Severe Dysphagia Predicts Poststroke Fever.

Background and Purpose: Fever is a common observation after ischemic or hemorrhagic stroke and is associated with a worse clinical outcome. Infections, stroke severity, preexisting medical conditions, insertion of catheters, and dysphagia have been implicated in causing poststroke fever. Given that dysphagia has not been evaluated in detail yet, the aim of this study was to investigate if the severity of dysphagia assessed by a detailed swallowing assessment predicts poststroke fever. Methods: In this retrospective monocentric cohort study, all patients admitted for ischemic or hemorrhagic stroke within 12 months were included. Patients underwent a detailed standardized swallowing assessment including a clinical exam by a speech therapist and fiberoptic endoscopic evaluation in a subset of patients. Patients who developed fever within 5 days were compared with patients without fever regarding swallowing parameters and other clinical characteristics relevant for the prediction of poststroke fever. Results: Nine hundred twenty-three patients with acute ischemic or hemorrhagic stroke were included. One hundred twenty-seven (13.8%) patients developed fever. In multivariable analyses, fever was independently predicted by moderate-to-severe dysphagia in clinical assessments (odds ratio [95% CI], 3.05 [1.65­5.66]) and also by dysphagia with proven risk of aspiration as a combined end point of clinical and instrumental assessments (1.79 [1.07­3.00]). Other independent predictors were stroke severity (odds ratio, 1.06 per point on the National Institutes of Health Stroke Scale score [1.01­1.11]) and the presence of an urinary catheter (odds ratio, 2.03 [1.13­3.65]). Conclusions: Severe dysphagia evaluated by a detailed clinical assessment complemented by instrumental testing predicts the development of poststroke fever. Early identification of patients with severe dysphagia after stroke followed by consequent monitoring and treatment might be effective in reducing poststroke fever.

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer.

Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental. Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis. Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm. Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%. Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental.

Bevacizumab is associated with cerebral microstructural alterations: a DTI study in high-grade glioma.

Background: For recurrent high-grade glioma, especially glioblastoma, no standard of care treatment exists. Due to the prolongation of progression-free survival and a cortiocosteroid-sparing effect, bevacizumab is often used in this condition. Despite initial clinical responses, there is growing evidence that bevacizumab may potentiate microstructural alterations which may cause cognitive decline, mostly affecting learning and memory. Methods: To investigate bevacizumab-associated microstructural damage of defined regions of interest (ROIs) in the white matter, diffusion tensor imaging (DTI) was performed in 10 patients with a case history or third-party report for neurological dysfunction concerning cognitive performance. Serial DTI data before and under bevacizumab were collected and longitudinal changes of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were assessed in mesiotemporal (hippocampal), frontal, and occipital regions. Results: The longitudinal DTI data under bevacizumab compared to DTI prior to bevacizumab demonstrated a significant decrease in FA and increase in AD and RD both in mesiotemporal (hippocampal) regions and in frontal regions, whereas occipital regions showed no significant alterations in DTI metrics. Conclusion: The regionally impaired microstructure in mesiotemporal (hippocampal) regions and in frontal regions is in line with the fact that neurocognitive impairment in learning and memory is mostly related to hippocampal integrity and attentional control in frontal regions. Further studies could investigate the potential of DTI to assess bevacizumab-associated microstructural damages in vulnerable brain regions.

First Report of Tumor Treating Fields (TTFields) Therapy for Glioblastoma in Comorbidity with Multiple Sclerosis.

Tumor Treating Fields (TTFields) therapy is FDA approved and has the CE mark for treatment of newly diagnosed and recurrent glioblastoma. To our knowledge, to date TTFields therapy remains unstudied in glioblastoma patients with multiple sclerosis (MS) as a comorbidity. Here, we present a patient who was diagnosed with MS at the age of 34. Treatment included several corticoid pulse treatments and therapies with interferon beta-1a and sphingosine-1-phosphate receptor modulator fingolimod. At the age of 52 the patient was diagnosed with glioblastoma, after experiencing worsening headaches which could not be attributed to the MS condition. After subtotal resection and concomitant radiochemotherapy, the patient received temozolomide in combination with TTFields therapy. For two years, the tumor condition remained stable while the patient showed high adherence to TTFields therapy with low-grade skin reactions being the only therapy-related adverse events. After two years, the tumor recurred. The patient underwent re-resection and radiotherapy and restarted TTFields therapy together with chemotherapy and is currently still on this therapy regime. Although having not been studied systematically, the case presented here demonstrates that TTFields therapy may be considered for newly diagnosed and recurrent glioblastoma patients with previously diagnosed multiple sclerosis.

