Circulating biomarkers in familial cerebral cavernous malformation.

BACKGROUND: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. METHODS: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. FINDINGS: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. INTERPRETATION: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.

Conventional and Advanced Magnetic Resonance Imaging Assessment of Non-Enhancing Peritumoral Area in Brain Tumor.

The non-enhancing peritumoral area (NEPA) is defined as the hyperintense region in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images surrounding a brain tumor. The NEPA corresponds to different pathological processes, including vasogenic edema and infiltrative edema. The analysis of the NEPA with conventional and advanced magnetic resonance imaging (MRI) was proposed in the differential diagnosis of solid brain tumors, showing higher accuracy than MRI evaluation of the enhancing part of the tumor. In particular, MRI assessment of the NEPA was demonstrated to be a promising tool for distinguishing high-grade gliomas from primary lymphoma and brain metastases. Additionally, the MRI characteristics of the NEPA were found to correlate with prognosis and treatment response. The purpose of this narrative review was to describe MRI features of the NEPA obtained with conventional and advanced MRI techniques to better understand their potential in identifying the different characteristics of high-grade gliomas, primary lymphoma and brain metastases and in predicting clinical outcome and response to surgery and chemo-irradiation. Diffusion and perfusion techniques, such as diffusion tensor imaging (DTI), diffusional kurtosis imaging (DKI), dynamic susceptibility contrast-enhanced (DSC) perfusion imaging, dynamic contrast-enhanced (DCE) perfusion imaging, arterial spin labeling (ASL), spectroscopy and amide proton transfer (APT), were the advanced MRI procedures we reviewed.

Magnetic susceptibility as a 1-year predictor of outcome in familial cerebral cavernous malformations: a pilot study.

OBJECTIVES: To test whether quantitative susceptibility mapping (QSM) of cerebral cavernous malformations (CCMs) assessed at baseline may predict the presence or absence of haemorrhagic signs at 1-year follow-up. METHODS: Familial CCM patients were enrolled in the longitudinal multicentre study Treat-CCM. The 3-T MRI scan allowed performing a semi-automatic segmentation of CCMs and computing the maximum susceptibility in each segmented CCM (QSMmax) at baseline. CCMs were classified as haemorrhagic and non-haemorrhagic at baseline and then subclassified according to the 1-year (t1) evolution. Between-group differences were tested, and the diagnostic accuracy of QSMmax in predicting the presence or absence of haemorrhagic signs in CCMs was calculated with ROC analyses. RESULTS: Thirty-three patients were included in the analysis, and a total of 1126 CCMs were segmented. QSMmax was higher in haemorrhagic CCMs than in non-haemorrhagic CCMs (p < 0.001). In haemorrhagic CCMs at baseline, the accuracy of QSMmax in differentiating CCMs that were still haemorrhagic from CCMs that recovered from haemorrhage at t1 calculated as area under the curve (AUC) was 0.78 with sensitivity 62.69%, specificity 82.35%, positive predictive value (PPV) 93.3% and negative predictive value (NPV) 35.9% (QSMmax cut-off ≥ 1462.95 ppb). In non-haemorrhagic CCMs at baseline, AUC was 0.91 in differentiating CCMs that bled at t1 from stable CCMs with sensitivity 100%, specificity 81.9%, PPV 5.1%, and NPV 100% (QSMmax cut-off ≥ 776.29 ppb). CONCLUSIONS: The QSMmax in CCMs at baseline showed high accuracy in predicting the presence or absence of haemorrhagic signs at 1-year follow-up. Further effort is required to test the role of QSM in follow-up assessment and therapeutic trials in multicentre CCM studies. KEY POINTS: • QSM in semi-automatically segmented CCM was feasible. • The maximum magnetic susceptibility in a single CCM at baseline may predict the presence or absence of haemorrhagic signs at 1-year follow-up. • Multicentric studies are needed to enforce the role of QSM in predicting the CCMs' haemorrhagic evolution in patients affected by familial and sporadic forms.

Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): a randomised, open-label, blinded-endpoint, phase 2 pilot trial.

