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Background and ObjectivesClinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy.MethodsRetrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE.ResultsForty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course.DiscussionThe disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

The 4q deletion syndrome defines a disorder, which may involve patients affected by either the deletion of the interstitial region from the centromere to 4q31 or by the deletion of the terminal region from 4q31 to 4qter. Here, we describe clinical phenotypes of two unrelated children of the same age followed at the same time, with case 1 presenting with 4q interstitial and case 2 with terminal 4q deletion, and compare them each other and with those reported in the literature. Both children showed complex, heterogeneous clinical manifestations, including craniofacial features, pre-postnatal growth failure, speech and developmental delay. In case 2, thyroid and cholesterol dysfunction were also found. Analyzing these data, clinical differences between interstitial and terminal 4q deletions are scanty and no significant phenotype differences were found between the 4q regions deleted as observed in the comparison of the two children and the related cases of the literature. The term 4q deletion syndrome - inclusive for both the interstitial and terminal 4q regions deleted - seems to be appropriate. To note, the dysfunction of cholesterol metabolism and thyroid presented by case 2 may be clinically worthwhile, whether confirmed by other observations.

Pure dephasing originates from the non-dissipative information exchange between quantum systems and environments, and plays a key-role in both spectroscopy and quantum information technology. Often pure dephasing constitutes the main mechanism of decay of quantum correlations. Here we investigate how pure dephasing of one of the components of a hybrid quantum system affects the dephasing rate of the system transitions. We find that, in turn, the interaction, in the case of a light-matter system, can significantly affect the form of the stochastic perturbation describing the dephasing of a subsystem, depending on the adopted gauge. Neglecting this issue can lead to wrong and unphysical results when the interaction becomes comparable to the bare resonance frequencies of subsystems, which correspond to the ultrastrong and deep-strong coupling regimes. We present results for two prototypical models of cavity quantun electrodynamics: the quantum Rabi and the Hopfield model.

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.

Introduction: Novel targeted and tailored therapies can substantially improve the prognosis for optic pathway glioma (OPG), especially when implemented in a timely manner. However, their tremendous potential remains underestimated. Therefore, in this study, we provide an updated overview of the clinical trials, current trends, and future perspectives for OPG’s novel therapeutic strategies. Methods: We completed an extensive literature review using the PubMed, MEDLINE, and ClinicalTrials.gov databases. We analyzed and reported the data following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Thioguanine, procarbazine, lomustine, and vincristine/vinblastine, as well as cisplatin-etoposide, provided excellent results in advanced-phase trials. Selumetinib and trametinib, two oral MEK inhibitors, have been approved for recurrent or refractory OPGs in association with the angiogenetic inhibitor bevacizumab. Among the mTOR inhibitors, everolimus and sirolimus showed the best results. Stereotactic radiosurgery and proton beam radiation therapy have advantages over conventional radiotherapy regimens. Timely treatment is imperative for acute visual symptoms with evidence of tumor progression. This latest evidence can help define a novel “T-Dimension” for pediatric OPG therapies. Conclusion: The novel “T-Dimension” for pediatric OPGs is based on recent evidence-based treatments, including combination chemotherapy regimens, molecular targeted therapies, stereotactic radiosurgery, and proton beam radiation therapy. Additional clinical trials are essential for validating each of these new therapies.

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).

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.

BackgroundIgG antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) define a subset of associated disorders (myelin oligodendrocyte glycoprotein associated disorders (MOGAD)) that can have a relapsing course. However, information on relapse predictors is scarce. The utility of retesting MOG-IgG over time and measuring their titres is uncertain. We aimed to evaluate the clinical relevance of longitudinal MOG-IgG titre measurement to predict relapses in patients with MOGAD.MethodsIn this retrospective multicentre Italian cohort study, we recruited patients with MOGAD and available longitudinal samples (at least one >3 months after disease onset) and tested them with a live cell-based assay with endpoint titration (1:160 cut-off). Samples were classified as ‘attack’ (within 30 days since a disease attack (n=59, 17%)) and ‘remission’ (≥31 days after attack (n=295, 83%)).ResultsWe included 102 patients with MOGAD (57% adult and 43% paediatric) with a total of 354 samples (83% from remission and 17% from attack). Median titres were higher during attacks (1:1280 vs 1:640, p=0.001). Median onset titres did not correlate with attack-related disability, age or relapses. Remission titres were higher in relapsing patients (p=0.02). When considering the first remission sample available for each patient, titres >1:2560 were predictors of relapsing course in survival (log rank, pConclusionsPersistent MOG-IgG positivity and high remission titres are associated with an increased relapse risk. Longitudinal MOG-IgG titres could be useful to stratify patients to be treated with long term immunosuppression.

