The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review
Abstract
:1. Introduction
1.1. Ovarian Teratoma
1.2. Paraneoplastic Neurological Syndrome (PNS) and Anti-N-Methyl-D-Aspartate Receptor (Anti-NMDAR) Encephalitis
2. The Association of Anti-NMDAR Encephalitis and Ovarian Teratoma
3. The Hypothetical Mechanisms and Models of the Pathogenesis
3.1. The Triggers and Peculiar Cell Composition in the Ovarian Teratomas with Anti-NMDAR Encephalitis
3.2. The Microenvironment Involving in Ovarian Teratomas with Anti-NMDAR Encephalitis
3.3. The Association with Teratoma-Related Anti-NMDAR Encephalitis and Blood–Brain Barrier Integrity
3.4. The Molecular Basis for Structures and Physiological Features of NMDAR
3.5. The Role of NMDARs in Ovarian Teratomas with Anti-NMDAR Encephalitis
3.6. The Hypothetical Mechanism of the Pathogenesis and Evidence of Animal Models
4. Treatment and Detection for Patients with Ovarian Teratomas and Anti-NMDAR Encephalitis
5. Outcome and Associations of Ovarian Teratoma-Related Anti-NMDAR Encephalitis
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Antigen | Autoantibody | Main Neurological Syndromes | Cancer Types |
---|---|---|---|
HuD | Hu-IgG (ANNA1) | Sensory neuronopathy, limbic encephalitis, and cerebellar ataxia. | SCLC, NSCLC, and extra-thoracic cancers. |
Cdr-2 | Yo-IgG (PCA1) | PCD (majority), brainstem encephalitis, and myelopathy. | Ovarian, breast and fallopian tube carcinoma; gastrointestinal cancer in males. |
SOX1 | SOX1-IgG | LEMS, PCD, and limbic encephalitis | SCLC, NSCLC, and extra-thoracic cancers. |
Unknown | ANNA-3 | Limbic encephalitis, neuropathies, cerebellar ataxia, myelopathy, and brain stem encephalitis. | SCLC, NSCLC, and other tobacco-related airway cancers. |
NOVA1 and NOVA2 | Ri-IgG (ANNA2) | Brainstem encephalitis, opsoclonus, laryngospasm, and jaw dystonia | Breast, lung, and neuroblastoma. |
Ma1 and Ma2 | Ma and/or Ma2-IgG | Limbic encephalitis and brain stem encephalitis | Testicular, lung, and others (mainly gastrointestinal). |
ZIC4 | ZIC4-IgG | PCD, and others. | SCLC, and ovarian adenocarcinoma. |
Antigen | Autoantibody | Main Neurological Syndromes | Tumor Types | Frequency of Tumor |
---|---|---|---|---|
DNER | DNER-IgG (PCA-Tr) | PCD. | Hodgkin lymphoma. | >95% |
GluA1, GluA2 | AMPAR-IgG | Limbic encephalitis. | SCLC, NSCLC, breast, and thymoma. | 60–70% |
P/Q-type VGCC | P/Q-type VGCC-IgG | LEMS, and PCD. | SCLC. | 60% |
β1 subunits | GABAbR-IgG | Limbic encephalitis, isolated status epilepticus, cerebellar ataxia, and opsoclonus myoclonus. | SCLC, thymoma, and extra-thoracic cancers. | 60% |
GluD2 | GluD2-IgG | Opsoclonus myoclonus ataxia syndrome. | Neuroblastoma, and ovarian teratoma. | 50% |
α1, β3, γ2 subunits | GABAaR-IgG | Encephalitis with seizures, cognitive impairment, and behavior changes. | Thymoma, and Hodgkin lymphoma. | 40% |
GluN1 | NMDAR-IgG | Encephalitis with initial psychiatric disturbances, followed by catatonia, dystonia, seizures, aphasia, coma, and central hypoventilation. | Ovarian teratoma. | 20–40% |
Muscle AChR | Anti-AChR | Myasthenia gravis. | Thymoma. | 15% |
mGluR1 | mGluR1-IgG | Cerebellar ataxia. | Hematologic malignancies, and prostate adenocarcinoma. | 10% |
DPPX/Kv4.2 | DPPX-IgG | Diarrhea, weight loss, cognitive dysfunction, and CNS hyperexcitability. | B-cell neoplasms. | 10% |
