDA receptor encephalitis are lacking. Further research is needed.

Highlights

• •Anti-NMDA receptor encephalitis with ovarian teratoma requires prompt recognition.
• •NMDA antibodies in cerebrospinal fluid are diagnostic, despite nonspecific imaging.
• •Patients with NMDA receptor encephalitis often display dysautonomic sequelae.
• •Surgical intervention with immunotherapy was associated with gradual recovery.

1. Introduction

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a rare, rapidly progressive condition that can be associated with ovarian teratomas [1], [2], [3], [4], [5], [6], [7]. Ovarian teratomas are germ cell tumors, most commonly presenting in young women of childbearing age, with a very low risk of malignant transformation [4]. Ovarian teratomas contain two to three germ layers and have been found to contain neural tissue that may express NMDA receptor-related antigens and trigger an autoimmune response [1], [6], [7], [8]. Appropriate medical and surgical management is controversial and debated [4]. Timing of surgery, along with the selection of the surgical procedure, appears to influence the reversibility of deficits and recurrence rate, along with the likelihood of full recovery [3], [6], [7], [9], [10]. This case is presented to raise awareness of this rare condition among gynecologists in the event of surgical consultation with an emphasis on the complete recovery of this patient following surgical intervention [4], [11], [12].

2. Case Presentation

A 27-year-old woman with an unremarkable past medical history initially presented to an outside hospital emergency room four days prior to admission for evaluation following a syncopal episode in her home that caused her to hit her head. Notably, following the syncopal event, the patient endorsed brain fog followed by worsening confusion. Upon presentation to the outside hospital, initial workup with computed tomography (CT) of the brain was unremarkable for parenchymal or meningeal attenuation. An electrocardiogram (EKG) showed evidence of new-onset atrial fibrillation. Mobile cardiac outpatient telemetry (MCOT) and echocardiogram were arranged to support outpatient management and the patient was discharged.

The following day, the patient presented to her gynecologist office for further evaluation of continued confusion, now accompanied by memory loss. Her gynecologist referred the patient to the outside hospital emergency room once more, secondary to the patient's clinical presentation. On re-presentation to the outside hospital emergency room, the initial workup was performed by the emergency room physician. Her vital signs were stable and her physical exam, including a neurological exam, revealed decreased concentration without additional abnormalities. A complete blood count (CBC) and comprehensive metabolic panel (CMP) were unremarkable. Additional laboratory tests for zoonotic infectious causes were obtained and were negative for West Nile virus antibody, Rocky Mountain spotted fever virus antibody, and Lyme disease. Neurology was consulted and the patient was admitted to the outside hospital for further workup.

3. Diagnostic Assessment

Brain magnetic resonance imaging (MRI) with and without contrast, obtained at the outside hospital, demonstrated no visible enhancement of brain parenchyma or meninges. A lumbar puncture with cerebrospinal fluid (CSF) studies was obtained and was remarkable for protein elevation (64.0) with normal values for glucose and cell count. Her meningitis/ encephalitis panel was negative. CSF anti-NMDA receptor antibodies were positive (1:80), confirming the diagnosis.

The patient began demonstrating hallucinatory behavior, progressive agitation and subsequently became combative and unresponsive to de-escalation. The patient was intubated, mechanically ventilated, and sedated. An electroencephalogram (EEG) revealed abnormal findings predominantly during the sleep state, with mild to moderate generalized slowing consistent with generalized encephalopathy, but no evidence of epileptiform findings. The patient was later deemed appropriate for extubation; however, she continued to exhibit altered mental status and dysautonomia.

Upon presentation to the tertiary care center, EKG findings indicated continued atrial fibrillation with variable atrioventricular (AV) block. Transthoracic echocardiogram showed no significant abnormalities. The patient continued to demonstrate inability to swallow, with episodes of coughing and choking on her saliva and oral secretions with episodic decreased oxygen saturation while utilizing nasal cannula for oxygenation support. With concern for potential aspiration of oral secretions, a chest CT scan with contrast was obtained and demonstrated patchy ground glass opacities but was otherwise unremarkable.

As the patient demonstrated continued deterioration after arrival at the tertiary care center, the decision was made to obtain a CT scan of the abdomen/ pelvis with contrast, given the discovery of positive CSF anti-NMDA receptor antibodies earlier in her hospital course. The scan revealed a right adnexal mass measuring 3.1 cm × 4.0 cm containing fluid, fat, and calcifications, consistent with an ovarian teratoma. A transvaginal ultrasound scan was then obtained, which demonstrated a 3.7 cm × 5.4 cm × 5.2 cm right ovary with normal arterial and venous flow, remarkable for foci of hyperechogenicity and shadowing within the right ovary, consistent with ovarian teratoma.

