Publications by authors named "Valentina De Giorgis"

58 Publications

Impact of the inversion time on regional brain perfusion estimation with clinical arterial spin labeling protocols.

MAGMA 2021 Oct 13. Epub 2021 Oct 13.

Department of Brain and Behavioral Sciences, University of Pavia, Via Forlanini 6, 27100, Pavia, Italy.

Objective: Evaluating the impact of the Inversion Time (TI) on regional perfusion estimation in a pediatric cohort using Arterial Spin Labeling (ASL).

Materials And Methods: Pulsed ASL (PASL) was acquired at 3 T both at TI 1500 ms and 2020 ms from twelve MRI-negative patients (age range 9-17 years). A volume of interest (VOIs) and a voxel-wise approach were employed to evaluate subject-specific TI-dependent Cerebral Blood Flow (CBF) differences, and grey matter CBF Z-score differences. A visual evaluation was also performed.

Results: CBF was higher for TI 1500 ms in the proximal territories of the arteries (PTAs) (e.g. insular cortex and basal ganglia - P < 0.01 and P < 0.05 from the VOI analysis, respectively), and for TI 2020 ms in the distal territories of the arteries (DTAs), including the watershed areas (e.g. posterior parietal and occipital cortex - P < 0.001 and P < 0.01 from the VOI analysis, respectively). Similar differences were also evident when analyzing patient-specific CBF Z-scores and at a visual inspection.

Conclusions: TI influences ASL perfusion estimates with a region-dependent effect. The presence of intraluminal arterial signal in PTAs and the longer arterial transit time in the DTAs (including watershed areas) may account for the TI-dependent differences. Watershed areas exhibiting a lower perfusion signal at short TIs (~ 1500 ms) should not be misinterpreted as focal hypoperfused areas.
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http://dx.doi.org/10.1007/s10334-021-00964-7DOI Listing
October 2021

Systematic review of executive functions in children with self-limited epilepsy with centrotemporal spikes.

Epilepsy Behav 2021 10 21;123:108254. Epub 2021 Aug 21.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy.

Self-limited Epilepsy with Centrotemporal Spikes (ECTS) is a self-limiting childhood epilepsy with an overall good prognosis. The neurocognitive profile of ECTS shows various degrees of neuropsychological impairment, with speech impairment and executive dysfunction being the most prominent. This review aimed to clarify the executive function (EF) profile of children with ECTS and the clinical variables' impact on these abilities. We conducted a systematic review of the relevant literature for articles published up to January 2021. Demographic and clinical characteristics were abstracted from the original records. EF tasks used in the studies were classified according to Diamond's model, which identified four components: working memory, inhibitory control, cognitive flexibility, and higher order EFs. Twenty-three studies were included. Among the included records, 14 studies examined working memory, 15 inhibitory control, 15 flexibility, 4 higher order EFs, and 2 general EFs. Results confirmed the presence of a specific impairment in two abilities: inhibitory control and cognitive flexibility. This review confirms the need to assess each EF both in verbal and visual-spatial tasks. The early detection of children with ECTS at risk of developing neuropsychological impairment could activate interventions and prevent worse school achievement, social functioning, and a poor quality of life. Systematic review registration: PROSPERO: CRD42021245959.
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http://dx.doi.org/10.1016/j.yebeh.2021.108254DOI Listing
October 2021

Ketogenic Dietary Therapies in Patients with Autism Spectrum Disorder: Facts or Fads? A Scoping Review and a Proposal for a Shared Protocol.

Nutrients 2021 Jun 16;13(6). Epub 2021 Jun 16.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, 27100 Pavia, Italy.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing incidence. An expanding body of literature is examining connections between ASD and dietary interventions. Existing reports suggest a beneficial effect of ketogenic dietary therapies (KDTs) in improving behavioral symptoms in ASD. In this context, the purpose of this scoping review was to identify and map available evidence in the literature about the feasibility and potential efficacy of KDTs in pediatric patients with ASD and to inform clinical practice in the field. Moreover, based on the resulting data from the literature review, we aimed to provide a shared protocol to develop a personalized KDT intervention in patients with ASD. A comprehensive and structured web-based literature search was performed using PubMed and Scopus and it yielded 203 records. Seven papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study designs and dietary aspects emerged among selected studies. Results supported the effectiveness of KDTs in promoting behavioral improvements. Clinical recommendations on which patients may benefit most from KDTs implementation and difficulties in dietary adherence were discussed.
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http://dx.doi.org/10.3390/nu13062057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234312PMC
June 2021

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox-Gastaut Syndrome.

Front Neurol 2021 20;12:673135. Epub 2021 May 20.

Pediatric Neurology and Epileptology Unit, Brotzu Hospital Trust, Cagliari, Italy.

Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.
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http://dx.doi.org/10.3389/fneur.2021.673135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173151PMC
May 2021

Diagnostic Yield and Cost-Effectiveness of "Dynamic" Exome Analysis in Epilepsy with Neurodevelopmental Disorders: A Tertiary-Center Experience in Northern Italy.

Diagnostics (Basel) 2021 May 25;11(6). Epub 2021 May 25.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, 27100 Pavia, Italy.

Background: The advent of next-generation sequencing (NGS) techniques in clinical practice led to a significant advance in gene discovery. We aimed to describe diagnostic yields of a "dynamic" exome-based approach in a cohort of patients with epilepsy associated with neurodevelopmental disorders.

Methods: We conducted a retrospective, observational study on 72 probands. All patients underwent a first diagnostic level of a 135 gene panel, a second of 297 genes for inconclusive cases, and finally, a whole-exome sequencing for negative cases. Diagnostic yields at each step and cost-effectiveness were the objects of statistical analysis.

Results: Overall diagnostic yield in our cohort was 37.5%: 29% of diagnoses derived from the first step analysis, 5.5% from the second step, and 3% from the third. A significant difference emerged between the three diagnostic steps ( < 0.01), between the first and second ( = 0.001), and the first and third ( << 0.001). The cost-effectiveness plane indicated that our exome-based "dynamic" approach was better in terms of cost savings and higher diagnostic rate.

