Publications by authors named "Daniela Longo"

70 Publications

Reliability on multiband diffusion NODDI models: A test retest study on children and adults.

Neuroimage 2021 Jun 4;238:118234. Epub 2021 Jun 4.

Medical Physics Department, Bambino Gesù Children's Hospital IRCCS, Rome, Italy. Electronic address:

Neurite Orientation Dispersion and Density Imaging (NODDI) and Bingham-NODDI diffusion MRI models are nowadays very well-known models in the field of diffusion MRI as they represent powerful tools for the estimation of brain microstructure. In order to efficiently translate NODDI imaging findings into the diagnostic clinical practice, a test-retest approach would be useful to assess reproducibility and reliability of NODDI biomarkers, thus providing validation on precision of different fitting toolboxes. In this context, we conducted a test-retest study with the aim to assess the effects of different factors (i.e. fitting algorithms, multiband acceleration, shell configuration, age of subject and hemispheric side) on diffusion models reliability, assessed in terms of Intra-class Correlation Coefficient (ICC) and Variation Factor (VF). To this purpose, data from pediatric and adult subjects were acquired with Simultaneous-MultiSlice (SMS) imaging method with two different acceleration factor (AF) and four b-values, subsequently combined in seven shell configurations. Data were then fitted with two different GPU-based algorithms to speed up the analysis. Results show that each factor investigated had a significant effect on reliability of several diffusion parameters. Particularly, both datasets reveal very good ICC values for higher AF, suggesting that faster acquisitions do not jeopardize the reliability and are useful to decrease motion artifacts. Although very small reliability differences appear when comparing shell configurations, more extensive diffusion parameters variability results when considering shell configuration with lower b-values, especially for simple model like NODDI. Also fitting tools have a significant effect on reliability, but their difference occurs in both datasets and AF, so it appears to be independent from either misalignment and motion artifacts, or noise and SNR. The main achievement of the present study is to show how 10 min multi-shell diffusion MRI acquisition for NODDI acquisition can have reliable results in WM. More complex models do not appear to be more prone to less data acquisition as well as noisier data thus stressing the idea of Bingham-NODDI having greater sensitivity to true subject variability.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118234DOI Listing
June 2021

Ethylmalonic encephalopathy and liver transplantation: long-term outcome of the first treated patient.

Orphanet J Rare Dis 2021 May 19;16(1):229. Epub 2021 May 19.

Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.

Background: Ethylmalonic encephalopathy (EE) is a severe intoxication-type metabolic disorder with multisystem clinical features and leading to early death. In 2014, based on the promising results obtained by liver-targeted gene therapy in Ethe1 mouse model, we successfully attempted liver transplantation in a 9-month-old EE girl. Here we report her long-term follow-up, lasting over 6 years, with a comprehensive evaluation of clinical, instrumental and biochemical assessments.

Results: Neurological signs initially reverted, with a clinical stabilization during the entire follow-up course. Accordingly, gross motor functions improved and then stabilized. Psychomotor evaluations documented an increasing communicative intent, the acquisition of new social skills and the capability to carry out simple orders. Neurophysiological assessments, which included EEG, VEP/ERG and BAEPs, remained unchanged. Brain MRI also stabilized, showing no further lesions and cerebral atrophy improvement. Compared to pre-transplant assessments, urinary ethylmalonic acid strikingly reduced, and plasma thiosulphate fully normalized. The child maintained good clinical conditions and never experienced metabolic crises nor epileptic seizures.

Conclusions: The long-term follow-up of the first EE transplanted patient demonstrates that liver transplantation stabilizes, or even improves, disease course, therefore representing a potentially elective option especially in early-diagnosed patients, such as those detected by newborn screening, before irreversible neurological damage occurs.
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http://dx.doi.org/10.1186/s13023-021-01867-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136189PMC
May 2021

Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease.

Hum Mutat 2021 Jun 11;42(6):745-761. Epub 2021 May 11.

Department of Translational Medicine, Federico II University, Naples, Italy.

KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate transfer RNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical, and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction, and immuno-hematological problems are emerging phenotypes in KARS1-related disorder. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients.
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http://dx.doi.org/10.1002/humu.24210DOI Listing
June 2021

Morphometric Analysis of Brain in Newborn with Congenital Diaphragmatic Hernia.

