Abnormal Neurons in Teratomas in NMDAR Encephalitis

Abstract

IMPORTANCE Ovarian teratomas are frequently described in patients with N-methyl-Daspartate receptor (NMDAR) encephalitis, yet NMDAR encephalitis is rarely described in patients with ovarian teratomas. Understanding why a minority of patients with teratomas are seen with autoimmune encephalitis may improve the management of NMDAR encephalitis and other teratoma-associated autoimmune diseases. OBJECTIVE To characterize the unique organization of neuroglial elements within ovarian teratomas resected from patients with NMDAR encephalitis. DESIGN Case-control study comparing the pathological features of ovarian teratomas resected from consecutively accrued cases with NMDAR encephalitis SETTING Pathology tissue database at a tertiary academic care center. PARTICIPANTS Five cases with teratoma-associated NMDAR encephalitis and serum or cerebrospinal fluid autoantibodies against central nervous system (CNS) NMDAR and 38 controls (39 ovarian teratomas) without neurological symptoms or signs.EXPOSURES Formalin-fixed, paraffin-embedded ovarian teratomas were examined for the presence of CNS tissue and inflammatory infiltrates using direct microscopy, enhanced with standard histopathological and immunological stains.MAIN OUTCOMES AND MEASURES Frequency of detection of atypical (dysplastic) CNS neuronal elements in ovarian teratomas resected from cases vs controls, as well as characterization of the relationship between atypical neurons and immune infiltrates. RESULTS Central nervous system neuronal elements were detected in 4 of 5 teratomas resected from cases with NMDAR encephalitis and in 20 of 39 controls (P = .36). Atypical neurons were seen within teratomas resected from 4 of 5 cases but not in 39 controls, reliably distinguishing teratomas associated with NMDAR encephalitis (P < .001). If found within the CNS, these histological abnormalities would have received the diagnosis of gangliogliomas (n = 3) and ganglioneuroblastoma (n = 1). Reactive changes were present in teratomas from controls, including ferruginated neurons and Rosenthal fibers. Abnormal neuroglial elements were closely related to immune infiltrates in teratomas resected from 4 of 4 cases. Inflammatory infiltrates were not associated with neuroglial tissue in 20 controls, further differentiating these populations (P < .001).CONCLUSIONS AND RELEVANCE Abnormal neurons within teratomas distinguish cases with NMDAR encephalitis from controls and may promote the development of autoimmunity. quantify rates of cellular proliferation. Inflammatory cell lineages were characterized using stains specific for leukocyte common antigen, B cells, T cells, and histiocytes. Pathological diagnoses and classification or staging of ovarian teratomas were based on accepted critiera. 11 Abnormal neuronal elements within teratomas were described using World Health Organization terminology for neuroglial tumors, 12,13 acknowledging that this terminology was developed for the diagnosis of CNS tumors.

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

“…This effect may be through antigen‐dependent B cell generation or through polyclonal bystander activation of preformed memory B cells. By analogy, the ovarian teratomas express the NR1 autoantigen and neurons with abnormal morphology, which may break immune tolerance 3, 4. In addition, we and others have observed intra‐teratoma lymphocyte‐rich structures with dense T and B cell infiltrations,31 and our data show that these tumor‐resident B cells also have the capacity to generate NR1‐specific antibodies.…”

“…The autoantibodies are typically present in serum and cerebrospinal fluid (CSF) at disease onset and persist for several years despite various immunotherapies. Around 20% of patients have an associated ovarian teratoma which expresses the NR1 subunit of the NMDAR,3, 4 making this a likely site of primary immunization. This finding, together with the higher concentrations of NR1‐IgG in serum than CSF,2, 5 suggest that the autoantibodies are initially generated in the periphery.…”

Dysplastic Neurons in Ovarian Teratomas in NMDAR Encephalitis

“…The authors propose that pathological examination of teratomas removed from patients with NMDAR encephalitis should first focus on areas containing CNS tissue and second on neurons closely approximated by inflammatory infiltrates. The colocalization of dysplastic CNS neurons and inflammatory infiltrates support an autoimmune cause for the clinical encephalitic presentation [1].…”

“…US had high sensitivity (100%) and specificity (93%) in detecting grade III GMH but poor sensitivity (0%) in detection of intraventricular hemorrhage (grade II GMH). US is first line of imaging for brain injury in the evaluation of premature neonates with suspected intracranial hemorrhage, but usefulness of MRI and susceptibility-weighted imaging for predicting long-term neurological outcome remains to be determined [1].…”

“…COMMENTARY. Suggested guidelines for rituximab treatment in children with neuroimmunologic conditions are listed in an editorial [1]. Originally approved by the FDA in 1997 for the treatment of B-cell non-Hodgkin lymphoma and later for rheumatoid arthritis, more recently it has been used in a variety of autoimmune disorders including multiple sclerosis.…”