Aquaporin-4 | Aquaporin-4-IgG | Neuromyelitis optica spectrum disorders (optic neuritis, longitudinally extensive transverse myelitis, and area postrema syndrome). | Thymoma, breast, and lung. | 5% |
Criteria | ||
---|---|---|
Probable Case | Rapid onset (<3 months) of at least 4 of the 6 major groups of symptoms: | Major groups of symptoms:
|
Additionally, at least one of the laboratory studies: |
| |
Or 3 of the above groups of symptoms and identification of a systemic teratoma | ||
Exclude the recent history of herpes simplex virus encephalitis or Japanese B encephalitis, resulting in relapsing immune-mediated neurological symptoms. | ||
Definite Case | One or more of the 6 major groups of symptoms and IgG GluN1 antibodies (antibody testing should include CSF); if only serum is available, confirmatory tests should be included (e.g., live neurons or tissue immunohistochemistry, in addition to a cell-based assay) | |
Exclude the recent history of herpes simplex virus encephalitis or Japanese B encephalitis, resulting in relapsing immune-mediated neurological symptoms. |
Author/Reference | Study Design | GCT Case Number/Age | Ovarian GCT | Size and Laterality/ Time to Diagnosis | Prodromal Symptoms and PNS | Encephalitis Relapse Rate | GCT Incidence Rate | Note | |
---|---|---|---|---|---|---|---|---|---|
1 | Florance et al. [31] | Single institutional observational study. | 32 patients (>18 y/o: 24 cases; ≤18 y/o: 8 cases) | Teratomas, subtype not mentioned. | N/A | Prodromal symptoms: 48%$ Autonomic instability: 86%$ Movement disorder: 84%$Seizures: 77%$ Behavior/personality: 59%$ | 0% | 32/69 (46.4%) | 69 female patients with anti-NMDAR encephalitis (>18 y/o: 43 cases; ≤18 y/o: 26 cases). $: the percentages were based on cases assessable in the original study. |
2 | Titulaer et al. [32] | Multi-institutional observational study. | 207 patients (<12 y/o: 4 cases; 12–44 y/o: 199 cases; ≥45 y/o: 4 cases) | Teratomas, subtype not mentioned. | N/A | Prodromal symptoms: N/A Behavior/cognition: >95% Movement disorder: ~80% Seizures/memory deficits/ speech disorder: 70~80% | 12/207 (5.8%) | 207/468 (44.2%) | Among 468 female patients with anti-NMDAR encephalitis, 207 had ovarian teratomas, 4 had extraovarian teratomas, and 9 had other tumors. |
3 | Bost et al. [33] | Single-center retrospective observational study. | 51 patients; MT: the median age of 25 years (range: 15–45) IT: the median age of 22 years (range: 12–38) | MTs: 45 cases; ITs: 6 cases (grade 1: 2 cases, grade 2: 3 cases, grade 3: 1 case). | Median (range):MT: 7 days (−26~643); IT: 0 day (−6~131). | Prodromal symptoms: N/A Behavior/personality: 82%- Cognition: 32~100%- Movement disorder: 12~78%- Autonomic instability: 2~74%- Seizures: 8~64%- | 1/6 (16.7%)+ | 51/195 (26.2%) | There were 195 female patients with anti-NMDAR encephalitis (169 patients were above 12 years of age). +: among the 6 ITs patients −: percentages range from first and subsequent symptoms |
4 | Dai et al. [30] | A single-center prospective study. | 29 patients (mean age: 23.1, range: 10–36) | MTs: 28 cases; ITs: 1 case (grade 1). | Mean size: 4.6 cm (1–12 cm). | Prodromal symptoms: 53%; Mental/behavioral disorder: 89.7%; Seizures: 79.3%; Decreased consciousness: 65.5%; Hyperhidrosis: 62.1%; Speech disorder: 55.2%. | 4/29 (13.8%) | 29/108 (26.9%) | There were 108 female patients with anti-NMDAR encephalitis and a mean age of 23.4 years (range: 5–72). |
