Teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis: A case report and literature review.

RATIONALE: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disease associated with the NMDA receptor and has a good response to treatment. However, only few cases related to teratoma have been reported. Here, we report a case of teratoma-associated anti-NMDAR encephalitis. PATIENT CONCERNS: A 25-year-old woman presenting with fever for 20 days and psychiatric symptoms for 9 days was admitted to the hospital. The patient progressed to a minimally conscious state consistent with encephalitis. DIAGNOSIS: Considering the possibility of autoantibody-mediated encephalitis, laboratory tests were conducted to detect anti-NMDAR antibodies in cerebrospinal fluid and serum. Results confirmed the diagnosis of anti-NMDAR encephalitis. Furthermore, gynecological ultrasound investigation detected teratoma in the left ovary.
INTERVENTIONS: After resection of the teratoma with laparoscopic adnexectom, the patient was treatment with immunosuppressive therapy. OUTCOMES: The patient recovered gradually and was discharged 2 months after the operation. LESSONS: Anti-NMDAR encephalitis remains difficult to diagnose because of its vague manifestations, and no clinical practice guidelines for prevention and treatment of the disease have been established yet. The clinical data of a case of teratoma-related anti-NMDAR encephalitis were analyzed, and relevant studies were reviewed.

Introduction

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare form of encephalitis and is associated with presence of antibodies against the NR1 or NR2 subunits of the NMDA receptor in cerebrospinal fluid (CSF) and serum.[ This disease occurs often in young women who manifest neuropsychiatric disturbances, including restlessness, central hypoventilation, oral facial dyskinesia, affective disturbance, psychosis, hallucination, memory loss, dyskinesia, vegetative deregulation, and autonomic dysfunction[; NMDAR encephalitis coexists with ovarian pathologies in several cases. Majority of patients with anti-NMDAR encephalitis respond to immunotherapy. For patients who also have ovarian lesions, gynecologic surgical procedures are strongly recommended.

Case report

A 25-year-old nulliparous Chinese female patient started to have fever (body temperature of 38.2 °C) and headache from April 1st, 2018. After 10 days, she began to develop amnesia, followed by delirium, urinate and defecate, and discontinuous confusion. On April 13th, the patient had onset of epileptic seizures, 4 or 5 times a day, each lasted for minutes, and also possessed rigid bilateral upper extremities with shouting but without frothing and twitching limbs. During this stage, the patient went to 2 different hospitals but the diagnosis remained unclear. Upon admission to the Department of Infectious Diseases of another hospital on April 16th, the results of CSF examination were as follows: 3.1 mmol/L Glu, 124 mmol/L Cl−, 349 mg/L protein, 28 × 106/L leucocytes, 1:32 (+++) NMDA, and 1:10 (+) NMDA in serum. No abnormalities were found from the brain magnetic resonance imaging (MRI) scans. Therefore, the patient was diagnosed with anti-NMDAR encephalitis and given pulse therapy of immunoglobulin (IVIG) (22.5 g/d, 0.4 g/kg) for 5 days, methylprednisolone (1 g/d) for 7 days (the dosage was decreased every 7 days), olanzapine (5 mg/d), and levetiracetan (2.0 g/d). Meanwhile, gynecological ultrasound detected a nodule (9.4 mm × 9.6 mm × 9.7 mm) in the left ovary. The nodule was considered to be teratoma (Fig. 1).

Figure 1

Gynecologic ultrasonography of the patient.

The patient was transferred to the Department of Gynecology of our hospital for further surgical treatment on April 21. Single-site laparoscopic resection of the left ovary, mesangial cystectomy of the right fallopian tube, and incision exploration of the right ovary were performed on April 24. The surgical specimen showed that the tumor was 1 cm in diameter and appeared polycystic (Fig. 2). Pathological examination confirmed the diagnosis of mature cystic teratoma in the left ovary. A small amount of mature brain tissues was also found. After the surgery, the patient was orally given with sodium valproate, levetiracetam, and olanzapine to control the epileptic and mental symptoms. On the night of May 5, the patient suddenly got delirium and hallucination. From May 6 to May 10, the patient was given 2 courses of IVIG (22.5 g/d, 0.4 g/kg). The patient's conditions gradually improved after the treatment. She started to obey commands and perform spontaneous eye opening and talking.

Figure 2

Left ovary tissue after incision reveals a mature cystic teratoma.

One month later, the patient mobilized independently with no further involuntary movements or seizures. No abnormalities were found in her routine CSF test, CSF bacteriology, and brain MRI. After 3 months, she remained well and was fully independent in all acts of daily living.

The ethical approval was not necessary for this case report. Informed written consent was obtained from the patient for publication of this case report and accompanying images.

Discussion

Method of obtaining information and data

Here, we reviewed studies on teratoma-associated anti-NMDAR encephalitis published up to January 2018 and stored in various databases sources, including PubMed, Web of Science, and the California encephalitis project.[ The following key words were used for literature retrieval: (“case report”) and (“teratoma”) and (“anti-NMDAR encephalitis” or “anti-N-methyl D-aspartate receptors encephalitis”). We also manually identified the references of the selected articles for supplement studies. Overall, 11 cases published from 2010 to 2017 were obtained after strict selection (Table 1).

