Maria Camilla Rossi Espagnet

Gadolinium-Based Contrast Agent-Related Toxicities

In recent years, gadolinium-based contrast agents have been associated with different types of toxicity. In particular, nephrogenic systemic fibrosis, a progressive sclerotic-myxedematous systemic disease of unknown etiology, is related to gadolinium-based contrast agent administration in patients with kidney dysfunction. More recently, evidence of magnetic resonance signal intensity changes on pre-contrast T1-weighted images after multiple gadolinium-based contrast agent administrations resulted in the hypothesis of gadolinium brain accumulation in patients with normal renal function, subsequently confirmed in pathological samples. However, there is limited current data and further investigations are necessary before drawing definite conclusions on the clinical consequences of gadolinium-based contrast agent accumulation in human tissues and particularly in the brain. Gadolinium-based contrast agent-related toxicity appears connected to molecular stability, which varies together with the pharmacokinetic properties of the compound and depends on the individual characteristics of the subject. During a lifetime, the physiological changes occurring in the human body may influence its interaction with gadolinium-based contrast agents: the integrity and developmental stage of the organs has an effect on the dynamics of gadolinium-based contrast agent distribution and excretion, thus leading to different possible mechanisms of deposition and toxicity. Therefore, the aim of this work is to discuss the pharmacokinetics and pharmacodynamics of gadolinium-based contrast agents, with a special focus on the brain, and to explore potential predominant gadolinium-based contrast agent-related toxicity in two cornerstone periods of the human life cycle: fetal/neonatal and adulthood/aged.

Multiparametric evaluation of low grade gliomas at follow-up: comparison between diffusion and perfusion MR with 18F-FDOPA PET

OBJECTIVEnTo compare MRI using perfusion and diffusion techniques with 6-[(18)F]-fluoro-L-3,4-dihydroxyphenylalanine ((18)F-FDOPA) positron emission tomography (PET) in the follow-up of low-grade gliomas (LGGs) and to identify the best imaging parameter to differentiate patients with different prognosis.nnnMETHODSnBetween 2010 and 2015, 12 patients with a pathology-proven diagnosis of LGG and MR (with perfusion and diffusion sequences) and a PET study during their follow-up were retrospectively included in our study. Cerebral blood volume (CBV) and apparent diffusion coefficient (ADC) maps on MR studies and PET images were evaluated using a region of interest-based method. All patients were categorized as stable or as having progressive disease at 1-year follow-up. Statistical analysis was performed using Pearsons correlation test and multivariate analysis of variance (pu2009<u20090.05).nnnRESULTSnNo significant correlations were found between PET parameters [maximum tumour-to-controlateral normal brain ratio (T/Nmax) and tumour-to-striatum ratio] and ADC or relative CBV values measured in both PET hotspot regions and areas of maximum signal alterations. T/Nmax demonstrated a good sensitivity (83%) and specificity (100%) for differentiating two subgroups of patients with different outcomes at 1-year-follow-up (pu2009<u20090.05).nnnCONCLUSIONnPerfusion and diffusion MR images provide different information compared with (18)F-FDOPA PET in LGGs during follow-up and therefore, they should be considered as complementary tools in the evaluation of these tumours. (18)F-FDOPA PET showed a significant prognostic role in the follow-up of LGGs and appeared to be a better tool than MR advanced techniques for outcome prediction. These results need to be confirmed with longitudinal studies on a larger population.nnnADVANCES IN KNOWLEDGEnThis is the first study that compared (18)F-FDOPA PET with perfusion and diffusion MR in LGGs during follow-up. These preliminary results highlight the importance of a multimodality approach in this field and evidence a potential role for (18)F-FDOPA PET to predict patients at risk for tumour progression.

Magnetic resonance imaging patterns of treatment-related toxicity in the pediatric brain: an update and review of the literature

Treatment-related neurotoxicity is a potentially life-threatening clinical condition that can represent a diagnostic challenge. Differentiating diagnoses between therapy-associated brain injury and recurrent disease can be difficult, and the immediate recognition of neurotoxicity is crucial to providing correct therapeutic management, ensuring damage reversibility. For these purposes, the knowledge of clinical timing and specific treatment protocols is extremely important for interpreting MRI patterns. Neuroradiologic findings are heterogeneous and sometimes overlapping, representing the compounding effect of the different treatments. Moreover, MRI patterns can be acute, subacute or delayed and involve different brain regions, depending on (1) the mechanism of action of the specific medication and (2) which brain regions are selectively vulnerable to specific toxic effects. This review illustrates the most common radiologic appearance of radiotherapy, chemotherapy and medication-associated brain injury in children, with special focus on the application of advanced MRI techniques (diffusion, perfusion and proton spectroscopy) in the diagnosis of the underlying processes leading to brain toxicity.