Conclusions: Our findings suggested that "dynamic" NGS techniques applied to well-phenotyped individuals can save both time and resources. In patients with unexplained epilepsy comorbid with NDDs, our approach might maximize the number of diagnoses achieved.
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http://dx.doi.org/10.3390/diagnostics11060948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228291PMC
May 2021

Sensitive period for the plasticity of alpha activity in humans.

Dev Cogn Neurosci 2021 06 21;49:100965. Epub 2021 May 21.

U-VIP: Unit for Visually Impaired People, Istituto Italiano di Tecnologia, 16152, Genova, Italy. Electronic address:

Visual experience is crucial for the development of neural processing. For example, alpha activity development is a vision-dependent mechanism. Indeed, studies report no alpha activity is present in blind adults. Nevertheless, studies have not investigated the developmental trajectory of this activity in infants and children with blindness. Here, we hypothesize that the difference in neural activity of blind compared to sighted subjects is: absent at birth, progressive with age, specifically occipital and linked to a gradual motor impairment. Therefore, we consider spectral power of resting-state EEG and its association with motor impairment indices, in blind subjects and in sighted controls between 0 and 11 years of age. Blind subjects show posterior alpha activity during the first three years of life, although weaker and slower maturing compared to sighted subjects. The first great differentiation between blind and sighted subjects occurs between 3 and 6 years of age. Starting in this period, reduced alpha activity increases the probability of motor impairment in blind subjects, likely because of impaired perception/interaction. These results show that visual experience mediates the neural mechanisms generating alpha oscillations during the first years of life, suggesting that it is a sensitive period for the plasticity of this process.
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http://dx.doi.org/10.1016/j.dcn.2021.100965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167822PMC
June 2021

Novel insights into the clinico-radiological spectrum of phenotypes associated to PIGN mutations.

Eur J Paediatr Neurol 2021 Jul 18;33:21-28. Epub 2021 May 18.

Advanced Imaging and Radiomics Center, Neuroradiology Department, IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Objectives: Autosomic recessive mutations in the PIGN gene have been described in less than 30 subjects to date, in whom multiple congenital anomalies combined with severe developmental delay, hypotonia, epileptic encephalopathy, and cerebellar atrophy have been described as crucial features. A clear-cut neuroradiological characterization of this entity, however, is still lacking. We aim to present three pediatric PIGN mutated cases with an in-depth evaluation of their brain abnormalities.

Methods: We present the neuroradiological, clinical, and genetic characterization of three Caucasian pediatric subjects with pathogenic/likely pathogenic variants in the PIGN gene revealed by Next Generation Sequencing analysis.

Results: We identified three subjects (two siblings, one unrelated case) presenting with encephalopathy with early-onset epilepsy, hypotonia, and severe global developmental delay. No additional severe multiple congenital anomalies were detected. Neuroradiological evaluation showed extensive quantitative reduction of white matter, severe and progressive cortical atrophy, with frontal predominance and an anteroposterior gradient, combined with cerebellar and brainstem atrophy.

Conclusions: Our findings broaden and systematize the neuroradiological spectrum of abnormalities in PIGN related encephalopathy. Furthermore, our dataset confirms that mutations in PIGN gene appear to be pan-ethnic and represent an underestimated cause of early-onset encephalopathy.
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http://dx.doi.org/10.1016/j.ejpn.2021.05.008DOI Listing
July 2021

Characterization of Speech and Language Phenotype in GLUT1DS.

Children (Basel) 2021 Apr 27;8(5). Epub 2021 Apr 27.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, 27100 Pavia, Italy.

Background: To analyze the oral motor, speech and language phenotype in a sample of pediatric patients with GLUT 1 transporter deficiency syndrome (GLUT1DS).

Methods: eight Italian-speaking children with GLUT1DS (aged 4.6-15.4 years) in stable treatment with ketogenic diet from a variable time underwent a specific and standardized speech and language assessment battery.

Results: All patients showed deficits with different degrees of impairment in multiple speech and language areas. In particular, orofacial praxis, parallel and total movements were the most impaired in the oromotor domain; in the speech domain patients obtained a poor performance in the diadochokinesis rate and in the repetition of words that resulted as severely deficient in seven out of eight patients; in the language domain the most affected abilities were semantic/phonological fluency and receptive grammar.

Conclusions: GLUT1DS is associated to different levels of speech and language impairment, which should guide diagnostic and therapeutic intervention. Larger population data are needed to identify more precisely a speech and language profile in GLUT1DS patients.
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http://dx.doi.org/10.3390/children8050344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146076PMC
April 2021

One Month of Classic Therapeutic Ketogenic Diet Decreases Short Chain Fatty Acids Production in Epileptic Patients.

Front Nutr 2021 29;8:613100. Epub 2021 Mar 29.

Department of Food, Environmental and Nutritional Sciences DeFENS, University of Milan, Milan, Italy.

Ketogenic diet (KD), a high fat and very low carbohydrates diet, is used worldwide for the treatment of drug resistant epilepsy but, due to its composition, it might exert an impact on gut health. Even though data of KD effects on intestinal microbiota changes are recently emerging, its influence on the gut environment has been scarcely addressed so far. The aim of this study was to investigate whether 1 month of KD affects the gut environment in epileptic patients, by analyzing short chain fatty acids (SCFA) production and fecal water toxicity. A total of seven patients were enrolled. Stool samples were collected before (T0) and after 1 month of KD (4:1 ketogenic ratio) (T1). SCFA were determined by GC-FID and fecal water toxicity in Caco-2 cell culture by comet assay. Concentrations of SCFA significantly decreased after KD ( < 0.05): in particular, we found a 55% reduction of total SCFA level, a 64% reduction of acetate, 33% of propionate, and 20% of butyrate ( < 0.05). Cytotoxicity of fecal water extracted from stool samples was not significantly altered by diet, while genotoxicity was slightly decreased after KD ( < 0.05). Genotoxicity values were consistent with data previously obtained from a healthy Italian population. The present study suggests that 1 month of KD significantly reduce SCFA production. Since SCFA produced by gut microbiota exert many health promoting effects on either the gut environment or human metabolism, these results open a new branch of investigation into KD effects.
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http://dx.doi.org/10.3389/fnut.2021.613100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039123PMC
March 2021

Novel insight into GLUT1 Deficiency Syndrome: screening for emotional and behavioral problems in youths following ketogenic diet.

