A case of anti-NMDA receptor encephalitis in a woman with a NMDA-R+ small cell lung carcinoma (SCLC)

doi:10.1016/j.clim.2016.03.011

Clinical Immunology

Volumes 166–167, May 2016, Pages 96-99

https://doi.org/10.1016/j.clim.2016.03.011 Get rights and content

Abstract

The association of small cell lung cancer with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is rare. We report a 62 year old patient who developed psychiatric disorders followed by epilepsy, movement disorders, mutism and hypoventilation. Flair weighted brain MRI sequences showed diffuse high signals in the limbic system. Anti-NMDAR antibodies were detected in the serum and CSF. The patient's IgGs reacted with the patient's own tumor cells and with 2 out of 4 small cell lung cancers of patients without neurological syndrome.

Introduction

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterized by IgG autoantibodies directed against the NR1 subunit of the NMDA glutamate receptor [1]. The disease commonly occurs in young females and in this range of sex and age is associated in about 50% of cases with ovarian teratoma [1], [2], [3]. Cases have also been reported in older patients, predominantly men, but cancer is less frequent in this age range [4]. Other tumors than teratoma are rare. They represent less than 5% of cases [1] and can develop from a wide range of organ [1], [3]. We report here a case of anti-NMDAR encephalitis associated with small cell lung cancer (SCLC).

Section snippets

Case history

A 62 years old, heavy smoker (30 packs/year), woman experienced mood and behavioral changes four weeks prior to hospitalization in the intensive care unit. She was diagnosed with a severe depression and received antidepressant, benzodiazepines and neuroleptic treatments but her condition rapidly deteriorated with catatonic state, mutism, oppositional attitude, followed by complex partial seizures, orofacial dyskinesia, dystonic movements in the left side of the body and finally severe

Small cell lung cancer cells immunoreactivity with the patient serum

Detection of autoantibodies against the NR1 subunit of the NMDA glutamate receptor was performed in the serum or CSF by indirect immunofluorescence with NMDAR HEK transfected cells (Euroimmun, Germany). IgG from the patient and from a control normal subject diluted 1:10 in PBS-Tween 0.1% and revealed with FITC labelled anti-human IgG were used to detect NMDAR expression in the patient's tumor and in four SCLC from patients without neurological syndrome. Tumor cells were taken from lymph node

Discussion

The case reported here had the typical clinical and chronological pattern of anti-NMDAR AB encephalitis marked by initial psychiatric symptoms followed within a few weeks by loss of consciousness, seizures, dysautonomia, abnormal movements and central hypoventilation [3]. Extreme delta brush on EEG was also typical of the disorder [5] and anti-NMDAR antibodies were detected both in the serum and the CSF. However, this case displays several unusual features. First the encephalitis affected a

Conflict of interest

No conflict of interest.