Predictive role of dynamic contrast enhanced T1-weighted MR sequences in pre-surgical evaluation of macroadenomas consistency

PurposeOur hypothesis was that pituitary macroadenomas show different areas of consistency detectable by enhanced magnetic resonance imaging (MRI) with Dynamic study during gadolinium administration.Materials and methodsWe analysed 21 patients with pituitary macroadenomas between June 2013 and June 2015. All patients underwent trans-sphenoidal surgery and neurosurgeon described macroadenomas consistency. Similarly, two neuroradiologists manually drew regions of interest (ROIs) inside the solid-appearing portions of macroadenoma and in the normal white matter both on dynamic and post-contrast acquisitions. The ratio between these ROIs, defined as Signal Intensity Ratio (SIR), allowed obtaining signal intensity curves over time on dynamic acquisition and a single value on post-contrast MRI. SIR values best differentiating solid from soft macroadenoma components were calculated and correlated with pathologic patterns. A two-sample T test and empiric receiver operating characteristic (ROC) curve of SIR was performed.ResultsAccording to ROC analysis, the SIR value of 1.92, obtained by dynamic acquisition, best distinguished soft and hard components. All the specimens from soft components were characterized by high cellularity, high representation of vascularization and micro-haemorrhage and low percentage of collagen content. The reverse was evident in hard components.ConclusionsWe demonstrated that dynamic MRI acquisition could distinguish with good accuracy macroadenomas consistency.

Reply to Radbruch et al.: ‘interpreting signal-intensity ratios without visible T1 hyperintensities in clinical gadolinium retention studies’

Dear Editors, We thank Dr. Radbruch and Dr. Quattrocchi for their interest in our article [1] and for pointing out a common limitation present in all studies of this kind. There are indeed no clear explanations of what is causing signal hyperintensity after multiple administrations of gadolinium-based contrast agents and consequently it is difficult to be conclusive on either the absence or the presence of high signal. In line with this lack of information, the purpose of our study was hence to investigate the effect of multiple administrations on the signal-intensity ratio with an exclusive use of a macrocyclic gadolinium-based contrast agent. Our aim was specifically to evaluate signal-intensity changes over time, by considering each time point in every patient during such gadolinium-based contrast agent exposure. To the best of our knowledge, only a few studies so far have examined signal-intensity modifications in the enrolled population over time by measuring signal-intensity ratios in each time point [2–6]. On the other hand, most studies have limited the statistical analysis to the comparison between the first and last examinations, considering the number of administrations as a variable in the statistical analysis and providing different results [7–11]. Moreover, the relationship between signal intensity in specific brain structures and visible hyperintensity is not clear. The number of patients with a clear hyperintensity on T1-weighted images on visual inspection has not been reported in every study published on this topic. For example, Kanda et al. [3] reported that only 9 patients out of 73 exposed to linear (7/9) or mixed-type (2/9) gadolinium-based contrast agents had this radiologic finding despite a significant increase of the dentate nucleus-to-cerebellum signal-intensity ratio in the group exposed to a linear gadolinium-based contrast agent. More recently, Roberts et al. [12], using an advanced measurement technique (laser ablation inductively coupled plasma mass spectroscopy), demonstrated gadolinium deposits throughout the cerebellum of a patient exposed to multiple linear gadolinium-based contrast agent administrations, despite no clear hyperintensity on MR images. We can only speculate about the reasons for there being no sign of signal hyperintensity in our data. As correctly pointed out, Frenzel et al. [13] demonstrated the presence of soluble forms after administration of macrocyclic gadolinium-based contrast agent hypothetically suggestive of retention of the intact contrast agent chelate. First of all, signal changes due to gadolinium-based contrast agent are caused not just by its concentration but also by its relaxivity-inducing characteristics. Because the paper by Frenzel showed similar concentrations for the brain deposit of the soluble forms for all gadolinium-based contrast agent molecules, it is likely that the relatively little relaxivity change caused by gadoterate meglumine might explain the absent hyperintensity in our images. In conclusion, we believe that any explanation trying to merge region-of-interest-based studies and ex vivo autoptic studies has to be considered with extreme caution. Furthermore, we think that the methodology used in all * Maria Camilla Rossi Espagnet camilla.rossiespagnet@gmail.com