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

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy.

Background: Glucose Transporter Type 1 Deficiency Syndrome (GLUT1DS) is a rare disorder with a broad spectrum of neurological manifestations. The ketogenic diet (KD) is, to date, the gold standard treatment. Behavioral problems, well recognized in patients with chronic conditions, have not been, so far, deeply investigated in GLUT1DS patients. We performed an exploratory study to assess the risk of emotional and behavioral problems and investigated the potential role of influencing factors related to the pathology itself or KD treatment.

Methods: This was a mono-center retrospective study involving youths patients with GLUT1Ds treated with KD and a group of migraine patients age- and gender-matched. Patients were included if the main caregiver completed the Child Behavior Check List 6-18 (CBCL). Descriptive statistics for demographic and clinical data and questionnaire scores were computed. Correlational analyses were used to assess the potential associations of clinical variables and age and time from KD introduction with CBCL scores in GLUT1DS patients.

Results: We enrolled nine youths with GLUT1DS and 9 with migraine. In the GLUT1DS group, none of the mean scores of the CBCL items fell within the borderline/clinical range, except for social problems located in the borderline range. Investigation for influencing factors revealed the patient's age related to withdrawn/depressive (r=.709, p=.032) and social problems (r=.684, p=.042). Time from the introduction of KD was related to social problems (r=.827, p=.006). From the comparison with the scores obtained from migraine patients, significantly higher scores emerged in the latter group in internalizing problems (Z= -2.48, p = .01), externalizing problems (Z= -3.49, p < .001), anxious/depressed subscale (Z= -2.37, p=.014), somatic complaints subscale (Z= -2.624, p=.008), aggressive behavior subscale (Z= -2.539, p=.011).

Conclusions: Although highly exploratory in its nature, this study provides a novel insight into GLUT1DS. Our data suggested that the risk for internalizing problems in GLUT1DS youths was related to higher age and higher time elapsed from KD introduction. They occurred at a sub-clinical level, making them difficult to detect, if not expressly and systematically investigated.
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http://dx.doi.org/10.23736/S2724-5276.21.05923-1DOI Listing
April 2021

The epileptology of Aicardi-Goutières syndrome: electro-clinical-radiological findings.

Seizure 2021 Mar 1;86:197-209. Epub 2020 Dec 1.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Objective: Although epileptic seizures occur in approximately a quarter of patients with Aicardi-Goutières syndrome (AGS), their phenotypic and electrophysiological characterization remains elusive. The aim of our study was to characterize epilepsy phenotypes and electroencephalographic (EEG) patterns in AGS and look for possible correlations with clinical, genetic and neuroradiological features.

Methods: We selected patients with an established AGS diagnosis followed at three Italian reference centers. Medical records, EEGs and MRI/CT findings were reviewed. EEGs were independently and blindly reviewed by three board-certified pediatric epileptologists. Chi square and Fisher's exact tests were used to test associations between epilepsy and EEG feature categories and clinical, radiological and genetic variables.

Results: Twenty-seven patients were enrolled. We reviewed 63 EEGs and at least one brain MRI scan per patient. Epilepsy, mainly in the form of epileptic spasms and focal seizures, was present in 37 % of the cohort; mean age at epilepsy onset was 9.5 months (range 1-36). The presence of epilepsy was associated with calcification severity (p = 0.016) and startle reactions (p = 0.05). Organization of EEG electrical activity appeared to be disrupted or markedly disrupted in 73 % of cases. Severe EEG disorganization correlated with microcephaly (p < 0.001) and highly abnormal MRI T2-weighted signal intensity in white matter (p = 0.022). Physiological organization of the EEG was found to be better preserved during sleep (87 %) than wakefulness (38 %). Focal slow activity was recorded in more than one third of cases. Fast activity, either diffuse or with frontal location, was more frequent in the awake state (78 %) than in sleep (50 %). Interictal epileptiform discharges (IEDs) were present in 33 % of awake and 45 % of sleep recordings. IEDs during sleep were associated with a higher risk of a epileptic seizures (p = 0.008).

Significance: The hallmarks of EEG recordings in AGS were found to be: disruption of electrical organization, the presence of focal slow and fast activity, and the presence of IEDs, both in patients with and in those without epilepsy. The associations between epilepsy and calcification and between EEG pattern and the finding of a highly abnormal white matter T2 signal intensity suggest a common anatomical correlate. However, the complex anatomical-electroclinical basis of AGS-related epilepsy still requires further elucidation.
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http://dx.doi.org/10.1016/j.seizure.2020.11.019DOI Listing
March 2021

Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features.

Pediatr Neurol 2021 02 2;115:1-6. Epub 2020 Nov 2.

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address:

Background: Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy characterized by early onset of severe neurological injury with intracranial calcifications, leukoencephalopathy, and systemic inflammation. Increasingly, a spectrum of neurological dysfunction and presentation beyond the infantile period is being recognized in AGS. The aim of this study was to characterize late-infantile and juvenile-onset AGS.

Methods: We conducted a multi-institution review of individuals with AGS who were older than one year at the time of presentation, including medical history, imaging characteristics, and suspected diagnoses at presentation.

Results: Thirty-four individuals were identified, all with pathogenic variants in RNASEH2B, SAMHD1, ADAR1, or IFIH1. Most individuals had a history of developmental delay and/or systemic symptoms, such as sterile pyrexias and chilblains, followed by a prodromal period associated with increasing symptoms. This was followed by an abrupt onset of neurological decline (fulminant phase), with a median onset at 1.33 years (range 1.00 to 17.68 years). Most individuals presented with a change in gross motor skills (97.0%), typically with increased tone (78.8%). Leukodystrophy was the most common magnetic resonance imaging finding (40.0%). Calcifications were less common (12.9%).