BACKGROUND: Observations in people with cerebral cavernous malformations, and in preclinical models of this disorder, suggest that the ß-blocker propranolol might reduce the risk of intracerebral haemorrhage. We aimed to evaluate the safety and efficacy of prolonged treatment with propranolol to reduce the incidence of symptomatic intracerebral haemorrhage or focal neurological deficit in people with familial cerebral cavernous malformations. METHODS: We conducted a randomised, open-label, blinded-endpoint, phase 2 pilot trial (Treat_CCM) at six national reference centres for rare diseases in Italy. People aged 18 years or older with symptomatic familial cerebral cavernous malformation were eligible for enrolment. Participants were randomly assigned (2:1) to receive either oral propranolol (20-320 mg daily) plus standard care (intervention group), or standard care alone (control group), for 24 months. Participants, caregivers, and investigators were aware of treatment group assignment. Participants had clinical assessments and 3 T brain MRI at baseline and at 12 and 24 months. The primary outcome was new occurrence of symptomatic intracerebral haemorrhage or focal neurological deficit attributable to cerebral cavernous malformation over 24 months. Outcome assessors were masked to treatment group assignment. The primary analysis was done in the intention-to-treat population. Because of the pilot study design, we chose a one-sided 80% CI, which could either exclude a clinically meaningful effect or show a signal of efficacy. This trial is registered with EudraCT, 2017-003595-30, and ClinicalTrials.gov, NCT03589014, and is closed to recruitment. FINDINGS: Between April 11, 2018, and Dec 5, 2019, 95 people were assessed for eligibility and 83 were enrolled, of whom 57 were assigned to the propranolol plus standard care group and 26 to the standard care alone group. The mean age of participants was 46 years (SD 15); 48 (58%) were female and 35 (42%) were male. The incidence of symptomatic intracerebral haemorrhage or focal neurological deficit was 1·7 (95% CI 1·4-2·0) cases per 100 person-years (two [4%] of 57 participants) in the propranolol plus standard care group and 3·9 (3·1-4·7) per 100 person-years (two [8%] of 26) in the standard care alone group (univariable hazard ratio [HR] 0·43, 80% CI 0·18-0·98). The univariable HR showed a signal of efficacy, according to predefined criteria. The incidence of hospitalisation did not differ between groups (8·2 cases [95% CI 7·5-8·9] per 100 person-years in the propranolol plus standard care group vs 8·2 [95% CI 7·1-9·3] per 100 person-years in the standard care alone group). One participant in the standard care alone group died of sepsis. Three participants in the propranolol plus standard care group discontinued propranolol due to side-effects (two reported hypotension and one reported weakness). INTERPRETATION: Propranolol was safe and well tolerated in this population. Propranolol might be beneficial for reducing the incidence of clinical events in people with symptomatic familial cerebral cavernous malformations, although this trial was not designed to be adequately powered to investigate efficacy. A definitive phase 3 trial of propranolol in people with symptomatic familial cerebral cavernous malformations is justified. FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro, Swedish Science Council, Knut and Alice Wallenberg Foundation, CARIPLO Foundation, Italian Ministry of Health.

Complete agenesis of corpus callosum and unilateral cortical formation anomalies detected on fetal MR imaging: a phenotype strongly associated with the male fetuses.

INTRODUCTION: In a previous study of classifying fetuses with cortical formation abnormalities (CFA) with fetal MR, we noticed a cluster of cases with unilateral CFA and complete agenesis of the corpus callosum (ACC). In this study, we provide a detailed morphological analysis of such fetuses using fetal MR to determine if there are indicators (such as the gender of the fetus) that could be used to delineate a genetic substrate of the phenotype in order to inform future studies. METHODS: We have studied 45 fetuses with the unilateral CFA/ACC phenotype and analysed through an expert consensus panel the location and fine detail of the CFA and the associated findings such as associated anomalies, head size, and sex of the fetus. RESULTS: The frontal lobe was significantly more frequently involved by CFA when compared with other lobes (p < 0.001) but no preference for the left or right hemisphere. CFA most often consisted of excessive/dysmorphic sulcation. The CFA/ACC phenotype was overwhelmingly more frequent in male fetuses (M:F 4.5:1-p < 0.0001). The most frequent associated findings were: ventriculomegaly (16/45 fetuses) and interhemispheric cysts (12/45 cases). CONCLUSIONS: This report highlights the specific phenotype of unilateral CFA/ACC that is much more common in male fetuses. This finding provides a starting point to study possible sex-linked genetic abnormalities that underpin the unilateral CFA/ACC phenotype. KEY POINTS: • We collected fetuses with unilateral cortical formation abnormality and callosal agenesis. • That distinctive neuroimaging phenotype has a strong male gender prevalence (over 80%). • This observation forms the basis of studies about outcomes and genetic substrates.