Brain Sci 2021 Apr 2;11(4). Epub 2021 Apr 2.

Medical Physics Department, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

Congenital diaphragmatic hernia (CDH) is a severe pediatric disorder with herniation of abdominal viscera into the thoracic cavity. Since neurodevelopmental impairment constitutes a common outcome, we performed morphometric magnetic resonance imaging (MRI) analysis on CDH infants to investigate cortical parameters such as cortical thickness (CT) and local gyrification index (LGI). By assessing CT and LGI distributions and their correlations with variables which might have an impact on oxygen delivery (total lung volume, TLV), we aimed to detect how altered perfusion affects cortical development in CDH. A group of CDH patients received both prenatal (i.e., fetal stage) and postnatal MRI. From postnatal high-resolution T2-weighted images, mean CT and LGI distributions of 16 CDH were computed and statistically compared to those of 13 controls. Moreover, TLV measures obtained from fetal MRI were further correlated to LGI. Compared to controls, CDH infants exhibited areas of hypogiria within bilateral fronto-temporo-parietal labels, while no differences were found for CT. LGI significantly correlated with TLV within bilateral temporal lobes and left frontal lobe, involving language- and auditory-related brain areas. Although the causes of neurodevelopmental impairment in CDH are still unclear, our results may suggest their link with altered cortical maturation and possible impaired oxygen perfusion.
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http://dx.doi.org/10.3390/brainsci11040455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065764PMC
April 2021

Brain auditory evoked potentials in pediatric intensive care unit: diagnostic role on encephalopathy and central respiratory failure on infants.

Minerva Pediatr (Torino) 2021 Apr 2. Epub 2021 Apr 2.

Neurophysiology Unit, Neurology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Encephalopathy of different etiologies in infants is often the reason for central respiratory insufficiency which eventually leads patients to the paediatric intensive care unit. Magnetic resonance imaging (MRI) and brainstem auditory evoked potentials (BAEPs) may be useful to identify brainstem alterations among patients with respiratory insufficiency of central origin. MRI is a compulsory technique to identify brain abnormalities, but may fail to detect brainstem lesions of small dimensions. BAEPs play a highly sensitive role on brainstem dysfunction identification because of the generators of different peaks which are related to specific brainstem structures. The early identification of brainstem lesions in mechanically ventilated infants with encephalopathy may reduce the weaning off mechanical ventilation's attempt numbers and provide early informative discussions with families and clinical caregivers about treatment options, such as tracheostomy, long term ventilation and the reduction of their lenght of PICU stay. Furthermore, this would support the evaluation process concerning the affected children, their families and the needs of other social groups, including health systems.
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http://dx.doi.org/10.23736/S2724-5276.21.05931-0DOI Listing
April 2021

Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation.

Hum Mutat 2021 Jun 25;42(6):699-710. Epub 2021 Mar 25.

Department of Neurosciences, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next-generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis, and western blot analysis. All patients displayed novel homozygous mutations in the NDUFA12 gene, leading to the virtual absence of the corresponding protein. Surprisingly, despite the fact that in none of the analyzed patients, NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect.
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http://dx.doi.org/10.1002/humu.24195DOI Listing
June 2021

The Ketogenic Diet Increases In Vivo Glutathione Levels in Patients with Epilepsy.

Metabolites 2020 Dec 10;10(12). Epub 2020 Dec 10.

Child Neurology Unit, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.

The Ketogenic Diet (KD) is a high-fat, low-carbohydrate diet that has been utilized as the first line treatment for contrasting intractable epilepsy. It is responsible for the presence of ketone bodies in blood, whose neuroprotective effect has been widely shown in recent years but remains unclear. Since glutathione (GSH) is implicated in oxidation-reduction reactions, our aim was to monitor the effects of KD on GSH brain levels by means of magnetic resonance spectroscopy (MRS). MRS was acquired from 16 KD patients and seven age-matched Healthy Controls (HC). We estimated metabolite concentrations with linear combination model (LCModel), assessing differences between KD and HC with -test. Pearson was used to investigate GHS correlations with blood serum 3-B-Hydroxybutyrate (3HB) concentrations and with number of weekly epileptic seizures. The results have shown higher levels of brain GSH for KD patients (2.5 ± 0.5 mM) compared to HC (2.0 ± 0.5 mM). Both blood serum 3HB and number of seizures did not correlate with GSH concentration. The present study showed a significant increase in GSH in the brain of epileptic children treated with KD, reproducing for the first time in humans what was previously observed in animal studies. Our results may suggest a pivotal role of GSH in the antioxidant neuroprotective effect of KD in the human brain.
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http://dx.doi.org/10.3390/metabo10120504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763157PMC
December 2020

Multiparametric Imaging for Presurgical Planning of Craniopagus Twins: The Experience of Two Tertiary Pediatric Hospitals with Six Sets of Twins.

