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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.We retrospectively analyzed the medical records of patients18-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.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).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.

Background and ObjectivesWe sought to identify early factors associated with relapse and outcome in paediatric-onset myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD).MethodsIn a multicenter retrospective cohort of pediatric MOGAD (≤18 years), onset features and treatment were compared in patients with monophasic vs relapsing disease (including cases with follow-up ≥12 months after onset or relapse at any time) and in patients with final Expanded Disability Status Scale (EDSS) 0 vs ≥1 at last follow-up (including cases with follow-up >3 months after last event or EDSS0 at any time). Multivariable logistic regression models were used to evaluate factors associated with relapsing disease course and EDSS ≥ 1 at final follow-up.ResultsSeventy-five children were included (median onset age 7 years; median 30 months of follow-up). Presentation with acute disseminated encephalomyelitis was more frequent in children aged 8 years or younger (66.7%, 28/42) than in older patients (30.3%, 10/33) (p= 0.002), whereas presentation with optic neuritis was more common in children older than 8 years (57.6%, 19/33) than in younger patients (21.4%, 9/42) (p= 0.001). 40.0% (26/65) of patients relapsed. Time to first relapse was longer in children aged 8 years or younger than in older patients (median 18 vs 4 months) (p= 0.013). Factors at first event independently associated with lower risk of relapsing disease course were immunotherapy p= 0.009), corticosteroid treatment for ≥5 weeks (6.7-fold reduced odds of relapse, OR 0.15, 95% CI 0.03–0.80,p= 0.026), and abnormal optic nerves on onset MRI (12.5-fold reduced odds of relapse, OR 0.08, 95% CI 0.01–0.50,p= 0.007). 21.1% (15/71) had EDSS ≥ 1 at final follow-up. Patients with a relapsing course had a higher proportion of final EDSS ≥ 1 (37.5%, 9/24) than children with monophasic disease (12.8%, 5/39) (p= 0.022, univariate analysis). Each 1-point increment in worst EDSS at onset was independently associated with 6.7-fold increased odds of final EDSS ≥ 1 (OR 6.65, 95% CI 1.33–33.26,p= 0.021).DiscussionAt first attack of pediatric MOGAD, early immunotherapy, longer duration of corticosteroid treatment, and abnormal optic nerves on MRI seem associated with lower risk of relapse, whereas higher disease severity is associated with greater risk of final disability (EDSS ≥ 1).

Sydenham’s chorea (SC) is a post-streptococcal autoimmune disorder of the central nervous system, and it is a major criterium for the diagnosis of acute rheumatic fever (ARF). SC typically improves in 12–15 weeks, but patients can be affected for years by persistence and recurrencies of both neurological and neuropsychiatric symptoms. We enrolled 48 patients with a previous diagnosis of ARF, with or without SC, in a national multicenter prospective study, to evaluate the presence of neuropsychiatric symptoms several years after SC’s onset. Our population was divided in a SC group (n = 21), consisting of patients who had SC, and a nSC group (n = 27), consisting of patients who had ARF without SC. Both groups were evaluated by the administration of 8 different neuropsychiatric tests. The Work and Social Adjustment Scale (WSAS) showed significantly (p = 0.021) higher alterations in the SC group than in the nSC group. Furthermore, 60.4% (n = 29) of the overall population experienced neuropsychiatric symptoms other than choreic movements at diagnosis and this finding was significantly more common (p = 0.00) in SC patients (95.2%) than in nSC patients (33.3%). The other neuropsychiatric tests also produced significant results, indicating that SC can exert a strong psychopathological impact on patients even years after its onset.

Background: Poirier–Bienvenu Neurodevelopmental Syndrome (POBINDS) is a rare disease linked to mutations of the CSNK2B gene, which encodes for a subunit of caseinkinase CK2 involved in neuronal growth and synaptic transmission. Its main features include early-onset epilepsy and intellectual disability. Despite the lack of cases described, it appears that POBINDS could manifest with a wide range of phenotypes, possibly related to the different mutations of CSNK2B. Methods: Our multicentric, retrospective study recruited nine patients with POBINDS, detected using next-generation sequencing panels and whole-exome sequencing. Clinical, laboratory, and neuroimaging data were reported for each patient in order to assess the severity of phenotype, and eventually, a correlation with the type of CSNK2B mutation. Results: We reported nine unrelated patients with heterozygous de novo mutations of the CSNK2B gene. All cases presented epilepsy, and eight patients were associated with a different degree of intellectual disability. Other features detected included endocrinological and vascular abnormalities and dysmorphisms. Genetic analysis revealed six new variants of CSNK2B that have not been reported previously. Conclusion: Although it was not possible to assess a genotype–phenotype correlation in our patients, our research further expands the phenotype spectrum of POBINDS patients, identifying new mutations occurring in the CSNK2B gene.