Peri-lead edema and local field potential correlation in post-surgery subthalamic nucleus deep brain stimulation patients.

Implanting deep brain stimulation (DBS) electrodes in patients with Parkinson's disease often results in the appearance of a non-infectious, delayed-onset edema that disappears over time. However, the time window between the DBS electrode and DBS stimulating device implant is often used to record local field potentials (LFPs) which are used both to better understand basal ganglia pathophysiology and to improve DBS therapy. In this work, we investigated whether the presence of post-surgery edema correlates with the quality of LFP recordings in eight patients with advanced Parkinson's disease implanted with subthalamic DBS electrodes. The magnetic resonance scans of the brain after 8.5 ± 1.5 days from the implantation surgery were segmented and the peri-electrode edema volume was calculated for both brain hemispheres. We found a correlation (ρ = -0.81, p < 0.0218, Spearman's correlation coefficient) between left side local field potentials of the low beta band (11-20 Hz) and the edema volume of the same side. No other significant differences between the hemispheres were found. Despite the limited sample size, our results suggest that the effect on LFPs may be related to the edema localization, thus indicating a mechanism involving brain networks instead of a simple change in the electrode-tissue interface.

A practical overview of CT and MRI features of developmental, inflammatory, and neoplastic lesions of the sphenoid body and clivus.

The sphenoid bone is an unpaired bone that contributes to the formation of the skull base. Despite the enormous progress in transnasal endoscopic visualisation, imaging techniques remain the cornerstones to characterise any pathological condition arising in this area. In the present review, we offer a bird's-eye view of the developmental, inflammatory, and neoplastic alterations affecting the sphenoid body and clivus, with the aim to propose a practical diagnostic aid for radiologists based on clinico-epidemiological, computed tomography, and magnetic resonance imaging features.

Assessment of brain tumors by magnetic resonance dynamic susceptibility contrast perfusion-weighted imaging and computed tomography perfusion: a comparison study.

PURPOSE: To investigate the association and agreement between magnetic resonance dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) and computed tomography perfusion (CTP) in determining vascularity and permeability of primary and secondary brain tumors. MATERIAL AND METHODS: DSC-PWI and CTP studies from 97 patients with high-grade glioma, low-grade glioma and solitary brain metastasis were retrospectively reviewed. Normalized cerebral blood flow (nCBF), cerebral blood volume (nCBV), capillary transfer constant (nK2) and permeability surface area product (nPS) values were obtained. Variables among groups were compared, and correlation and agreement between DSC-PWI and CTP were tested. RESULTS: All DSC-PWI and CTP parameters were higher in high-grade than in low-grade gliomas (p < 0.01 and p < 0.001). Metastases had greater DSC-PWI nCBV (p < 0.05), nCTP-CBF (p < 0.05), nCTP-CBV (p < 0.01) and nCTP-PS (p < 0.0001) than low-grade gliomas and more elevated nCTP-PS (p < 0.01) than high-grade gliomas. The correlation was strong between DSC-PWI nCBF and CTP nCBF (r = 0.79; p < 0.00001) and between DSC-PWI nCBV and CTP nCBV (r = 0.83; p < 0.00001), weaker between DSC-PWI nK2 and CTP nPS (r = 0.29; p < 0.01). Bland-Altman plots indicated that the agreement was strong between DSC-PWI nCBF and CTP nCBF, good between DSC-PWI nCBV and CTP nCBV and poorer between DSC-PWI nK2 and CTP nPS. CONCLUSION: DSC-PWI and CTP CBF and CBV maps were comparable and interchangeable in the assessment of tumor vascularity, unlike DSC-PWI K2 and CTP PS maps that were more discordant in the analysis of tumor permeability. CTP could be an alternative method to quantify tumor neoangiogenesis when MRI is not available or when the patient does not tolerate it.

