NMDAR encephalitis and teratoma - fraternal or fraternal?

As the most common autoimmune encephalitis in neurology, anti-NMDAR encephalitis is believed to be familiar to everyone, and teratoma seems to be a must-screen item for it
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In fact, the synergy between the two is not very frequent, and it seems that there is some special relationship between the pair of friends
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So, what is the entanglement between the "brothers" and how should we treat them correctly? This article will take you to find out
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Author: Tsai This article is published with the authorization of the author, and please do not reprint without authorization
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Background of traffic stars Anti-NMDAR encephalitis, as the most common type of autoimmune encephalitis, has now become a "traffic star" in the neuroimmune field
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Specifically, the disease is associated with IgG targeting the GluN1 (NR1) subunit of the extracellular epitope of NMDAR in cerebrospinal fluid (CSF)
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Autoantibodies mediate NMDAR internalization by cross-linking and blocking NR1 subunits, resulting in reduced surface density of synaptic NMDAR clusters and glutamatergic synaptic dysfunction
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The disease is more common in people aged 20-40, mainly in women.
It can start with viral prodromal symptoms and be followed by a series of characteristic symptoms, including psychiatric symptoms, memory loss, cognitive dysfunction, epileptic seizures, disturbance of consciousness, sleep disturbance and other symptoms
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In addition, anti-NMDAR encephalitis is associated with a variety of tumors, including teratoma, small cell lung cancer, and ovarian cystadenofibroma, of which ovarian teratoma is the most common
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 Ovarian teratoma is the most common ovarian germ cell tumor (GCT), and benign cystic teratoma is the most common (>95%)
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Teratomas, on the other hand, refer to tumors differentiated from somatic cell populations, often including cell populations naturally derived from ectoderm, endoderm, and mesoderm
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Its classification includes mature teratoma (mature teratoma, MT), malignant transformation of MT, immature teratoma (immature teratoma, IT) and highly specialized monodermal teratoma (Table 1)
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Most teratomas are generally benign, with rare malignant lesions resulting from somatic mutations
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Table 1 Classification and characteristics of teratoma GCT: germ cell tumor; IT: immature teratoma; MT: mature teratoma
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In 2007, Professor Dalmau's team first reported the association between anti-NMDAR encephalitis and ovarian teratoma.
Ovarian teratoma is mainly associated with female adolescents and adults, suggesting its potential etiology
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Subsequent studies on the correlation and characteristics of female ovarian teratoma and anti-NMDAR encephalitis have gradually become a hot topic (Table 2)
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① Demographic characteristics: The average age of patients with overall anti-NMDAR encephalitis was 23.
14±6.
59 years old, and some studies suggested that it was 23.
3 years old (range 14-36 years old), while the overall mean age of patients with ovarian teratoma was 23.
97 years old, ranging For 7-55 years old
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According to the type of anti-NMDAR encephalitis combined with teratoma, it can be divided into two categories, including most patients with MT, but also about 11.
8% of patients with IT, which is directly related to a higher risk of death
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In terms of age of onset, patients with MT were between 15-45 years old (median 25), while those with IT were relatively younger at 12-38 years (median 22)
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Furthermore, in an ethnic study of anti-NMDAR encephalitis, Asians and Africans had higher rates of teratoma than white or Hispanic patients
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Two alleles, HLA-A and HLA-DRB1, may be associated with disease susceptibility
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② Histopathological findings: Most of the ovarian teratomas combined with anti-NMDAR encephalitis patients were unilateral MT, with multiple on the right side (no statistical difference); the average size of ovarian teratoma associated with encephalitis was 3.
48 cm, the minimum is 1cm
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Furthermore, IT lesions were larger (9–11 cm) than MT
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In addition, 96% of the anti-NMDAR encephalitis-related teratomas contained neural tissue, and there was more inflammatory infiltration of B cells, T cells, and mature dendritic cells, suggesting that the presence of neural tissue may be involved in the pathogenesis
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③ Clinical manifestations: About 64.
7% of patients with anti-NMDAR encephalitis complicated with ovarian teratoma will have prodromal symptoms and neurological symptoms
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Prodromal symptoms were defined as signs that preceded the first neurological symptom and included headache, signs of infection (fever, upper respiratory symptoms), and gastrointestinal symptoms (vomiting, diarrhea)
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The neurological symptoms are more diverse, mainly including mental and behavioral disorders, memory disorders, seizures, decreased consciousness, involuntary movements, speech disorders, autonomic dysfunction, and central ventilation or ventilator performance
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④ Prognosis: Relapse is defined as the worsening of previous symptoms or the onset of new symptoms after at least two months of improvement or stabilization.
promotion of second-line treatment
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Symptomatic worsening generally refers to an increase in mRS of ≥1 point, and studies have found that teratoma removal is critical to achieving eventual recovery, reducing the risk of recurrence, and improving long-term outcomes
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⑤ Incidence of teratoma: Women account for about 80% of patients with anti-NMDAR encephalitis, and they are the predisposing population of ovarian teratoma (the overall incidence is about 37.
