Synchronous versus metachronous spinal metastasis: a comparative study of survival outcomes following neurosurgical treatment.

PURPOSE: Patients with spinal metastases (SM) from solid neoplasms typically exhibit progression to an advanced cancer stage. Such metastases can either develop concurrently with an existing cancer diagnosis (termed metachronous SM) or emerge as the initial indication of an undiagnosed malignancy (referred to as synchronous SM). The present study investigates the prognostic implications of synchronous compared to metachronous SM following surgical resection. METHODS: From 2015 to 2020, a total of 211 individuals underwent surgical intervention for SM at our neuro-oncology facility. We conducted a survival analysis starting from the date of the neurosurgical procedure, comparing those diagnosed with synchronous SM against those with metachronous SM. RESULTS: The predominant primary tumor types included lung cancer (23%), prostate cancer (21%), and breast cancer (11.3%). Of the participants, 97 (46%) had synchronous SM, while 114 (54%) had metachronous SM. The median overall survival post-surgery for those with synchronous SM was 13.5 months (95% confidence interval (CI) 6.1-15.8) compared to 13 months (95% CI 7.7-14.2) for those with metachronous SM (p = 0.74). CONCLUSIONS: Our findings suggest that the timing of SM diagnosis (synchronous versus metachronous) does not significantly affect survival outcomes following neurosurgical treatment for SM. These results support the consideration of neurosurgical procedures regardless of the temporal pattern of SM manifestation.

Machine learning based prediction of length of stay in acute ischaemic stroke of the anterior circulation in patients treated with thrombectomy.

BACKGROUND: Length of stay is an important factor for managing the limited resources of a hospital. The early, accurate prediction of hospital length of stay leads to the optimized disposition of resources particularly in complex stroke treatment. OBJECTIVE: In the present study we evaluated different machine learning techniques in their ability to predict the length of stay of patients with stroke of the anterior circulation who were treated with thrombectomy. MATERIAL AND METHODS: This retrospective study evaluated four algorithms (support vector machine, generalized linear model, K-nearest neighbour and Random Forest) to predict the length of hospitalization of 113 patients with acute stroke who were treated with thrombectomy. Input variables encompassed baseline data at admission, as well as periprocedural and imaging data. Ten-fold cross-validation was used to estimate accuracy. The accuracy of the algorithms was checked with a test dataset. In addition to regression analysis, we performed a binary classification analysis to identify patients that stayed longer than the mean length of stay. RESULTS: Mean length of stay was 10.7 days (median 10, interquartile range 6-15). The sensitivity of the best-performing Random Forest model was 0.8, the specificity was 0.68 and the area under the curve was 0.73 in the classification analysis. The mean absolute error of the best-performing Random Forest Model was 4.6 days in the test dataset in the regression analysis. CONCLUSION: Machine learning has potential use to estimate the length of stay of patients with acute ischaemic stroke that were treated with thrombectomy.

Undetected pseudoprogressions in the CeTeG/NOA-09 trial: hints from postprogression survival and MRI analyses.

PURPOSE: In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO). METHODS: We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T1-enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined. RESULTS: Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T1-enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm. CONCLUSION: The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09.

The Diagnostic Value of Cerebrospinal Fluid Lactate for Detection of Sepsis in Community-Acquired Bacterial Meningitis.

Community-acquired bacterial meningitis conveys significant morbidity and mortality due to intracranial and systemic complications, and sepsis is a major contributor to the latter. While cerebrospinal fluid (CSF) analysis is essential in the diagnosis of bacterial meningitis, its predictive utility for detection of sepsis is unknown. We investigated the diagnostic performance of CSF parameters for sepsis defined by the Sepsis-3 criteria in a retrospective cohort of patients with community-acquired bacterial meningitis. Among 103 patients, 69.5% developed sepsis. CSF lactate was associated with sepsis with an odds ratio of 1.11 (p = 0.022), while CSF cell counts, glucose and protein levels were not (all p > 0.4). Employing the optimal cutoff of 8.2 mmol/L, elevated CSF lactate resulted in a sensitivity of 81.5% and specificity of 61.5% for sepsis. In exploratory analyses, CSF lactate was also associated with in-hospital mortality with an odds ratio of 1.21 (p = 0.011). Elevated CSF lactate might contribute to early diagnosis of sepsis as well as prognostication in patients with community-acquired bacterial meningitis.

