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Abstract
In young women with anti-N-methyl-D-aspartate receptor (anti-NMDAR) autoimmune encephalitis (AE), co-occurrence with ovarian teratoma is common. While the management of mature teratoma with AE is well documented, literature on managing immature teratoma (IT) in tandem with AE is relatively scarce. Here, we report a case of a female patient in her early adolescence who presented with abdominal pain and was diagnosed with grade 3 IT combined with anti-NMDAR AE after an ovarian tumour was discovered and resected. Postsurgery, the patient received immunotherapy, chemotherapy and antiepileptic therapy, and two follow-up evaluations showed no signs of recurrence or sequelae. This case highlights the importance of a high index of suspicion for concurrent AE in the presence of ovarian teratoma, particularly IT, and the crucial role of concurrent administration of immunotherapy and chemotherapy following tumour resection in impacting prognosis.
- Paediatrics (drugs and medicines)
- Paediatric oncology
- Epilepsy and seizures
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Background
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis (AE) subtype, with an incidence rate of 0.6/100 000.1 While individuals of any age may be affected, ovarian teratoma is often associated with NMDAR encephalitis in young females.2 3 A cohort study in east Asia involving 220 NMDAR antibody-positive AE patients demonstrated that 69 individuals were under the age of 18, and 9 out of 41 young female patients with ovarian teratoma were under the age of 18, accounting for 22% of all young female patients.4 Additionally, the study noted that young patients may manifest with seizures, fever, memory and speech impairments, and altered consciousness. Surgical resection of the teratoma and immunotherapy constitute the primary management approach for AE patients with ovarian teratoma.5 Immature teratoma (IT) represents around 1% of all teratomas,6 and due to the risk of dissemination and deterioration, patients with coexisting IT and AE require combined immunotherapy and chemotherapy after teratoma resection to prevent disease progression.7 8
Case presentation
A female patient in her early adolescence presented at a local hospital having abdominal pain. Subsequent ultrasonography revealed the presence of an ovarian tumour. Two days later, the patient was referred to a tertiary specialist unit where laboratory testing revealed the elevated levels of AFP(Alpha-fetoprotein) at 647 ng/mL, CEA at 7.24 ng/mL, carbohydrate antigen 125 (CA125) at 144.63 U/mL, CA19-9 at 145.49 U/mL and squamous cell carcinoma antigen (SCCA) at 3.8 ng/mL. Rectal ultrasound and abdominal/pelvic CT scans were conducted, revealing a sizeable pelvic mass with features suggestive of a teratoma. During the hospitalisation, the patient underwent a battery of laboratory tests, including blood, urine, and stool routine, liver and kidney function, electrolyte balance, and fluid immunity tests, as well as an assessment of six sex hormone levels (follicle stimulating hormone, luteinising hormone, oestradiol, progesterone, testosterone, prolactin). No significant abnormalities were detected in any of these tests.
On the fifth day following comprehensive diagnostic investigations at the tertiary specialist unit, the patient underwent surgical resection of the ovarian tumour. The mass was solid-cystic in nature, irregularly shaped and situated on the left ovary, measuring approximately 11×12×10 cm. Histopathological examination of the tumour specimen confirmed the presence of an IT. Two days prior to the surgery, the patient displayed symptoms of anxiety, including unprovoked episodes of laughter, crying and fear, as well as auditory hallucinations. Following the surgical intervention, the patient manifested emotional lability and a proclivity for aggressive behaviour. The patient’s medical history was unremarkable, although a familial history of epilepsy involving the patient’s aunt and grandmother was documented.
On the fourth day postsurgery, laboratory testing revealed a decline in AFP levels to 286.46 ng/mL, a decrease in CEA levels to 3.87 ng/mL, a reduction in CA125 levels to 111.10 U/mL, a drop in CA19-9 levels to 66.14 U/mL and a decrease in SCCA levels to 0.8 ng/mL.
Investigations
On the fifth day postsurgery, the patient was transferred to our hospital after experiencing three episodes of altered consciousness within a 3-hour time frame. During the episodes, the patient was unresponsive, with closed eyes and clenched fists, but without lip cyanosis, foaming from the mouth or incontinence. Comprehensive diagnostic evaluations, including blood, urine and stool analyses, an assessment of blood gas levels, thyroid function tests, calcitonin assays, as well as nucleic acid tests for EB (epstein-barr) virus, COVID-19, hepatitis B, syphilis, HIV, herpes simplex virus I/II, influenza A/B, adenovirus, respiratory syncytial virus and pneumonia mycoplasma antigen detection, all yielded normal results. Additionally, normal head MRI and pelvic ultrasound results were obtained. Given the patient’s family history of epilepsy, the symptoms were interpreted as indicative of a seizure. During the patient’s ICU stay, one seizure per day was observed and managed with sedation using midazolam and oral administration of risperidone tablets (RTs).
On the second day of admission to our hospital, a diagnostic lumbar puncture was performed, and subsequent testing of the cerebrospinal fluid (CSF) and blood serum revealed a positive result for anti-NMDAR antibodies. The titre for anti-NMDAR antibodies was 1:32 in the CSF and 1:320 in the blood serum.
