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Background The syndrome of transient Headache and Neurological Deficits with cerebrospinal fluid (CSF) Lymphocytosis (HaNDL) is classified among secondary headaches attributed to “non-infectious, inflammatory intracranial disease”. Despite its classification among secondary headaches, the current definition of HaNDL does not contemplate a causal agent. Thus, the aetiology, as well as the pathogenesis of both the headache and the transient focal deficits, remains unknown. Case presentation We describe a 29-year-old healthy male developing episodes of thunderclap headaches associated with recurrence of hemiparesis/hemi-paraesthesia; CSF showed lymphocytosis 200/mm 3 and increased albumin; brain MRI revealed widespread leptomeningeal enhancement and a non-enhancing, circular diffusion restriction in the splenium of corpus callosum. Screening for neurotropic pathogens detected Epstein-Barr (EBV) DNA in serum and CSF, interpreted as a primary EBV infection once the seroconversion of EBV nuclear antigen (EBNA) IgM to IgG was proven on follow-up. Transcranial Doppler detected, during headache, increased flow velocity in middle cerebral arteries, possibly indicating vasospasm. Oral nimodipine was administered, with prompt clinical recovery, resolution of CSF/MRI abnormalities, and normalization of flow velocities in middle cerebral arteries. Case-based review Although the definition of HaNDL does not contemplate a viral trigger or abnormal brain imaging, we found other literature cases of HaNDL associated with direct or indirect signs of CNS infection. Conclusions At least in a proportion of patients, a viral aetiology may have a role in HaNDL. Whatever the aetiology, we suggest that the pathogenic mechanism may rely on the (viral or other) agent ultimately triggering cerebral vasoconstriction, which would explain both focal symptoms and headache. Calcium channel blockers might be a therapeutic option.

Purpose To assess early microstructural changes of meningiomas treated with proton therapy through quantitative analysis of intravoxel incoherent motion (IVIM) and diffusion-weighted imaging (DWI) parameters. Methods Seventeen subjects with meningiomas that were eligible for proton therapy treatment were retrospectively enrolled. Each subject underwent a magnetic resonance imaging (MRI) including DWI sequences and IVIM assessments at baseline, immediately before the 1st (t0), 10th (t10), 20th (t20), and 30th (t30) treatment fraction and at follow-up. Manual tumor contours were drawn on T2-weighted images by two expert neuroradiologists and then rigidly registered to DWI images. Median values of the apparent diffusion coefficient (ADC), true diffusion (D), pseudo-diffusion (D*), and perfusion fraction (f) were extracted at all timepoints. Statistical analysis was performed using the pairwise Wilcoxon test. Results Statistically significant differences from baseline to follow-up were found for ADC, D, and D* values, with a progressive increase in ADC and D in conjunction with a progressive decrease in D*. MRI during treatment showed statistically significant differences in D values between t0 and t20 ( p  = 0.03) and t0 and t30 ( p  = 0.02), and for ADC values between t0 and t20 ( p  = 0.04), t10 and t20 ( p  = 0.02), and t10 and t30 ( p  = 0.035). Subjects that showed a volume reduction greater than 15% of the baseline tumor size at follow-up showed early D changes, whereas ADC changes were not statistically significant. Conclusion IVIM appears to be a useful tool for detecting early microstructural changes within meningiomas treated with proton therapy and may potentially be able to predict tumor response.

BackgroundHeterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson’s disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF).Methods and analysisIn this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat.Ethics and disseminationThe study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences.Trial registration numbersNCT05287503, EudraCT 2021-004565-13.

In this study we used nitroglycerin (NTG)-induced migraine attacks as a translational human disease model. Static and dynamic functional connectivity (FC) analyses were applied to study the associated functional brain changes. A spontaneous migraine-like attack was induced in five episodic migraine (EM) patients using a NTG challenge. Four task-free functional magnetic resonance imaging (fMRI) scans were acquired over the study: baseline, prodromal, full-blown, and recovery. Seed-based correlation analysis (SCA) was applied to fMRI data to assess static FC changes between the thalamus and the rest of the brain. Wavelet coherence analysis (WCA) was applied to test time-varying phase-coherence changes between the thalamus and salience networks (SNs). SCA results showed significantly FC changes between the right thalamus and areas involved in the pain circuits (insula, pons, cerebellum) during the prodromal phase, reaching its maximal alteration during the full-blown phase. WCA showed instead a loss of synchronisation between thalami and SN, mainly occurring during the prodrome and full-blown phases. These findings further support the idea that a temporal change in thalamic function occurs over the experimentally induced phases of NTG-induced headache in migraine patients. Correlation of FC changes with true clinical phases in spontaneous migraine would validate the utility of this model.