HARM revisited: Etiology of subarachnoid hyperintensities in brain FLAIR MRI.

BACKGROUND: The hyperintense acute reperfusion marker (HARM) describes a phenomenon with a hyperintense signal in the subarachnoid space in Fluid-Attenuated Inversion Recovery (FLAIR) magnetic resonance imaging (MRI) sequences, presumably based on blood-brain barrier breakdown in acute stroke with reperfusion. However, this imaging phenomenon was described in other medical conditions. AIM: Determination of the prevalence and associated clinical findings of this phenomenon in a large sample of patients with different neurological conditions. METHODS: This is retrospective, single-center, observational study of 23,948 cerebral MRIs acquired in a Neurological University Clinic over 5 years. The prevalence of HARM, the underlying diagnosis, and damage pattern were examined by chart analysis; MRI was analyzed regarding the type of acute lesions, extent of microangiopathic lesions, and whether gadolinium-based contrast agent (GBCA) was given. RESULTS: Among the MRI data, 84 images (0.35%) from 61 patients were HARM-positive without a subarachnoid signal abnormality in any other sequence. Etiologies were heterogeneous; 35 patients had a cerebrovascular disease (CVD; 19 patients received recanalization therapy), 12 patients had an inflammatory central nervous system (CNS) disease and 14 patients had epilepsy. GBCA was applied to 64% of the patients. CONCLUSION: HARM was a rare radiological finding in a range of different neurological pathologies, not limited to stroke, or to previous reperfusion therapy and was not dependent on previous GBCA administration. Our data suggest that the term is too narrow in terms of the concepts of the underlying pathology. We propose to use the term FLAIR Subarachnoid Hyperintensity ("FLASH") phenomenon which might better reflect the observation that the radiological sign can be associated with a variety of central neurological conditions without a straightforward association with therapy.

Morphological alterations of the hypothalamus in idiopathic intracranial hypertension.

Background: The pathophysiology of idiopathic intracranial hypertension (IIH), a condition characterized by raised intracranial pressure, is not well understood. Objectives: We hypothesized that the hypothalamus might exhibit alterations in patients with IIH, based on its established association with obesity and the potential role of hormonal and metabolic factors in IIH. Design: Retrospective single-center cohort study. Methods: Thirty-three individuals with IIH and 40 matched healthy individuals were studied, including levels of the hormones and proteins leptin, adiponectin, ghrelin, insulin, growth/differentiation factor 15 (GDF15), somatostatin, and melatonin. In vivo high-resolution T1-weighted magnetic resonance imaging (MRI) data were analyzed by quantification of hypothalamic volumes using a well-established segmentation method, separate for the anterior and the posterior hypothalamic subvolumes. An additional analysis was performed using age, gender, and BMI-matched subgroups of 20 IIH patients and 20 controls. Results: The analysis of laboratory values showed significantly increased insulin, leptin, and melatonin levels for IIH patients in comparison to controls, while adiponectin levels were decreased in IIH; however, only melatonin level differences could be confirmed in the analysis with BMI matching. There was no statistical difference in total hypothalamus volumes between IIH and controls, but the hypothalamic morphology was altered in IIH patients with a lower volume of the anterior part of the hypothalamus and a higher volume of the posterior part; these results were identical in the analysis of the BMI-matched groups. The correlation analyses between hormonal changes and hypothalamic morphology did not achieve significant results. Conclusion: In this exploratory study, morphological abnormalities of the hypothalamus were observed to be associated with the IIH complex, although the mechanism remains to be unraveled. These findings expand the metabolic phenotype of IIH, but further functional studies are necessary to corroborate these data.

A Prospective Validation Study of the Functional Bedside Aspiration Screen with Endoscopy: Is It Clinically Applicable in Acute Stroke?