On eighth day of hospitalisation, the histopathological examination conducted at the tertiary specialist unit confirmed the diagnosis of (1) grade 3 IT of the left ovary, measuring approximately 12×12×6 cm, (2) left fallopian tube tissue and (3) fibrous adipose tissue with localised mesothelial hyperplasia and a significant number of lymphocytes aggregating in the peritoneum of the greater omentum, left and right pelvic peritoneum, rectouterine pouch, bladder reflection peritoneum and left and right colonic sulcus (figure 1).
Histopathology of tumours.
Differential diagnosis
The patient presented with various psychiatric symptoms of different intensities both prior to and following the surgery. On admission to our hospital, the patient’s serum and CSF tests revealed elevated levels of anti-NMDAR antibodies beyond the normal range, suggesting a diagnosis of AE. Additionally, a pathological examination conducted after tumour resection at an external medical facility indicated a grade 3 IT, confirming the diagnosis of IT. Prior to hospitalisation, the patient experienced three episodes of transient loss of consciousness within a 3-hour time frame, characterised by unresponsiveness, closed eyes and rigid posturing with clenched hands. Subsequently, after hospitalisation, the patient continued to experience at least one seizure per day, leading to a diagnosis of status epilepticus (SE).
Treatment
After the confirmed diagnosis, the patient received a comprehensive treatment regimen, including immunotherapy and chemotherapy, tailored to address AE and paediatric malignant germ cell tumours. Symptomatic treatment was also administered to manage seizure-like episodes that occurred on admission to the hospital.
During the patient’s hospitalisation, intravenous IG therapy was initiated on days 3–4 at a dosage of 1 g/kg/day. Concurrently, methylprednisolone sodium succinate (MSS) was administered intravenously at a dose of 20 mg/kg/day on days 3–5, followed by a reduced dosage of 10 mg/kg/day on days 6–7, as part of the pulse therapy regimen for AE. Fever was observed during the hospital stay, prompting the initiation of intravenous piperacillin-tazobactam therapy for antimicrobial treatment from day 4 to day 17. On days 4–5, the patient demonstrated improved consciousness, with regained limb mobility and lucid responsiveness to medical inquiries. Despite these improvements, the patient continued to experience one seizure per day. Consequently, the antiepileptic regimen was adjusted to include an unspecified antiepileptic therapy (RT), along with Debagin and oral administration of nitrazepam tablets (NTs). The patient exhibited suboptimal oral intake throughout the hospitalisation, remaining in a state of drowsiness after medication administration. Intravenous nutritional support was provided, while the administration of NTs was discontinued on day 11 to mitigate potential neural suppression.
During the maintenance phase of treatment, the patient was administered MSS intravenously for maintenance therapy on days 8–17. Simultaneously, the patient underwent the first cycle of chemotherapy, consisting of etoposide (VP16), carboplatin (CBP) and bleomycin (BLM), administered from days 13 to 16 for IT management. Significant improvement in the patient’s mental state was observed during the treatment, evidenced by the absence of somnolence and seizure episodes. Subsequently, the immunotherapy regimen was refined to include intravenous IG therapy at a dose of 1 g/kg/day from days 18 to 19, along with MSS administered intravenously at a dosage of 10 mg/kg/day from days 18 to 20, targeting the management of AE. With the condition showing stability, the patient was discharged and initiated oral treatment with prednisone acetate tablets (PATs) on day 21. The specific treatment timeline is outlined in figure 2.
Main treatment drugs used during the first hospitalisation.
In figure 2, the shaded cells indicate the duration of use. MSS is shaded with two colours to denote its use in both pulse therapy (20–24 June and 5–7 July) and maintenance therapy (25 June–4 July). Following discharge, the patient received oral PAT (8 July–16 December), Debagin (27 June–16 November) and RT (20 June–mid-August). Figure 2 illustrates the colour-coded representation denoting the duration of medication usage. The presence of dual colours for MSS signifies its application in both pulse therapy, administered during days 3–7 and 18–20 of hospitalisation, and maintenance therapy, implemented from day 8 to day 17. Following discharge, the patient persisted with oral administration of PAT for a period exceeding 5 months, Debagin for over 4 months and RT for over 1 month.
After being discharged, the patient was advised to attend regular appointments at our hospital for five cycles of VP16+CBP+BLM therapy, accompanied by comprehensive diagnostic evaluations.Throughout the therapy, a progressive decline in the patient’s AFP levels was observed. This was substantiated by the subsequent re-evaluation on the 12th day after the initial discharge, which reported an AFP level of 7.69 ng/mL. Subsequent AFP assessments, conducted at approximately 20-day intervals, demonstrated further reduction, with values of 4.1 ng/mL, 3.43 ng/mL, 3.58 ng/mL and 2.54 ng/mL, respectively. The treatment was successfully concluded within approximately 3 months following the initial discharge, without any significant complications observed throughout the course.
