Publications by authors named "Thomas Foiadelli"

46 Publications

Alexander disease evolution over time: data from an Italian cohort of pediatric-onset patients.

Mol Genet Metab 2021 Nov 24. Epub 2021 Nov 24.

Unit of Pediatric Neurology, V. Buzzi Children's Hospital, Milan, Italy; C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, Milan, Italy. Electronic address:

Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by dominant variants in the Glial Fibrillary Acidic Protein gene. Three main classifications are currently used, the traditional one defined by the age of onset, and two more recent ones based on both clinical features at onset and brain MRI findings. In this study, we retrospectively included patients with genetically confirmed pediatric-onset AxD. Twenty-one Italian patients were enrolled, and we revised all their clinical and radiological data. Participants were divided according to the current classification systems. We qualitatively analyzed data on neurodevelopment and neurologic decline in order to identify the possible trajectories of the evolution of the disease over time. One patient suffered from a Neonatal presentation and showed a rapidly evolving course which led to death within the second year of life (Type Ia). 16 patients suffered from the Infantile presentation: 5 of them (here defined Type Ib) presented developmental delay and began to deteriorate by the age of 5. A second group (Type Ic) included patients who presented a delay in neuromotor development and started deteriorating after 6 years of age. A third group (Type Id) included patients who presented developmental delay and remained clinically stable beyond adolescence. In 4 patients, the age at last evaluation made it not possible to ascertain whether they belonged to Type Ic or Id, as they were too young to evaluate their neurologic decline. 4 patients suffered from the Juvenile presentation: they had normal neuromotor development with no or only mild cognitive impairment; the subsequent clinical evolution was similar to Type Ic AxD in 2 patients, to Id group in the other 2. In conclusion, our results confirm previously described findings about clinical features at onset; based on follow-up data we might classify patients with Type I AxD into four subgroups (Ia, Ib, Ic, Id). Further studies will be needed to confirm our results and to better highlight the existence of clinical and neuroradiological prognostic factors able to predict disease progression.
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http://dx.doi.org/10.1016/j.ymgme.2021.11.009DOI Listing
November 2021

Tailored therapies for primary immunodeficiencies.

Acta Biomed 2021 Nov 29;92(S7):e2021520. Epub 2021 Nov 29.

Department of Pediatrics, Giovanni XXIII Pediatric Hospital, University of Bari, Bari, Italy.

Primary immunodeficiency disorders (PIDs) are rare inherited monogenic disorders of the immune system, characterized by an increased risk of infection, immune dysregulation and malignancies. To date, more than 420 PIDs have been identified. The recent introduction of high throughput sequencing technologies has led to identifying the molecular basis of the underlying aberrant immune pathway, and candidate targets to develop precision treatment, aimed at modifying the clinical course of the disease. In PID, targeted therapies are especially effective to manage immune dysregulation and autoimmunity, also reducing the incidence of side effects compared to conventional treatments, sparing the use of steroids and immunosuppressive drugs. Moreover, in the last years, the approach of conventional treatments such as immunoglobulin replacement therapies has evolved and the indication has expanded to new diseases, leading to individualized strategies to both improve infection control and quality of life.  Similarly, the new advent of gene therapy in selected PIDs has introduced the benefit to correct the immunological defect, reducing at the same time the complications related to the hematopoietic stem cell transplantation. Here, we illustrate the most recent findings on tailored treatments for PIDs.
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http://dx.doi.org/10.23750/abm.v92iS7.12406DOI Listing
November 2021

Component resolved diagnosis and risk assessment in food allergy.

Acta Biomed 2021 Nov 29;92(S7):e2021528. Epub 2021 Nov 29.

Pediatric Clinic, Department of Medicine and Surgery, Unversity of Parma, Parma, Italy.

 Allergy testing should only be performed in the context of the clinical history as history provides the cornerstone of diagnosis. In food allergy, some allergy tests often give rise to false positive results and thus can lead to unnecessary avoidance or delay on foods introduction. The use of Component Resolved Diagnosis in combination with conventional sensitization testing improves analytical and diagnostic performance and can lead to the reduction of diagnostic oral food challenges. Component Resolved Diagnosis can be helpful in identifying some risks for the allergic child. Molecular diagnosis can help also in predicting the development of the allergy march, in severe reactions (lipid transfer protein, seed storage proteins, etc.) in food allergy and for potential clinical cross-reactivity.
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http://dx.doi.org/10.23750/abm.v92iS7.12421DOI Listing
November 2021

A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors.

Eur J Paediatr Neurol 2021 Nov 6;36:1-6. Epub 2021 Nov 6.

Pediatric Rheumatology, Pediatric University Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.

Objectives: Sydenham's Chorea (SC) is a neuropsychiatric disorder and a major manifestation of acute rheumatic fever. The erroneous assumption that SC is a benign and self-limiting disease, has led to a lack of high-quality scientific evidence of the therapeutical and prognostic features of SC.

Study Design: We retrospectively analyzed the medical records of patients <18-years old with SC in 17 Italian pediatric centers. Recorded data included clinical, instrumental and laboratory parameters. Prognostic risk factors including treatment regimens were assessed with univariate and multivariate sub-analysis.

Results: We included 171 patients with SC. 66% had generalized chorea, and 34% hemichorea. 81% had carditis (subclinical in 65%). Additional neurological symptoms were reported in 60% of the patients, mainly dysarthria and dysgraphia. 51% had neuropsychiatric symptoms at onset, which persisted after 12 months in 10%. Among psychiatric manifestations, the most common was anxiety disorder/depression (77%). Neurological remission was reached by 93% of the patients at 6 months; 9% relapsed. Patients were treated as follows: 11% penicillin alone, 37% immunomodulatory therapy, 16% symptomatic drugs (i.e. anti-seizure medication, dopamine antagonists) and 37% both symptomatic and immunomodulatory treatment. Neurological outcome did not differ between groups. Patients receiving symptomatic drugs had a higher risk of relapse on multivariate analysis (p = 0.045).