Parameters Associated with the Required Drug Dose of Intravenous Immunoglobulin in Stable Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

BACKGROUND: Intravenous immunoglobulin (IVIg) is efficient and one of very few treatment options for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, finding the optimal dose of IVIg for individual CIDP patients remains challenging. The dose of IVIg needs to be adjusted individually. Considering the high healthcare costs of IVIg therapy, the overtreatment of some patients seen in placebo studies and the shortage of IVIg we recently experienced, as well as identifying factors associated with the required dose of IVIg in maintenance treatment, is extremely important. Thus, in this retrospective study, we analyze characteristics of patients with stable CIDP, which are associated with the required drug dose. METHODS: 32 patients with stable CIDP treated with IVIg between July 2021 and July 2022 were identified from our database and included in this retrospective study. Patients' characteristics were registered, and parameters were identified that were associated with the IVIg dose. RESULTS: Age, cerebrospinal fluid protein elevation, disease duration, delay between symptom onset/diagnosis, Inflammatory Neuropathy Cause and Treatment (INCAT) score, and Medical Research Council Sum Score (MRC SS) were significantly associated with the required drug dose. In addition, an association of age, sex, elevated CSF protein, time interval between symptom onset and diagnosis, and the MRC SS with the required IVIg dose could be demonstrated in the multivariable regression analysis. CONCLUSIONS: Our model, which is based on routine parameters that are simple to address in the clinical practice, can be useful in adjusting the IVIg dose in patients with stable CIDP.

IL-17A Facilitates Entry of Autoreactive T-Cells and Granulocytes into the CNS During EAE.

Interleukin-17A plays a crucial role in multiple sclerosis and other autoimmune diseases. Although the link between IL-17 and disease activity has been clearly demonstrated, the precise function of this cytokine remains elusive. Here, we investigated the function of astrocyte-targeted IL-17A production in GF/IL-17 transgenic mice during EAE. In particular, IL-17A is important during disease induction. In mice with transgenic IL-17A production, disease occurs earlier and peak disease is more severe, whereas remission is unimpaired. IL-17A synthesis is associated with increased infiltration of granulocytes into the CNS and microglial activation. Moreover, IL-17A synthesis allows induction of MOG-EAE without the additional administration of the co-adjuvant pertussis toxin. Examination of double transgenic GF/IL-17 2D2 mice revealed that, in addition, local IL-17A production facilitates spontaneous infiltration of immune cells into the CNS in mice expressing a MOG-specific T-cell receptor. Overall, we provide evidence for a crucial effect of IL-17A in the induction phase of EAE, facilitating the infiltration of granulocytes and autoreactive T-cells into the CNS.

Progressive Multifocal Leukoencephalopathy Treated by Immune Checkpoint Inhibitors.

OBJECTIVE: Our aim was to assess the real-world effectiveness of immune checkpoint inhibitors for treatment of patients with progressive multifocal leukoencephalopathy (PML). METHODS: We conducted a multicenter survey compiling retrospective data from 79 PML patients, including 38 published cases and 41 unpublished cases, who received immune checkpoint inhibitors as add-on to standard of care. One-year follow-up data were analyzed to determine clinical outcomes and safety profile. Logistic regression was used to identify variables associated with 1-year survival. RESULTS: Predisposing conditions included hematological malignancy (n = 38, 48.1%), primary immunodeficiency (n = 14, 17.7%), human immunodeficiency virus/acquired immunodeficiency syndrome (n = 12, 15.2%), inflammatory disease (n = 8, 10.1%), neoplasm (n = 5, 6.3%), and transplantation (n = 2, 2.5%). Pembrolizumab was most commonly used (n = 53, 67.1%). One-year survival was 51.9% (41/79). PML-immune reconstitution inflammatory syndrome (IRIS) was reported in 15 of 79 patients (19%). Pretreatment expression of programmed cell death-1 on circulating T cells did not differ between survivors and nonsurvivors. Development of contrast enhancement on follow-up magnetic resonance imaging at least once during follow-up (OR = 3.16, 95% confidence interval = 1.20-8.72, p = 0.02) was associated with 1-year survival. Cerebrospinal fluid JC polyomavirus DNA load decreased significantly by 1-month follow-up in survivors compared to nonsurvivors (p < 0.0001). Thirty-two adverse events occurred among 24 of 79 patients (30.4%), and led to treatment discontinuation in 7 of 24 patients (29.1%). INTERPRETATION: In this noncontrolled retrospective study of patients with PML who were treated with immune checkpoint inhibitors, mortality remains high. Development of inflammatory features or overt PML-IRIS was commonly observed. This study highlights that use of immune checkpoint inhibitors should be strictly personalized toward characteristics of the individual PML patient. ANN NEUROL 2023;93:257-270.

Central role of B cells in interleukin-23 dependent neuroinflammation in the GF-IL23 model.

