A 67-year-old female was admitted to our hospital in September 2019 with progressing dizziness, unsteady gait, and speech difficulty. The patient was previously healthy without history of tumor, HIV, or organ transplantation, and without the usage of immunosuppressants or monoclonal antibodies. Any autoimmune diseases/immunodeficiency were not known before. Physical examination showed a serious dysfunction of cognition, with a decrease in emotion, memory, and intelligence. Barthel index for activities of daily living (ADL) on admission scored 35 points, indicating a severe dependency. Infectious sources, including blood, urine, and CSF were negative. T cell subsets in peripheral blood, including CD3, CD4 and CD8, were detected normal. And the ratio of CD4/CD8 was 1.26. But some parameters, such as angiotensin converting enzyme (ACE), neopterin, interleukin (IL-)-2-receptor-antibodies, lysozyme, oligoclonal bands, and JCV, were not analyzed in CSF and serum. Contrast-enhanced chest and abdominal computed tomography showed no mass lesions or swollen lymph nodes.
Serial MRI on admission revealed multifocal subcortical lesions in both hemispheres, which were hypointense on T1 and hyperintense on T2 or FLAIR imaging with a slight dotted enhancement in the center (Fig. 1A-F). Almost all lesions grew around the lateral ventricle, and the largest lesion was located on the left parietal lobe. Intravenous corticosteroids were administered initially, however the mental status of the patient worsened. Surgical biopsy was performed, and a large mass of tissue on the left parietal lobe was obtained for further pathological and genomic detection (Fig. 1G). Lymphoid cell infiltration was observed in the frozen sample. The patient was stuporous after surgery, similar to her mental status prior to surgery.
Histopathological specimens revealed infiltration of plasma cells, lymphoid cells, and abundant macrophages. Some cells with enlarged or bizarre-shaped nuclei were present, suggesting infected cells (Fig. 1I). Immunohistochemistry (IHC) analysis showed GFAP (+), Olig2 (+), ATRX (+), EMA (-), NeuN (-), and S-100 (+) in glial cells; P53 (+), Ki67 (+) in cells with bizarre-shaped nuclei; CD163 (+), CD68 (+), and CD1a (-) in macrophages and plasma cells; and CD3 (+), CD20 (+), and CD30 (-) in lymphoid cells. In addition, special stains for fungi were negative. Genetic profiling did not detect mutations in V600E, the TERT promoter, H3F3A/HIST1H3B, or IDH1/2. Subsequently, “High-throughput DNA Gene Detection of Pathogenic Microorganisms”, a Next Generation Sequencing (NGS) method, was performed by BGI Genomics [3]. In a total of 25,578,487 reads, 16,376 reads of JC virus were detected at 97.01% coverage (Fig. 1J).
This patient was diagnosed with JC virus-induced progressive multifocal leukoencephalopathy. Mirtazapine (Remeron, MSD) at a daily dose of 15 mg orally was administered, and mefloquine (Lariam, Roche) was administered at a dose of 250 mg weekly one month later. At the same time, Chinese traditional medical herbs, such as Acorus tatarinowii, Poria cocos, Rhizoma pinelliae, and Scutellaria baicalensis Georgi, were also given every day. There was a slight improvement in the patient’s condition after one month of treatment, but she remained obtunded and her cognition was severely damaged. After more than two years of postoperative follow-up, her clinical symptoms were still stable and Barthel index scored 35, although there was some progress on radiological imaging (Fig. 1H).