Radiology 2021 01 3;298(1):18-27. Epub 2020 Nov 3.

From the Department of Neuroradiology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, England (K.A.E., A.R., F.R., J.C., K.M., F.D.); Department of Radiology, University of Cambridge School of Clinical Medicine, Box 218, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, England (K.A.E.); Neuroradiology Unit, Imaging Department, Bambino Gesù Children's Hospital, Rome, Italy (M.C.R.E., D.L., M.R.); Neuroscienze Salute Mentale e Organi di Senso Department, Sapienza University, Rome, Italy (M.C.R.E.); Department of Craniofacial Surgery, Great Ormond Street Hospital, London, England (S.S., J.O., D.D., N.O.J.); Advanced Cardiovascular Imaging Unit (A.S., L.B.), Department of General and Thoracic Surgery (A.I.), Medical Physics Department (A.N.), Neurosurgery Unit (C.E.M.), Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy; Department of Anesthesia and Critical Care, Ospedale Pediatrico Bambino Gesù, Rome, Italy (S.P.).

Conjoined twins are rare and pose a challenge to radiologists and surgeons. Craniopagus twins, where conjunction involves the cranium, are especially rare. Even in large pediatric centers, radiologists are unlikely to encounter more than one such event in their medical careers. This rarity makes it daunting to select a CT and MRI protocol for these infants. Using the experience of two tertiary pediatric hospitals with six sets of craniopagus twins, this multidisciplinary and multimodal integrated imaging approach highlights the key questions that need addressing in the decision-making process for possible surgical intervention.
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http://dx.doi.org/10.1148/radiol.2020202216DOI Listing
January 2021

Early Onset Epilepsy Caused by Low-Grade Epilepsy-Associated Tumors and Focal Meningeal Involvement.

Brain Sci 2020 Oct 18;10(10). Epub 2020 Oct 18.

Rare and Complex Epilepsies, Department of Neurological Science, Bambino Gesù Children's Hospital, IRCCS, Member of European Reference Network EpiCARE, 00165 Rome, Italy.

: Low-grade epilepsy-associated neuroepithelial tumors (LEATs) are a frequent etiology in pediatric patients with epilepsy undergoing surgery. : To identify differences in clinical and post-surgical follow-up between patients with focal meningeal involvement (MI) and those without MI within our cohort of pediatric patients with LEATs. : We retrospectively reviewed all pediatric patients (<18 y) who underwent epilepsy surgery between 2011 and 2017 at our hospital. Cohort inclusion required histological diagnosis of LEATs and post-surgical follow-up of ≥2 y. We subsequently stratified patients according to presence of neuroradiological MI. : We identified 37 patients: five with MI and 32 without. Half of patients (19) were drug sensitive at surgery; similar between groups. The group with MI differed mainly for age of epilepsy-onset (0.6 vs. 7.0 y) but not for epilepsy duration (0.9 vs. 1.5 y). Post-surgery radiological follow-up (median 4.0 y; IQR 2.8-5.0 y) did not indicate disease progression. Seizure outcome was excellent in both groups, with 34 patients overall being both drug- and seizure-free. : Our study identified a new subgroup of LEATs with focal MI and excellent post-surgical outcome. Moreover, this highlights the effectiveness of early surgery in pediatric LEATs.
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http://dx.doi.org/10.3390/brainsci10100752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603244PMC
October 2020

Mannose Binding Lectin, S100 B Protein, and Brain Injuries in Neonates With Perinatal Asphyxia.

Front Pediatr 2020 17;8:527. Epub 2020 Sep 17.