Reply to Lancelot et al.: ‘Lack of evidence of a relationship between magnetic resonance signal intensity changes in the globus pallidus and dentate nucleus, and repeated administrations of gadoterate meglumine in children’

Dear Editors, We appreciate the interest shown by Lancelot et al. [1] in our work [2]. It is unequivocally clear from the results of autopsy studies that gadolinium deposition occurs with both linear and macrocyclic gadolinium-based contrast agents even after a single injection [3]. However, imaging studies have produced inconsistent results even with the same gadolinium-based contrast agents [4, 5]. It must be underlined that all imaging studies available to date have been singlecenter and retrospective in design, which has inherent limitations. Selection and information bias cannot be excluded. Patient populations, imaging protocols, image evaluation methods, and frequency and time of exposure to gadolinium-based contrast agents, and potential carryover effects from previous exposures to a gadolinium-based contrast agents that are different from the one under study could have affected precision in the determination of changes in signal intensity ratio values associated with a certain number of administrations of a specific gadolinium-based contrast agent. We strongly believe our work was performed using methodology that has been widely applied in similar studies and published in peer-reviewed journals despite these well-known limitations. The fact that our results differ in some respect from findings obtained in other studies [6–8] may reflect the complexity of the issues involved. Age-matching was performed at both first and last MR examinations, as stated, and the statistical analysis was not presented for the last examination because the aim of the study was to investigate the dependence of the signal ratio on the number of gadolinium administrations. Moreover, Lancelot et al. [1] cited the study by Hu et al. [9] in their letter. It should be noted that Hu et al. did not include an age-matched control at the last examination: “Although our study included controls who were similar in age to the GBCA [gadolinium-based contrast agent] patients at their first MRI exam, a more appropriate choice would have been to age-match the controls to the age of the GBCA patients at their most recent MRI exam” [9]. It seems inconsistent to criticize our study for apparent methodological concerns while at the same time lauding another work that raises precisely the same concerns. The aim of scientific research is not necessarily to be consistent with data from previous studies; it is rather to present and discuss the findings of the specific research in question. As Lancelot et al. [1] were keen to point out, there are differences between linear and macrocyclic agents in terms of T1weighted signal changes, and reports showing an absence of correlation between globus pallidus-to-thalamus and dentate nucleus-to-pons signal intensity ratios and the number of gadolinium-based contrast agent injections with linear agents do not necessarily reflect the situation with macrocyclic agents. All agents are different and should be evaluated separately. Because of the nature of these endpoints and the abovementioned limitations of all imaging studies that assess the presence of T1-weighted hyperintensity in deep brain nuclei (i.e. retrospective design with potential selection and personal bias and the tremendous variability in region-of-interest placements), results can be inconsistent even within the same study. We are surprised that Lancelot et al. should criticize our study * Maria Camilla Rossi Espagnet camilla.rossiespagnet@gmail.com

Reversible lesions of the splenium of the corpus callosum in children — additional evidence from a Caucasian population