Tmax Volumes Predict Final Infarct Size and Functional Outcome in Ischemic Stroke Patients Receiving Endovascular Treatment.

OBJECTIVE: The objective of this paper was to explore the utility of time to maximum concentration (Tmax )-based target mismatch on computed tomography perfusion (CTP) in predicting radiological and clinical outcomes in patients with acute ischemic stroke (AIS) with anterior circulation large vessel occlusion (LVO) selected for endovascular treatment (EVT). METHODS: Patients with AIS underwent CTP within 24 hours from onset followed by EVT. Critically hypoperfused tissue and ischemic core volumes were automatically calculated using Tmax thresholds >9.5 seconds and >16 seconds, respectively. The difference between Tmax > 9.5 seconds and Tmax > 16 seconds volumes and the ratio between Tmax > 9.5 seconds and Tmax > 16 seconds volumes were considered ischemic penumbra and Tmax mismatch ratio, respectively. Final infarct volume (FIV) was measured on follow-up non-contrast computed tomography (CT) at 24 hours. Favorable clinical outcome was defined as 90-day modified Rankin Scale 0 to 2. Predictors of FIV and outcome were assessed with multivariable logistic regression. Optimal Tmax volumes for identification of good outcome was defined using receiver operating curves. RESULTS: A total of 393 patients were included, of whom 298 (75.8%) achieved successful recanalization and 258 (65.5%) achieved good outcome. In multivariable analyses, all Tmax parameters were independent predictors of FIV and outcome. Tmax  > 16 seconds volume had the strongest association with FIV (beta coefficient = 0.596 p <0.001) and good outcome (odds ratio [OR] = 0.96 per 1 ml increase, 95% confidence interval [CI] = 0.95-0.97, p < 0.001). Tmax  > 16 seconds volume had the highest discriminative ability for good outcome (area under the curve [AUC] = 0.88, 95% CI = 0.842-0.909). A Tmax  > 16 seconds volume of ≤67 ml best identified subjects with favorable outcome (sensitivity = 0.91 and specificity = 0.73). INTERPRETATION: Tmax target mismatch predicts radiological and clinical outcomes in patients with AIS with LVO receiving EVT within 24 hours from onset. ANN NEUROL 2022;91:878-888.

Delayed perihematomal hypoperfusion is associated with poor outcome in intracerebral haemorrhage.

BACKGROUND: The aim of this study was to characterize the temporal evolution and prognostic significance of perihematomal perfusion in acute intracerebral haemorrhage (ICH). METHODS: A single-centre prospective cohort of patients with primary spontaneous ICH receives computed tomography perfusion (CTP) within 6 h from onset (T0) and at 7 days (T7). Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the manually outlined perihematomal low-density area. Poor functional prognosis (modified Rankin Scale 3-6) at 90 days was the outcome of interest, and predictors were explored with multivariable logistic regression. RESULTS: A total of 150 patients were studied, of whom 52 (34.7%) had a mRS 3-6 at 90 days. Perihematomal perfusion decreased from T0 to T7 in all patients, but the magnitude of CBF and CBV reduction was larger in patients with unfavourable outcome (median CBF change -7.8 vs. -6.0 ml/100 g/min, p < .001, and median CBV change -0.5 vs. -0.4 ml/100 g, p = .010, respectively). This finding remained significant after adjustment for confounders (odds ratio [OR] for 1 ml/100 g/min CBF reduction: 1.33, 95% confidence interval [CI] (1.15-1.55), p < .001; OR for 0.1 ml/100 g CBV reduction: 1.67, 95% CI 1.18-2.35, p = .004). The presence of CBF < 20 ml/100 g/min at T7 was then demonstrated as an independent predictor of poor functional outcome (adjusted OR: 2.45, 95% CI 1.08-5-54, p = .032). CONCLUSION: Perihaemorrhagic hypoperfusion becomes more severe in the days following acute ICH and is independently associated with poorer outcome. Understanding the underlying biological mechanisms responsible for delayed decrease in perihematomal perfusion is a necessary step towards outcome improvement in patients with ICH.