Conclusions: Treatment of SC was largely heterogeneous. Based on our results, immunomodulatory therapy did not show higher efficacy at medium term, although it was associated to a slightly lower risk of relapse compared to symptomatic therapy. Longitudinal studies are needed to assess specific risk factors and best treatment options.
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http://dx.doi.org/10.1016/j.ejpn.2021.11.002DOI Listing
November 2021

Epilepsy in "Sunflower syndrome": electroclinical features, therapeutic response, and long-term follow-up.

Seizure 2021 Dec 2;93:8-12. Epub 2021 Oct 2.

Department of Pediatrics, University of Perugia, Italy.

Background: Sunflower syndrome (SFS) is a rare childhood-onset generalized epilepsy characterized by photosensitivity, heliotropism, and drug-resistant stereotyped seizures maybe self-induced by hand-waving maneuvers. Data on the long-term prognosis are scantly and evidence over best treatment strategies is lacking.

Methods: We retrospectively describe the electroclinical features, and therapeutic response in a group of 21 patients with SFS, without intellectual disability.

Results: 16 patients were female (67%), with a median age at onset of 7 years. In all patients, ictal episodes began with sun-staring, and hand-waving in front of the sunlight, accompanied by brief typical absence seizures. 17 patients (81%) showed interictal EEG abnormalities, mainly characterized by spike and polyspike-and-wave discharges. Ictal epileptiform activity occurred approximately less than one second after the start of hand-waving. At the last follow-up (median length 8.2 years), 12 patients (57%) were drug-resistant. Nine of them (75%) achieved seizure control with the use of tainted lenses, either alone or compared with anti-seizure medications (ASM). Disappearance of seizures was associated with EEG improvement/normalization when tinted glasses were used during EEG recordings.

Conclusion: While the clinical and EEG characteristics of SFS are well defined, the best therapeutic approaches are still under debate. Our data confirms a high rate of drug-resistance and frequent need of polytherapy. Of note, in drug-resistant patients, lenses (but not ASM) were able to suppress PPR in our patients while wearing lenses. Regarding the role of lenses, we do not only rely on the PPR reduction but also clinically by the reduction of seizures. Although additional data are needed, lenses seem to have a powerful potential role for the management of SFS.
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http://dx.doi.org/10.1016/j.seizure.2021.09.021DOI Listing
December 2021

Headache in progressive facial hemiatrophy (Parry-Romberg syndrome): A paradigmatic case and systematic review of the literature.

Cephalalgia 2021 Sep 26:3331024211043452. Epub 2021 Sep 26.

Pediatric Clinic, Maggiore Hospital, ASST Crema, Crema, Italy.

Background: Parry-Romberg syndrome is a neuro-cutaneous disease characterized by progressive hemifacial atrophy. Although common, headache in this population is scarcely reported in the literature.

Objective: To evaluate the clinical features of headache in pediatric and adult patients with Parry-Romberg syndrome, and to discuss diagnostic and treatment approaches of headache in Parry-Romberg syndrome.

Methods: We conducted a systematic review in accordance with PRISMA guidelines. We searched the MEDLINE database to identify eligible studies and identified patients with Parry-Romberg syndrome and headache. We further reported a paradigmatic case with a complex headache disorder and described its management and outcome.

Results: We identified 74 articles, 41 of which were included in the analysis. A total of 52 patients (55.8% female) were included for data analysis. The main age at onset of headache was 20 years (SD 15.2; range 3-56). A diagnosis of migraine was made in 53.9%. Abnormal brain imaging was found in 82.2% of patients.

Conclusion: Long-term follow-up of patients is required, because headache may develop (and evolve) at any time over the course of the disease. Primary and secondary headaches often co-occur in patients with Parry-Romberg syndrome. Further research into the underlying etiopathogenesis and therapeutic targets would be recommended.
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http://dx.doi.org/10.1177/03331024211043452DOI Listing
September 2021

The role of inflammatory mediators in epilepsy: Focus on developmental and epileptic encephalopathies and therapeutic implications.

Epilepsy Res 2021 05 18;172:106588. Epub 2021 Feb 18.

Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy.

In recent years, there has been an increasing interest in the potential involvement of neuroinflammation in the pathogenesis of epilepsy. Specifically, the role of innate immunity (that includes cytokines and chemokines) has been extensively investigated either in animal models of epilepsy and in clinical settings. Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of epileptic disorders, in which uncontrolled epileptic activity results in cognitive, motor and behavioral impairment. By definition, epilepsy in DEE is poorly controlled by common antiepileptic drugs but may respond to alternative treatments, including steroids and immunomodulatory drugs. In this review, we will focus on how cytokines and chemokines play a role in the pathogenesis of DEE and why expanding our knowledge about the role of neuroinflammation in DEE may be crucial to develop new and effective targeted therapeutic strategies to prevent seizure recurrence and developmental regression.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106588DOI Listing
May 2021

Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts.

Neurol Neuroimmunol Neuroinflamm 2021 03 12;8(2). Epub 2021 Jan 12.

From the Neuroncology Unit (G.B., E.V., E.M.), and Neuroradiology Unit (M.P., A.P.), IRCCS Mondino Foundation, Pavia; Molecular Virology Unit (G.C., F.B.), Microbiology and Virology Department, Diagnostic Radiology, Interventional Radiology and Neuroradiology Unit (A.M.S.), Bone Marrow Transplantation Unit (A.A.C., P.B., O.B.), Infectious and Tropical Diseases Unit (A.D.M.), Pediatric Clinic (V.R., T.F., S.S.), and Pediatric Hematology/Oncology (F.C., M.Z.), Fondazione IRCCS Policlinico San Matteo, Pavia; and Department of Brain and Behavioral Sciences (A.P.), Department of Molecular Medicine (P.B., O.B.), and Department of Clinical, Surgical, Diagnostic and Paediatric Sciences (F.B.), University of Pavia, Italy.