Nowadays, hadrontherapy is increasingly used for the treatment of various tumors, in particular of those resistant to conventional radiotherapy. Proton and carbon ions are characterized by physical and biological features that allow a high radiation dose to tumors, minimizing irradiation to adjacent normal tissues. For this reason, radioresistant tumors and tumors located near highly radiosensitive critical organs, such as skull base tumors, represent the best target for this kind of therapy. However, also hadrontherapy can be associated with radiation adverse effects, generally referred as acute, early-delayed and late-delayed. Among late-delayed effects, the most severe form of injury is radiation necrosis. There are various underlying mechanisms involved in the development of radiation necrosis, as well as different clinical presentations requiring specific treatments. In most cases, radiation necrosis presents as a single focal lesion, but it can be multifocal and involve a single or multiple lobes simulating brain metastasis, or it can also involve both cerebral hemispheres. In every case, radiation necrosis results always related to the extension of radiation delivery field. Multiple MRI techniques, including diffusion, perfusion imaging, and spectroscopy, are important tools for the radiologist to formulate the correct diagnosis. The aim of this paper is to illustrate the possible different radiologic patterns of radiation necrosis that can be observed in different MRI techniques in patients treated with hadrontherapy for tumors involving the skull base. The images of exemplary cases of radiation necrosis are also presented.

Purpose Meningiomas are mainly benign tumors, though a considerable proportion shows aggressive behaviors histologically consistent with atypia/anaplasia. Histopathological grading is usually assessed through invasive procedures, which is not always feasible due to the inaccessibility of the lesion or to treatment contraindications. Therefore, we propose a multi-parametric MRI assessment as a predictor of meningioma histopathological grading. Methods Seventy-three patients with 74 histologically proven and previously treated meningiomas were retrospectively enrolled (42 WHO I, 24 WHO II, 8 WHO III) and studied with MRI including T2 TSE, FLAIR, Gradient Echo, DWI, and pre- and post-contrast T1 sequences. Lesion masks were segmented on post-contrast T1 sequences and rigidly registered to ADC maps to extract quantitative parameters from conventional DWI and intravoxel incoherent motion model assessing tumor perfusion. Two expert neuroradiologists assessed morphological features of meningiomas with semi-quantitative scores. Results Univariate analysis showed different distributions ( p  < 0.05) of quantitative diffusion parameters (Wilcoxon rank-sum test) and morphological features (Pearson’s chi-square; Fisher’s exact test) among meningiomas grouped in low-grade (WHO I) and higher grade forms (WHO II/III); the only exception consisted of the tumor-brain interface. A multivariate logistic regression, combining all parameters showing statistical significance in the univariate analysis, allowed discrimination between the groups of meningiomas with high sensitivity (0.968) and specificity (0.925). Heterogeneous contrast enhancement and low ADC were the best independent predictors of atypia and anaplasia. Conclusion Our multi-parametric MRI assessment showed high sensitivity and specificity in predicting histological grading of meningiomas. Such an assessment may be clinically useful in characterizing lesions without histological diagnosis. Key points • When surgery and biopsy are not feasible, parameters obtained from both conventional and diffusion-weighted MRI can predict atypia and anaplasia in meningiomas with high sensitivity and specificity. • Low ADC values and heterogeneous contrast enhancement are the best predictors of higher grade meningioma

In this work, we develop a kinetic model of tumour growth taking into account the effects of clinical uncertainties characterising the tumours' progression. The action of therapeutic protocols trying to steer the tumours' volume towards a target size is then investigated by means of suitable selective-type controls acting at the level of cellular dynamics. By means of classical tools of statistical mechanics for many-agent systems, we are able to prove that it is possible to dampen clinical uncertainties across the scales. To take into account the scarcity of clinical data and the possible source of error in the image segmentation of tumours' evolution, we estimated empirical distributions of relevant parameters that are considered to calibrate the resulting model obtained from real cases of primary glioblastoma. Suitable numerical methods for uncertainty quantification of the resulting kinetic equations are discussed and, in the last part of the paper, we compare the effectiveness of the introduced control approaches in reducing the variability in tumours' size due to the presence of uncertain quantities.