In vivo magnetic resonance imaging evidence of olfactory bulbs changes in a newborn with congenital Citomegalovirus: a case report.

BACKGROUND: Citomegalovirus (CMV) infects approximately 1% of live newborns. About 10% of the infants affected by congenital CMV infection are symptomatic at birth and up to 60% of these infants will develop permanent neurological disabilities. Depending on gestational age (GA) at the time of infection, the involvement of central nervous system (CNS) can lead to malformations of cortical development, calcifications, periventricular white matter lesions and cysts, ventriculomegaly and cerebellar hypoplasia. CASE PRESENTATION: We report the MRI findings in a Caucasian female born at 32 weeks of post-menstrual age with post-birth diagnosis of congenital CMV infection showing an unusual and peculiar marked T2 hyperintensity of the inner part of olfactory bulbs in addition to the CMV related diffuse brain involvement. Despite the known extensively described fetal and neonatal Magnetic Resonance Imaging (MRI) findings in CMV infected fetuses and newborns, any in vivo MRI depiction of olfactory system damage have never been reported so far. Nevertheless, in murine studies CMV is known to infect the placenta during pregnancy showing particular tropism for neural stem cells of the olfactory system and previous neuropathologic study on CMV infected human fetal brains from 23 to 28 weeks of GA reported damage in the olfactory bulbs (OB) consisting in disseminated cytomegalic cells, inflammation, necrosis and neuronal and radial glial cell loss. Therefore, we assume an OB involvement and damage in congenital CMV infection. CONCLUSION: To our knowledge this is the first in vivo MRI evidence of OB damage in a newborn with congenital CMV infection that may give new insights on CMV infection.

Advanced Imaging of the Vestibular Endolymphatic Space in Ménière's Disease.

The diagnosis of "definite" Méniére's disease (MD) relies upon its clinical manifestations. MD has been related with Endolymphatic Hydrops (EH), an enlargement of the endolymphatic spaces (ES) (cochlear duct, posterior labyrinth, or both). Recent advances in Magnetic Resonance (MR) imaging justify its increasing role in the diagnostic workup: EH can be consistently recognized in living human subjects by means of 3-dimensional Fluid-Attenuated Inversion-Recovery sequences (3D-FLAIR) acquired 4 h post-injection of intra-venous (i.v.) Gadolinium-based contrast medium, or 24 h after an intratympanic (i.t.) injection. Different criteria to assess EH include: the comparison of the area of the vestibular ES with the whole vestibule on an axial section; the saccule-to-utricle ratio ("SURI"); and the bulging of the vestibular organs toward the inferior 1/3 of the vestibule, in contact with the stapedial platina ("VESCO"). An absolute link between MD and EH has been questioned, since not all patients with hydrops manifest MD symptoms. In this literature review, we report the technical refinements of the imaging methods proposed with either i.t. or i.v. delivery routes, and we browse the outcomes of MR imaging of the ES in both MD and non-MD patients. Finally, we summarize the following imaging findings observed by different researchers: blood-labyrinthine-barrier (BLB) breakdown, the extent and grading of EH, its correlation with clinical symptoms, otoneurological tests, and stage and progression of the disease.

Clinical, neuroradiological and genetic findings in a cohort of patients with multiple Cerebral Cavernous Malformations.