Objective: The aim of this study was to analyze the clinical, radiologic, and biological features associated with human herpesvirus 6 (HHV-6) encephalitis in immunocompetent and immunocompromised hosts to establish which clinical settings should prompt HHV-6 testing.

Methods: We performed a retrospective research in the virology database of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) for all patients who tested positive for HHV-6 DNA in the CSF and/or in blood from January 2008 to September 2018 and separately assessed the number of patients meeting the criteria for HHV-6 encephalitis in the group of immunocompetent and immunocompromised hosts.

Results: Of the 926 patients tested for HHV-6 during the period of interest, 45 met the study criteria. Among immunocompetent hosts (n = 17), HHV-6 encephalitis was diagnosed to 4 infants or children presenting with seizures or mild encephalopathy during primary HHV-6 infection (CSF/blood replication ratio <<1 in all cases). Among immunocompromised hosts (n = 28), HHV-6 encephalitis was diagnosed to 7 adolescents/adults with hematologic conditions presenting with altered mental status (7/7), seizures (3/7), vigilance impairment (3/7), behavioral changes (2/7), hyponatremia (2/7), and anterograde amnesia (1/7). Initial brain MRI was altered only in 2 patients, but 6 of the 7 had a CSF/blood replication ratio >1.

Conclusions: The detection of a CSF/blood replication ratio >1 represented a specific feature of immunocompromised patients with HHV-6 encephalitis and could be of special help to establish a diagnosis of HHV-6 encephalitis in hematopoietic stem cell transplant recipients lacking radiologic evidence of limbic involvement.
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http://dx.doi.org/10.1212/NXI.0000000000000942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963435PMC
March 2021

Abdominal pain as first manifestation of lyme neuroborreliosis in children, case report and review of literature.

Ital J Pediatr 2020 Nov 23;46(1):172. Epub 2020 Nov 23.

Department of Pediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Background: Lyme neuroborreliosis can cause a variety of neurological manifestations. European children usually present facial nerve palsy, other cranial nerve palsies and aseptic meningitis.

Case Presentation: We hereby report a case of Lyme neuroborreliosis in a 9-year-old boy with abdominal pain as first symptom and subsequent onset of attention deficit and ataxia. Diagnosis was made by detection of specific antibody in both serum and cerebrospinal fluid with neuro-radiological images suggestive for this infectious disease. A 12-months follow-up was performed during which no relevant neurological sequelae were revealed.

Conclusion: This case report shows that abdominal radiculitis, although extremely rare, could be the first manifestation of early Lyme neuroborreliosis in pediatric patients. Pediatricians must consider Lyme disease in the differential diagnosis of abdominal pain of unknown origin in children, especially in countries where the infection is endemic.
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http://dx.doi.org/10.1186/s13052-020-00936-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684897PMC
November 2020

Unilateral Lisch nodules in a pediatric patient: a sign for genetic mosaicism?

Minerva Pediatr 2020 Nov 17. Epub 2020 Nov 17.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, University of Genoa, Genoa, Italy.

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http://dx.doi.org/10.23736/S0026-4946.20.06134-4DOI Listing
November 2020

Posterior Reversible Encephalopathy Syndrome in infants and young children.

Eur J Paediatr Neurol 2021 Jan 28;30:128-133. Epub 2020 Oct 28.

Unit of Pediatric Oncology and Haematology "Lalla Seràgnoli", Department of Pediatrics, Sant'Orsola Hospital, University of Bologna, Bologna, Italy. Electronic address:

Aim: The aim of this study was to describe the characteristics of Posterior Reversible Encephalopathy Syndrome (PRES) in infants and young children (<6 years) and to compare them with the older pediatric population affected by PRES.

Methods: we retrospectively reviewed records of 111 children (0-17 years) diagnosed with PRES from 2000 to 2018 in 6 referral pediatric hospitals in Italy. The clinical, radiological and EEG features, as well as intensive care unit (ICU) admission rate and outcome of children aged <6 years were compared to those of older children (6-17 years). Factors associated with ICU admission in the whole pediatric cohort with PRES were also evaluated.

Results: Twenty-nine patients younger than 6 years (26%) were enrolled with a median age at onset of PRES of 4 years (range: 6 months-5 years). Epileptic seizures were the most frequent presentation at the disease onset (27/29 patients). Status epilepticus (SE) was observed in 21/29 patients: in detail, 11 developed convulsive SE and 10 presented nonconvulsive SE (NCSE). SE was more frequent in children <6 years compared with older children (72% vs 45%) as well as NCSE (35% vs 10%). Seventeen children aged <6 years required ICU admission. Prevalence of ICU admissions was higher within younger population compared to older (59% vs 37%). In the whole study population SE was significantly associated with ICU admission (p = 0.001).

Conclusions: PRES in children < 6 years differs from older children in clinical presentation suggesting a more severe presentation at younger age.
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http://dx.doi.org/10.1016/j.ejpn.2020.10.009DOI Listing
January 2021

SARS-CoV-2 infection in pediatric population.

Acta Biomed 2020 09 15;91(11-S):e2020003. Epub 2020 Sep 15.

Division of Paediatric Infectious Disease, Anna Meyer Children's University Hospital, Department of Health Sciences, University of Florence, Florence, Italy..

n December 2019, in Wuhan (Hubei, China), the first COVID-19 cases due to SARS-COV-2 had been reported. On July 1st 2020, more than 10.268.839 million people had developed the disease, with at least 506.064 deaths. At present, Italy is the third country considering the number of cases (n=240.760), after Spain, and the second for the cumulative number of deaths (n=249.271), after the United States. As regard pediatric COVID-19 cases, more than 4000 cases (have been reported; however, these figures are likely to be underestimated since they are influenced by the number of diagnostic tests carried out. Three pediatric deaths have been reported in Italy to date. We aimed to review the peculiar aspects of SARS-COV-2 infection in the pediatric population.
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http://dx.doi.org/10.23750/abm.v91i11-S.10298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023063PMC
September 2020

Cough Remedies for Children and Adolescents: Current and Future Perspectives.