The purpose of this study was to investigate the reliability of the novel Functional Bedside Aspiration Screen (FBAS) to predict aspiration risk in acute stroke and to guide initial therapy needs. We conducted a prospective validation study of the FBAS 10-point scale in 101 acute ischemic stroke patients. Outcome measures were compared with the Penetration Aspiration Scale (PAS) via the Flexible Endoscopic Swallowing Study. Correlations with the Functional Oral Intake Scale (FOIS) and the Therapy Requirement Scale (TRS) were analyzed. We observed a 65.8% sensitivity and 70.2% specificity (p = 0.004) for predicting penetration risk (for PAS score ≥ 3) and a 73% sensitivity and 62% specificity for predicting aspiration risk (PAS score ≥ 6). For patients with a modified ranking scale 0-2 (n = 44) on admission, the predictive measurements of the FBAS yielded sensitivity and specificity values of 66.7% and 88.6% (p = 0.011). A significant negative correlation was found with PAS measurements, whereas a positive correlation was observed regarding FOIS. Significantly lower FBAS scores were observed in patients with high requirements for therapeutic interventions and dietary modification. FBAS may be regarded as an alternative time-efficient clinical support tool in settings in which instrumentation is not directly accessible. Further studies including a larger cohort of acute stroke patients with more severe neurological deficits are necessary.

Advanced magnetic resonance imaging to support clinical drug development for malignant glioma.

Even though the treatment options and survival of patients with glioblastoma multiforme (GBM), the most common type of malignant glioma, have improved over the past decade, there is still a high unmet medical need to develop novel therapies. Complexity in pathology and therapy require biomarkers to characterize tumors, to define malignant and active areas, to assess disease prognosis, and to quantify and monitor therapy response. While conventional magnetic resonance imaging (MRI) techniques have improved these assessments, limitations remain. In this review, we evaluate the role of various non-invasive biomarkers based on advanced structural and functional MRI techniques in the context of GBM drug development over the past 5 years.

What Animal Cancers teach us about Human Biology.

Cancers in animals present a large, underutilized reservoir of biomedical information with critical implication for human oncology and medicine in general. Discussing two distinct areas of tumour biology in non-human hosts, we highlight the importance of these findings for our current understanding of cancer, before proposing a coordinated strategy to harvest biomedical information from non-human resources and translate it into a clinical setting. First, infectious cancers that can be transmitted as allografts between individual hosts, have been identified in four distinct, unrelated groups, dogs, Tasmanian devils, Syrian hamsters and, surprisingly, marine bivalves. These malignancies might hold the key to improving our understanding of the interaction between tumour cell and immune system and, thus, allow us to devise novel treatment strategies that enhance anti-cancer immunosurveillance, as well as suggesting more effective organ and stem cell transplantation strategies. The existence of these malignancies also highlights the need for increased scrutiny when considering the existence of infectious cancers in humans. Second, it has long been understood that no linear relationship exists between the number of cells within an organism and the cancer incidence rate. To resolve what is known as Peto's Paradox, additional anticancer strategies within different species have to be postulated. These naturally occurring idiosyncrasies to avoid carcinogenesis represent novel potential therapeutic strategies.

Identical patterns of cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A tract of interest-based MRI study.

Background: There is an ongoing debate whether primary lateral sclerosis (PLS) should be regarded as an independent disease entity separate from amyotrophic lateral sclerosis (ALS) or as a slowly progressive variant of ALS. Objective: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from PLS patients by a hypothesis-guided tract-of-interest-based approach compared with 'classical' ALS patients and healthy controls, in order to identify microstructural changes according to the neuropathologically defined ALS affectation pattern in vivo. Methods: DTI-based white matter mapping was performed both by an unbiased voxelwise statistical comparison and by a hypothesis-guided tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 50 PLS and 50 ALS patients vs 50 matched controls. Results: The analysis of white matter integrity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in PLS patients and ALS patients. In the tract-specific analysis according to the ALS-staging pattern, PLS and ALS affectation patterns showed identical significant alterations of ALS-related tract systems when compared with controls and no differences when compared with each other. Conclusions: This DTI study showed the same microstructural affectation patterns in PLS patients as in ALS, in support of the hypothesis that PLS is a phenotypical variant of ALS.

Cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A two-centre tract of interest-based DTI analysis.