Interleukin (IL)-23 is one of the critical cytokines in autoimmune neuroinflammation. To further clarify the local function of IL-23 on the course of neuroinflammation, we recently established a transgenic mouse model with astrocyte-specific expression of IL-23 (GF-IL23). The GF-IL23 mice spontaneously developed a progressive ataxic phenotype with cerebellar infiltration with high amounts of B cells most prominent in the subarachnoid and perivascular space. To enlighten the B cell role in GF-IL23 mice, we generated GF-IL23 mice on a B cell knockout (k.o.) background (GF-IL23 B cell k.o.). GF-IL23 B cell k.o. mice compared with GF-IL23 mice had no infiltrates or only minor infiltration, and no antibody deposition was detected in the cerebellum. Furthermore, microglia, astrocyte activation, hypervascularization and demyelination were reduced in GF-IL23 B cell k.o. mice compared with GF-IL23 mice. Cytokines and chemokine receptors like IL-12a, cerebrospinal fluid 2 and CXCR3 were downregulated. Our study indicates that B cells are essential in IL-23-dependent neuroinflammation in the GF-IL23 model.

MOG-Specific T Cells Lead to Spontaneous EAE with Multilocular B Cell Infiltration in the GF-IL23 Model.

Although IL-23 and downstream signal transduction play essential roles in neuroinflammation, the local impact of IL-23 in multiple sclerosis is still not fully understood. Our previous study revealed that the central nervous system (CNS)-restricted expression of IL-23 in a mouse model with astrocyte-specific expression of IL-23, called GF-IL23 mice, leads to spontaneous formation of infiltrates in the brain, especially in the cerebellum. To further investigate the impact of CNS-specific IL-23-expression on neuroinflammation, we studied the GF-IL23 model in mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (GF23-2D2 mice). The GF23-2D2 mice developed a chronic progressive experimental autoimmune encephalomyelitis with myelitis and ataxia without requiring additional immunization. CNS-production of IL-23 alone induced pronounced neuroinflammation in the transgenic MOG-specific T cell receptor model. The GF23-2D2 mice spontaneously developed multilocular infiltrates with a high number of B cells, demyelination and a proinflammatory cytokine milieu indicating that the interaction of encephalitogenic T cells and B cells via co-stimulatory factors seemed to be crucial.

Microglia-Derived Interleukin 23: A Crucial Cytokine in Alzheimer's Disease?

Neuronal cell death, amyloid ß plaque formation and development of neurofibrillary tangles are among the characteristics of Alzheimer's disease (AD). In addition to neurodegeneration, inflammatory processes such as activation of microglia and astrocytes are crucial in the pathogenesis and progression of AD. Cytokines are essential immune mediators of the immune response in AD. Recent data suggest a role of interleukin 23 (IL-23) and its p40 subunit in the pathogenesis of AD and corresponding animal models, in particular concerning microglia activation and amyloid ß plaque formation. Moreover, in animal models, the injection of anti-p40 antibodies resulted in reduced amyloid ß plaque formation and improved cognitive performance. Here, we discuss the pathomechanism of IL-23 mediated inflammation and its role in AD.

Astrocyte-specific expression of interleukin 23 leads to an aggravated phenotype and enhanced inflammatory response with B cell accumulation in the EAE model.

BACKGROUND: Interleukin 23 is a critical cytokine in the pathogenesis of multiple sclerosis. But the local impact of interleukin 23 on the course of neuroinflammation is still not well defined. To further characterize the effect of interleukin 23 on CNS inflammation, we recently described a transgenic mouse model with astrocyte-specific expression of interleukin 23 (GF-IL23 mice). The GF-IL23 mice spontaneously develop a progressive ataxic phenotype with cerebellar tissue destruction and inflammatory infiltrates with high amounts of B cells most prominent in the subarachnoid and perivascular space. METHODS: To further elucidate the local impact of the CNS-specific interleukin 23 synthesis in autoimmune neuroinflammation, we induced a MOG35-55 experimental autoimmune encephalomyelitis (EAE) in GF-IL23 mice and WT mice and analyzed the mice by histology, flow cytometry, and transcriptome analysis. RESULTS: We were able to demonstrate that local interleukin 23 production in the CNS leads to aggravation and chronification of the EAE course with a severe paraparesis and an ataxic phenotype. Moreover, enhanced multilocular neuroinflammation was present not only in the spinal cord, but also in the forebrain, brainstem, and predominantly in the cerebellum accompanied by persisting demyelination. Thereby, interleukin 23 creates a pronounced proinflammatory response with accumulation of leukocytes, in particular B cells, CD4+ cells, but also γδ T cells and activated microglia/macrophages. Furthermore, transcriptome analysis revealed an enhanced proinflammatory cytokine milieu with upregulation of lymphocyte activation markers, co-stimulatory markers, chemokines, and components of the complement system. CONCLUSION: Taken together, the GF-IL23 model allowed a further breakdown of the different mechanisms how IL-23 drives neuroinflammation in the EAE model and proved to be a useful tool to further dissect the impact of interleukin 23 on neuroinflammatory models.