5 | Zhang et al. [34] | Multi-institutional observational study. | 26 patients (mean age: 23.3, range: 14–36) | MTs: 23 cases ITs: 3 cases | N/A | Prodromal symptoms: 38%; Psychiatric symptoms: 92.3%; Speech dysfunction: 84.6%; Seizures: 80.8%; Movement disorder: 76.9%; Decreased consciousness: 61.5%. | 3/26 (11.5%) | 26/56 (46.4%) | There were 56 female patients with anti-NMDAR encephalitis |
6 | Yaguchi et al. [35] | Case series. | 4 patients (mean age: 28, range: 23–31) | MTs: 3 cases. ITs: 1 case. | N/A | Prodromal symptoms: N/A; Psychosis: 100%; Seizures: 100%; Status epilepticus: 100%. (present 4 out of 4) | 0% | 4/343 (1.17%)# | All ovarian teratomas: 343 patients; MTs: 327 cases; ITs: 16 cases; (131 of 343 ovarian teratomas had neuroectodermal tissue.) #: incidence of encephalitis among patients with teratomas. |
4/6 (66.7%) | There were 6 female patients with anti-NMDAR encephalitis. Four of them had ovarian teratomas. | ||||||||
7 | Xu et al. [36] | Single-center prospective study. | 42 patients (>18 y/o: 33 cases; ≤18 y/o: 9 cases) | Teratomas, subtype not mentioned. | N/A | Prodromal symptoms: 48.2%; Psychosis: 82.7%; Seizures: 80.9%; Decreased consciousness: 53.2%; Memory deficit: 48.2%; Speech disturbance: 45.5%. | 5/42 (11.9%) | 42/143 (29.4%) | There were 143 female patients with anti-NMDAR encephalitis (>18 y/o: 102 cases; ≤18 y/o: 41 cases). |
8 | Acién et al. [37] | A systematic review of reported cases. | 174 patients (mean age: 23.9, range: 7–54) | MTs: 99 cases; ITs: 29 cases; Mixed MTs and ITs: 6 cases; Unknown: 40 cases. | Mean size: 6.7 cm (range: 0.1–22 cm); Right: 56 cases; Left: 46 cases; Bilateral: 20 case; Unknown: 52 cases; Mean time: 28 days (3 to 455 days). | N/A | N/A | N/A | Collected cases and data before 2014. |
9 | Chiu et al. [38] | Case series. | 5 patients (mean age: 18.6, range: 7–28) | MTs: 5 cases; Ovarian fibroma: 1 case. | Mean size: 2.65 cm (2–3.3 cm); Right side: 1 case; Left side: 1 case; Not marked: 3 cases; Mean time: 59.6 days (7 to 150 days). | Prodromal symptoms: 60%; Autonomic dysfunction: 80%; Psychosis: 80%; Seizures: 80%; Decreased consciousness: 60%; Impaired speech: 60%. | 1/5 (20%) | 5/13 (38.5%) | 13 female patients with anti-NMDAR encephalitis (mean age: 19.9, range: 7–28). |
10 | Yan et al. [39] | Case report and literature review. | 15 patients (mean age: 21, range: 7–33) | MTs: 10 cases; ITs: 2 cases; Unknown: 3 cases. (5 of 10 MTs had mature brain tissues.) | Right: 5 cases; Left: 2 cases; Bilateral: 1 case; Unknown: 7 cases. | Prodromal symptoms: 66.7%; Nervous and mental symptoms: 93.3%; Seizures: 53.3%; Dyskinesia: 40%; Autonomic instability: 38.5%. | N/A | N/A | 14 published case reports during 2010 to 2019 and one presented case. NMDAR-Ab was positive in CSF. |
11 | Yu et al. [40] | Case series. | 6 patients (mean age: 25, range: 21–27) | MTs: 6 cases (4 of 6 had mature brain tissues). | Mean size: 1.73 cm; Right side: 3 cases; Left side: 3 cases; Mean time: 22.5 days (5 days to 3 months). | Prodromal symptoms: 50%; Psychotic symptoms: 100%; Cognitive decline: 100%; Abnormal movement: 100%; Seizures: 100%; Autonomic dysfunction: 66.7%. | N/A | N/A | NMDAR-Ab was positive in CSF. |