Although ovarian cystic teratoma is the most common ovarian tumor, complications are quite rare. However, it is important to be recognized by the radiologist in order to avoid inaccurately diagnosing them as malignant lesions. This case report describes a 61-year-old postmenopausal woman, who presented to the emergency room with abdominal pain following a minor blunt abdominal trauma. In this context, a CT scan was performed, which showed the presence of round, hypodense masses randomly distributed in the peritoneum, with coexisting ascites in moderate amount; ovarian carcinoma with peritoneal carcinomatosis was suspected. The patient was hospitalized and an MRI of the abdomen and pelvis was recommended for a more detailed lesion characterization. Following this examination, the patient was diagnosed with mature cystic ovarian teratoma complicated by rupture. Surgery was performed, and the outcome was favorable. The cases of ruptured cystic teratomas are rare, and to our knowledge, this is the first occurrence described in literature. Special attention must be paid when confronting with such a case in medical practice, since it can easily misdiagnosed as peritoneal carcinomatosis.

Hemorrhage is a detrimental event present in traumatic injury, surgery, and disorders of bleeding that can become life-threatening if not properly managed. Moreover, uncontrolled bleeding can complicate surgical interventions, altering the outcome of surgical procedures. Therefore, to reduce the risk of complications and decrease the risk of morbidity and mortality associated with hemorrhage, it is necessary to use an effective hemostatic agent that ensures the immediate control of bleeding. In recent years, there have been increasingly rapid advances in developing a novel generation of biomaterials with hemostatic properties. Nowadays, a wide array of topical hemostatic agents is available, including chitosan-based biomaterials that have shown outstanding properties such as antibacterial, antifungal, hemostatic, and analgesic activity in addition to their biocompatibility, biodegradability, and wound-healing effects. This review provides an analysis of chitosan-based hemostatic biomaterials and discusses the progress made in their performance, mechanism of action, efficacy, cost, and safety in recent years.

Post-Traumatic Stress Disorder (PTSD) is often considered challenging to treat due to factors that contribute to its complexity. In the last decade, more attention has been paid to non-pharmacological or non-psychological therapies for PTSD, including neurofeedback (NFB). NFB is a promising non-invasive technique targeting specific brainwave patterns associated with psychiatric symptomatology. By learning to regulate brain activity in a closed-loop paradigm, individuals can improve their functionality while reducing symptom severity. However, owing to its lax regulation and heterogeneous legal status across different countries, the degree to which it has scientific support as a psychiatric treatment remains controversial. In this state-of-the-art review, we searched PubMed, Cochrane Central, Web of Science, Scopus, and MEDLINE and identified meta-analyses and systematic reviews exploring the efficacy of NFB for PTSD. We included seven systematic reviews, out of which three included meta-analyses (32 studies and 669 participants) that targeted NFB as an intervention while addressing a single condition—PTSD. We used the MeaSurement Tool to Assess systematic Reviews (AMSTAR) 2 and the criteria described by Cristea and Naudet (Behav Res Therapy 123:103479, 2019, https://doi.org/10.1016/j.brat.2019.103479) to identify sources of research waste and increasing value in biomedical research. The seven assessed reviews had an overall extremely poor quality score (5 critically low, one low, one moderate, and none high) and multiple sources of waste while opening opportunities for increasing value in the NFB literature. Our research shows that it remains unclear whether NFB training is significantly beneficial in treating PTSD. The quality of the investigated literature is low and maintains a persistent uncertainty over numerous points, which are highly important for deciding whether an intervention has clinical efficacy. Just as importantly, none of the reviews we appraised explored the statistical power, referred to open data of the included studies, or adjusted their pooled effect sizes for publication bias and risk of bias. Based on the obtained results, we identified some recurrent sources of waste (such as a lack of research decisions based on sound questions or using an appropriate methodology in a fully transparent, unbiased, and useable manner) and proposed some directions for increasing value (homogeneity and consensus) in designing and reporting research on NFB interventions in PTSD.