4%), but these incidences may be related to the calculation method
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Table 2 Summary of the correlation and characteristics of female ovarian teratoma and anti-NMDAR encephalitis GCT: germ cell tumor; IT: immature teratoma; MT: mature teratoma
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According to the figure, the mechanism to explore ovarian teratoma is considered as the inducement of anti-NMDAR encephalitis
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Previous studies have suggested that NMDAR may be expressed on the surface of ovarian teratoma cells, and the immune response against NMDAR on tumor cells leads to the production of anti-NMDAR autoantibodies
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Ovarian teratoma cells are derived from human embryonic stem cells, express various somatic derivatives, and may contain glial cells and neural structures such as NMDAR (more expressed in anti-NMDAR encephalitis-associated ovarian teratoma)
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Glial tissue may be involved in triggering or maintaining the antitumor response associated with autoimmune encephalitis, and dysplastic neurons within it may be a potential source of NMDAR autoantigens
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Overall, ovarian teratomas with anti-NMDAR encephalitis had more primary inflammatory infiltration of glial components, and overexpression of B cells, plasma cells, and dendritic cells, consistent with tertiary lymphoid architecture (TLS) (Figure)
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There is also evidence that tumor-infiltrating B cells can synthesize NMDAR antibodies in vitro
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 Fig.
Hypothetical mechanisms for the pathogenesis of ovarian teratoma-associated anti-NMDAR encephalitis ), NMDAR is expressed on the surface of ovarian teratoma cells
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(B) TLS of ovarian teratoma includes CD4+ T cell domain, CD20+ B cell domain, plasma cells, anti-NMDAR autoantibodies, central memory cells, and mature dendritic cells
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Mature dendritic cells capture NMDAR antigens and present antigen fragments to CD4 + T cells via MHC class II complexes, inducing T cell activation, differentiation and proliferation; activated CD4 + T cells then induce B cells to differentiate into plasma cells , followed by the production of IgG autoantibodies, followed by immune cells and autoantibodies circulating in the bloodstream and lymphatic system and crossing the blood-brain barrier into the CSF
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(C) Autoantibodies primarily target NMDARs in the hippocampus and prefrontal cortex of the brain, inducing their binding to crosslinks, altering their surface dynamics and disrupting interactions with synaptic proteins such as Ephrin-B2 receptors, ultimately Leads to internalization and degradation of NMDAR, reducing synaptic and extrasynaptic NMDAR density
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(D) The original composition of NMDAR consists of four domains: extracellular amino-terminal domain (ATD), bilobal agonist-binding domain (ABD), pore-forming transmembrane domain (TMD), and intracellular carboxy-terminal domain domain (CTD), which together form a central ion channel pore
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 The disease association between ovarian teratoma and anti-NMDAR encephalitis is currently unclear
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Ovarian mucinous cystadenoma may also cause anti-NMDAR encephalitis, suggesting a broader spectrum of tumors associated with anti-NMDAR encephalitis
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Similarly, ovarian teratoma may also cause opsoclonus-ataxia syndrome (involuntary polytropic saccades and loss of autonomic coordination)
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 Brilliant eyes, each breakthrough ① Identification and diagnosis of combined ovarian teratoma and anti-NMDAR encephalitis Screening and identification are very important for early treatment to improve prognosis: In terms of clinical manifestations, patients often present with acute onset neuropsychiatric symptoms, and antipsychotic symptoms.
In the absence of drug response, the differential diagnosis can be made by laboratory tests (serum and CSF) and imaging studies, including pelvic ultrasound, MRI, CT, and EEG
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About 67% of patients have normal brain MRI, but 90% of patients with anti-NMDAR encephalitis have abnormal EEG, and FDG-PET can help evaluate changes in the patient's brain and screen for possible tumors
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In terms of diagnosis, when anti-NMDAR encephalitis is combined with ovarian teratoma, more severe neurological symptoms often appear, which are more complex and non-specific, and are often mistaken for viral encephalitis, primary mental disorders, drug abuse, neuroleptic malignant syndrome
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IgG autoantibodies against the GluN1 subunit of the receptor in the patient's CSF or blood are currently the only specific diagnostic test, but screening for teratoma is still required when antibodies are negative
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② Treatment As a predisposing factor for anti-NMDAR encephalitis, ovarian teratoma resection is considered an important step in disease treatment, which can improve patient prognosis and reduce recurrence
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Many neurologists believe that ovarian teratoma should be promptly removed once detected, and that systemic and neurological complications should not be considered contraindications to surgery
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In addition, immunomodulatory therapy is also critical
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These include first-line treatments such as steroids, intravenous immune globulin, or plasma exchange, and second-line treatments such as rituximab or cyclophosphamide
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Third-line therapy, such as bortezomib (a proteasome inhibitor) or tocilizumab (an IL6R antagonist), can be used for the remaining approximately 10% of refractory patients
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Most patients will respond to immunotherapy, but immunosuppressive agents alone are often unable to cure the disease, and removal of teratoma may be curative.
Combining surgery and immunotherapy can maximize clinical effects and adequate recovery
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③ Outcome assessment At present, there are many studies on the outcome of patients with anti-NMDAR encephalitis complicated with teratoma
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Early tumor resection and immunotherapy were considered predictors of good outcome (mRS); whereas delay of treatment ≥ 4 weeks and no improvement within 4 weeks of initiation of therapy were considered predictors of poor functional status (mRS ≥ 4) at 1 year of onset factor
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≥75% of patients recovered completely or had only minor sequelae after tumor resection, which may be associated with recurrence of ovarian teratoma in patients with refractory anti-NMDAR encephalitis
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 Conclusion The overall incidence of anti-NMDAR encephalitis-type ovarian teratoma is 37.
4%, but the incidence of anti-NMDAR encephalitis in patients with ovarian teratoma is still unclear
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There is a complex association between the two, and timely screening and identification, early tumor resection and immunotherapy can help improve disease outcomes
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