Cerebral cavernous malformations (CCM) consist of clusters of irregular dilated capillaries and represent the second most common type of vascular malformation affecting the central nervous system. CCM might be asymptomatic or cause cerebral hemorrhage, seizures, recurrent headaches and focal neurologic deficits. Causative mutations underlining CCM have been reported in three genes: KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3. Therapeutic avenues are limited to surgery. Here we present clinical, neuroradiological and molecular findings in a cohort of familial and sporadic CCM patients. Thirty subjects underwent full clinical and radiological assessment. Molecular analysis was performed by direct sequencing and MLPA analysis. Twenty-eight of 30 subjects (93%) experienced one or more typical CCM disturbances with cerebral/spinal hemorrhage being the most common (43%) presenting symptom. A molecular diagnosis was achieved in 87% of cases, with three novel mutations identified. KRIT1/CCM1 patients displayed higher risk of de novo CCMs appearance and bleedings. Magnetic Resonance Imaging (MRI) showed that infratentorial region was more frequently affected in mutated subjects while brainstem was often spared in patients with negative genetic testing.

Iron deposition in Parkinsonisms: A Quantitative Susceptibility Mapping study in the deep grey matter.

PURPOSE: The aim of the study is to quantify the susceptibility in deep grey nuclei that are affected by pathological processes related to iron accumulation in patients with Parkinson's disease and primary atypical parkinsonisms such as Progressive Supranuclear Palsy, Multiple System Atrophy and Cortico-Basal Degeneration, in order to assist the differential diagnosis among parkinsonian syndromes. METHODS: We enrolled 49 patients with Parkinson's disease and 26 patients with primary atypical parkinsonisms. Automatic segmentation of putamen, globus pallidus, caudate nucleus and thalamus and manual segmentation of red nuclei and substantia nigra were performed, and region of interest-based Quantitative Susceptibility Mapping analysis were performed. Statistical comparisons of the mean susceptibility values in the segmented brain regions were performed among primary atypical parkinsonisms and Parkinson's disease. RESULTS: Susceptibility values in red nuclei were increased in Progressive Supranuclear Palsy patients compared to parkinsonian phenotype Multiple System Atrophy (p = 0.004), and Parkinson's disease patients (p = 0.006). Susceptibility in thalamus was decreased in Cortico-Basal Degeneration patients compared to Parkinson's disease (p = 0.006), Multiple System Atrophy with cerebellar phenotype (p = 0.031) and parkinsonian phenotype (p = 0.001) patients, and in Progressive Supranuclear Palsy patients compared to Multiple System Atrophy with parkinsonian phenotype patients (p = 0.012). CONCLUSIONS: Quantitative Susceptibility Mapping allows the depiction and quantification of different patterns of iron deposition in the deep gray nuclei occurring in primary atypical parkinsonisms and Parkinson's disease and it may help as a non-invasive tool in the differential diagnosis between parkinsonian syndromes.

18F-FDG PET/CT in Labrune Syndrome.

A 69-year-old woman presented with cognitive impairment related to attentive, executive, and mnemonic functions; progressive worsening of walking, speaking, writing, and reading ability; and double sphincter incontinence. Leukoencephalopathy, cystic lesions, and calcifications, suspected for Labrune syndrome, were observed at MRI and CT brain images. Generalized wave abnormalities were also visible at electroencephalogram. Functional brain imaging performed with F-FDG PET/CT demonstrated a decreased glucose metabolism in impaired brain regions, in accordance with MRI findings. Genetic testing confirmed a mutation of SNORD118.

Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. METHODS: Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40-80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). DISCUSSION: Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial. TRIAL REGISTRATION: ClinicalTrails.gov, NCT03589014. Retrospectively registered on 17 July 2018.

Effects of in-utero exposure to chemotherapy on fetal brain growth.