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.

We show that spontaneous Raman scattering of incident radiation can be observed in cavity-QED systems without external enhancement or coupling to any vibrational degree of freedom. Raman scattering processes can be evidenced as resonances in the emission spectrum, which become clearly visible as the cavity-QED system approaches the ultrastrong coupling regime. We provide a quantum mechanical description of the effect, and show that ultrastrong light-matter coupling is a necessary condition for the observation of Raman scattering. This effect, and its strong sensitivity to the system parameters, opens new avenues for the characterization of cavity QED setups and the generation of quantum states of light.

BackgroundPathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia.MethodsWe used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse.ResultsWe delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5−/− mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/−, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5−/− mice. In contrast, Gnb5−/− mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients.ConclusionsOur data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5−/− mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening.

The Thomas–Reiche–Kuhn (TRK) sum rule is a fundamental consequence of the position–momentum commutation relation for an atomic electron, and it provides an important constraint on the transition matrix elements for an atom. Here, we propose a TRK sum rule for electromagnetic fields which is valid even in the presence of very strong light–matter interactions and/or optical nonlinearities. While the standard TRK sum rule involves dipole matrix moments calculated between atomic energy levels (in the absence of interaction with the field), the sum rule here proposed involves expectation values of field operators calculated between general eigenstates of the interacting light–matter system. This sum rule provides constraints and guidance for the analysis of strongly interacting light–matter systems and can be used to test the validity of approximate effective Hamiltonians often used in quantum optics.

IntroductionRecent studies prompted the identification of neuroinflammation as a potential target for the treatment of epilepsy, particularly drug-resistant epilepsy, and refractory status epilepticus. This work provides a systematic review of the clinical experience with anti-cytokine agents and agents targeting lymphocytes and aims to evaluate their efficacy and safety for the treatment of refractory epilepsy. Moreover, the review analyzes the main therapeutic perspectives in this field.MethodsA systematic review of the literature was conducted on MEDLINE database. Search terminology was constructed using the name of the specific drug (anakinra, canakinumab, tocilizumab, adalimumab, rituximab, and natalizumab) and the terms “status epilepticus,” “epilepsy,” and “seizure.” The review included clinical trials, prospective studies, case series, and reports published in English between January 2016 and August 2021. The number of patients and their age, study design, specific drugs used, dosage, route, and timing of administration, and patients outcomes were extracted. The data were synthesized through quantitative and qualitative analysis.ResultsOur search identified 12 articles on anakinra and canakinumab, for a total of 37 patients with epilepsy (86% febrile infection-related epilepsy syndrome), with reduced seizure frequency or seizure arrest in more than 50% of the patients. The search identified nine articles on the use of tocilizumab (16 patients, 75% refractory status epilepticus), with a high response rate. Only one reference on the use of adalimumab in 11 patients with Rasmussen encephalitis showed complete response in 45% of the cases. Eight articles on rituximab employment sowed a reduced seizure burden in 16/26 patients. Finally, one trial concerning natalizumab evidenced a response in 10/32 participants.ConclusionThe experience with anti-cytokine agents and drugs targeting lymphocytes in epilepsy derives mostly from case reports or series. The use of anti-IL-1, anti-IL-6, and anti-CD20 agents in patients with drug-resistant epilepsy and refractory status epilepticus has shown promising results and a good safety profile. The experience with TNF inhibitors is limited to Rasmussen encephalitis. The use of anti-α4-integrin agents did not show significant effects in refractory focal seizures. Concerning research perspectives, there is increasing interest in the potential use of anti-chemokine and anti-HMGB-1 agents.

