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Hypertrophic pachymeningitis (HP) is a rare immune-mediated disease characterized by thickening of the dura mater with consecutive cranial neuropathy. While HP is usually treated with systemic immunotherapies, response to therapy is variable and may be limited by insufficient drug concentrations in the brain. We report on a 57-year-old patient with HP manifesting with vision and hearing loss who had sustained clinical progression despite various systemic immunotherapies. Intraventricular chemotherapy with methotrexate, cytarabine, and dexamethasone was initiated. We present clinical, imaging and cerebrospinal fluid (CSF) findings, including cytokine levels before and after intraventricular treatment: rapid decrease of cell count, lactate and profibrotic cytokine levels in the CSF following intraventricular chemotherapy was paralleled by a mild reduction of dura thickness in MRI. The already severely impaired visual acuity and hearing loss did not progress further. Treatment was complicated by exacerbation of previously subtle psychiatric symptoms. Follow-up was terminated after 6 months as the patient suffered from a fatal ischemic stroke. Autopsy revealed neurosarcoidosis as the underlying cause of HP. This case report suggests that intrathecal chemotherapy can reduce the inflammatory milieu in the CNS and should be considered for treatment-refractory HP before irreversible damage of cranial nerves has occurred.

Abstract Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. We studied the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n = 38). Patients with herpes simplex virus encephalitis (HSVE, n = 10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n = 28) served as controls. We used proteomics, enzyme-linked immunoassays, and semiquantitative cytokine arrays to characterize inflammatory proteins. Autoantibody screening was performed with cell-based assays and native tissue staining. RNA sequencing of long-non-coding RNA and circular RNA was done to study the transcriptome. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients with, e.g., downregulation of the apolipoproteins and extracellular matrix proteins. Protein upregulation of the complement system, the serpin proteins pathways, and other proteins including glycoproteins alpha-2 and alpha-1 acid. Importantly, calculation of interleukin-6, interleukin-16, and CXCL10 CSF/serum indices suggest that these inflammatory mediators reach the CSF from the systemic circulation, rather than being produced within the CNS. Antibody screening revealed no pathological levels of known neuronal autoantibodies. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly (p

Objectives: Studies on coronavirus disease 2019 (COVID-19) usually focus on middle-aged and older adults. However, younger patients may present with severe COVID-19 with potentially fatal outcomes. For optimized, more specialized therapeutic regimens in this particular patient group, a better understanding of the underlying pathomechanisms is of utmost importance. Methods: Our study investigated relevant, pre-existing medical conditions, clinical histories, and autopsy findings, together with SARS-CoV-2-RNA, determined by qPCR, and laboratory data in six COVID-19 decedents aged 50 years or younger, who were autopsied at the Charité University Hospital. Results: From a total of 76 COVID-19 patients who underwent an autopsy at our institution, six (7.9%) were 50 years old or younger. Most of these younger COVID-19 decedents presented with pre-existing medical conditions prior to SARS-CoV-2 infection. These included overweight and obesity, arterial hypertension, asthma, and obstructive sleep apnea, as well as graft-versus-host disease following cancer and bone marrow transplantation. Furthermore, clinical histories and autopsy results revealed a disproportionally high prevalence of thromboembolism and ischemic organ damage in this patient cohort. Histopathology and laboratory results indicated coagulopathies, signs of immune dysregulation, and liver damage. Conclusions: In conclusion, pre-existing health conditions may increase the risk of severe and fatal COVID-19 in younger patients, who may be especially prone to developing thromboembolic complications, immune dysregulation, and liver damage.

Multimodal tumor treatment settings consisting of radiotherapy and immunomodulating agents such as immune checkpoint inhibitors are more and more commonly applied in clinics. In this context, the immune phenotype of tumor cells has a major influence on the anti-tumor immune response as well as the composition of the tumor microenvironment. A promising approach to further boost anti-tumor immune responses is to add hyperthermia (HT), i.e., heating the tumor tissue between 39 °C to 45 °C for 60 min. One key technique is the use of radiative hyperthermia systems. However, knowledge is limited as to how the frequency of the used radiative systems affects the immune phenotype of the treated tumor cells. By using our self-designed in vitro hyperthermia system, we compared cell death induction and expression of immune checkpoint molecules (ICM) on the tumor cell surface of murine B16 melanoma and human MDA-MB-231 and MCF-7 breast cancer cells following HT treatment with clinically relevant microwaves at 915 MHz or 2.45 GHz alone, radiotherapy (RT; 2 × 5 Gy or 5 × 2 Gy) alone or in combination (RHT). At 44 °C, HT alone was the dominant cell death inductor with inactivation rates of around 70% for B16, 45% for MDA-MB-231 and 35% for MCF-7 at 915 MHz and 80%, 60% and 50% at 2.45 GHz, respectively. Additional RT resulted in 5–15% higher levels of dead cells. The expression of ICM on tumor cells showed time-, treatment-, cell line- and frequency-dependent effects and was highest for RHT. Computer simulations of an exemplary spherical cell revealed frequency-dependent local energy absorption. The frequency of hyperthermia systems is a newly identified parameter that could also affect the immune phenotype of tumor cells and consequently the immunogenicity of tumors.