4. Therapeutic Intervention

Five days after re-presentation to the outside hospital emergency department with subsequent admission, intravenous methylprednisolone sodium succinate (Solu-Medrol) (1 g daily) and intravenous immunoglobulin (IVIG, 0.4 g/kg) were initiated, each for five days. The patient was then transferred to a tertiary care center for further neurologic evaluation and treatment accompanied by ongoing family concerns regarding the patient's health status. Neurologic evaluation revealed moaning without identifiable words and purposeless movements of both arms that progressed to erratic hand clapping. The patient's mental status continued to deteriorate and she began to demonstrate catatonia-like symptoms, including mutism and inability to swallow. Psychiatry was consulted for further recommendations and management of catatonia-like symptoms. Intravenous lorazepam (Ativan) 2 mg every six hours, memantine 5 mg twice per day, and a one-on-one patient sitter were recommended.

The patient demonstrated several supraventricular tachycardia bursts with heart rates in the 180 s, non-sustained ventricular tachycardia, and intermittent atrial fibrillation on EKG on hospital day 2 at the tertiary care center. During these episodes, her systolic blood pressure remained in normal range. High-sensitivity troponin-I was 0.01, B-type natriuretic peptide (BNP) was 287, and thyroid-stimulating hormone (TSH) was 0.94. Cardiology was consulted for further evaluation and management. Diltiazem 60 mg four times daily and intravenous metoprolol as needed for treatment of breakthrough supraventricular tachycardia were initiated. The patient began demonstrating episodes of atrial fibrillation with rapid ventricular response and sustained narrow complex supraventricular tachycardia with a heart rate up to 185 requiring abortive intravenous pushes of adenosine. The patient required an esmolol drip initially which was subsequently discontinued and an amiodarone drip was initiated. Attempts to decrease the amiodarone drip resulted in episodes of atrioventricular nodal reentry tachycardia (AVNRT) and intermittent atrial fibrillation when not in AVNRT. Subsequently, the patient received a digoxin 250 μg load followed by 125 μg every six hours. Electrophysiology was consulted; however, a decision was made to defer potential cardiac ablation, as the patient's anti-NMDA receptor encephalitis was thought to contribute to autonomic instability, resulting in the development of various arrhythmias, given that the patient did not have a previous history of arrhythmias.

Following the discovery of the right ovarian teratoma, gynecologic oncology was consulted for surgical management. Secondary to the patient's worsening paroxysmal atrial fibrillation and new-onset episodes of AVNRT following the discovery of the ovarian teratoma, surgical intervention was delayed approximately seven days until she was deemed hemodynamically stable. The patient underwent a robotic-assisted right salpingo-oophorectomy with surgical pathology revealing a mature ovarian teratoma. Approximately 48 h following ovarian teratoma removal, the patient displayed seizure-like activity with unchanged brain MRI and EEG findings when compared to prior evaluation. Due to continued concerns regarding catatonia-like symptoms and mutism five days following ovarian teratoma removal, a right internal jugular central line was placed, and a course of rituximab was administered. Forty-eight hours following the initiation of rituximab, the patient was arousable but somewhat agitated, intermittently followed commands, and she began to make purposeless movements with her upper extremities. Ninety-six hours following the initiation of rituximab, the patient began to demonstrate evidence of experiencing hallucinations along with confusion and paranoia. Approximately 7 days following the initiation of rituximab, the patient was alert and oriented to person, place, and time, she answered questions appropriately, was able to sit up in bed, and eat pureed foods as well as swallow oral medications. At this time, a prednisone taper was started, and the patient was evaluated by physical and occupational therapy.

5. Follow-up and Outcomes

The patient was discharged to an acute neurorehabilitation facility following a 37-day hospital course. Her hospital course was complicated by AVNRT and paroxysmal atrial fibrillation, for which she was administered intravenous amiodarone and digoxin, later transitioned to oral medication with outpatient follow-up. The patient completed a taper of prednisone, memantine, and lorazepam. At the time of writing, the patient continues regular follow-up with a neurological specialty clinic. It has been noted that she has resumed most of her personality characteristics. She reported two episodes of bed-wetting and facial asymmetry, but otherwise her anatomic and cognitive functional status had returned to her baseline. The patient completed neurorehabilitation and neuropsychological testing, which did not demonstrate neurologic impairment. The patient returned to work four months after hospitalization and continues regular follow-up with neurology, psychiatry, cardiology, and gynecologic oncology. She most recently underwent a cardiac ablation for continued AVNRT. She herself reports complete recovery.