Abnormal subpopulations of monocytes in the cerebrospinal fluid of patients with Parkinson's disease.

We performed immune cell profiling by multiparameter flow cytometry in cerebrospinal fluid (CSF) and peripheral blood (PB) of Parkinson's Disease (PD) patients (n = 9) and healthy controls (n = 8). Classical and non-classical monocytes were increased in the CSF of PD patients.

Reduced inflammatory response and accelerated functional recovery following sciatic nerve crush lesion in CXCR3-deficient mice.

Despite the regenerative capacity of the peripheral nerve system (PNS), functional recovery after mechanical nerve trauma is often incomplete, resulting in motor, sensory, and autonomic deficits. The elucidation of key molecules involved in trauma-induced Wallerian degeneration and the ensuing regeneration processes is a prerequisite for the development of disease modifying drugs. The chemokine (C-X-C motif) receptor 3 (CXCR3) has been implicated in the recruitment of macrophages, the major immune cell population during the process of Wallerian degeneration. In this study, we examined whether deletion of CXCR3 affects macrophage recruitment, the expression of the proinflammatory cytokine tumor necrosis factor (TNF)- α and the CXCR3 agonist interferon gamma-induced protein 10 (CXCL10), and functional recovery in the sciatic nerve crush model. CXCR3 mice displayed significantly reduced macrophage counts preceded by diminished expression of CXCL10 and TNF- α. Furthermore, functional recovery of sciatic nerve motor function was significantly accelerated. In summary, these data indicate that the deletion of CXCR3 leads to a diminished inflammatory response and an accelerated functional recovery following sciatic nerve crush injury. Therefore, CXCR3 may be an interesting target for therapeutic interventions after traumatic nerve lesions.

CNS-Specific Synthesis of Interleukin 23 Induces a Progressive Cerebellar Ataxia and the Accumulation of Both T and B Cells in the Brain: Characterization of a Novel Transgenic Mouse Model.

Interleukin 23 (IL-23) is a key mediator in neuroinflammation in numerous autoimmune diseases including multiple sclerosis (MS). However, the pathophysiology of IL-23 and how it contributes to neuroinflammation is poorly defined. To further clarify the role of IL-23 in CNS inflammation, we generated a transgenic mouse model (GF-IL23) with astrocyte-targeted expression of both IL-23 subunits, IL-23p19, and IL-23p40. These GF-IL23 mice spontaneously develop a progressive ataxic phenotype, which corresponds to cerebellar tissue destruction, and inflammatory infiltrates most prominent in the subarachnoidal and perivascular space. The CNS-cytokine milieu was characterized by numerous inflammatory mediators such as IL-17a and IFNγ. However, the leukocytic infiltrates were surprisingly predominated by B cells. To further examine the impact of the CNS-specific IL-23 synthesis on an additional systemic inflammatory stimulus, we applied the LPS-induced endotoxemia model. Administration of LPS in GF-IL23 mice resulted in early and pronounced microglial activation, enhanced cytokine production and, in sharp contrast to control animals, in the formation of lymphocytic infiltrates. Our model confirms a critical role for IL-23 in the induction of inflammation in the CNS, in particular facilitating the accumulation of lymphocytes in and around the brain. Thereby, CNS-specific synthesis of IL-23 is able to induce a cascade of inflammatory cytokines leading to microglia activation, astrocytosis, and ultimately tissue damage. The presented transgenic model will be a useful tool to further dissect the role of IL-23 in neuroinflammation.

IL-17A Promotes Granulocyte Infiltration, Myelin Loss, Microglia Activation, and Behavioral Deficits During Cuprizone-Induced Demyelination.

Recent evidence suggests a pivotal role of the proinflammatory cytokine interleukin - 17A (IL-17) in demyelinating autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS). Nevertheless, it remains unclear if this cytokine exerts direct effects on CNS resident cells during MS or modulates the function of infiltrating immune cells towards a more detrimental phenotype. Here, we investigated the effects of locally produced IL-17 during experimental demyelination of the CNS using the cuprizone (CPZ) model in mice with (GF/IL17) or without transgenic production of IL-17 by astrocytes in the CNS. During early demyelination, GF/IL17 mice demonstrated enhanced activity and decreased anxiety-related behavior in the elevated plus maze suggesting a more severe disease course. Furthermore, in GF/IL17 mice, toxic demyelination was accelerated and synthesis of myelin proteins was reduced. Early demyelination was accompanied by an increased ratio of infiltrating granulocytes in GF/ILl17 mice. The presence of IL-17 during CPZ treatment increased the accumulation of activated microglia and sustained microglial proliferation during myelin loss. Taken together, our results argue for a detrimental role of IL-17 during demyelinating diseases.