Paediatr Drugs 2020 Dec;22(6):617-634

Pediatric Clinic, Pediatrics Department, Policlinico San Matteo, University of Pavia, Pavia, Italy.

Cough is a widespread symptom in children and adolescents. Despite advances in scientific knowledge about the neurophysiological mechanisms underlying the cough reflex, the best therapeutic approaches for children and adolescents who cough remain unclear, and many needs are still unmet. Many remedies for cough are self-prescribed, reflecting strong demand, but significant evidence of their efficacy and safety is missing in pediatric populations. Moreover, as most coughs are part of self-limited illnesses, treatment could be considered unnecessary in some patients. Drug therapy to relieve cough and other symptoms is an essential part of treating a child with cough. However, unfortunately, the number of studies in each category of cough medications is minimal, and dosing and treatment duration varies significantly among studies. Some treatments have been shown to be no more effective than placebo. Lack of clear indications for dosing and treatment duration, the number of available drugs, the numerous active ingredients in products, and multiple caregivers administering medication to children have been considered contributors to an increased risk of inappropriate prescribing, accidental overdosing, and adverse events. This review presents the most recent evidence on the safety and efficacy of available cough remedies, focusing on the pediatric age group, and includes H receptor antagonists, mucolytics and expectorants, drugs acting peripherally on the cough reflex, drugs acting centrally on the cough reflex, drugs acting both peripherally and centrally on the cough reflex, and other compounds, including menthol, glycerol, honey, and medical devices composed of complex natural substances. Future perspectives on new therapeutic targets are also discussed.
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http://dx.doi.org/10.1007/s40272-020-00420-4DOI Listing
December 2020

Challenges and management of neurological and psychiatric manifestations in SARS-CoV-2 (COVID-19) patients.

Neurol Sci 2020 Sep 6;41(9):2353-2366. Epub 2020 Aug 6.

Pediatric Neurology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

COVID-19 is a pandemic caused by human coronavirus (HCoV) SARS-CoV-2, which originated in Wuhan, China, at the end of 2019 and spread globally during 2020. Due to the difficulty of clinical decision-making during this period, our study group reviewed current literature focusing on the neurological and psychiatric aspects of COVID-19. Despite the knowledge on this newly discovered virus which is constantly evolving, different pieces of evidence reported an association between COVID-19 and neurological symptoms like headache, dizziness, taste and smell disorders and complications involving the nervous system eventually triggered by the pathologic processes elicited by SARS-CoV-2. It seems that younger patients are less prone to develop severe forms of COVID-19. However, neurological signs have been reported in paediatric patients as well, and in some cases, the infection presented neurological sequelae. Furthermore, children with particular neurological diseases or treated with specific drugs (e.g. immune-suppressant therapies) must be carefully monitored during this pandemic. Neurologists should be aware of the main drug-drug interactions and the neurological side effects of COVID-19 treatments. Notably, adverse mental health impact has been reported in patients with SARS-CoV-2, which could be related either to the social strain or to the eventual neurotropic effects of the virus, which in other infections have been proven to promote the onset of psychiatric symptoms. Further, psychiatric population may be more vulnerable to the infection and at higher risk for adverse outcomes.
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http://dx.doi.org/10.1007/s10072-020-04544-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410516PMC
September 2020

Pai syndrome: a review.

Childs Nerv Syst 2020 11 10;36(11):2635-2640. Epub 2020 Jul 10.

Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Background: Pai syndrome is a rare idiopathic developmental condition characterized by midline craniofacial abnormalities. It was originally described as the presence of a median cleft lip, cutaneous polyps of the nasal mucosa and face, and midline lipomas of the central nervous system, mostly at the corpus callosum. However, there is great phenotypical variability and these characteristics are rarely all present at once.

Objective: The aim of this review was to analyze the available evidence regarding Pai syndrome in order to better delineate this rare condition and its features.

Methods: We analyzed the PubMed database using the words "Pai syndrome", "frontonasal dysplasia", "cleft lip", "nasal polyp", "facial polyp", and "corpus callosum lipoma", including reviews, case reports and case series.

Conclusion: There is no consensus regarding the diagnostic criteria of Pai syndrome up to date. It is usually diagnosed at birth, and its incidence is often underestimated. At present, the etiology of Pai syndrome is unknown. Several hypotheses regarding its genetic background have been made; however, there are not enough data yet to elucidate this point. An improved awareness could help in diagnosing the condition and performing the necessary investigations. These patients should have a multidisciplinary follow-up.
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http://dx.doi.org/10.1007/s00381-020-04788-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575485PMC
November 2020

Cell-based assays for the detection of MOG antibodies: a comparative study.

J Neurol 2020 Dec 4;267(12):3555-3564. Epub 2020 Jul 4.

Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy.

Background: The detection of antibodies to myelin oligodendrocyte glycoprotein (MOG) is fundamental for the identification of MOG antibody-associated disorders (MOGAD), and the differential diagnosis of acquired demyelinating syndromes of the CNS, among which multiple sclerosis (MS). We compared the diagnostic performance of four cell-based assays (CBAs) for their detection.