Conclusions: This is the first study to characterize the presentation of late-infantile and juvenile onset AGS and its phenotypic spectrum. Late-onset AGS can present insidiously and lacks classical clinical and neuroimaging findings. Signs of early systemic dysfunction before fulminant disease onset and loss of motor symptoms were common. We strongly recommend genetic testing when there is concern for sustained inflammation of unknown origins or changes in motor skills in children older than one year.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856674PMC
February 2021

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

Neurology 2021 03 4;96(9):e1319-e1333. Epub 2020 Dec 4.

From the Department of Brain and Behavioural Neurosciences (S.M., A.P., M. Formica, S.O.) and Department of Public Health Experimental and Forensic Medicine, Biostatistic and Clinical Epidemiology Unit (P. Borrelli), University of Pavia; Pediatric Neurology Unit (S.M., M. Mastrangelo, P.V.), V. Buzzi Children's Hospital, Milan; Department of Neuroradiology (A.P.), Child Neurology and Psychiatry Unit (R.B., V.D.G., S.O.), and Department of Internal Medicine and Therapeutics, Member of the ERN EpiCARE, University of Pavia and Clinical Trial Center (E.P.), IRCCS Mondino Foundation Pavia; Neuroimaging Lab (F.A.) and Neuropsychiatry and Neurorehabilitation Unit (R.R.), Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco; Child Neuropsychiatric Unit (P.A., L.G.), Civilian Hospital, Brescia; Scientific Institute (P. Bonanni, A.D., E.O.), IRCCS E. Medea, Epilepsy and Clinical Neurophysiology Unit, Conegliano, Treviso; UOC Child Neuropsychiatry (B.D.B., F.D.), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Italy; Département de Neurologie Pédiatrique (N.D.), Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Belgium; AdPueriVitam (O.D.), Antony; Service d'Explorations Fonctionnelles (S.G.), Centre de Médecine du Sommeil, l'Hôpital Àntoine Béclère, AP-HP, Clamart; Pediatrics Departement (S.G.), André-Grégoire Hospital, Centre Hospitalier Inter Communal, Montreuil, France; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department (R.G., M. Montomoli, M.C.) and Radiology (M. Mortilla), A. Meyer Children's Hospital, Member of the ERN EpiCARE, University of Florence; IRCCS Stella Maris Foundation (R.G.), Pisa; Child Neuropsychiatry Unit, Epilepsy Center (F.L.B., A.V.), San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan; Child Neurology, NESMOS Department (P.P.), Faculty of Medicine & Psychology, Sant'Andrea Hospital, Sapienza University, Rome; Department of Neuroradiology (L.P.), Pediatric Neuroradiology Section, ASST Spedali Civili, Brescia; Pediatric Neuroradiology Unit (M.S.), IRCCS Istituto Giannina Gaslini, Genova; Neurology Unit, Department of Neuroscience, Member of the ERN EpiCARE (F.V.), Oncological Neuroradiology Unit, Department of Imaging, IRCCS (G.C.), and Department of Neuroscience and Neurorehabilitation (A.F.), Bambino Gesù Children's Hospital, Rome, Italy; Institut Imagine (N.B.-B.), Université Paris Descartes-Sorbonne Paris Cités; Pediatric Neurology (N.B.-B., I.D.), Necker Enfants Malades Hospital, Member of the ERN EpiCARE, Assistance Publique-Hôpitaux de Paris; INSERM UMR-1163 (N.B.-B., A. Arzimanoglou), Embryology and Genetics of Congenital Malformations, France; UOC Neurochirurgia (A. Accogli, V.C.), Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa (F.Z.), and Laboratory of Neurogenetics and Neuroscience, IRCCS (F.Z.), Istituto Giannina Gaslini, Genoa, Italy; Neurochirurgie Pédiatrique (M.B.), Hôpital NEM, Paris, France; Centre Médico-Chirurgical des Eaux-Vives (V.C.-V.), Swiss Medical Network, Genève, Switzerland; Neuroradiology Unit (L.C.) and Developmental Neurology Unit (S.D.), Foundation IRCCS C. Besta Neurological Institute, Milan; Service de Génétique (M.D.-F.), AMH2, CHU Reims, UFR de Médecine, Reims, France; Epilepsy Centre-Clinic of Nervous System Diseases (G.d.), Riuniti Hospital, Foggia, Italy; MediClubGeorgia Co Ltd (N.E.), Tbilisi, Georgia; Epilepsy Center (N.E.), Medical Center, Faculty of Medicine, University of Freiburg, Germany; Child and Adolescence Neurology and Psychiatry Unit (E. Fazzi), ASST Civil Hospital, Department of Clinical and Experimental Sciences, University of Brescia; Child Neurology Department (E. Fiorini), Verona, Italy; Service de Genetique Clinique (M. Fradin, P.L., C.Q.), CLAD-Ouest, Hospital Sud, Rennes, France; Child Neurology Unit, Pediatric Department (C.F., C.S.), Azienda USL-IRCCS di Reggio Emilia; Department of Pediatric Neuroscience (T.G., R.S.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Member of the ERN EpiCARE, Milan, Italy; Department of Epilepsy Genetics and Personalized Treatment (K.M.J., R.S.M.), The Danish Epilepsy Centre, Dianalund; Institute for Regional Health Services (K.M.J., R.S.M.), University of Southern Denmark, Odense; Unit of Pediatric Neurology and Pediatric Neurorehabilitation (S.L.), Woman-Mother-Child Department, Lausanne University Hospital CHUV, Switzerland; Unit of Neuroradiology (D.M.), Fondazione CNR/Regione Toscana G. Monasterio, Pisa; Pediatric Neurology Unit and Epilepsy Center (E.R., A.R.), Fatebenefratelli Hospital, Milan, Italy; KJF Klinik Josefinum GmbH (C.U.), Klinik für Kinder und Jugendliche, Neuropädiatrie, Augsburg, Germany; Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology (A. Arzimanoglou), University Hospitals of Lyon, Coordinator of the ERN EpiCARE, France; and Pediatric Epilepsy Unit, Child Neurology Department (P.V.), Hospital San Juan de Dios, Member of the ERN EpiCARE and Universitat de Barcelona, Spain.