Outcome and follow-up
Two post-treatment follow-up examinations were conducted at 1-month and 4-month intervals, respectively. Pelvic enhanced MRI evaluations during both visits exhibited no discernible anomalies. Furthermore, the chromosomal karyotyping of the patient revealed an absence of abnormal chromosomal clones, as depicted in figure 3 .
Karyotype test result of the patient’s chromosomes. AE; autoimmune encephalitis; BLM, bleomycin; CBP, carboplatin; IT; immature teratoma; MSS, methylprednisolone sodium succinate; NT, nitrazepam tablet; PAT, prednisone acetate tablet; RT, risperidone tablet; SE, status eilepticus; VP16, Etoposide.
Discussion
Ovarian teratoma is a predominant benign ovarian germ cell tumour and accounts for approximately 60% of all ovarian tumours in individuals under 20 years old. In women, anti-NMDAR encephalitis is more prevalent. Several studies have demonstrated that anti-NMDAR encephalitis is associated with tumours, mainly teratomas and viruses.9 The absence of common viral infections in the patient’s diagnostic workup and the notable elevation of tumour-associated AFP levels prior to surgical intervention provide strong support for the teratoma as the etiological basis for the anti-NMDAR encephalitis in this case. The subsequent marked decline in AFP levels following both surgical resection of the tumour and the initiation of appropriate therapeutic measures further bolsters this hypothesis.
In a study of 244 cases of anti-NMDAR AE in western China, epilepsy was found in 76.2% of the patients, with 38 cases having tumours, including 28 cases of ovarian teratoma in women.10 Another study of 21 paediatric patients with ovarian teratoma and anti-NMDAR AE in southern China reported that 3 out of 20 patients (15%) who underwent surgery had IT.11 Similarly, a retrospective study by Acién et al12 of 174 patients with ovarian teratoma and anti-NMDAR AE, published between 1997 and 2013 in PubMed and SCOPUS, identified 29 cases (16.7%) with a definitive diagnosis of IT, which is much higher than the proportion of IT in all teratomas. These findings suggest that anti-NMDAR AE may be more frequently associated with IT compared with mature teratoma.
Animal experiments have demonstrated that ovarian teratoma may trigger the production of anti-NMDAR antibodies in the body.13 These antibodies are capable of crossing the blood–brain barrier and causing neurological symptoms in humans.9 Therefore, it is crucial to consider the possibility of AE in cases where the patient in this study is diagnosed with IT of the ovary and presents with personality changes.
In previous studies, surgical resection of ovarian teratoma and immunotherapy were the primary treatments for AE. However, in the case presented here, the patient had IT, which carries a higher risk of metastasis (lymph nodes, liver and other organs) and recurrence, particularly in grade 3 tumours. Thus, surgical resection followed by chemotherapy was recommended to minimise these risks.9 14 AE that causes SE has a poor prognosis, and it can cause irreversible brain damage in children. The mortality rate is approximately 16%, with 35% of affected children experiencing significant limitations in daily activities.15 Therefore, immunotherapy and chemotherapy were performed to improve the patient’s prognosis. Throughout the treatment, the patient exhibited a generally positive progression, with the exception of their initial hospitalisation following surgery, which required more intensive care. The patient’s condition markedly improved after a reduction in nervous system-inhibiting medications and the provision of nutritional support during the initial treatment. Immunotherapy, which has been shown to confer beneficial effects, may also have contributed to the patient’s progression. Nevertheless, this case highlights the need to be cognizant of the potential adverse effects of excessively suppressing the nervous system through medications or malnutrition during treatment. Subsequent follow-up examinations conducted after the administration of immunotherapy and chemotherapy demonstrated no indications of AE recurrence or new tumours in the primary lesion, indicating the effectiveness of the treatment.
Previous case studies on grade 3 IT of the ovary have reported variable outcomes depending on the presence of karyotype abnormalities. For example, in a study involving five cases with karyotype abnormalities, one patient died, and three others experienced recurrence after treatment. Only one case remained free of recurrence during a 22-month follow-up period.16–18 Among the four cases receiving no karyotype test, two patients had recurrences, one patient remained free of recurrence for a follow-up period of 95 months and the remaining patient provided information only about surgical and chemotherapy procedures without subsequent follow-up19–22 (table 1). In the current case, the absence of recurrence in the patient thus far may be attributed to their normal karyotypes. However, given the varying recurrence times reported in prior studies, ranging from 6 months to 16 years, long-term follow-up investigations are necessary to confirm the absence of recurrence.
Recurrence of grade 3 IT in previous studies
Learning points
The incidence of anti-N-methyl-D-aspartate receptor (anti-NMDAR) autoimmune encephalitis (AE) is notably higher in cases of immature teratoma (IT) as opposed to mature teratoma.
Concomitant administration of chemotherapy, following surgical resection of IT and immunotherapy for anti-NMDAR AE, is feasible and warrants consideration.
Patients with IT and normal chromosomal karyotype, in addition to anti-NMDAR AE, have a relatively favourable treatment response and prognosis.
Ethics statements
Patient consent for publication
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: ZK-J, LX-J and HX-H.The following authors gave final approval of the manuscript: ZK-J, LX-J and HX-H.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.