Methods: Consecutive sera from 204 patients with 'possible MOGAD' (55), MS (112), and other neurological disorders (OND, 37) were tested for MOG-IgG with a live-CBA with anti-heavy-and-light chain secondary-antibody (LCBA-IgG), and a live-CBA for IgG (LCBA-IgG). A subgroup of 71 patients was additionally tested with a live-CBA with anti-Fcγ secondary-antibody (LCBA-IgG), and a commercial fixed-CBA with anti-Fcγ secondary-antibody (FCBA-IgG) RESULTS: Fifty-seven/204 patients (27.9%) were MOG-IgG-positive. Sensitivity was 89.1% (CI:77.8-95.9) and specificity 93.3% (CI:88.0-96.7) for LCBA-IgG, and 74.6% (CI:61.0-85.3) and 100% (CI:97.6-100) for LCBA-IgG. Eighteen of 57 (31%) samples showed discrepant results (all negative on LCBA-IgG); of these, three with 'possible MOGAD' showed high-titer MOG-IgG (≥ 1:640), and positivity for MOG-IgG, whereas 15/18 had low-titer MOG-IgG (1:160/1:320) and mixed diagnoses (5 'possible MOGAD', 6 MS, 4 OND). In the subgroup analysis, sensitivity was 92.3% (CI:79.1-98.4) and specificity 97.0% (CI:83.8-99.9) for LCBA-IgG, and 87.2% (CI:72.6-95.7) and 97.0% (CI:83.8-99.9) for FCBA-IgG.

Conclusions: LCBA-IgG showed the highest specificity but can miss MOG-IgG reactivities, whose meaning warrants further investigations. Titration of samples tested with LCBA-IgG/ IgG is important for meaningful interpretation of the results. In the subgroup analysis, LCBA-IgG yielded the highest accuracy, and FCBA-IgG good specificity, but it was at risk of false-negative results.
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http://dx.doi.org/10.1007/s00415-020-10024-0DOI Listing
December 2020

Advanced pharmacological therapies for neurofibromatosis type 1-related tumors.

Acta Biomed 2020 06 30;91(7-S):101-114. Epub 2020 Jun 30.

Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the NF1 gene, which encodes a protein called neurofibromin. The absence of neurofibromin causes increased activity in the Rat sarcoma protein (RAS) signalling pathway, which results in an increased growth and cell proliferation. As a result, both oncological and non-oncological comorbidities contribute to a high morbidity and mortality in these patients. Optic pathways gliomas, plexiform neurofibromas and malignant peripheral nerve sheath tumor (MPNST) are the most frequent NF1-associated tumors. The treatment of these complications is often challenging, since surgery may not be feasible due to the location, size, and infiltrative nature of these tumors, and standard chemotherapy or radiotherapy are burdened by significant toxicity and risk for secondary malignancies. For these reasons, following the novel discoveries of the pathophysiological mechanisms that lead to cell proliferation and tumorigenesis in NF1 patients, emerging drugs targeting specific signalling pathways (i.e. the MEK/ERK cascade), have been developed with promising results.
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http://dx.doi.org/10.23750/abm.v91i7-S.9961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975824PMC
June 2020

Targeting the medulloblastoma: a molecular-based approach.

Acta Biomed 2020 06 30;91(7-S):79-100. Epub 2020 Jun 30.

Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.

Background: The lack of success of standard therapies for medulloblastoma has highlighted the need to plan a new therapeutic approach. The purpose of this article is to provide an overview of the novel treatment strategies based on the molecular characterization and risk categories of the medulloblastoma, also focusing on up-to-date relevant clinical trials and the challenges in translating tailored approaches into clinical practice.

Methods: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites about molecular classification of medulloblastomas, ongoing clinical trials and new treatment strategies. Only articles in the English language and published in the last five years were selected. The research was refined based on the best match and relevance.

Results: A total 58 articles and 51 clinical trials were analyzed. Trials were of phase I, II, and I/II in 55%, 33% and 12% of the cases, respectively. Target and adoptive immunotherapies were the treatment strategies for newly diagnosed and recurrent medulloblastoma in 71% and 29% of the cases, respectively.

Conclusion: Efforts are focused on the fine-tuning of target therapies and immunotherapies, including agents directed to specific pathways, engineered T-cells and oncoviruses. The blood-brain barrier, chemoresistance, the tumor microenvironment and cancer stem cells are the main translational challenges to be overcome in order to optimize medulloblastoma treatment, reduce the long-term morbidity and increase the overall survival.
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http://dx.doi.org/10.23750/abm.v91i7-S.9958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975825PMC
June 2020

Potential roads for reaching the summit: an overview on target therapies for high-grade gliomas.

Acta Biomed 2020 06 30;91(7-S):61-78. Epub 2020 Jun 30.

Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.

The tailored targeting of specific oncogenes represents a new frontier in the treatment of high-grade glioma in the pursuit of innovative and personalized approaches. The present study consists in a wide-ranging overview of the target therapies and related translational challenges in neuro-oncology.

Methods: A review of the literature on PubMed/MEDLINE on recent advances concerning the target therapies for treatment of central nervous system malignancies was carried out. In the Medical Subject Headings, the terms "Target Therapy", "Target drug" and "Tailored Therapy" were combined with the terms "High-grade gliomas", "Malignant brain tumor" and "Glioblastoma". Articles published in the last five years were further sorted, based on the best match and relevance. The ClinicalTrials.gov website was used as a source of the main trials, where the search terms were "Central Nervous System Tumor", "Malignant Brain Tumor", "Brain Cancer", "Brain Neoplasms" and "High-grade gliomas".

Results: A total of 137 relevant articles and 79 trials were selected. Target therapies entailed inhibitors of tyrosine kinases, PI3K/AKT/mTOR pathway, farnesyl transferase enzymes, p53 and pRB proteins, isocitrate dehydrogenases, histone deacetylases, integrins and proteasome complexes. The clinical trials mostly involved combined approaches. They were phase I, II, I/II and III in 33%, 42%, 16%, and 9% of the cases, respectively.

Conclusion: Tyrosine kinase and angiogenesis inhibitors, in combination with standard of care, have shown most evidence of the effectiveness in glioblastoma. Resistance remains an issue. A deeper understanding of the molecular pathways involved in gliomagenesis is the key aspect on which the translational research is focusing, in order to optimize the target therapies of newly diagnosed and recurrent brain gliomas.
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http://dx.doi.org/10.23750/abm.v91i7-S.9956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975828PMC
June 2020

The impact of stem cells in neuro-oncology: applications, evidence, limitations and challenges.