Objective: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed.

Methods: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed.

Results: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported).

Conclusion: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome.

Classification Of Evidence: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.
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http://dx.doi.org/10.1212/WNL.0000000000011237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055324PMC
March 2021

Impact of COVID-19 pandemic in pediatric patients with epilepsy with neuropsychiatric comorbidities: A telemedicine evaluation.

Epilepsy Behav 2021 02 28;115:107519. Epub 2020 Nov 28.

Department of Child Neurology and Psychiatry, IRCSS Mondino Foundation, Pavia, Italy. Electronic address:

Objective: The objective of this study was to evaluate care needs, emotional and behavioral changes, and parental stress indices in a cohort of pediatric patients with epilepsy with neurocognitive and emotional comorbidities at the time of the coronavirus disease 2019 (COVID-19) pandemic.

Methods: This is a prospective observational study involving pediatric patients with epilepsy with neurocognitive and emotional comorbidities. Included patients were admitted to our hospital between August 2019 and February 2020 for epilepsy and neuropsychiatric assessment, and Child Behavior Checklist (CBCL) questionnaires were filled in by parents. Those patients and their families accepted to participate in a phone follow-up visit in April-May 2020 and to refill CBCL and Parenting Stress Index-Short Form (PSI-SF) questionnaires. Descriptive statistics for demographic and clinical data, CBCL questionnaire scores before and during the COVID-19 pandemic, and PSI-SF scores have been computed. Moreover, results of a short phone survey on the psychological burden during COVID lockdown have been reported.

Results: This study provides the parental-proxy report of emotional and behavioral profile changes of 23 pediatric patients with epilepsy and neurocognitive and emotional comorbidities during the COVID-19 pandemic. Concerns for therapy monitoring at the time of lockdown emerged in 43% of families, and 30% of patients showed worries for an altered contact with the referring medical team. Patients with neurocognitive comorbidities were more likely to exhibit behavioral problems, especially externalizing problems compared with patients with a diagnosis of anxiety/depression.

Conclusion: Our data suggest the importance to monitor disease trajectory and behavior and affective symptoms with telehealth strategies to provide effective care to patients and their families.
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http://dx.doi.org/10.1016/j.yebeh.2020.107519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695947PMC
February 2021

Childhood Epilepsy with Centrotemporal Spikes: Clinical and Neuropsychological Outcomes 5 Years after Remission.

Diagnostics (Basel) 2020 Nov 10;10(11). Epub 2020 Nov 10.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, 27100 Pavia, Italy.

Although specific neuropsychological deficits have been recognized during the active phase of epilepsy with centrotemporal spikes (ECTS), the natural cognitive and neuropsychological history after remission has not been elucidated so far. We evaluated the natural cognitive and neuropsychological outcomes five years after disease remission and investigated possible predictors of long-term outcome among socio-demographic and electro-clinical variables. We performed an observational cross-sectional study. Electro-clinical characteristics during the active phase of epilepsy, as well as antiepileptic treatment and premorbid neurodevelopmental concerns were reviewed for 70 patients. At least five years after epilepsy remission, all patients were contacted, and 46 completed a structured questionnaire about patients' current education and academic skills, general health, and parents' socio-economic status. Among them, 23 patients underwent an ad hoc cognitive and neuropsychological protocol and emotional-behavioral assessment. Chi-square tests and -tests were carried out to define the role of putative predictors of neuropsychological outcomes. Mean cognitive and neuropsychological performances appeared to be overall adequate, except for the dictation. Positive family history for epilepsy ( = 0.01769) and familial socioeconomic status (mother's schooling ( = 0.04169), father's schooling ( = 0.01939), mother's income ( = 0.0262), father's income ( = 0.01331)) were identified as predictors of outcomes. Our data suggest that ECTS with typical electro-clinical features depicts an overall preserved cognitive and neuropsychological long-term outcome. We suggest particular attention should be paid to patients with socio-economic disadvantage and familial history of epilepsy, as they may experience worse neurocognitive post-morbid performances.
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http://dx.doi.org/10.3390/diagnostics10110931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696372PMC
November 2020

Families' Perception of Classic Ketogenic Diet Management in Acute Medical Conditions: A Web-Based Survey.

Nutrients 2020 Sep 24;12(10). Epub 2020 Sep 24.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, 27100 Pavia, Italy.

To describe families' experiences in managing epileptic patients undergoing ketogenic dietary therapies (KDTs) in acute medical settings. We conducted a short online survey addressed to the families of patients undergoing a classic ketogenic diet (cKD) for at least three months. The survey was composed of 18 questions exploring the following issues: demographic characteristics, epilepsy diagnosis, ketogenic-diet treatment history, the reason for emergency-ward admission and patient management, surgery-procedure management, and outcomes. A sample of 50 families agreed to participate. Out of 50 patients, 33 (66%) had been undergoing a cKD for more than two years. Fifteen (30%) patients had been admitted at least once to the Emergency Room (ER), and 8.2% had undergone surgical procedures during cKD treatment. The causes of ER admission were the following: seizures, infection, trauma, and gastrointestinal or respiratory problems. In 75% of cases, blood ketonemia was not monitored during ER admission, and according to 46% of responders, the medical staff intervening did not have a basic knowledge of KDTs. According to both our experience and caregivers' reports, it might be useful to search for standardized specific approaches to patients undergoing KDTs in the emergency setting.
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http://dx.doi.org/10.3390/nu12102920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598657PMC
September 2020

Commentary on "Catatonia in a Patient with Aicardi-Goutières Syndrome Efficiently Treated with Immunoadsorption".

Schizophr Res 2020 10 12;224:188-189. Epub 2020 Sep 12.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1016/j.schres.2020.08.023DOI Listing
October 2020

Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group.

