PMC10294282_01
Lumbar CSF findings during disease course and treatment over time. Note, that the first Y-axis on the right refers to protein in mg/L, the second to lactate in mg/dL.
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F1
Despite treatment with various further immunosuppressants (for synopsis, see Fig. 1), symptoms slowly worsened over the years and inflammatory markers remained elevated.
Ventricular CSF parameters, radiological findings, and cytokine levels during intraventricular treatment. After beginning of intraventricular treatment (blue background, treatment sessions as diamonds), a falling trend was seen for cell count and lactate (a). In (a), the first right-bound Y-axis corresponds to protein in mg/L and the second to lactate in mg/dL. T1-contrast dural enhancement in MRI remained constant over the years (left side, image from 2017) and a slight improvement followed intraventricular treatment as demonstrated here for the tentorium in January 2021 (b). Note that comparability is limited as images were acquired in different scanners (T3 vs. T1.5) due to cochlea implant and that this device accounts for an artifact in the posttreatment images. In (c) cytokine levels detected in CSF are depicted. Cytokine levels were measured with an 18-plex immunoassay (Invitrogen ; https://www.thermofisher.com/order/catalog/product/EPX180-12165-901). Each point represents the average of three technical replicates +- standard deviation. The CSF of three patients with neurodegenerative diseases served as controls (CTRL 1-3). The first two values in all graphs are (1) at reservoir implantation and (2) immediately before the first intraventricular instillation. Blue background represents time from first instillation.
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F2
During the course of intrathecal treatment, CSF cell count and lactate levels decreased (Fig. 2a). Furthermore, an 18-plex immunoassay of CSF detected several cytokines before treatment (IL-6, IL-10, IL-17A, IL-27, TNF-alpha, GM-CSF) that were not present in CSF of 3 control patients with neurodegenerative diseases (Fig. 2c). IL-6 and IL-10 decreased. In addition, follow-up cerebral MRI 3 months after intraventricular chemotherapy showed reduced meningeal enhancement (Fig. 2b), as far as comparable due to artifacts after cochlear implantation in the posttreatment images.
Cerebral autopsy showed granulomatous inflammation in the meninges around the brainstem. Here, leptomeninges are shown around the medulla oblongata (marked with # in a). We identified meningeal non-necrotizing granulomas with central histiocytes (marked with * in b) surrounded by dense lymphocytic and plasma cell infiltrates (arrow in b and inlay). Central histiocytes show expression of CD68 (c) as well as multinucleated cells. Infiltrates included only scattered IgG4-positive plasma cells (d). Scale bars: 500 microm (a); 100 mum (b + d); 50 mum (c).
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F3
Inflammatory changes included granulomatous formations without necrosis and mixed infiltrations with clusters of lymphocytes, plasma cells, macrophages and eosinophilic granulocytes, typical of sarcoidosis (Fig. 3).