Table 1

Literature review of cases of ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis.

Epidemiology

Anti-NMDAR encephalitis was first described in 2007.[ The disease mostly occurs in women and rarely in men and adolescents. The association of psychiatric and neurological symptoms with ovarian teratoma was previously reported in Hong Kong.[ The overall incidence of the condition remains unknown, but it is high among individuals of Asian or African origin.[

Clinical presentation

Patients with anti-NMDAR encephalitis manifest psychiatric symptoms, usually preceded by fever and headache. Most patients also develop seizures followed by dyskinesia, autonomic symptoms, decreased level of consciousness, and central hypoventilation that requires frequent mechanical ventilation.[ The development of anti-NMDAR encephalitis can be divided into 5 stages that have distinctive clinical manifestations but their boundaries are not strict[: prodromal stage, psychiatric symptom stage, no reaction stage, excessive movement stage, and recovery stage.

Diagnostic testing

The ectopic expression of the teratoma is speculated to have an anti-NMDAR antibody, which leads to the disease.[ The possibility of anti-NMDAR encephalitis should be considered for women who present signs of acute abnormal mental behavior, posture and movement disorders (mainly abnormal movements of the mouth, face, and limbs), epilepsy, autonomic dysfunction, and ventilatory disorders. NMDAR-Ab may be found in serum and/or CSF. In several cases, electroencephalogram reveals diffuse delta slowing waves. MRI examination may produce normal results or abnormally high signals, which briefly appear in the cerebral cortex, cerebellum, or medial temporal lobe. Meanwhile, ultrasound, a simple and feasible test, often reveals ovarian occupying that exhibits high echoes, contributing to the diagnosis in time.

In the course of diagnostics, viral and autoimmune diseases and metabolic, toxic, and other types of paraneoplastic limbic encephalitis (such as anti-AMPA receptor encephalitis[ and anti-GABA receptor encephalitis[) should be excluded. The presence of anti-NMDAR antibodies should be confirmed in serum or CSF. All patients should be examined for the presence of tumors, especially ovarian teratoma or testicular germ cell cancer. In a recent case of incidental finding of ovarian teratoma, anti-NMDA-R and glial fibrillary acidic protein (GFAP) antibodies were detected in CSF; as such, GFAP could be a novel biomarker of autoimmune meningoencephalitis.[

Treatment

An increasing number of studies have reported on anti-NMDAR encephalitis in recent years.[ This disease is closely associated with the development of a tumor, particularly teratoma. Identifying the causative factor at the early stage often results in good prognosis.[ Basic therapeutic management for anti-NMDA encephalitis mainly includes tumor resection and immune therapy[; of which, tumor resection is important to the treatment. Furthermore, for most young women, avoiding residual disease is vital to the surgery considering the fertility requirements and protection of the ovary. Therefore, the laparoscopic operation technique of the operator is highly demanded. In the present case, the tumor is only 1 cm in diameter and can be easily neglected. For example, the nerve tissue containing the NMDAR subunit in residual lesions is used as an antigen-inducing antibody, and the patient cannot recover after the operation. For teratoma, laparoscopic surgery should be conducted to prevent leakage of cyst fluid, avoid residual lesions, and protect ovarian function. The use of anesthetics that could target at NMDARs remains controversial because it may alter the activation of the central nervous system by excitatory or inhibitory neurons.[

Prognosis

The prognosis of anti-NMDAR encephalitis is usually better than other types of paraneoplastic encephalitis.[ Dalmau et al[ reported that approximately 75% of patients recovered completely or only suffered minor disabilities. Compared with other types of paraneoplastic encephalitis, anti-NMDAR encephalitis differs because it results in a highly specific syndrome, is associated with benign tumors, usually affects young women, and has good prognosis with early treatment. Despite the presence of a tumor, the immune response is not maintained. As such, the contributory role of the prodromal “viral-like” disorder, which by itself or in combination with teratoma set off or enhances the autoimmune response, should be considered. Further investigations must be conducted to understand this disorder. Meanwhile, awareness and diagnosis of anti-NMDAR encephalitis are of extreme importance to pediatricians, gynecologists, general practitioners, and psychiatrists. Complete recovery of patients with anti-NMDAR encephalitis can only be achieved after surgical resection despite the severity of symptoms. Young patients presenting with neuropsychiatric symptoms are occasionally misdiagnosed with psychiatric illness or viral encephalitis.

Given the small number of cases of anti-NMDAR encephalitis reported, comparative results should be interpreted with caution and the disorder must be further investigated.

Conclusion

Teratoma-related anti-NMDAR encephalitis is a rare disease that has uncertain etiology and pathogenesis. Emphasis is placed on detecting ovarian teratomas and anti-NMDAR antibodies in young women presenting symptoms such as sudden onset of psychiatric symptoms, seizures, decreased level of consciousness, and movement disorders after common cold. Confirming the diagnosis with serological and imaging methods as early as possible and timely laparoscopic surgery may lead to good prognosis.

Author contributions

Conceptualization: Weihua Lou.

Investigation: Bin Yan.

Methodology: Bin Yan.

Resources: Ying Zhang.

Supervision: Weihua Lou.

Writing – original draft: You Wang.

Writing – review & editing: You Wang, Wen Di.