Unit of Epidemiology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Perinatal asphyxia triggers an acute inflammatory response in the injured brain. Complement activation and neuroinflammation worsen brain damage after a systemic ischemia/reperfusion insult. The increase of mannose binding lectin (MBL) during asphyxia may contribute to the brain damage, via activation of the complement lectin pathway. The possible role of gene variants in influencing the severity of post-asphyxia brain injuries is still unexplored. This retrospective study included 53 asphyxiated neonates: 42 underwent therapeutic hypothermia (TH) and 11 did not because they were admitted to the NICU later than 6 h after the hypoxic insult. Blood samples from TH-treated and untreated patients were genotyped for gene variants, and biomarker plasma levels (MBL and S100 B protein) were measured at different time points: during hypothermia, during rewarming, and at 7-10 days of life. The timing of blood sampling, except for the T1 sample, was the same in untreated infants. Highest (peak) levels of MBL and genotypes were correlated to neuroimaging brain damage or death and long-term neurodevelopmental delay. wild-type genotype was associated with the highest MBL levels and worst brain damage on MRI ( = 0.046) at 7-10 days after hypoxia. MBL increased in both groups and S100B decreased, slightly more in treated than in untreated neonates. The progressive increase of MBL ( = 0.08) and to be untreated with TH ( = 0.08) increased the risk of brain damage or death at 7-10 days of life, without affecting neurodevelopmental outcomes at 1 year. The effect of TH on MBL plasma profiles is uncertain.
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http://dx.doi.org/10.3389/fped.2020.00527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527601PMC
September 2020

Correction to: Spinal cord involvement in Kearns-Sayre syndrome: a neuroimaging study.

Neuroradiology 2020 Dec;62(12):1725

Neuroradiology Unit, Imaging Department, Bambino Gesù Children's Hospital, P.zza Sant'Onofrio 4, 00165, Rome, Italy.

The original article was published with an incorrect presentation of all author names.
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http://dx.doi.org/10.1007/s00234-020-02573-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852945PMC
December 2020

Management of accidental lumbar epidural catheter breakage in a 5-month-old infant.

Paediatr Anaesth 2020 11 6;30(11):1278-1279. Epub 2020 Oct 6.

Department of Anesthesiology, Bambino Gesù Children's Hospital Reasearch Institute, Rome, Italy.

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http://dx.doi.org/10.1111/pan.14022DOI Listing
November 2020

Langerhans cell histiocytosis in a young patient with Pitt-Hopkins syndrome.

Am J Med Genet A 2020 11 18;182(11):2746-2750. Epub 2020 Sep 18.

Rare Diseases and Genetic Unit, University Department of Paediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Pitt-Hopkins syndrome (PTHS, MIM #610954) is a rare neurodevelopmental disease characterized by the association of intellectual disability, characteristic facial gestalt and episodes of abnormal and irregular breathing. PTHS is due to heterozygous loss-of-function variants in the TCF4 gene (transcription factor 4, MIM #602272) encoding for a basic helix-loop-helix transcription factor. TCF4 is highly expressed during early development of the nervous system, and it is involved in cellular differentiation and proliferation. Since the first clinical description in 1978, less than 200 PTHS patients have been described. A comprehensive phenotype, especially regarding cancer predisposition, is not yet well defined. We report the case of a 7-year-old boy affected by PTHS with a 4-week history of progressive swelling of the frontal bones diagnosed with Langerhans cell histiocytosis.
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http://dx.doi.org/10.1002/ajmg.a.61840DOI Listing
November 2020

Microcephalic osteodysplastic primordial dwarfism type II and pachygyria: Morphometric analysis in a 2-year-old girl.

Am J Med Genet A 2020 10 3;182(10):2372-2376. Epub 2020 Aug 3.