We study the interaction of a two-level atom with a single-mode nonlinear electromagnetic resonator, considering coupling strengths ranging from zero to the so-called deep strong coupling regime. When the qubit-resonator coupling is very strong, the standard Kerr model for the resonator becomes questionable. Moreover, recently, it has been shown that extra care is needed when constructing gauge-independent theories in the presence of approximations as the truncation of the Hilbert space of the matter system. Such a truncation can ruin gauge invariance leading to non-physical results, especially when the light-matter interactions strength is very high. Here we face and solve this issues to provide a consistent nonlinear-resonator quantum Rabi model satisfying the gauge principle., Comment: 10 pages, 4 figures

Background and purpose: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. Methods: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. Results: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5-8). The median time of follow-up was 7.9 years (range = 2-27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003-0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. Conclusions: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life.

The hopping mechanism plays a key role in collective phenomena emerging in many-body physics. The ability to create and control systems that display this feature is important for next generation quantum technologies. Here we study two cavities separated by a vibrating two-sided perfect mirror and show that, within currently available experimental parameters, this system displays photon-pair hopping between the two electromagnetic resonators. In particular, the two-photon hopping is not due to tunneling, but rather to higher order resonant processes. Starting from the classical problem, where the vibrating mirror perfectly separates the two sides of the cavity, we quantize the system and then the two sides can interact. This opens the possibility to investigate a new mechanism of photon-pair propagation in optomechanical lattices., Comment: 9 pages, 4 figures

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal ofMED subunit 11 may affect its binding efficiency to otherMED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.

Purpose: Triple X syndrome, is an often undiagnosed chromosomal abnormality with an incidence of 1/1000 females. Main associated disorders are urogenital malformations, premature ovarian failure or primary amen-orrhea, gastrointestinal problems, psychiatric disorders and epilepsy. To date, triple X is not related to a specific epileptic syndrome. Therefore, the purpose of this clinical series is to analyze seizure semiology, electroen-cephalogram features and the long-term outcome of 13 patients with epilepsy and triple X syndrome.Methods: We retrospectively evaluated the long-term seizure outcome in patients with triple X syndrome who had been referred to 11 Epilepsy Centers in Italy. A close electroclinical follow-up was made for at least 2 years and outcomes were reported.Results: Our case series confirms that epilepsy is not an occasional finding but part of the phenotypic spectrum of this syndrome. The seizure semiology shows an higher prevalence of focal seizures in 62% of patients. EEG findings of focal epileptic activity were reported in 85% of patients. Anti-seizure medications were successful in all our patients whom in most cases were responsive to monotherapy.Conclusion: According to our case series most successful drugs were VPA and LEV. Long term prognosis of epi-lepsy in our case series was good. Our experience suggests that all triple X patients achieve good seizure control and in 69% of cases normalization of the EEG.

A quantum dipole interacting with an optical cavity is one of the key models in cavity quantum electrodynamics (cavity-QED). To treat this system theoretically, the typical approach is to truncate the dipole to two levels. However, it has been shown that in the ultrastrong-coupling regime, this truncation naively destroys gauge invariance. By truncating in a manner consistent with the gauge principle, we introduce master equations for open systems to compute gauge-invariant emission spectra, photon flux rates, and quantum correlation functions which show significant disagreement with previous results obtained using the standard quantum Rabi model. Explicit examples are shown using both the dipole gauge and the Coulomb gauge., We acknowledge funding from the Canadian Foundation for Innovation and the Natural Sciences and Engineering Research Council of Canada. F.N. is supported in part by: Nippon Telegraph and Telephone Corporation (NTT) Research, the Japan Science and Technology Agency (JST) [via the Quantum Leap Flagship Program (Q-LEAP) program, the Moonshot R&D Grant Number JPMJMS2061, and the Centers of Research Excellence in Science and Technology (CREST) Grant No. JPMJCR1676], the Japan Society for the Promotion of Science (JSPS) [via the Grants-in-Aid for Scientific Research (KAKENHI) Grant No. JP20H00134 and the JSPS–RFBR Grant No. JPJSBP120194828], the Army Research Office (ARO) (Grant No. W911NF-18-1-0358), the Asian Office of Aerospace Research and Development (AOARD) (via Grant No. FA2386-20-1-4069), and the Foundational Questions Institute Fund (FQXi) via Grant No. FQXi-IAF19-06. S.S. acknowledges the Army Research Office (ARO) (Grant No. W911NF1910065).