Background: Developmental delay and intellectual disability are two pivotal elements of the phenotype of Pallister–Killian Syndrome (PKS). Our study aims to define the cognitive, adaptive, behavioral, and sensory profile of these patients and to evaluate possible correlations between the different aspects investigated and with the main clinical and demographic variables. Methods: Individuals of any age with genetically confirmed PKS were recruited. Those ≤ 42 months were administered the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III), and those > 42 months the Vineland Adaptive Behavior Scales—Second Edition (Vineland-II). Stereotyped behaviors (Stereotypy Severity Scale, SSS) and aggressive behaviors (Behavior Problems Inventory—Short Version, BPIs) were assessed in all subjects > 1 year; sensory profile (Child Sensory Profile 2, C-SP2) in all aged 2–18 years. Results: Twenty-two subjects were enrolled (11 F/11 M; age 9 months to 28 years). All subjects ≤ 42 months had psychomotor developmental delay. Of the subjects > 42 months, 15 had low IQ deviation, and 1 in the normal range. Stereotypies were frequent (median SSS-total score 25/68). Lower Vineland-II values corresponded to greater intensity and frequency of stereotypies (p = 0.004 and p = 0.003), and self-injurious behaviors (p = 0.002 and p = 0.002). Patients with severe low vision had greater interference of stereotypies (p = 0.027), and frequency and severity of aggressive behaviors (p = 0.026; p = 0.032). The C-SP2, while not homogeneous across subjects, showed prevalence of low registration and sensory seeking profiles and hypersensitivity to tactile and auditory stimuli. Lower Vineland-II scores correlated with higher Registration scores (p = 0.041), while stereotypies were more frequent and severe in case of high auditory sensitivity (p = 0.019; p = 0.007). Finally, greater sleep impairment correlated with stereotypies and self-injurious behaviors, and lower Vineland-II scores. Conclusions: The present study provides a further step in the investigation of the etiopathogenesis of the syndrome. Furthermore, these aspects could guide rehabilitation therapy through the identification of targeted protocols.

Status Epilepticus (SE) is a neurological emergency resulting from the failure of mechanisms of seizure termination or from the initiation of mechanisms that lead to prolonged seizures. The International League Against Epilepsy (ILAE) identified 13 chromosomal disorders associated with epilepsy (CDAE); data regarding SE occurrence in these patients is lacking. A systematic scoping review was conducted to outline current literature evidence about clinical features, treatments, and outcomes of SE in pediatric and adult patients with CDAE. A total of 373 studies were identified with the initial search; 65 of these were selected and regarded as SE in Angelman Syndrome (AS, n = 20), Ring 20 Syndrome (R20, n = 24), and other syndromes (n = 21). Non-convulsive status epilepticus (NCSE) is frequently observed in AS and R20. No specific, targeted therapies for SE in CDAE are available to date; anecdotal reports about SE treatment are described in the text, as well as various brief- and long-term outcomes. Further evidence is needed to precisely portray the clinical features, treatment options, and outcomes of SE in these patients.

Background Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population. Methods Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0–4; t2 = 5–12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed. Results Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ± 2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ± 0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5–13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam. Conclusions Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy.

Mowat-Wilson Syndrome (MWS) (OMIM # 235730) is a rare disorder due to ZEB2 gene defects (heterozygous mutation or deletion). The ZEB2 gene is a widely expressed regulatory gene, extremely important for the proper prenatal development. MWS is characterized by a specific facial gestalt and multiple musculoskeletal, cardiac, gastrointestinal, and urogenital anomalies. The nervous system involvement is extensive and constitutes one of the main features in MWS, heavily affecting prognosis and life quality of affected individuals. This review aims to comprehensively organize and discuss the neurological and neurodevelopmental phenotype of MWS. First, we will describe the role of ZEB2 in the formation and development of the nervous system by reviewing the preclinical studies in this regard. ZEB2 regulates the neural crest cell differentiation and migration, as well as in the modulation of GABAergic transmission. This leads to different degrees of structural and functional impairment that have been explored and deepened by various authors over the years. Subsequently, the different neurological aspects of MWS (head and brain malformations, epilepsy, sleep disorders, and enteric and peripheral nervous system involvement, as well as developmental, cognitive, and behavioral features) will be faced one at a time and extensively examined from both a clinical and etiopathogenetic point of view, linking them to the ZEB2 related pathways.