Acta Biomed 2020 06 30;91(7-S):51-60. Epub 2020 Jun 30.

Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.

Background: Stem cells (SCs) represent a recent and attractive therapeutic option for neuro-oncology, as well as for treating degenerative, ischemic and traumatic pathologies of the central nervous system. This is mainly because of their homing capacity, which makes them capable of reaching the inaccessible SC niches of the tumor, therefore, acting as living drugs. The target of the study is a comprehensive overview of the SC-based therapies in neuro-oncology, also highlighting the current translational challenges of this type of approach.

Methods: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites, restricting it to the most pertinent keywords regarding the systematization of the SCs and their therapeutic use for malignant brain tumors. A large part of the search was dedicated to clinical trials. Only preclinical and clinical data belonging to the last 5 years were shortlisted. A further sorting was implemented based on the best match and relevance.

Results: The results consisted in 96 relevant articles and 31 trials. Systematization involves a distinction between human embryonic, fetal and adult, but also totipotent, pluripotent or multipotent SCs. Mesenchymal and neuronal SCs were the most studied for neuro-oncological illnesses. 30% and 50% of the trials were phase I and II, respectively.

Conclusion: Mesenchymal and neuronal SCs are ideal candidates for SCs-based therapy of malignant brain tumors. The spectrum of their possible applications is vast and is mainly based on the homing capacity toward the tumor microenvironment. Availability, delivery route, oncogenicity and ethical issues are the main translational challenges concerning the use of SCs in neuro-oncology.
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http://dx.doi.org/10.23750/abm.v91i7-S.9955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975826PMC
June 2020

Gene therapies for high-grade gliomas: from the bench to the bedside.

Acta Biomed 2020 06 30;91(7-S):32-50. Epub 2020 Jun 30.

Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.

Background: Gene therapy is the most attractive therapeutic approach against high-grade gliomas (HGGs). This is because of its theoretical capability to rework gene makeup in order to yield oncolytic effects. However, some factors still limit the upgrade of these therapies at a clinical level of evidence. We report an overview of glioblastoma gene therapies, mainly focused on the rationale, classification, advances and translational challenges.

Methods: An extensive review of the online literature on gene therapy for HGGs was carried out. The PubMed/MEDLINE and ClinicalTrials.gov websites were the main sources. Articles in English published in the last five years were sorted according to the best match with the multiple relevant keywords chosen. A descriptive analysis of the clinical trials was also reported.

Results: A total of 85 articles and 45 clinical trials were selected. The main types of gene therapies are the suicide gene, tumor suppressor gene, immunomodulatory gene and oncolytic therapies (virotherapies). The transfer of genetic material entails replication-deficient and replication-competent oncolytic viruses and nanoparticles, such as liposomes and cationic polymers, each of them having advantages and drawbacks. Forty-eight clinical trials were collected, mostly phase I/II.

Conclusion: Gene therapies constitute a promising approach against HGGs. The selection of new and more effective target genes, the implementation of gene-delivery vectors capable of greater and safer spreading capacity, and the optimization of the administration routes constitute the main translational challenges of this approach.
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http://dx.doi.org/10.23750/abm.v91i7-S.9953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975827PMC
June 2020

Adoptive immunotherapies in neuro-oncology: classification, recent advances, and translational challenges.

Acta Biomed 2020 06 30;91(7-S):18-31. Epub 2020 Jun 30.

Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.

Background: Adoptive immunotherapies are among the pillars of ongoing biological breakthroughs in neuro-oncology, as their potential applications are tremendously wide. The present literature review comprehensively classified adoptive immunotherapies in neuro-oncology, provides an update, and overviews the main translational challenges of this approach.

Methods: The PubMed/MEDLINE platform, Medical Subject Heading (MeSH) database, and ClinicalTrials.gov website were the sources. The MeSH terms "Immunotherapy, Adoptive," "Cell- and Tissue-Based Therapy," "Tissue Engineering," and "Cell Engineering" were combined with "Central Nervous System," and "Brain." "Brain tumors" and "adoptive immunotherapy" were used for a further unrestricted search. Only articles published in the last 5 years were selected and further sorted based on the best match and relevance. The search terms "Central Nervous System Tumor," "Malignant Brain Tumor," "Brain Cancer," "Brain Neoplasms," and "Brain Tumor" were used on the ClinicalTrials.gov website.

Results: A total of 79 relevant articles and 16 trials were selected. T therapies include chimeric antigen receptor T (CAR T) cell therapy and T cell receptor (TCR) transgenic therapy. Natural killer (NK) cell-based therapies are another approach; combinations are also possible. Trials in phase 1 and 2 comprised 69% and 31% of the studies, respectively, 8 of which were concluded. CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) was demonstrated to reduce the recurrence rate of glioblastoma after standard-of-care treatment.

Conclusion: Adoptive immunotherapies can be classified as T, NK, and NKT cell-based. CAR T cell therapy redirected against EGFRvIII has been shown to be the most promising treatment for glioblastoma. Overcoming immune tolerance and immune escape are the main translational challenges in the near future of neuro-oncology.
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http://dx.doi.org/10.23750/abm.v91i7-S.9952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975830PMC
June 2020

Innovative therapies for malignant brain tumors: the road to a tailored cure.

Acta Biomed 2020 06 30;91(7-S):5-17. Epub 2020 Jun 30.

Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Uni-versity of Pavia, Pavia, Italy.

Background: Immune tolerance, immune escape, neoangiogenesis, phenotypic changes, and glioma stem cells are all responsible for the resistance of malignant brain tumors to current therapies and persistent recurrence. The present study provides a panoramic view of innovative therapies for malignant brain tumors, especially glioblastoma, aimed at achieving a tailored approach.

