A 54-year-old male presented with disturbance of consciousness, psychiatric symptoms and behavioral change, cognitive impairment, seizure and hypotension for 11 days. His family history was unremarkable. Exposure to toxic substances was denied. The day before his first symptom, a resection of his right colon was performed in a local hospital, and aGCC was diagnosed by the pathologist.
Brain magnetic resonance imaging (MRI;  Figure 1A ), routine cerebral spinal fluid (CSF) analyses ( Supplementary file ), and routine laboratory tests were unremarkable ( Table 1 ), except for increased carbohydrate antigen 125 (35.2 U/ml; normal range, < 24 U/ml) and blood ammonia (53.7 micromol/L; normal range, 9-33 micromol/L). The anti-amphiphysin antibody tested by immunoblotting (EUROIMMUN, Lubeck, Germany) was positive in both CSF and serum. The diagnosis of amphiphysin-positive LE associated with aGCC was made. A high dose of methylprednisolone (1000 mg/d for 5 days) was administered, followed by a tapered course of prednisone. The symptoms of psychiatric symptoms and seizures then disappeared one month later, but the patient remained cognitive dysfunction (Mini-mental State Examination score = 9).
Unfortunately, seven months later, the patient was readmitted to the hospital with progressive head and trunk tremors, dysarthria and gait instability for over 1 month. Neurological examination revealed head and trunk tremors, cognitive dysfunctions, bilateral gaze-evoked nystagmus and cerebellar ataxia (Vedio1). CSF analysis remained unchanged. Brain MRI showed mild cerebellar atrophy ( Figure 1B ). Amphiphysin-IgG was still present in CSF and serum. Positron emission tomography with computed tomography (PET/CT) scans revealed no tumor metastasis. The patient received IV cyclophosphamide (200 mg/d) and oral mycophenolate mofetil (500 mg/d) therapy. There was no improvement or deterioration of the neurological symptoms 3 months later. The evaluation of PNSs process is summarized in  Figure 1C .
To investigate a possible paraneoplastic origin of amphiphysin-PNSs in this patient, tissue blocks of the aGCC were examined pathologically. Immunohistochemical staining for CK20, CDX-2, carcinoembryonic antigen (CEA) and neuroendocrine markers (synaptophysin and chromogranin) were positive ( Figures 2A-F ), which meets the diagnostic pathological diagnostic criteria of Agcc according to the 2019 WHO.2 The expression of Ki67 protein was about 10%. MUC1 and MUC2 were also positive. Immunohistochemistry revealed positive CD3+ T cells, CD8+ T cells and CD20+ B cells in the tumor tissue ( Figures 2G-I ). However, CK7, CD138+ plasma cells, CD68+ macrophages, and IgG were negative in the tissue. Tumor cells showed reactivity with amphiphysin-Abs ( Figure 2H ), which indicates that the aGCC might play a role in triggering amphiphysin-IgG autoimmunity. Tissue-based indirect immunofluorescence assay (TBA) of the patient's serum revealed IgG antibody to Purkinje cells of the monkey cerebellum and dentate gyrus glia cells of the monkey hippocampus ( Figures 2K, L ).
According to the clinical manifestations, tumor, positive anti-amphiphysin antibody in CSF and serum, and well response to immunotherapy, aGCC associated amphiphysin-IgG autoimmunity was considered in this patient.