Background Cyclic Vomiting Syndrome (CVS) is a rare functional gastrointestinal disorder, which has a considerable burden on quality of life of both children and their family. Aim of the study was to evaluate the diagnostic modalities and therapeutic approach to CVS among Italian tertiary care centers and the differences according to subspecialties, as well as to explore whether potential predictive factors associated with either a poor outcome or a response to a specific treatment. Methods Cross-sectional multicenter web-based survey involving members of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP). Results A total of 67 responses were received and analyzed. Most of the respondent units cared for less than 20 patients. More than half of the patients were referred after 3 to 5 episodes, and a quarter after 5 attacks. We report different diagnostic approaches among Italian clinicians, which was particularly evident when comparing gastroenterologists and neurologists. Moreover, our survey demonstrated a predilection of certain drugs during emetic phase according to specific clinic, which reflects the cultural background of physicians. Conclusion In conclusion, our survey highlights poor consensus amongst clinicians in our country in the diagnosis and the management of children with CVS, raising the need for a national consensus guideline in order to standardize the practice.

The prototypical system constituted by a two-level atom interacting with a quantized single-mode electromagnetic field is described by the quantum Rabi model (QRM). The QRM is potentially valid at any light-matter interaction regime, ranging from the weak (where the decay rates exceeds the coupling rate) to the deep strong coupling (where the interaction rate exceeds the bare transition frequencies of the subsystems). However, when reaching the ultrastrong coupling regime, several theoretical issues may prevent the correct description of the observable dynamics of such a system: (i) the standard quantum optics master equation fails to correctly describe the interaction of this system with the reservoirs; (ii) the correct output photon rate is no longer proportional to the intracavity photon number; and (iii) the appears to violate gauge invariance. Here, we study the photon flux emission rate of this system under the incoherent excitation of the two-level atom for any light-matter interaction strength, and consider different effective temperatures. The dependence of the emission spectra on the coupling strength is the result of the interplay between energy levels, matrix elements of the observables, and the density of states of the reservoirs. Within this approach, we also study the occurence of light-matter decoupling in the deep strong coupling regime, and show how all of the obtained results are gauge invariant., 25 pages, 21 figures

The complex association between neuroinflammation and seizures has been widely investigated in recent years. As mediators of inflammatory response, cytokines like tumor necrosis factor- a (TNF-a) are potential therapeutic targets for epileptic disorders. TNF-a is a pleiotropic cytokine with a controversial role in epileptogenesis, seemingly capable to both favor the genesis of seizures and elicit neuromodulatory responses. Anti-TNF agents are a group of monoclonal antibodies engineered to inhibit the response to this cytokine for antinflammatory purposes. The clinical experience of the use of these drugs in neurological conditions like multiple sclerosis showed controversial results. Evidence in favor of the employment of anti-TNF agents for the treatment of epilepsy are still limited to certain forms of disorders, notably Rasmussen encephalitis, and in carefully selected patients.

In recent years, there has been a significant increase in the diagnosis of asymptomatic Late-Onset Pompe Disease (LOPD) patients, who are detected via family screening or Newborn Screening (NBS). The dilemma is when to start Enzyme Replacement Therapy (ERT) in patients without any clinical sign of the disease, considering its important benefits in terms of loss of muscle but also its very high cost, risk of side effects, and long-term immunogenicity. Muscle Magnetic Resonance Imaging (MRI) is accessible, radiation-free, and reproducible; therefore, it is an important instrument for the diagnosis and follow-up of patients with LOPD, especially in asymptomatic cases. European guidelines suggest monitoring in asymptomatic LOPD cases with minimal MRI findings, although other guidelines consider starting ERT in apparently asymptomatic cases with initial muscle involvement (e.g., paraspinal muscles). We describe three siblings affected by LOPD who present compound heterozygosis and wide phenotypic variability. The three cases differ in age at presentation, symptoms, urinary tetrasaccharide levels, and MRI findings, confirming the significant phenotypic variability of LOPD and the difficulty in deciding when to start therapy.