Medical Physics Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Microcephalic osteodysplastic primordial dwarfism (MOPD) type II is a rare disorder characterized by skeletal dysplasia, severe proportionate short stature, insulin resistance and cerebrovascular abnormalities including cerebral aneurysms and moyamoya disease. MOPD type II is caused by mutations in the pericentrin (PCNT) gene, which encodes a protein involved in centrosomes function. We report a 2 year old girl affected by MOPD type II caused by two compound heterozygous loss-of-function variants in PCNT gene, of which one is a novel variant (c.5304delT; p.Gly1769AlafsTer34). The patient presented atypical brain magnetic resonance imaging (MRI) findings consistent with pachygyria. This was confirmed by morphometric analysis of cortical thickness (CT) and gyrification index by comparing MRI data of the patient with a group of eight age-matched healthy controls. The statistical analysis revealed a significant and diffuse increase of CT with an anterior-predominant pattern and diffuse reduced gyrification (p < .05). These findings provide new evidences to the emergent concept that malformations of cortical development are complex disorders and that new genetic findings contribute to the fading of classification borders.
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http://dx.doi.org/10.1002/ajmg.a.61771DOI Listing
October 2020

Spinal cord involvement in Kearns-Sayre syndrome: a neuroimaging study.

Neuroradiology 2020 Oct 22;62(10):1315-1321. Epub 2020 Jul 22.

Neuroradiology Unit, Imaging Department, Bambino Gesù Children's Hospital, P.zza Sant'Onofrio 4, 00165, Rome, Italy.

Purpose: Spinal cord involvement in Kearns-Sayre (KSS) syndrome could be more frequent than commonly thought. Our aims were to evaluate the involvement of the spinal cord in patients with KSS by means of MRI and to investigate possible correlations of spinal and brain disease with patient disability.

Methods: Eleven patients with KSS disease and spinal cord MRI were retrospectively recruited. The severity of spinal disease was defined as follows: grade 0 (none), grade 1 (focal), and grade 2 (extensive). We calculated a radiologic score of brain involvement based on typical features. We performed a chi-square test to correlate spinal cord and brain MRI involvement to patient disability. For significant variables, a contingency coefficient, phi factor, and Cramer's V were also computed.

Results: Spinal cord lesions were detected in 6/11 patients, showing four patterns: involvement of gray matter, gray matter and posterior columns, posterior columns, and anterior columns. The severity of spinal disease was grade 1 in two and grade 2 in four patients. All patients showed brain involvement (9-point average for patients with spinal involvement and 10 for the others). A significant correlation was found between disability score and spinal cord involvement (χ = 7.64; p = 0.022) or brain score (χ = 26.85; p = 0.043). Significance for brain score-disability correlation increased with the spinal cord as a cofactor (χ = 24.51; p = 0.017, phi factor = 1.201, Cramer's V = 0.849, contingency effect = 0.767; p = 0.017).

Conclusion: Spinal cord lesions are common in KSS. Patients with spinal disease show higher disability than patients without spinal cord lesions, supporting the inclusion of dedicated acquisitions to routine MRI of the brain in patients with KSS.
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http://dx.doi.org/10.1007/s00234-020-02501-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479017PMC
October 2020

Non-congenital viral infections of the central nervous system: from the immunocompetent to the immunocompromised child.

Pediatr Radiol 2020 11 10;50(12):1757-1767. Epub 2020 Jul 10.

Neuroradiology Unit, NESMOS Department, Sapienza University, Rome, Italy.

Non-congenital viral infections of the central nervous system in children can represent a severe clinical condition that needs a prompt diagnosis and management. However, the aetiological diagnosis can be challenging because symptoms are often nonspecific and cerebrospinal fluid analysis is not always diagnostic. In this context, neuroimaging represents a helpful tool, even though radiologic patterns sometimes overlap. The purpose of this pictorial essay is to suggest a schematic representation of different radiologic patterns of non-congenital viral encephalomyelitis based on the predominant viral tropism and vulnerability of specific regions: cortical grey matter, deep grey matter, white matter, brainstem, cerebellum and spine.
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http://dx.doi.org/10.1007/s00247-020-04746-6DOI Listing
November 2020

Staphylococcal meningitis therapy with linezolid in a young infant: efficacy, CSF levels and side effects.

Ital J Pediatr 2020 Jun 29;46(1):90. Epub 2020 Jun 29.

Department of Pediatric Medicine, Laboratory of Metabolic Biochemistry Unit, Bambino Gesù Children's Hospital, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Linezolid is a synthetic antibiotic which is active against most Gram-positive bacteria, especially on Staphylococcus aureus. Its administration can be required when the infection is due to staphylococcus strains, which are resistant to vancomycin. Although mostly well tolerated, some mild to moderate side effects have been reported.