OBJECTIVE: Children exposed to chemotherapy in the prenatal period demonstrate normal neurocognitive development at 3 years but concerns regarding fetal brain growth remain high considering its vulnerability to external stimuli. Our aim was to evaluate the impact of in-utero chemotherapy exposure on brain growth and its effects on neurodevelopmental outcome. METHODS: The protocol was approved by the local ethics committee. Brain regional volumes at term postmenstrual age were measured by MRI in children exposed to in-utero chemotherapy and compared with normal MRI controls. Brain segmentation was performed by Advanced Normalization Tools (ANTs)-based transformations of the Neonatal Brain Atlas (ALBERT). Neurodevelopmental assessment (Bayley-III scales) was performed at 18 months corrected age in both exposed infants and in a group of healthy controls. Multiple linear regressions and false discovery rate correction for multiple comparisons were performed. RESULTS: Twenty-one newborns prenatally exposed to chemotherapy (epirubicin administered in 81% of mothers) were enrolled in the study: the mean gestational age was 36.4±2.4 weeks and the mean birthweight was 2,753±622 g. Brain MRI was performed at mean postmenstrual age of 41.1±1.4 weeks. No statistically significant differences were identified between the children exposed to chemotherapy and controls in both the total (398±55 cm3 vs 427±56 cm3, respectively) and regional brain volumes. Exposed children showed normal Bayley-III scores (cognitive 110.2±14.5, language 99.1±11.3, and motor 102.6±7.3), and no significant correlation was identified between the brain volumes and neurodevelopmental outcome. CONCLUSION: Prenatal exposure to anthracycline/cyclophosphamide-based chemotherapy does not impact fetal brain growth, thus supporting the idea that oncological treatment in pregnant women seems to be feasible and safe for the fetus.

Monozygotic Twins with Frontotemporal Dementia Due To Thr272fs GRN Mutation Discordant for Age At Onset.

We report the case of two monozygotic twins with Thr272fs mutation in progranulin gene. Both patients developed frontotemporal dementia with 5 years difference in age at onset (Twin 1:73 years, Twin 2:68 years), with early behavioral, language, dysexecutive, and memory problems. They had the same formal education (5 years), but while Twin 1 dedicated more to social and leisure activity, Twin 2 worked all her life. At neuroimaging (MRI for Twin 1 and CT for Twin 2), they both showed asymmetric atrophy with left predominance. The two were discordant for total tau levels in cerebrospinal fluid, neuropsychological testing, and smoking habits. The description of the twins can help identify environmental factors that influence the onset and phenotype of frontotemporal dementia.

Neuroradiological findings in three cases of pontocerebellar hypoplasia type 9 due to AMPD2 mutation: typical MRI appearances and pearls for differential diagnosis.

Pontocerebellar hypoplasia type 9 (PCH9) is a rare autosomal recessive neurodegenerative disorder with prenatal onset caused by mutations in adenosine monophosphate deaminase 2 (AMPD2). PCH9 patients demonstrate severe neurodevelopmental delay with early onset and typical magnetic resonance imaging (MRI) findings consisting in: pontine hypoplasia or atrophy with dragonfly cerebellar atrophy appearance on coronal images, reduction in size of the pons and middle cerebellar peduncles, abnormal midbrain describing a figure of "8" on axial images, diffuse loss of cerebral white matter with striking periventricular leukomalacia (PVL), and absence or extreme thinning of the corpus callosum. A review of the literature on PCH9 shows that the MRI phenotype observed in the series herein presented is similar to the eleven cases of PCH9 previously reported. Finally, the main radiological elements which differentiate this diagnosis from other PCH subtypes are described.

Flat-panel CT versus 128-slice CT in temporal bone imaging: Assessment of image quality and radiation dose.

OBJECTIVE: We compared the image quality and radiation dose of flat-panel CT (FPCT) and multi-slice CT (MSCT) performed respectively with an angiographic unit and a 128-slice CT scanner. We investigated whether the higher spatial resolution of FPCT translated into higher image quality and we sought to eliminate inter-subject variability by scanning temporal bone specimens with both techniques. MATERIALS AND METHODS: Fifteen temporal bone specimens were imaged with FPCT and MSCT. Two neuroradiologists experienced in otoradiology evaluated 30 anatomical structures with a 0-2 score; 18 structures important from a clinical perspective were assigned a twofold value in calculation of the overall score. The radiation dose was calculated through the use of an anthropomorphic phantom. RESULTS: The image quality was significantly higher for FPCT than MSCT for 10 of the 30 anatomical structures; the overall score was also significantly higher for FPCT (p = 0.001). The equivalent dose of the two techniques was very similar, but with different effective doses to the organs. CONCLUSION: FPCT performed on an angiographic unit provides higher image quality in temporal bone assessment compared to MSCT performed on a 128-slice CT scanner thanks to its higher spatial resolution, with comparable equivalent doses but different effective doses to the organs.