Methods: PubMed/Medline and ClinicalTrials.gov were the main sources of an extensive literature review in which "Regenerative Medicine," "Cell-Based Therapy," "Chemotherapy," "Vaccine," "Cell Engineering," "Immunotherapy, Active," "Immunotherapy, Adoptive," "Stem Cells," "Gene Therapy," "Target Therapy," "Brain Cancer," "Glioblastoma," and "Malignant Brain Tumor" were the search terms. Only articles in English published in the last 5 years were included. A further selection was made according to the quality of the studies and level of evidence.

Results: Cell-based and targeted therapies represent the newest frontiers of brain cancer treatment. Active and adoptive immunotherapies, stem cell therapies, and gene therapies represent a tremendous evolution in recent years due to many preclinical and clinical studies. Clinical trials have validated the effectiveness of antibody-based immunotherapies, including an in-depth study of bevacizumab, in combination with standard of care. Preclinical data highlights the role of vaccines, stem cells, and gene therapies to prevent recurrence.

Conclusion: Monoclonal antibodies strengthen the first-line therapy for high grade gliomas. Vaccines, engineered cells, stem cells, and gene and targeted therapies are good candidates for second-line treatment of both newly diagnosed and recurrent gliomas. Further data are necessary to validate this tailored approach at the bedside.
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http://dx.doi.org/10.23750/abm.v91i7-S.9951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975829PMC
June 2020

Seizures and myelin oligodendrocyte glycoprotein (MOG) antibodies: Two paradigmatic cases and a review of the literature.

Mult Scler Relat Disord 2020 Jun 22;41:102011. Epub 2020 Feb 22.

Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, University of Pavia,V.le C. Golgi, 19 - 27100 Pavia, Pavia, Italy.

Background: Myelin oligodendrocyte glycoprotein (MOG) antibodies (Abs) have been associated with a heterogeneous range of acquired CNS demyelinating disorders. More recently, increasing evidence correlates the presence of such Abs with seizures, occurring in concomitance with CNS demyelinating events, or even as isolated phenomena. In this scenario, the full clinical spectrum of MOG Ab-associated seizures and the contribution of such Abs to epileptogenesis are unclear.

Methods: We report on two paradigmatic cases of MOG Ab-associated seizures, one showing isolated seizures, without evidence of encephalopathy or MRI changes, followed by a demyelinating event one month later, and the other presenting with seizures as the main manifestation of an acute disseminated encephalomyelitis (ADEM) event. To better frame this topic, we performed a literature review, identifying 49 patients with MOG Ab-associated disorders presenting seizures at any stage of their disease, and analysed the clinico-therapeutic, brain MRI, cerebrospinal fluid, and EEG features.

Results: MOG Ab-associated seizures occurred mostly during encephalitis, including: a) "cortical encephalitis", a clinically poorly defined syndrome characterised by gray matter lesions on brain MRI, with or without subcortical white matter involvement; b) ADEM; c) NMDAR encephalitis with demyelinating features. Seizures can also occur in isolation, often in clusters of focal motor seizures, in patients with normal brain MRI, heralding the more typical MOG Ab-associated demyelinating syndrome by days to months.

Conclusion: Testing for MOG Abs should be considered in children with isolated and unexplained seizures, and in adults with suspected encephalitis and/or seizures. In these cases, MOG Abs detection is highly relevant for patients' clinical management.
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http://dx.doi.org/10.1016/j.msard.2020.102011DOI Listing
June 2020

Subtraction Ictal SPECT coregistered to MRI (SISCOM) as a guide in localizing childhood epilepsy.

Epilepsia Open 2020 Mar 26;5(1):61-72. Epub 2019 Dec 26.

Department of Development and Regeneration University Hospitals Leuven Leuven Belgium.

Objective: To assess feasibility and efficacy of subtraction ictal SPECT coregistered to MRI (SISCOM) for epilepsy localization in children who are candidates for resective surgery.

Methods: We retrospectively reviewed all patients ≤16 years with drug-resistant epilepsy screened for epilepsy surgery in the University Hospital of Leuven from January 2009 to January 2018. Fifty-eight hospitalizations for ictal SPECT and 51 SISCOM analyses in 44 patients were included. Mean age was 9.1 years. Hospitalizations for SISCOM were analyzed in terms of multiple variables affecting feasibility and efficacy. The localization of SISCOM was compared with the localization of the presumed epileptogenic zone (PEZ) as determined by video-EEG.

Results: SISCOM was feasible in terms of chronic medication management, rescue antiepileptic therapy during hospitalization, and operative timings. Radiotracer injection occurred within 30 seconds from seizure onset in 91.4% of the patients. ictal SPECT imaging was performed within two hours from injection in 100% of the patients (mean: 40 minutes). SISCOM was able to localize the PEZ in 51.0% (26/51) and to additionally lateralize the PEZ in 17.6% (9/51), achieving better localizations than ictal SPECT, FDG-PET, and MRI ( < .01). SISCOM was useful to localize the PEZ in 25% of patients with poorly localizing video-EEG and in 27.8% of MRI-negative cases. The occurrence of habitual seizures during injection for ictal SPECT and the temporal localization of the PEZ both correlated with a better SISCOM localization ( < .05). 36.4% (16/44) patients were finally selected for resective surgery, with a 87.5% seizure-free rate at 12 months. A localizing SISCOM was associated with seizure freedom in 66.7% and with a Engel I-II in 75.0% of our patients.

Significance: SISCOM is a reliable tool to localize the epileptogenic zone in clinical practice and is both feasible and useful in children, adding precious presurgical information especially in patients with noninformative MRI or a poorly localizing video-EEG.
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http://dx.doi.org/10.1002/epi4.12373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049808PMC
March 2020

Current and emerging biologic therapies for allergic rhinitis and chronic rhinosinusitis.

Expert Opin Biol Ther 2020 06 19;20(6):609-619. Epub 2020 Feb 19.

Allergy Clinic, Casa di Cura Villa Montallegro, Genoa, Italy.