Case Presentation: This case report describes an infant with multiloculated hydrocephalus, staphylococcal meningitis and prolonged linezolid therapy, in which we observed the association between linezolid administration and a lengthened QTc interval at the electrocardiogram (ECG). To rule out toxic levels during the therapy, plasma and cerebro-spinal fluid concentrations of linezolid were measured and reported.

Conclusions: Although generally well tolerated in neonates and infants, linezolid prolonged administration seems be able to cause QTc interval prolongation. Therefore, its administration in such patients should be limited to cases of bacterial resistance to other antibiotics. In addition to well-known close monitoring of the platelet level, we suggest serial ECG controls before and during linezolid administration. In the case we report, linezolid plasma concentrations resulted within the therapeutic range during therapy, while cerebrospinal fluid (CSF) concentrations appeared lower than those considered effective.
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http://dx.doi.org/10.1186/s13052-020-00854-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325046PMC
June 2020

Quantitative MRI-Based Analysis Identifies Developmental Limbic Abnormalities in PCDH19 Encephalopathy.

Cereb Cortex 2020 10;30(11):6039-6050

Child Neurology Unit and Laboratories, Neuroscience Department, Children's Hospital A. Meyer - University of Florence, 50139 Florence, Italy.

Protocadherin-19 (PCDH19) is a calcium dependent cell-adhesion molecule involved in neuronal circuit formation with prevalent expression in the limbic structures. PCDH19-gene mutations cause a developmental encephalopathy with prominent infantile onset focal seizures, variably associated with intellectual disability and autistic features. Diagnostic neuroimaging is usually unrevealing. We used quantitative MRI to investigate the cortex and white matter in a group of 20 PCDH19-mutated patients. By a statistical comparison between quantitative features in PCDH19 brains and in a group of age and sex matched controls, we found that patients exhibited bilateral reductions of local gyrification index (lGI) in limbic cortical areas, including the parahippocampal and entorhinal cortex and the fusiform and lingual gyri, and altered diffusivity features in the underlying white matter. In patients with an earlier onset of seizures, worse psychiatric manifestations and cognitive impairment, reductions of lGI and diffusivity abnormalities in the limbic areas were more pronounced. Developmental abnormalities involving the limbic structures likely represent a measurable anatomic counterpart of the reduced contribution of the PCDH19 protein to local cortical folding and white matter organization and are functionally reflected in the phenotypic features involving cognitive and communicative skills as well as local epileptogenesis.
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http://dx.doi.org/10.1093/cercor/bhaa177DOI Listing
October 2020

Reply to: Viability of diffusion tensor imaging for assessing retrochiasmatic involvement in Kearns-Sayre syndrome remains elusive.

Neuroradiology 2020 02 14;62(2):133-134. Epub 2019 Dec 14.

Neuroradiology Unit, Imaging Department, Bambino Gesù Children's Hospital, Piazza Sant'Onofrio 4, IRCCS, 00100, Rome, Italy.

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http://dx.doi.org/10.1007/s00234-019-02344-4DOI Listing
February 2020

Visual pathways evaluation in Kearns Sayre syndrome: a diffusion tensor imaging study.

Neuroradiology 2020 Feb 4;62(2):241-249. Epub 2019 Nov 4.

Neuroradiology Unit, Imaging Department, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00100, Rome, Italy.

Purpose: Kearns Sayre syndrome (KSS) is a mitochondrial disorder characterized by development of visual impairment. Electroretinogram (ERG) and visual evoked potentials are not able to provide topographical information of optic damage. The purpose of this study was to explore retrochiasmatic optic pathway alteration in KSS with diffusion tractographic analysis and to compare it with different tracts.

Methods: DTI from 8 KSS subjects (14.7 years) and 10 healthy controls (HC) were acquired on a 3T scanner. Optic radiations (OR), optic tracts (OT), inferior frontooccipital fasciculus (IFOF) and corticospinal tract (CST) were reconstructed with probabilistic tractography. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), radial (RD), and axial diffusivity (AD) were calculated, evaluating group differences. T test on diffusion parameters identified significantly different track portions among cohorts.