Epilepsia Open 2020 Sep 13;5(3):354-365. Epub 2020 Aug 13.

Department of Neurology and Pediatrics Vagelos College of Physicians and Surgeons at Columbia University New York NY USA.

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. linical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.
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http://dx.doi.org/10.1002/epi4.12414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469861PMC
September 2020

Comment on: Ketogenic diet therapy provision in the COVID-19 pandemic: Dual-center experience and recommendations.

Epilepsy Behav 2020 11 13;112:107399. Epub 2020 Aug 13.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Via Mondino, 2, 27100 Pavia, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.yebeh.2020.107399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425539PMC
November 2020

3D facial morphometry in Italian patients affected by Aicardi syndrome.

Am J Med Genet A 2020 10 15;182(10):2325-2332. Epub 2020 Aug 15.

Functional Anatomy Research Center (FARC), Laboratorio di Anatomia Funzionale dell'Apparato Stomatognatico (LAFAS), Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy.

Aicardi syndrome (AIC) is a rare congenital neurodevelopmental disorder of unknown etiology, that affects almost exclusively females, originally characterized by corpus callosum agenesis, chorioretinal lacunae, and infantile spasms. The current diagnostic criteria also include qualitative facial features (prominent premaxilla, upturned nasal tip, decreased nasal bridge angle, sparse lateral eyebrows, and microphthalmia) that still need quantification. A three-dimensional (3D) photogrammetric assessment of 11 Italian females, age 7-32 years, who satisfied AIC criteria, was performed. Linear distances and angles were computed from soft-tissue facial landmarks coordinates. The z-score values were calculated using data of 850 healthy reference females matched for age and compared by Mann-Whitney test (p < .01). Patients showed a shorter philtrum and right side orbital height (mean z-scores: -1.7, -0.9), shorter superior, middle, and inferior facial depths (mean z-scores: -1.3, -2.2, -2.3), and a smaller length of mandibular ramus (mean z-score: -2.1); conversely, they showed larger nasal and lower facial widths, and lower facial convexity (mean z-scores: 1.7, 1.4, 2.4). The inclinations of the orbit versus the true horizontal were increased bilaterally (mean z-scores: 1.8, 1.1). Some common facial abnormalities were quantified in AIC patients using a noninvasive instrument. They may help clinicians in performing a definite AIC diagnosis in atypical or doubt cases.
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http://dx.doi.org/10.1002/ajmg.a.61791DOI Listing
October 2020

Aicardi Syndrome: Key Fetal MRI Features and Prenatal Differential Diagnosis.

Neuropediatrics 2020 08 3;51(4):276-285. Epub 2020 Jul 3.

Department of Pediatric Radiology and Neuroradiology, Children's Hospital V. Buzzi, Milan, Italy.

Objective: This study was aimed to investigate the prenatal findings in Aicardi syndrome (AIC) by intrauterine magnetic resonance imaging (iuMRI) suggesting possible diagnostic criteria and differential diagnosis.

Methods: The iuMRI features of nine AIC confirmed cases were described and then compared with those of postnatal MRI. Furthermore, all iuMRI cases with both corpus callosum (CC) agenesis-dysgenesis and cortical malformation (AIC mimickers) were retrospectively reviewed and compared with iuMRI AIC cases, in order to identify possible neuroradiological predictors of AIC syndrome. For this purpose, Chi-square statistic and binary logistic regression analysis were performed.

Results: In all AIC cases, iuMRI was able to detect CC agenesis-dysgenesis and cortical development anomalies. Postnatal MRI revealed some additional findings mainly including further cystic lesions and in two cases small coloboma. A statistically significant difference between AIC and AIC mimicker were found regarding sex, nodular heterotopias, posterior fossa abnormalities, coloboma, and cortical gyration abnormalities. The most predictive variables in the logistic regression model were cortical gyration abnormalities, coloboma, and sex.

Conclusion: The iuMRI findings may suggest prenatal diagnosis of AIC syndrome with significant impact on parental counseling. Among possible differential diagnoses, tubulinopathies emerged.
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http://dx.doi.org/10.1055/s-0040-1710528DOI Listing
August 2020

Use of Remote Monitoring by E-mail for Long-Term Management of the Classic Ketogenic Diet.

Nutrients 2020 Jun 19;12(6). Epub 2020 Jun 19.

Human Nutrition and Eating Disorder Research Center, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Via Agostino Bassi, 21, 27100 Pavia, Italy.

The classic ketogenic diet (cKD) requires constant nutritional monitoring over time both to ensure its effectiveness and to reduce the likelihood of short- and long-term adverse effects. We retrospectively described the use of remote monitoring by e-mail during the first year of follow-up on cKD in 34 children (47% males; age range: 2-17 years) diagnosed with drug-resistant epilepsy (DRE; n = 14) or glucose transporter type 1 deficiency syndrome (GLUT1-DS; n = 20). All the e-mails were evaluated analyzing their frequency and content at 3, 6 and 12 months. Three families never sent e-mails. A median of 36.0 (IQR 23.0-64.0) e-mails per family were sent during the 12 follow-up months by the 31 patients. GLUT1-DS patients sent a greater number of e-mails than the DRE group (median 39.0 (IQR 25.5-56.5) vs. median 26.0 (IQR 19.0-65.0)). At the end of the follow-up period, a greater number of e-mails had been exchanged between the nutritional team and the families belonging to the group that increased its linear growth (median 83.5; IQR 48.0-102.0), compared to the other ones. Constant remote monitoring by e-mail could be a feasible and effective way for a better cKD management.
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http://dx.doi.org/10.3390/nu12061833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353224PMC
June 2020

Relationship between saliva and plasma rufinamide concentrations in patients with epilepsy.

Epilepsia 2020 07 20;61(7):e79-e84. Epub 2020 Jun 20.

Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r  = .78, P < .0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose-normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme-inducing or enzyme-inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.
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http://dx.doi.org/10.1111/epi.16584DOI Listing
July 2020

The assessment of esophageal pressure using different devices: a validation study.