BACKGROUND: After the demonstration of a corticoefferent propagation pattern in amyotrophic lateral sclerosis (ALS) by neuropathological studies, this concept has been used for in vivo staging of individual patients by diffusion tensor imaging (DTI) techniques, both in `classical` ALS and in restricted phenotypes such as primary lateral sclerosis (PLS). OBJECTIVE: The study was designed to investigate that microstructural changes according to the neuropathologically defined ALS alteration pattern in PLS patients could be confirmed to be identical to ´classical´ ALS patients. The novelty in this approach is that the results were independent of the subject samples and the data acquisition parameters (as was validated in two samples from two different centres). That way, reproducibility across (international) centres in addition to harmonisation/standardisation of data analysis has been addressed, for the possible use of MRI-based staging to stratify patients in clinical trials. METHODS: Tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern was applied to DTI data (pooled from two ALS centres) of 88 PLS patients and 88 ALS patients with a 'classical' phenotype in comparison to 88 matched controls in order to identify white matter integrity alterations. RESULTS: In the tract-specific analysis, alterations were identical for PLS and ALS in the tract systems corresponding to the ALS staging pattern, independent of the subject samples and the data acquisition parameters. The individual categorisation into ALS stages did not differ between PLS and ALS patients. CONCLUSIONS: This DTI study in a two-centre setting demonstrated that the neuropathological stages can be mapped in vivo in PLS with high reproducibility and that PLS-associated cerebral propagation, although showing the same corticofugal patterns as ALS, might have a different time course of neuropathology, in analogy to its much slower clinical progression rates.

Radiation and Brain Tumors: An Overview.

The use of radiation is an essential part of both modern cancer diagnostic assessment and treatment. Next-generation imaging devices create 3D visualizations, allowing for better diagnoses and improved planning of precision treatment. This is particularly important for primary brain cancers such as diffuse intrinsic pontine glioma or the most common primary brain tumor, glioblastoma, because radiotherapy is often the only treatment modality that offers a significant improvement in survival and quality of life. In this review, we give an overview of the different imaging techniques and the historic role of radiotherapy and its place in modern cancer therapy. Finally, we discuss three key areas of risks associated with the use of ionizing radiation: (1) brain tumor induction mainly as a consequence of the diagnostic use of radiation; (2) cognitive decline as a consequence of treating childhood brain tumors as an example of long term consequences often neglected in favor of highlighting secondary primary cancers; and (3) pro-proliferative and pro-invasive alterations that occur in tumor cells that survive radiotherapy. Throughout the discussion, we highlight areas of potential future research.

Bevacizumab in temozolomide refractory high-grade gliomas: single-centre experience and review of the literature.

BACKGROUND: Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV's efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained. Here, we illustrate the effectiveness of BEV in recurrent HGG by summarizing our single-centre experience. METHODS: We have retrospectively investigated the effect of BEV in temozolomide refractory HGG in 39 patients treated at the University Hospital of Ulm, Germany. RESULTS: Median duration of BEV treatment was 12.5 weeks; 23% of patients received BEV for more than 6 months and 15% for more than 1 year, until clinical or radiological tumour progression led to discontinuation. Furthermore, Karnofsky performance status increased in 30.6% and steroid dose decreased in 39% of all patients. CONCLUSIONS: The review of literature reveals that phase II and III studies support BEV as an effective therapy in recurrent HGG, at least with regard to progression-free survival (PFS), but landmark phase III trials failed to prove benefit concerning OS. Here, we discuss reasons that may account for this observation. We conclude that prolonging PFS with maintenance of neurological function and personal and economic independency justifies the off-label use of BEV.

Cerebral Microstructural Alterations after Radiation Therapy in High-Grade Glioma: A Diffusion Tensor Imaging-Based Study.

OBJECTIVE: To investigate radiation therapy-induced microstructural damage of white matter in patients with high-grade glioma by diffusion tensor imaging (DTI). METHODS: DTI was performed in 18 patients with high-grade glioma (WHO grades III and IV) and 13 healthy controls. DTI images were cross-sectionally aligned for the calculation of baseline fractional anisotropy (FA). Interhemispheric FA values in patients with high-grade glioma before or without brain radiation therapy were compared with the interhemispheric FA values in patients after radiation therapy and in healthy controls. In a subgroup without any clinical or diagnostic evidence of tumor progression, serial DTI data (5-11 scans) before and after radiation therapy were collected and longitudinal interhemispheric FA changes were assessed and compared to longitudinal data from the control group.In addition, interhemispheric axial, mean, and radial diffusivity was assessed. RESULTS: Global interhemispheric FA reductions could be detected cross-sectionally in patients after radiation therapy; these were significantly different from global interhemispheric FA differences both in patients without radiation and in healthy controls. Longitudinal scans in patients with radiation therapy confirmed these findings and revealed progressive microstructural white matter damage after partial brain radiotherapy. The additional DTI metrics axial diffusion, mean diffusivity, and radial diffusion confirmed interhemispheric differences in patients without or before radiation therapy, which were lower than the differences in patients after radiation therapy, although not reaching significance. CONCLUSION: Interhemispheric global FA differences could potentially serve as a biological marker for irradiation-induced microstructural white matter damage.