Results: All patients had optic pathway alterations at electrophysiological examination. Significant lower FA were found in OT, IFOF, and CST of KSS group. RD was significantly higher in bilateral OR, IFOF, CST, and right OT, while ADC was higher in bilateral OR and CST. RD values were higher in the proximal and distal portion of OR bilaterally and in the distal portion of right OT, while widespread differences were found in IFOF and CST. No significant differences were found for AD. FA profiles analysis demonstrated significant differences between groups in several regions of OT, IFOF, and CST, while ADC assessment revealed spread differences in OR and CST.

Conclusions: DTI evaluation of retrochiasmatic tracks may represent a useful tool to topographically investigate retrochiasmatic visual impairment in KSS.
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http://dx.doi.org/10.1007/s00234-019-02302-0DOI Listing
February 2020

Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia.

Orphanet J Rare Dis 2019 08 23;14(1):208. Epub 2019 Aug 23.

Division of Metabolism, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.

Background: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare disorder of urea cycle characterized by progressive pyramidal and cerebellar dysfunction, whose pathophysiology is not yet fully understood. Here we describe the spectrum of the long fibers involvement in HHH syndrome, attempting a correlation between clinical, electrophysiological and neuro-radiological data.

Methods: Nine HHH patients were longitudinally evaluated by clinical examination, neurophysiological assessment including motor (MEPs), somato-sensory evoked potentials (PESS) and nerve conduction velocity (NCV), brain and spinal cord MRI RESULTS: All patients had pyramidal dysfunction and 3/9 an overt spastic paraplegia. Mild to moderate cerebellar signs were found in 7/9, intellectual disability in 8/9. At lower limbs, MEPs resulted abnormal in 7/8 patients and PESS in 2/8; peripheral sensory-motor neuropathy was found in 1/9. MRI documented atrophic changes in supra-tentorial brain regions in 6/9 patients, cerebellum in 6/9, spinal cord in 3/7.

Conclusions: A predominant corticospinal dysfunction is evident in HHH syndrome, along with milder cerebellar signs, intellectual disability of variable degree and rare peripheral neuropathy. Phenotypical similarities with other disorders affecting the urea cycle (argininemia and pyrroline-5-carboxylate synthetase deficiency) suggest possible common mechanisms contributing in the maintenance of the corticospinal tract integrity. HHH syndrome phenotype largely overlaps with complex Hereditary Spastic Paraplegias (HSPs), in the list of which it should be included, emphasizing the importance to screen all the unsolved cases of HSPs for metabolic biomarkers.
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http://dx.doi.org/10.1186/s13023-019-1181-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708179PMC
August 2019

A new MRI severity score to predict long-term adverse neurologic outcomes in children with congenital Cytomegalovirus infection.

J Matern Fetal Neonatal Med 2021 Mar 3;34(6):859-866. Epub 2019 Jun 3.

Ospedale Pediatrico Bambino Gesu, Rome, Italy.

Background: Congenital cytomegalovirus (CMV) infection is one of the main causes of deafness in childhood. It frequently causes serious long-term neurological sequelae. In children who are asymptomatic at birth, tests to accurately predict these sequelae are still unavailable.

Aims: We describe different brain MRI patterns of congenital CMV infection correlated with clinical data and propose a new MRI severity score to early predict long-term neurological sequelae.

Materials And Methods: We explored clinical records and neuroimaging data of 224 neonates and children with congenital Cytomegalovirus infection, 180 of them did not meet inclusion criteria. Forty-four babies met inclusion criteria and were enrolled in the study. We retrospectively collected clinical data concerning hospitalization, 2 years outpatient follow-up and brain MRI findings of those 44 children, symptomatic and asymptomatic at birth. Clinical data were then correlated with children's brain MRI examinations. We defined neurological and sensorial impairment (hearing or visual) as "adverse neurological outcomes". Brain MRI score was constructed assigning different values to white matter and ventricular dilation.

Results: In 44 children enrolled in the study we found that 28/35 (80%) with abnormal and 2/9 (22,2%) with normal MRI examination developed adverse neurological outcomes (OR = 3.6) (95% IC 1.0-12.0). Infants who were symptomatic at birth showed a probability of MRI brain lesions 3.2 times higher than those who were asymptomatic. Ten out of 17 (59%) children who were asymptomatic at birth showed MRI-WM alterations or ventriculomegaly.