: Allergic rhinitis and chronic rhinosinusitis, with and without nasal polyps, are the most common chronic inflammatory diseases of the upper airways. They both cause relevant respiratory symptoms and a substantial detriment to patients' quality of life, mainly in uncontrolled and severe patients.: This review aims to present the most recent evidence on current and emerging biologic therapies for allergic rhinitis and chronic rhinosinusitis and discuss their potential implementation in clinical practice. To select relevant literature for inclusion in this review, we conducted a literature search using the PubMed database, using terms 'biologics OR biological agents', 'allergic rhinitis' and 'chronic rhinosinusitis'. The literature review was performed for publication years 2009-2019, restricting the articles to humans and English language publications.: Biological therapies represent a potential step forward in providing individualized care for all patients with uncontrolled severe upper airway diseases. Biologics recently showed promising results for the treatment of severe uncontrolled allergic rhinitis and chronic rhinosinusitis with nasal polyps with or without associated asthma. Endotyping inflammatory pathways and identifying related biomarkers remain the major challenge for positioning biologics in the care pathway of chronic respiratory diseases.
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http://dx.doi.org/10.1080/14712598.2020.1729350DOI Listing
June 2020

Pediatric optic neuritis and anti MOG antibodies: a cohort of Italian patients.

Mult Scler Relat Disord 2019 Dec 24;39:101917. Epub 2019 Dec 24.

Unit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department, IRCCS Istituto Giannina Gaslini, Genova, Italy. Electronic address:

Background: recent studies reported that anti myelin oligodendrocyte glycoprotein (MOG) antibody (ab) related optic neuritis (ON) tend to have characteristics that differ from seronegative ones. The aim of our study was to investigate the clinical characteristics of pediatric anti-MOG ON by comparing anti MOG-ab-seropositive and seronegative patients with ON.

Methods: in this retrospective Italian multicentre study, participants were identified by chart review of patients evaluated for acquired demyelinating syndromes of the central nervous system (over the period 2009-2019). We selected patients presenting with ON as their first demyelinating event. Inclusion criteria were age < 18 years at symptoms onset; presentation consistent with ON; negativity of anti-aquaporin 4 antibodies (AQP4). Only patients who were tested for MOG-IgG1-ab with a live cell-based assay were included.

Results: 22 patients (10 MOG-ab-positive and 12 MOG-ab-negative) were included. Fundus oculi examination at onset showed disc swelling in 9/10 in the MOG-ab-positive cohort and 2/10 in the seronegative group (P = 0.002). Retinal Fiber Nerve Layer (RFNL) thickness measured by Spectral Domain Optical Coherence Tomography (S-OCT) was increased in the 5/5 MOG-ab-positive patients tested and was normal or reduced in the seronegative patients tested (4/4 patients) (P = 0.024). Visual acuity impairment at onset did not differ significantly between the two groups, but the MOG-ab-positive cohort showed better recovery at follow-up both regarding visual acuity (P = 0.025) and expanded disability status scale (EDSS) (P = 0.013). A final diagnosis of MS was frequent among seronegative patients (6/12, 50%), whereas none of the MOG-ab-positive group received a diagnosis of MS (P = 0.015). Clinical relapse frequency was low in both groups: 2/10 MOG-ab-positive and 2/12 seronegative cases relapsed, with a median follow up of 25 months.

Conclusion: optic disc swelling and increased RFNL at baseline are strongly associated with MOG-ab positivity. MOG-ab-positive patients with ON showed better recovery compared to the seronegative ones. The relapse rate was low and did not differ among the two groups.
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http://dx.doi.org/10.1016/j.msard.2019.101917DOI Listing
December 2019

Clinical variability in children with dolichoarteriopathies of the internal carotid artery.

Childs Nerv Syst 2020 03 7;36(3):621-628. Epub 2019 Nov 7.

Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Introduction: Dolichoarteriopathies of the internal carotid artery (DICA) are frequent non-atheromatous anatomical changes in the general population. The etiology of DICA is still controversial: several hypotheses have been suggested, including an anomaly of embryological development, or a degenerative loss of elasticity of the vessel wall. DICA have been related to a wide spectrum of clinical presentations in adults, varying from asymptomatic forms to acute cerebrovascular events. However, to date, only a few pediatric cases have been reported.

Methods And Results: We report seven patients with DICA, 6 males and 1 female, aged 3 to 13 years, presenting with variable clinical symptoms. Different imaging techniques, including color Doppler ultrasound and magnetic resonance angiography, were used to show loops and/or kinking of the ICA. Three of these patients received a diagnosis of Ehlers-Danlos syndrome (EDS).

Discussion: This study highlights the clinical variability in pediatric patients with DICA. We emphasize the need for close clinical management of pediatric DICA. Finally, considering the long-term prognostic implications of EDS, we recommend specific testing in children with DICA and suspicious clinical signs of this pathology.
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http://dx.doi.org/10.1007/s00381-019-04395-7DOI Listing
March 2020

Biologics in Children with Allergic Diseases.

Curr Pediatr Rev 2020 ;16(2):140-147

Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, University of Pavia, viale Golgi 19, 27100 Pavia, Italy.

The prevalence of allergic diseases has been remarkably increased in the last decades. The global health burden of these conditions is substantial, since patients may experience disability, anxiety and emotional distress, social restrictions, and reduced quality of life and productivity, in particular, in the most severe cases. Recent advances in understanding the pathophysiology of allergic disorders have allowed identifying novel therapeutic strategies for the treatment of severe and uncontrolled allergic diseases. Although most studies have been performed in allergic asthma, biological drugs targeting other allergic diseases such as chronic spontaneous urticaria, atopic dermatitis, and food allergy are showing promising results. In this review, the most recent evidence on biologic therapies for allergic diseases, focusing on the pediatric age has been presented.
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http://dx.doi.org/10.2174/1573396315666191029123822DOI Listing
March 2021
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