Case Report - (2022) Volume 7, Issue 5
Received: 31-Aug-2022, Manuscript No. IPJNO-22-14475; Editor assigned: 02-Sep-2022, Pre QC No. IPJNO-22-14475 (PQ); Reviewed: 16-Sep-2022, QC No. IPJNO-22-14475; Revised: 21-Sep-2022, Manuscript No. IPJNO-22-14475 (R); Published: 28-Sep-2022, DOI: 10.21767/2572-0376.22.7.53
We report the case of a woman with a history of atypical carcinoid tumor of the lung that developed a rapidly progressive memory impairment. Clinical presentation as well as brain MRI, cerebrospinal fluid and laboratory testing led to the diagnosis of seronegative paraneoplastic autoimmune limbic encephalitis. To the best of our knowledge, this is the first case in literature of such association. This case also highlights an exceptionally favorable outcome, both clinically and radiologically, after immunosuppression and tumor removal.
Encephalitis; Paraneoplastic; Atypical carcinoid; Immunosuppression; Cognitive impairment
Paraneoplastic autoimmune Limbic Encephalitis (LE) is a rare immune mediated neurological syndrome frequently associated with small cell lung carcinoma. Neurological prognosis critically depends on the ability to treat the accompanying tumor. Here we report the unusual association of seronegative paraneoplastic autoimmune LE and atypical carcinoid tumor of the lung. Early recognition of the paraneoplastic nature of LE and prompt oncological treatment allowed a favorable neurological outcome.
A 75 year old woman with a history of hypertension and atypical carcinoid of the lung was referred to our outpatient clinic for assessment of a rapidly progressive memory impairment and topographic disorientation over a few months. The neoplastic disease had been diagnosed 8 years earlier, in 2010, and treated surgically. A tumoral relapse with mediastinal lymph nodes was diagnosed in 2015, treated with surgery and radiotherapy. In 2018, a few weeks prior to visiting our outpatient clinic, the patient was diagnosed with a second relapse, consisting of an isolated hepatic and an acetabular metastasis. The liver metastasis was confirmed by a liver biopsy and subsequently by a liver resection. The histology and immunohistochemistry showed a tumor cell proliferation with solid and trabecular architecture with focal necrosis and diffuse positivity for synaptophysin consistent with an atypical carcinoid (Figure 1).
Figure 1: Histopathological findings. (A) Tumor cell proliferation with solid and trabecular architecture with focal necrosis, consistent with an atypical carcinoid (H&E stain; 200x). (B) Tumor cells stain diffusely for synaptophysin (400x).
Initial cognitive assessment showed severe verbal episodic memory impairment and executive dysfunction (Montreal Cognitive Assessment, MoCA, score 16/30). Brain MRI revealed bilateral mesial temporal and insular T2 hyperintensities predominating on the left side, in addition to an extensive frontal subcortical vascular leukoencephalopathy (Figure 2a). An isolated theta element on the left posterior temporal region was identified on electroencephalography. Cerebrospinal fluid analysis revealed mild lymphocytic leucorachia (7 M/l), mild hyperproteinorachia (0.51 g/l), and type 3 oligoclonal bands. Extensive viral workup was unrevealing. Serum and CSF autoantibody screening, including cell surface or synaptic autoantibodies anti-GABAB, -CASPR2, -LGI1 receptor, -AMPA receptor, -NMDA receptor, and intracellular autoantibodies anti-amphyphysin, -GAD65, -Hu, -Cv2/CRMP5, -SOX1, was negative. The diagnosis of definite seronegative paraneoplastic autoimmune LE was retained based on Grau’s criteria [1]. The hepatic metastasis was removed, followed by 500 mg intravenous methylprednisolone daily for 5 days. Radiotherapy was performed on the acetabular metastasis. Infusions of an anti-CD20 monoclonal antibody (Rituximab) were initiated and continued for a total of 18 months after metastasis removal, with a total of three doses administered 6 months apart. Three months after surgery and Rituximab initiation, the patient’s cognitive performance improved significantly (MoCA 25/30). One year after treatment, she was independent in almost all daily activities, requiring help only for administrative tasks. Detailed neuropsychological assessment revealed persistent executive dysfunction but significant memory improvement. Brain MRI showed notable regression of bilateral mesial temporal lobe hyperintensities (Figure 2b). Two years after treatment, cognitive performance remained stable despite mesial temporal lobe atrophy (Figure 2c).
Figure 2: Coronal FLAIR sequences show a hypersignal in the left and right temporal lobes as well as a cortico-subcortical atrophy of both temporal lobes, which are subtle in the baseline MRI (a) and increase on a 13 months (b) and a 21 months (c) follow-up MRI.
The association of sub-acute limbic system dysfunction and bronchial carcinoma was first characterized in 1968. In this seminal paper, Corsellis et al. described brain post mortem findings of three patients who presented with sub-acute short term memory deficits and neuropsychiatric symptoms in the context of small or large cell lung carcinoma, and revisited an additional 8 earlier cases [2]. They found extensive neuronal loss, astrogliosis, and mild lymphocytic perivascular inflammatory infiltrates focused in the limbic grey matter bilaterally. Importantly, no spread of tumor cells to the nervous system was identified, and the hypothesis of an immune mediated etiology was formulated. The identification of autoantibodies directed against antigens shared between the tumor and the nervous system in a majority of patients brought further evidence to support a paraneoplastic autoimmune etiology. Paraneoplastic autoimmune LE is now a well characterized neurological syndrome, and its prevalence is increasing, probably due to better recognition. Predominantly associated with small cell lung carcinoma, it can also occur in association with other bronchial, gynecological, and testicular tumors, as well as thymoma and lymphoma. In the right clinical and paraclinical setting, detection of an autoantibody is not necessary to retain the diagnosis of definite paraneoplastic autoimmune LE, provided alternative causes have been excluded. Early recognition of its paraneoplastic nature is critical, as the neurological prognosis depends largely on the ability to treat the accompanying tumor promptly.
We report the case of an unusual association of a seronegative paraneoplastic autoimmune LE and an atypical carcinoid tumor of the lung with a favorable outcome after metastasis resection performed 4 months after onset of neurological symptoms and Rituximab treatment. Significant cognitive improvement 3 months after surgery was observed, particularly memory, and it continued to improve up to 1 year after treatment. We found three other cases of an association of LE and carcinoid tumors.
In the first report of LE and midgut carcinoid, no autoantibodies were searched [3]. In the second, anti-Ri antibodies were detected in a patient with lung carcinoid tumor [4], whereas in the third report describing an association with thyroid carcinoid, none was identified despite extensive screening. Together, these reports underscore the importance of considering paraneoplastic autoimmune LE in tumors not classically associated with such syndromes [5].
Our case showcases an exceptionally favorable outcome of a paraneoplastic LE associated with a carcinoid tumor of the lung after a combination of tumor removal and immunosuppression with Rituximab. This result is even more remarkable given that paraneoplastic LE usually shows a poor response to immunosuppressive agents.
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Citation: Marull Paretas E, Vito CD, Bernasconi F, Catalono S, Vargas MI, et al. (2022) Paraneoplastic Autoimmune Limbic Encephalitis Associated with an Atypical Carcinoid Tumor of the Lung. Neurooncol. 7:53.
Copyright: © 2022 Marull Paretas E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