Conclusions: Brain MRI abnormalities, such as WM alterations and ventriculomegaly, expressed as MRI score higher than 2 are associated with an increased probability of long-term adverse neurological outcome in congenitally CMV infected infants, symptomatic and asymptomatic at birth.
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http://dx.doi.org/10.1080/14767058.2019.1620725DOI Listing
March 2021

HHV6-related mild encephalopathy with reversible splenial lesion (MERS) presenting with urinary and fecal retention in an Italian adolescent.

Infez Med 2019 Mar;27(1):97-102

University Department of Pediatrics, Pediatric and Infectious Diseases Unit, Bambino Gesú Children's Hospital, IRCCS, Rome, Italy.

Mild encephalopathy with a reversible splenial lesion (MERS) is an uncommon clinico-radiological entity characterized by magnetic resonance imaging (MRI) findings of a reversible lesion in the splenium of corpus callosum associated with a significant neurological manifestation of encephalopathy. The majority of reported cases involve the Asiatic population and are closely associated with infection. We report the case of an adolescent with an HHV6-related MERS presenting with hyponatremia and urinary and fecal retention. To our knowledge, urinary retention is not a constant aspect of the disease and has rarely been described, while fecal retention has never been reported before. Despite the self-limiting nature of the disease, it is mandatory to suspect it for a faster diagnosis and it might be useful to know its rare occurrences in order to better understand its etiopathogenetic mechanisms.
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March 2019

Response to the Letter to the Editor: "Pediatric otogenic lateral sinus thrombosis: focus on the prognostic role of contralateral venous drainage".

Eur Arch Otorhinolaryngol 2019 06 14;276(6):1853-1854. Epub 2019 Mar 14.

Haemostasis and Thrombosis Center, Oncohematology Department, Bambino Gesù Pediatric Hospital, Rome, Italy.

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http://dx.doi.org/10.1007/s00405-019-05372-1DOI Listing
June 2019

Diagnosis of brain abscess: a challenge that Magnetic Resonance can help us win!

Epidemiol Infect 2018 09 4;146(12):1608-1610. Epub 2018 Jul 4.

Fatebenefratelli S. Pietro Hospital,Rome,Italy.

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http://dx.doi.org/10.1017/S0950268818001139DOI Listing
September 2018

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

Pediatr Radiol 2018 07 18;48(7):1035-1037. Epub 2018 May 18.

Neuroradiology Unit, Imaging Department,, Bambino Gesù Children's Hospital,, Piazza Sant'Onofrio 4, 00100, Rome, Italy.

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http://dx.doi.org/10.1007/s00247-018-4159-zDOI Listing
July 2018

Correction to: Gadolinium-Based Contrast Agent-Related Toxicities.

CNS Drugs 2018 06;32(6):601

Neuroradiology Unit, Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.

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.
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http://dx.doi.org/10.1007/s40263-018-0527-3DOI Listing
June 2018

Gadolinium-Based Contrast Agent-Related Toxicities.

CNS Drugs 2018 03;32(3):229-240

Neuroradiology Unit, Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.

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.
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http://dx.doi.org/10.1007/s40263-018-0500-1DOI Listing
March 2018

Dentate nucleus T1 hyperintensity: is it always gadolinium all that glitters?

Radiol Med 2018 Jun 27;123(6):469-473. Epub 2018 Jan 27.

Imaging Department, Bambino Gesù Children's Hospital, Rome, Italy.

In the last few years, several scientific papers and reports have demonstrated magnetic resonance (MR) signal intensity (SI) changes on pre-contrast T1-weighted images following multiple gadolinium-based contrast agents (GBCA) administrations, particularly following the exposure to linear GBCAs. Pathological animal and human post-mortem studies have confirmed the relationship between this radiological finding and the presence of gadolinium accumulation in vulnerable brain regions in patients with normal renal function. In this short communication, we report the case of a 15-year-old patient affected by b-cell acute lymphoblastic leukemia (bALL) who developed a hyperintense signal in the dentate nuclei following multiple administrations of a macrocyclic GBCA. The purpose of this report is to discuss possible differential diagnoses of this radiological finding with special focus on the differentiation between iron or manganese accumulation, post-irradiation changes and GBCA-related Gd deposition, highlighting the importance of the acquisition of accurate clinical data to improve our scientific knowledge.
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http://dx.doi.org/10.1007/s11547-017-0846-3DOI Listing
June 2018