Identifying ischemic stroke associated with cancer: a multiple model derived from a case-control analysis.

Ischemic stroke in patients with cancer is thought to be associated with a worse prognosis and might be the initial symptom of an unknown malignancy. However, diagnostic algorithms to reliably identify cancer-associated stroke have not been developed. In this retrospective single-centre analysis, 68 patients with ischemic stroke and an active solid malignancy were identified. Neurological assessment and outcome, cardiovascular risk factors, neuroimaging studies as well as laboratory findings were compared to 68 age- and sex-matched control subjects with ischemic stroke without diagnosis of cancer. Lung, pancreatic and renal cancer showed increased prevalences compared to those of the general population in Germany. Diagnosis of cancer was most often made within the 12 months preceding (32.4%) or during the diagnostic work-up for stroke (17.7%). Cancer-associated stroke was characterized by a more severe clinical deficit, frequent clinical deterioration (13.2 vs. 1.5%) or death (25 vs. 4.4%). Ischemic lesions often involved multiple territories (51.6 vs. 12.7%), more often with co-existing subacute and acute infarctions in imaging studies (54.8 vs. 11.1%). Patients with cancer had significantly higher levels of C-reactive protein, relative granulocytosis and serum lactate dehydrogenase activity. Using receiver operating characteristics-based multiple analysis, we developed a model using these parameters which detected cancer-associated stroke with a sensitivity of 75% and specificity of 95%. Our analysis suggests that a multiple algorithm combining the number of territories involved and laboratory signs of inflammation and cell turnover might identify patients with stroke suffering from previously unknown malignancy.

GFAP in early multiple sclerosis: A biomarker for inflammation.

OBJECTIVE: The role of Glial Fibrillic Acidic Protein (GFAP) as a potential biomarker for relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) has been controversially discussed. The aim was to characterize the added value of GFAP levels in the CSF of RRMS and CIS patients in correlation with MRI lesion load. MATERIALS & METHODS: GFAP levels in the CSF from 18 patients with RRMS, 8 patients with CIS and 35 controls were analyzed together with MRI data for acute and chronic inflammatory lesion load. RESULTS: GFAP levels of patients vs. controls were higher (p=0.005), while there was no difference between GFAP levels in RRMS and CIS. There was no correlation between the number of supra- or infratentorial gadolinium enhancing lesions and GFAP levels, while there was a correlation between GFAP levels with infratentorial chronic inflammatory lesion load (p=0.0035). Most importantly, a highly significant correlation could be observed between GFAP levels and the intensity of gadolinium-enhancement as a parameter for the acute activity of inflammatory processes (p=0.0002). CONCLUSIONS: GFAP seems to be a useful biomarker for highly active acute inflammation in patients with RRMS as well as with CIS.

Phosphoinositide 3-kinases upregulate system xc(-) via eukaryotic initiation factor 2α and activating transcription factor 4 - A pathway active in glioblastomas and epilepsy.

AIMS: Phosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth. The cystine/glutamate antiporter system xc(-) imports cystine while exporting glutamate, thereby promoting glutathione synthesis while increasing extracellular cerebral glutamate. The aim of this study was to analyze the pathway through which growth factor and PI3K signaling induce the cystine/glutamate antiporter system xc(-) and to demonstrate its biological significance for neuroprotection, cell growth, and epilepsy. RESULTS: PI3Ks induce system xc(-) through glycogen synthase kinase 3ß (GSK-3ß) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2α phosphorylation, and the subsequent translational up-regulation of activating transcription factor 4. This pathway is essential for PI3Ks to modulate oxidative stress resistance of nerve cells and insulin-induced growth in fibroblasts. Moreover, the pathway is active in human glioblastoma cells. In addition, it is induced in primary cortical neurons in response to robust neuronal activity and in hippocampi from patients with temporal lobe epilepsy. INNOVATION: Our findings further extend the concepts of how growth factors and PI3Ks induce neuroprotection and cell growth by adding a new branch to the signaling network downstream of GSK-3ß, which, ultimately, leads to the induction of the cystine/glutamate antiporter system xc(-). Importantly, the induction of this pathway by neuronal activity and in epileptic hippocampi points to a potential role in epilepsy. CONCLUSION: PI3K-regulated system xc(-) activity is not only involved in the stress resistance of neuronal cells and in cell growth by increasing the cysteine supply and glutathione synthesis, but also plays a role in the pathophysiology of tumor- and non-tumor-associated epilepsy by up-regulating extracellular cerebral glutamate.