(1) Background: Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by joint hypermobility and skin hyperextensibility with atrophic scarring. Many cEDS individuals carry variants in either the COL5A1 or COL5A2 genes. Mosaicism is relatively common in heritable connective tissue disorders but is rare in EDS. In cEDS, a single example of presumed gonosomal mosaicism for a COL5A1 variant has been published to date. (2) Methods: An 8-year-old girl with cEDS was analyzed by next-generation sequencing (NGS). Segregation was performed by Sanger sequencing in her unaffected parents. In the father, the mosaicism of the variant was further analyzed by targeted NGS and droplet digital PCR (ddPCR) in the blood and by Sanger sequencing in other tissues. (3) Results: The NGS analysis revealed the novel germline heterozygous COL5A1 c.1369G>T, p.(Glu457*) variant in the proband. Sanger chromatogram of the father’s blood specimen suggested the presence of a low-level mosaicism for the COL5A1 variant, which was confirmed by NGS and estimated to be 4.8% by ddPCR. The mosaicism was also confirmed by Sanger sequencing in the father’s saliva, hair bulbs and nails. (4) Conclusions: We described the second case of cEDS caused by paternal gonosomal mosaicism in COL5A1. Parental mosaicism could be an issue in cEDS and, therefore, considered for appropriate genetic counseling.

(1) Background: Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by joint hypermobility and skin hyperextensibility with atrophic scarring. Many cEDS individuals carry variants in either the COL5A1 or COL5A2 genes. Mosaicism is relatively common in heritable connective tissue disorders but is rare in EDS. In cEDS, a single example of presumed gonosomal mosaicism for a COL5A1 variant has been published to date. (2) Methods: An 8-year-old girl with cEDS was analyzed by next-generation sequencing (NGS). Segregation was performed by Sanger sequencing in her unaffected parents. In the father, the mosaicism of the variant was further analyzed by targeted NGS and droplet digital PCR (ddPCR) in the blood and by Sanger sequencing in other tissues. (3) Results: The NGS analysis revealed the novel germline heterozygous COL5A1 c.1369G>T, p.(Glu457*) variant in the proband. Sanger chromatogram of the father’s blood specimen suggested the presence of a low-level mosaicism for the COL5A1 variant, which was confirmed by NGS and estimated to be 4.8% by ddPCR. The mosaicism was also confirmed by Sanger sequencing in the father’s saliva, hair bulbs and nails. (4) Conclusions: We described the second case of cEDS caused by paternal gonosomal mosaicism in COL5A1. Parental mosaicism could be an issue in cEDS and, therefore, considered for appropriate genetic counseling.

The 4q deletion syndrome is an uncommon condition manifesting with broad clinical expression and phenotypic variability. We report a 5-year-old boy affected by 4q deletion syndrome who showed minor craniofacial features, growth failure, mild developmental delay, severe speech delay, and marked irascibility and aggressivity. Moreover, he showed precocious and crowded primary dentition, digital hyperlaxity, and congenital bilateral adducted thumbs, signs which were previously unreported in the syndrome. The array comparative genomic hybridization analysis revealed a 4q partial terminal deletion of ∼329.6 kb extending from 164.703.186 to 165.032.803 nt, which includes part of MARCH1 (membrane associated ring-CH-type finger 1) gene (OMIM#613331). Same rearrangement was found in his healthy mother. Clinical phenotype of the child and its relationship to the deleted region is presented with a revision of the cases having the same copy number losses from the literature and genomic variant databases.

The role of muscle biopsy in the diagnostic workup of floppy infants is controversial. Muscle sampling is invasive, and often, results are not specific. The rapid expansion of genetic approach has made the muscle histopathology analysis less crucial. This study aims to assess the role and efficacy of muscle histopathology in the diagnostic algorithm of hypotonia in early infancy through a retrospective analysis of 197 infants who underwent muscle biopsy in their first 18 months of life. Data analysis revealed that 92/197 (46.7%) of muscle biopsies were non-specific (80) or normal (12), not allowing a specific diagnosis. In 41/197 (20.8%) cases, biopsy suggested a metabolic or mitochondrial myopathy, while in 23/197 cases (11.7%), we found evidence of muscular dystrophy. In 19/197 cases (9.7%), histopathology characteristics of a congenital myopathy were reported. In 22/197 cases (11.7%), the histopathological study indicated presence of a neurogenic damage. Overall, 46 diagnoses were then achieved by oriented genetic tests. Muscle biopsy results were consistent with genetic results in 90% of cases. Diagnostic algorithms for the diagnosis of a floppy infant are largely missing. Muscle biopsy alone can lead to a diagnosis, help the clinician in the choice of a genetic test, or even modify a diagnosis made previously.