6. Discussion

This case highlights the unique presentation of anti-NMDA encephalitis, a rare complication of ovarian teratoma. The variable and progressive neurologic presentation of anti-NMDA encephalitis was not published in the literature until 2005 by Dalmau et al. [3] Since then, only a limited number of case reports and systematic reviews have been published. Dai et al. [11] suggest that initial neurologic deficits seen with anti-NMDA encephalitis tend to be more severe when associated with an underlying mature ovarian teratoma [2], [12]. Risk factors for anti-NMDA receptor encephalitis are not well established but almost all cases of anti-NMDA receptor encephalitis are noted in young women with ovarian tumor [10]. This case underscores the importance of further investigation and treatment strategies as they are critical to successful treatment.

Clinical features of anti-NMDA encephalitis are often varied and life-threatening. Psychiatric and neurologic manifestations are often noted. These often lead to misdiagnosis and delayed treatment. Symptoms such as brain fog, agitation, delusions, abrupt behavioral change, and hallucinations have all been described [13]. Continual progression of the disease can lead to more neurologic manifestations such as a seizure, dysautonomia, hyper/ hypoventilation, and autonomic instability [1], [10]. Life-threatening deterioration ultimately occurs, as seen in the present case. Often patients are admitted to intensive care units as central hypoventilation can ensue, indicating the need for assisted ventilation [6]. Progressive deterioration is often seen as other organ systems are likely to become involved; therefore, a multidisciplinary team is crucial to the treatment of the patient. Workup is often initiated to rule out an infectious cause, such as infectious encephalitis or meningitis. Brain MRI and CT are often unrevealing or display nonspecific findings. However, some published cases have shown diffuse cerebral edema on MRI and may be associated with a worse prognostic outcome [4]. Given the nonspecific nature of traditional imaging, transvaginal ultrasound may be considered as an initial evaluation for an ovarian teratoma [7]. However, additional imaging may be needed should the ultrasound be inconclusive or patient does not tolerate the exam [2].

EEG findings, again nonspecific, may show general slow wave changes or more specifically widespread, persistent low to high amplitude theta waves with accompanied high amplitude delta waves [1], [4], [5], [6]. Lumbar puncture often demonstrates elevated protein levels and should be further evaluated with CSF studies. CSF cytology may reveal pleocytosis or lymphocytosis [1], [6], [7], [12] and/or oligoclonal bands [1]. However, oligoclonal bands are not pathognomonic for anti-NMDA encephalitis [1]. While serum testing for anti-NMDA antibodies is available, serum anti-NMDA receptor antibody testing is less sensitive when compared to CSF testing [8], [13].

Treatment of anti-NMDA receptor encephalitis is multifactorial. Prompt surgical excision of the identified ovarian teratoma, by an experienced gynecologist/ gynecologic oncologist, has been demonstrated to be beneficial as the NMDA receptor may be aberrantly expressed within the neural tissue of the teratoma further perpetuating the disease process [2], [9], [11]. Early/ acute phase surgical removal of ovarian teratoma is safe and may reduce the risk of relapse and has been associated with better patient outcomes in some cases [2], [4], [11]. Careful intraoperative exploration is encouraged as teratomas associated with anti-NMDA encephalitis often have smaller diameters and may be missed [5], [10]. In the study conducted by Dai et al. [11], patients received combined immunotherapy, consisting of steroids, intravenous immunoglobulin (IVIG), and plasmapheresis alone or combined, before and after surgery. If first-line treatment failed, second-line immunotherapy (rituximab and/or cyclophosphamide) was initiated, as was seen in this patient.

Duration of hospital stay is widely variable; some patients may need to receive care at a rehabilitation facility until discharge home is feasible. The duration of recovery is also highly variable, and some patients may experience permanent deficits and/or have a relapse event within the first 24 months [12]. Neurology should follow anti-NMDA encephalitis cases at regular intervals following operative removal of ovarian teratoma to promote complete recovery.

Contributors

Aaron Adams contributed to the conception of the case report, acquiring and interpreting the data, drafting the manuscript and revising the article critically for important intellectual content.

Elizabeth Farabee contributed to patient care, drafting the manuscript and revising the article critically for important intellectual content.

Chelsae Nugent contributed to the conception of the case report, drafting the manuscript, undertaking the literature review and revising the article critically for important intellectual content.

Whitney Goldsberry contributed to patient care, conception of the case report, acquiring and interpreting the data, drafting the manuscript, undertaking the literature review and revising the article critically for important intellectual content.

All authors approved the final submitted manuscript.

Patient consent

Written informed consent was obtained from the patient for publication of the case report.

Provenance and peer review

This article was not commissioned and was peer reviewed.

Ethics declaration

The author(s) declare(s) that the study does not involve humans nor animal subjects.

Funding

No funding from an external source supported the publication of this case report.

Declaration of competing interest

The authors declare that they have no competing interest regarding the publication of this case report.