Minerva Anestesiol 2020 10 12;86(10):1047-1056. Epub 2020 Jun 12.

Department of Anesthesia and Intensive Care, ASST Santi Paolo e Carlo, San Paolo University Hospital, Milan, Italy.

Background: Although esophageal pressure measurement could help clinicians to improve the ventilatory management of acute respiratory distress syndrome (ARDS) patients, it has been mainly used in clinical research. Aim of this study was to compare the measurements of end-expiratory esophageal pressure, end-expiratory transpulmonary pressure and lung stress by three systems: a dedicated manual device, taken as gold standard, a new automatic system (Optivent) and a bedside equipment, consisting of a mechanical ventilator and a hemodynamic monitor.

Methods: In sedated and paralyzed mechanically ventilated ARDS patients the esophageal pressure was measured at three PEEP levels in random fashion (baseline level, 50% higher and 50% lower).

Results: Forty patients were enrolled (BMI 25 [23-28] kg/m2, PaO2/FiO2 187 [137-223] and PEEP 9±3 cmH2O). The mean esophageal pressure measured during an expiratory pause by the dedicated system, the bedside system and Optivent were 10.0±4.2, 10±4 and 9.9±4.0 cmH2O, respectively. The respective bias and limits of agreement between the dedicated system and Optivent and between the dedicated system and the bedside system were as follows: end-expiratory esophageal pressure, 0.2 cmH2O, (-0.4 to 0.9) and -0.1 cmH2O (-1.9 to 1.7); end-expiratory transpulmonary pressure, -0.6 cmH2O (-1.7 to 0.4) and -0.4 cmH2O, (-2.2 to 1.5); lung stress -0.9 cmH2O (-3.0 to 1.1) and -1.5 cmH2O (-4.4 to 1.4).

Conclusions: Both Optivent and the bedside system showed clinically acceptability if compared to the gold standard device. The possibility to apply one of these systems could allow a wider use of esophageal pressure in clinical practice.
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http://dx.doi.org/10.23736/S0375-9393.20.14458-4DOI Listing
October 2020

Effect of mechanical power on intensive care mortality in ARDS patients.

Crit Care 2020 05 24;24(1):246. Epub 2020 May 24.

Department of Anesthesia and Intensive Care, ASST Santi Paolo e Carlo, San Paolo University Hospital, Milan, Italy.

Background: In ARDS patients, mechanical ventilation should minimize ventilator-induced lung injury. The mechanical power which is the energy per unit time released to the respiratory system according to the applied tidal volume, PEEP, respiratory rate, and flow should reflect the ventilator-induced lung injury. However, similar levels of mechanical power applied in different lung sizes could be associated to different effects. The aim of this study was to assess the role both of the mechanical power and of the transpulmonary mechanical power, normalized to predicted body weight, respiratory system compliance, lung volume, and amount of aerated tissue on intensive care mortality.

Methods: Retrospective analysis of ARDS patients previously enrolled in seven published studies. All patients were sedated, paralyzed, and mechanically ventilated. After 20 min from a recruitment maneuver, partitioned respiratory mechanics measurements and blood gas analyses were performed with a PEEP of 5 cmHO while the remaining setting was maintained unchanged from the baseline. A whole lung CT scan at 5 cmHO of PEEP was performed to estimate the lung gas volume and the amount of well-inflated tissue. Univariate and multivariable Poisson regression models with robust standard error were used to calculate risk ratios and 95% confidence intervals of ICU mortality.

Results: Two hundred twenty-two ARDS patients were included; 88 (40%) died in ICU. Mechanical power was not different between survivors and non-survivors 14.97 [11.51-18.44] vs. 15.46 [12.33-21.45] J/min and did not affect intensive care mortality. The multivariable robust regression models showed that the mechanical power normalized to well-inflated tissue (RR 2.69 [95% CI 1.10-6.56], p = 0.029) and the mechanical power normalized to respiratory system compliance (RR 1.79 [95% CI 1.16-2.76], p = 0.008) were independently associated with intensive care mortality after adjusting for age, SAPS II, and ARDS severity. Also, transpulmonary mechanical power normalized to respiratory system compliance and to well-inflated tissue significantly increased intensive care mortality (RR 1.74 [1.11-2.70], p = 0.015; RR 3.01 [1.15-7.91], p = 0.025).

Conclusions: In our ARDS population, there is not a causal relationship between the mechanical power itself and mortality, while mechanical power normalized to the compliance or to the amount of well-aerated tissue is independently associated to the intensive care mortality. Further studies are needed to confirm this data.
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http://dx.doi.org/10.1186/s13054-020-02963-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245621PMC
May 2020

Pathways to quality of life in adolescents with genetic generalized epilepsy: The role of seizure features and affective symptoms.

Epilepsy Behav 2020 08 18;109:107115. Epub 2020 May 18.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy.

Both clinical features of seizures and affective problems (i.e., depressive and/or anxious symptoms) affect quality of life perception in patients with epilepsy. Although genetic generalized epilepsies (GGEs) represent one-third of all epilepsies, very few studies focused on the association among seizures, affective problems, and perceived quality of life in pediatric patients with GGE. Here, we assessed the relative contributions of seizure characteristics and affective symptoms on quality of life in patients with adolescence-onset GGE. Forty pediatric outpatients completed self-report questionnaires on affective symptoms and quality of life. Sociodemographic and clinical variables were obtained from medical charts. Affective symptoms were present in 40% of patients. Higher scores emerged in patients who were seizure-free at the time of the survey for both the physical and mental components of quality of life. Higher seizure frequency was significantly associated with lower quality of life scores in the mental component, whereas the presence of depressive and/or anxious symptoms was significantly associated with lower scores in the physical component. These associations were confirmed after controlling for sociodemographic confounders. These findings suggest that adolescents with GGE are at increased risk for affective symptoms. Moreover, both GGE-related clinical features (i.e., seizure frequency) and the presence of affective symptoms (i.e., depression, anxiety) are relevant and independent contributors to quality of life. The investigation of affective problems is warranted to be included in routine assessments of GGE in pediatric populations.
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http://dx.doi.org/10.1016/j.yebeh.2020.107115DOI Listing
August 2020

Glucose transporter 1 deficiency syndrome: nutritional and growth pattern phenotypes at diagnosis.