12 | Dalmau et al. [29] | Case series. | 12 patients (mean age: 24, range: 14–44) | MTs: 8 cases; ITs: 4 cases. | Mean size: 6.4 cm (1.5–22 cm); Right side: 4 cases; Left side: 6 cases; Bilateral: 1 case; Mediastium: 1 case; Mean time: 8 weeks (3 weeks to 5 months). | Prodromal symptoms: 83.3%; Seizures: 91.7%; Psychiatric symptoms: 83.3%; Memory deficit: 58.3%; Movement disorder: 50%; Decreased consciousness: 41.7%; Impaired speech: 41.7%; Autonomic dysfunction: 33.3%. | 0% | N/A | - |
13 | Ahmad et al. [41] | Case report. | 1 patient, 26 y/o | MT: 1 case. | Size: 2.5 cm; Right side. | Prodromal symptoms: 100% Psychosis: 100% Seizures: 100% Movement disorder: 100% Decreased consciousness: 100% | 0% | N/A | NMDAR-Ab was positive in CSF. |
14 | Omata et al. [42] | Case report. | 2 patients (mean age: 12.5, range: 11–14) | MTs: 2 cases. | Mean size: 2.8 cm (1.3–5 cm); Left side: 1 case; Bilateral: 1 case. | Prodromal symptoms: N/A Psychotic symptoms: 100% Movement disorder: 100% Abnormal speech: 50% | 0% | N/A | NMDAR-Ab was positive in CSF. |
15 | Mitra et al. [43] | Case report. | 1 patient, 22 y/o | MT: 1 case with neural elements resembling white matter. | Size: 1.4 cm; Right side. | Prodromal symptoms: N/A Altered mental status: 100% Psychosis: 100% Autonomic dysfunction: 100% Movement disorder: 100% | 0% | N/A | NMDAR-Ab was positive in CSF. |
16 | Lwin et al. [44] | Case report. | 1 patient, 12 y/o | MT: 1 case. | Size: 5 cm; Left side. | Prodromal symptoms: N/A Psychosis/Abnormal behavior: 100% Seizures: 100% | N/A | N/A | NMDAR-Ab was positive in CSF. |
17 | Lee et al. [45] | Case report. | 1 patient, 24 y/o | MT: 1 case with mature brain tissue. | Size: 1 cm; Right side. | Prodromal symptoms: 100% Abnormal movement: 100% Decreased mental status: 100% Autonomic dysfunction: 100% | N/A | N/A | NMDAR-Ab was positive in CSF. |
18 | Chernyshkova et al. [46] | Case report. | 1 patient, 55 y/o | MT: 1 case. | Left side. | Prodromal symptoms: N/A Altered mental status: 100% Autonomic dysfunction: 100% Seizures: 100% Movement disorder: 100% | N/A | N/A | This is a probable case based on Table 3 since autoantibodies in CSF were not detected. |
Total conclusion (for assessable cases) | Mean age: 23.97; (age range: 7~55) | MTs: 234 cases; ITs: 46 cases; Unknown: 330 cases. | Mean size: 3.48 cm; Right side: 72 cases; Left side: 61 cases; Bilateral: 23 cases. | Prodromal symptoms: 64.7%; Behavior/personality/ Psychosis: 89.8%; Seizures: 82.4%; Movement disorder: 79.6%; Decreased consciousness: 77.1%; Autonomic dysfunction: 70.5%; Speech disorder/memory deficit: 60.4%. | 26/367 (7.1%) | 396/1058 (37.4%) |
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Wu, C.-Y.; Wu, J.-D.; Chen, C.-C. The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review. Int. J. Mol. Sci. 2021, 22, 10911. https://doi.org/10.3390/ijms222010911
Wu C-Y, Wu J-D, Chen C-C. The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review. International Journal of Molecular Sciences. 2021; 22(20):10911. https://doi.org/10.3390/ijms222010911
Chicago/Turabian StyleWu, Cheng-Yang, Jiann-Der Wu, and Chien-Chin Chen. 2021. "The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review" International Journal of Molecular Sciences 22, no. 20: 10911. https://doi.org/10.3390/ijms222010911