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Anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis is a prevalent autoimmune condition marked by diverse neuropsychiatric symptoms, primarily impacting young females. The exact mechanisms underlying the development of NMDAr encephalitis have not been fully elucidated. Nonetheless, studies have demonstrated that auto-antibodies targeting the NR1-NR2 subunits of the NMDAr can trigger receptor dysfunction within the central nervous system, thus giving rise to the associated symptoms. Notably, an association exists between NMDAr encephalitis and an underlying neoplastic condition, with approximately 38% of cases exhibiting this paraneoplastic relationship with ovarian teratomas being the most commonly associated malignancy.
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Clinicopathological characteristics of dysplastic teratomous neuroglia with anti-N-methyl-D-aspartate receptor encephalitis
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Citation Excerpt :
NMDARs are firstly and primarily found in neurons and play an important role in the development of neurons and synaptic plasticity during brain development [2,3]. They are also found in neuralglial cells [4], brain endothelial cells [5], peripheral non-neural tissues [6,7], and carcinomas [8–13], especially in teratomas rich in NMDAR-bearing neural tissues [14–16]. Anti-NMDAR encephalitis is an autoimmune encephalitis mediated by anti-NMDAR antibodies that present with a subacute onset of individually variant symptoms such as psychiatric abnormalities, seizures, and involuntary movement followed by autonomic instability and disturbed consciousness.
In this study, we investigated whether unique pathological characteristics exist in teratomas that can trigger autoimmune anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. We compared a case of retroperitoneal teratoma associated with anti-NMDAR encephalitis and four control cases. The encephalitis-positive case showed that (i) more dysplastic neuroglia with higher Ki-67 labeling index values than the control cases, which met the diagnostic criteria of astrocytoma, (ii) the NMDAR subunit NR1 was expressed more abundantly in neuroglial tissue where many neuroglial cells co-expressed glial fibrillary acidic protein (GFAP) and NR1 and formed abnormally large cellular masses, (iii) intense NR1 expression occurs in squamous epithelium near neuroglial tissue and lymphocyte infiltration. This study showed that dysplastic neuroglial tissue resembling central nervous system tumors, which might promote autoimmunity, distinguished the case with NMDAR encephalitis from the controls. Additionally, abnormal expression of NR1 occurs in non-neural tissues and could be triggered by inflammation and participate in autoimmunity.
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Context: The pathologic diagnosis of neuroendocrine tumors of the lung requires integration of histologic and cytologic findings with clinical and radiologic consideration. Despite advances in diagnosis, challenges remain in their accurate classification.
Evidence acquisition: A search of relevant literature in PubMed was conducted with terms that included neuroendocrine, lung, and the terms in the chapter subheadings of individual entities combined with lung. In addition, review of archived cases in the file of Weill Cornell Pathology was conducted.
Results: Neuroendocrine tumors, including preinvasive lesions were described from the perspective of classification, clinical presentation, pathology, ancillary studies, molecular findings, and treatment impact. New information focused on diagnostic criteria for large cell neuroendocrine carcinoma including overlap with small cell carcinoma and adenocarcinoma, mitotic counting, specificity of CD56, and potential diagnostic pitfalls. The integration of clinical and radiologic findings to enhance diagnostic certainty was addressed.
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Anti-NMDA Receptor Encephalitis: Clinical Features and Basic Mechanisms
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Citation Excerpt :
Interestingly, isolated seizures as a presentation are more frequent in men than women for reasons that are unclear. Similarly, a large number of novel tumors are associated with anti-NMDAR, including hepatic neuroendocrine tumors, uterine neuroendocrine tumors, small cell lung cancer, and carcinoma of unknown origin (Afanasiev et al., 2016; Hara et al., 2011; Jeraiby, Depincé-Berger, Bossy, Antoine, & Paul, 2016; Wu, He, Zhang, Shi, & Zhang, 2016). The pathology of anti-NMDARE is consistent with a paraneoplastic limbic encephalitis.
In slightly more than 10 years, anti-NMDA receptor (NMDAR) encephalitis has changed from a rare paraneoplastic syndrome to the most common cause of nonviral encephalitis. It presents fulminantly with progressive psychosis, seizures, and autonomic dysfunction, leading to death if untreated. However, rapid recognition and treatment can lead to survival and a return to baseline levels of functioning in many patients. While initially associated with ovarian teratomas, it is now associated with other tumors and can reflect a postviral event. The antibodies to the NMDAR made in this syndrome are pathogenic and are directed at the extracellular domain of the GluN1 subunit. Such antibodies lead to internalization of NMDARs in model systems, leading to a physiological state characterized by NMDAR hypofunction. Analogous disorders, characterized by antibodies to other synaptic receptors, present with neurological and psychiatric dysfunction and also appear to reflect antibody-induced internalization of receptors. However, this simple pathophysiology may be too simplistic to reflect the complexity of events in anti-NMDAR encephalitis. Future scientific investigations may allow a more complete understanding of this disorder and improve treatment of anti-NMDAR encephalitis.
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Letter to the EditorA case of anti-NMDA receptor encephalitis in a woman with a NMDA-R+ small cell lung carcinoma (SCLC)

Abstract

Introduction

Section snippets

Case history

Small cell lung cancer cells immunoreactivity with the patient serum

Discussion

Conflict of interest

Lancet Neurol.

Lancet Neurol.

Lancet Neurol.

Rev. Neurol. (Paris)

Lancet Neurol.

Late-onset anti-NMDA receptor encephalitis

Neurology

Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis

Neurology

Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders

Front. Genet.

Letter to the Editor
A case of anti-NMDA receptor encephalitis in a woman with a NMDA-R⁺ small cell lung carcinoma (SCLC)