Background Measures to contain the Covid-19 pandemic led to significant lifestyle changes for children and adolescents mainly related to the closure of schools and recreational activities, reduced social interaction, and increased family concerns. Methods A cross-sectional online survey of 78 questions investigating social determinants of health, mood changes, symptoms of anxiety, increase in sleep disorders and unusual repetitive movements was offered to parents living in Italy with children ≤18 years; including families of children with disabilities, autism spectrum disorders, chronic diseases, and specific learning disabilities. The survey was conducted on the Qualtrics platform 6 months after the beginning of the pandemic and distributed in hospitals and paediatricians’ waiting rooms as well as through social networks. The primary outcomes were the increase in sleep disorders among children and adolescents. Possible risk factors were investigated through multivariable regression. Results Six thousand two hundred ten volunteer parents responded to the questions concerning mood changes, sleep disorders and unusual repetitive movements, and were included in the present study. The majority were female (91.8%) and Italian (97.0%). 72.7% answered that their children had become more nervous, worried, or sad (80.2% in children with learning disabilities); 77.6% reported feelings of loneliness and 69.3% more difficulties in children falling asleep, 30.2% in staying asleep, and 18.7% an increase in nightmares and/or sleep terrors. Statistical analysis identified socioeconomic status, parent’s job loss, food insecurity, family attitude toward the pandemic, and children’s mood swing, feelings of loneliness, or missing outdoor activities, as major risk factors for sleep disorders. Conclusion The first Covid-19 lockdown impacted children’s and adolescents’ health through an increase in sleep disorders. In the following phases of the pandemic, this evidence may be useful to investigate and treat these disorders as well as make decisions about containment health policies concerning this age group.

Background: Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a low-grade tumor characterized by diffuse leptomeningeal infiltrates. Symptoms are usually secondary to hydrocephalus. Hemiplegic migraine (HM)-like episodes have never been associated with DLGNT, but they have been reported with different inflammatory and tumoral entities involving leptomeninges. Observations: We report the case of a 10-year-old boy with recurrent episodes of right hyposthenia, aphasia, and headache lasting hours to days with complete remission. The electroencephalogram during the attack showed diffuse slower activity on the left hemisphere, which improved together with the symptoms. DLGNT was discovered during a follow-up magnetic resonance imaging and confirmed by biopsy. Conclusions: This is the first report of HM-like attacks in DLGNT. We discuss the pathogenetic hypotheses of our case and previously reported cases of “symptomatic” HM with leptomeningeal involvement.

The relationship between sensory profile and repetitive behaviours in autism spectrum disorder (ASD) has long been known. However, there is no consensus on the type of relationship that exists between them. This monocentric retrospective–prospective observational study aimed (a) to detect a clinical correlation between the severity of repetitive behaviours and the alterations of sensory profile in a sample of 50 children diagnosed with ASD; (b) to evaluate how different patterns of stereotypies and sensory alterations correlate with each other and with the main clinical–instrumental variables in the same sample. We enrolled 29 children in the retrospective phase of the study and 21 in the prospective phase. The Repetitive Behaviour Scale-Revised (RBS-R) and the Short Sensory Profile (SSP) were administered to the caregivers, and clinical–instrumental data were collected. SSP and RBS-R total scores directly correlated with a high significance rate. Among the subscales, the strongest correlations involved “Visual/Auditory Sensitivity”, related to “Stereotyped Behaviour” and “Sameness Behaviour”. “Under-Responsive/Seeks Sensation” related to “Stereotyped Behaviour”. Sex and intellectual disability significantly influenced both the stereotypies and the sensory alterations of the examined population. In conclusion, this study provides new insights into the relationship between sensory alterations and repetitive behaviours in ASD children by using direct medical observation and parent observation.

Background: To evaluate efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis, particularly in patients previously exposed to natalizumab. Method: Prospective observational single-centre second-line cohort study. Results: Among 71 patients treated with fingolimod 0.5 mg/day for a mean duration of 21.75 w 12.60 months, the annualized relapse rate was 0.66 (C.I. 95% 0.27-1.05) with a significant difference between 26 patients with prior natalizumab exposure (1.15; C.I. 95% 0.12-2.17) and 45 not exposed (0.38; C.I. 95% 0.18-0.57; p = 0.002). In a multivariate negative regression model, only previous exposure to natalizumab (p = 0.049) and duration of fingolimod treatment (p < 0.001) significantly correlated with the annualized relapse rate. Previous exposure to natalizumab (p = 0.028) and duration of treatment with fingolimod (p < 0.001) were confirmed by restricting the analysis to the first 12 months of treatment with fingolimod, but were no longer statistically significant by analysing only patients (n = 51) with at least 12 months of treatment with fingolimod (0.32; C.I. 95% 0.08-0.55 vs. 0.22; C.I. 95% 0.11-0.32; p = NS). No differences were observed in neuroradiological outcomes and disability progression in patients exposed to natalizumab and not exposed. The rate of discontinuation due to adverse events was 11.3%, with no differences between the two groups. Conclusions: Our study confirms efficacy and side effects of fingolimod in a second-line clinical practice cohort. Prior natalizumab exposure and duration of treatment with fingolimod are independent predictors of annualized relapse rate during the first 12 months of treatment with fingolimod, but not in the long-term, and may be influenced by the 3 months washout period between the two drugs. i 2014 S. Karger AG, Basel