Eur J Clin Nutr 2020 09 13;74(9):1290-1298. Epub 2020 May 13.

Department of Pediatrics, V. Buzzi Children's Hospital, University of Milan, Milan, Italy.

Background/objectives: Glucose Transporter 1 Deficiency Syndrome (GLUT1-DS; OMIM #606777) is a rare disease caused by dominant mutations in SLC2A1 encoding GLUT1, which is a ubiquitous transporter of glucose across plasma membranes, particularly across the blood-brain barrier. Hypoglycorrhachia symptoms are the cornerstones of GLUT1-DS, but delayed growth has also been suggested. This led us to investigate, at diagnosis, the relationship between the glycemia/glycorrhachia ratio and the nutritional and growth pattern phenotype of 30 GLUT-DS patients.

Subjects/methods: An assessment was made of body weight (BW), body length/height (BL, BH) and body composition by anthropometry and DEXA, and the results put with BL and BW at birth, genetic target, glycemia, insulinemia, and glycorrhachia values.

Results: At birth, 21% of patients had a BW below -1.645 z-score, whereas no patients had BL below the reference values. At diagnosis 23% of the patients had an impaired nutritional status, 19.2% and 3.8% being respectively underweight and overweight/obese; 10%, all under 10 years old, had BL/BH below -1.645 z-score, with no specific features related to body composition. Finally, there was no association between glycemia, glycorrhachia, and growth phenotype.

Conclusions: GLUT1-DS is associated with impaired BW but not BL intrauterine growth, with a slower than normal pattern of growth rather than growth failure. These data could be useful for the interpretation of any long-term effects of the ketogenic diet, e.g. nutritional and growth pattern decline.
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http://dx.doi.org/10.1038/s41430-020-0662-zDOI Listing
September 2020

Development of a neurologic severity scale for Aicardi Goutières Syndrome.

Mol Genet Metab 2020 06 2;130(2):153-160. Epub 2020 Apr 2.

Division of Neurology, Children's Hospital of Philadelphia, United States.

Background And Purpose: Aicardi Goutières Syndrome (AGS) is a severe, autoinflammatory leukodystrophy characterized by global neurologic dysfunction. Our goal was to create an easy-to-apply scale relevant to the unique developmental challenges associated with AGS.

Methods: All individuals were recruited through our natural history study. Individuals were classified by AGS severity as mild, moderate, or severe, and clinical encounters were assigned a composite score for neurologic function calculated from the sum of three functional classification scales. Through expert consensus, we identified 11 key items to reflect the severity of AGS across gross motor, fine motor, and cognitive skills to create the AGS Scale. There was strong interrater reliability. The AGS scale was applied across available medical records to evaluate neurologic function over time. The AGS scale was compared to performance on a standard measure of gross motor function (Gross Motor Function Measure-88, GMFM-88) and a putative diagnostic biomarker of disease, the interferon signaling gene expression score (ISG).

Results: The AGS scale score correlated with severity classifications and the composite neurologic function scores. When retrospectively applied across our natural history study, the majority of individuals demonstrated an initial decline in function followed by stable scores. Within the first 6 months of disease, the AGS score was the most dynamic. The AGS scale correlated with performance by the GMFM-88, but did not correlate with ISG levels.

Conclusions: This study demonstrates the utility of the AGS scale as a multimodal tool for the assessment of neurologic function in AGS. The AGS scale correlates with clinical severity and with a more labor-intensive tool, GMFM-88. This study underscores the limitations of the ISG score as a marker of disease severity. With the AGS scale, we found that AGS neurologic severity is the most dynamic early in disease. This novel AGS scale is a promising tool to longitudinally follow neurologic function in this unique population.
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http://dx.doi.org/10.1016/j.ymgme.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366613PMC
June 2020

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.

Hum Mutat 2020 04 14;41(4):837-849. Epub 2020 Jan 14.

Department of Allergy/Immunology, Spectrum Health Helen Devos Children's Hospital, Michigan State University College of Human Medicine, East Lansing, Michigan.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
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http://dx.doi.org/10.1002/humu.23975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457149PMC
April 2020

The effect of chronic neuroglycopenia on resting state networks in GLUT1 syndrome across the lifespan.

Hum Brain Mapp 2020 02 11;41(2):453-466. Epub 2019 Nov 11.

Neurology Unit, OCSAE Hospital, AOU Modena, Modena, Italy.

Glucose transporter type I deficiency syndrome (GLUT1DS) is an encephalopathic disorder due to a chronic insufficient transport of glucose into the brain. PET studies in GLUT1DS documented a widespread cortico-thalamic hypometabolism and a signal increase in the basal ganglia, regardless of age and clinical phenotype. Herein, we captured the pattern of functional connectivity of distinct striatal, cortical, and cerebellar regions in GLUT1DS (10 children, eight adults) and in healthy controls (HC, 19 children, 17 adults) during rest. Additionally, we explored for regional connectivity differences in GLUT1 children versus adults and according to the clinical presentation. Compared to HC, GLUT1DS exhibited increase connectivity within the basal ganglia circuitries and between the striatal regions with the frontal cortex and cerebellum. The excessive connectivity was predominant in patients with movement disorders and in children compared to adults, suggesting a correlation with the clinical phenotype and age at fMRI study. Our findings highlight the primary role of the striatum in the GLUT1DS pathophysiology and confirm the dependency of symptoms to the patients' chronological age. Despite the reduced chronic glucose uptake, GLUT1DS exhibit increased connectivity changes in regions highly sensible to glycopenia. Our results may portrait the effect of neuroprotective brain strategy to overcome the chronic poor energy supply during vulnerable ages.
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http://dx.doi.org/10.1002/hbm.24815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313681PMC
February 2020
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