Dear Editors, Le Bras and colleagues [1] recently reported an interesting case series describing seven children with reversible splenial lesion of the corpus callosum. Reversible splenial lesion syndrome is a recently introduced nosologic entity with a variety of clinical manifestations and of different aetiologies [2]. Possible causes include seizures, antiepileptic drugs withdrawal, infections, altered metabolic states such as hypoglycemia and hypernatremia and other associated clinical conditions such as X-linked Charcot-Marie-Tooth disease [1–3]. Clinical symptoms vary from altered consciousness (confusion, lethargy, delirium) to seizures or focal neurologic symptoms that are usually unrelated to the splenial lesion. MRI findings also vary from a single ovoid lesion centred in the splenium of corpus callosum with diffusion restriction (also referred to as mild encephalopathy/encephalitis with reversible splenial lesion type 1) to more diffuse involvement of corpus callosum and deep white matter alterations (mild encephalopathy/encephalitis with reversible splenial lesion type 2) or other associated radiologic findings [3]. It can be difficult to find the underlying diagnosis, select the correct laboratory tests, and decide on radiologic follow-up. The clinical prognosis might be unclear, in particular in children. To contribute additional evidence of this disorder, we would like to share our experience, in particular with mild encephalopathy/encephalitis with reversible splenial lesion type 1 disorder. In our opinion this represents a betterdefined entity, possibly associated with an infective or infection-related process. We retrospectively evaluated clinical, radiologic and laboratory data of eight Caucasian children (age range 7–16 years, mean 11 years) referred to our institution between 2010 and 2017 in whom clinical notes reported a reversible lesion in the splenium of corpus callosum at MRI. Three children presented with altered mental state, mainly consisting of psychomotor agitation. Two children had newonset seizures, two had oculomotor disturbances, and one asymptomatic child underwent MRI follow-up for previously diagnosed posterior reversible encephalopathy. Four children were pyrexial. MRI showed in all children a well-defined single lesion involving the splenium of the corpus callosum with diffusion restriction (Fig. 1). In all children the lesion was slightly hyperintense on T2-weighted imaging. Among the three children who underwent contrast-enhanced MRI, the lesion was nonenhancing. Five children did not have other MRI findings. In the remaining three children, MRI showed, respectively, diffuse leptomeningeal enhancement, radiologic signs consistent with previous cerebellitis and pontine white matter signal alterations consistent with osmotic demyelination syndrome caused by rapid correction of hyponatremia. In symptomatic children, the mean time between clinical onset and first MRI was 9 days (range 2–27 days). Follow-up MRI performed with a mean interval of 2 months (range 1–28 weeks) demonstrated complete resolution of the splenial lesion in all of these children. Regarding laboratory findings, we observed a slightly elevated C-reactive protein and positivity for human herpes virus-6 genome amplification (polymerase chain reaction of blood sample) in five children (four of themwere also positive for IgG antibodies while one also had IgM antibodies). One child was positive for human herpes virus-7 (polymerase chain reaction of blood sample). In one child specific laboratory exams were not performed while in another child all * Maria Camilla Rossi Espagnet camilla.rossiespagnet@gmail.com

Prediction of survival in patients affected by glioblastoma: histogram analysis of perfusion MRI

PurposeThe identification of prognostic biomarkers plays a pivotal role in the management of glioblastoma. The aim of this study was to assess the role of magnetic resonance dynamic susceptibility contrast imaging (DSC-MRI) with histogram analysis in the prognostic evaluation of patients suffering from glioblastoma.Materials and methodsSixty-eight patients with newly diagnosed pathologically verified GBM were retrospectively evaluated. All patients underwent MRI investigations, including DSC-MRI, surgical procedure and received postoperative focal radiotherapy plus daily temozolomide (TMZ), followed by adjuvant TMZ therapy. Relative cerebral blood volume (rCBV) histograms were generated from a volume of interest covering the solid portions of the tumor and statistically evaluated for kurtosis, skewness, mean, median and maximum value of rCBV. To verify if histogram parameters could predict survival at 1 and 2xa0years, receiver operating characteristic (ROC) curves were obtained. Kaplan–Meier method was used to calculate patient’s overall survival.ResultsrCBV kurtosis and rCBV skewness showed significant differences between subjects surviving >u20091xa0and >u20092xa0years, According to ROC analysis, the rCBV kurtosis showed the best statistic performance compared to the other parameters; respectively, values of 1 and 2.45 represented an optimised cut-off point to distinguish subjects surviving over 1 or 2xa0years. Kaplan–Meier curves showed a significant difference between subjects with rCBV kurtosis values higher or lower than 1 (respectively 1021 and 576 days; Log-rank test: pu2009=u20090.007), and between subjects with rCBV kurtosis values higher or lower than 2.45 (respectively 802 and 408 days; Log-rank test: pu2009=u20090.001).ConclusionThe histogram analysis of perfusion MRI proved to be a valid method to predict survival in patients affected by glioblastoma.

Correction to: Gadolinium-Based Contrast Agent-Related Toxicities

The name of the last author (as shown in the author listing on page 229) was incorrectly tagged during the journal production process, and so appears incorrectly in the PubMed record. The name should be indexed in PubMed as.