The mucosal-associated lymphoid tissues of the upper respiratory tract, including adenoids and palatine tonsils, are considered as the first line of defense against respiratory infections, being important effector organs in both mucosal-type and systemic-type adaptive immunity. They are strategically located for mediating both local and regional immune functions, as they are exposed to antigens from both the inhaled air (allergens and pathogens) and the alimentary tract. Adenoids play a major role in the early and effective immune responses against viral and bacterial upper airway infections, as well as in the development of allergic reactions to respiratory allergens, being influenced by several environmental antigens and pollutants, such as tobacco smoke. In addition, recent studies have focused on new immune-modulating strategies for adenoidal cells as a preventive and therapeutic approach for chronic upper airways inflammation.:Herein, we aimed to summarize what is known about the cellular and molecular mechanisms regulating adenoidal immune responses in the context of inflammation and allergy, with particular reference to scientific literature published within the last five years.

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. 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). 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.

Gradenigo’s syndrome is defined by the classic clinical triad of ear discharge, trigeminal pain, and abducens nerve palsy. It has become a very rare nosological entity after the introduction of antibiotics, so that has been defined as the “forgotten syndrome.” However, the underlying pathological process (apical petrositis) still represents a life-threatening condition that shall be immediately recognized in order to address the patient to the proper therapy. The therapy itself may be an argument of discussion: on a historical background ruled by surgery, reports of successful conservative antibiotic treatment have risen in recent years. We reported a case of Gradenigo’s syndrome in a child with an abscess of the left petrous apex and initial involvement of the carotid artery. After multidisciplinary evaluation, we decided to encourage conservative treatment, until complete regression was observed. The available literature of the last 10 years was reviewed, with particular attention to the presence of an apical abscess and the therapeutic approach. The principles of management with regard to conservative therapy versus surgical indications are therefore examined and discussed.

Introduction:In March 2020, SARS-CoV-2 declared a pandemic by the World Health Organization. Restrictive isolation measures have also brought psychological distress to the pediatric population. Building on the syndrome's characteristics, the present study explored the impact of lockdown on the clinical course of young people with PANDAS/PANS. The initial hypothesis considered both the reduced exposure to viral agents and the strategies of the parents and other containment actions as protective factors against the worsening of symptoms.Methods:One hundred and eight children, adolescents, and young adults were recruited according to the multicenter PANDAS/PANS research program. Parents participated in a web-based survey. Results: contrary to our hypothesis, the study results show an increase in symptoms during the block in 71% of the sample. Psychometric analyzes allowed us to exclude a relationship between the main symptoms of PANDAS and the increase in symptoms or the presence of symptoms before the block and their increase over time. The increase in symptoms is best explained by the presence of sleep disturbances and emotional lability. The exacerbation also appears to be linked to the onset of new symptoms in children and adolescents with depressed moods and eating problems. Furthermore, irritability and oppositionality are significant predictors of acute exacerbation. Equally statistically significant is the factor linked to the effects of pandemic stress, such as the fear of contracting the virus. No significant associations for symptom reduction have been identified between parental strategies or other parent-initiated actions, but the study demonstrates that caregiver perceived efficacy on the strategies used can reduce the risk of exacerbation.Conclusion:This preliminary study highlights the importance of studying the causes of increased symptoms in children with PANDAS/PANS. Life events can exacerbate the clinical condition or generate new symptoms in young patients. In particular, environmental, family, and social changes in the course of clinical symptoms in PANDAS/PANS patients should be investigated. It highlights the importance of emotional and behavioral management, which can be improved by enhancing coping strategies in young people with PANDAS/PANS and their caregivers through a combination treatment in which CBT and PMT are included, in line with guidelines.Limits:An experimental proxy-report questionnaire not yet standardized and validated on the PANS/PANDAS pediatric clinical sample was used for the exploratory study. There is also a small sample size (N= 108) and the absence of a control group (pre-lockdown or children without PANDAS/PANS). It would be interesting to evaluate the exact long-term dimensions to see the course of symptoms after covid and conduct a new study focusing on the impact of stressful events on the clinical course of the syndrome.

Plasmonic dimer cavities can induce extreme electric-field hot spots that allow one to access ultrastrong coupling regimes using Raman-type spectroscopy on single vibrating molecules. Using a generalized master equation, we study resonant Raman scattering in the strong coupling regime of cavity quantum electrodynamics, when also in the vibrational ultrastrong coupling regime, leading to ``phonon-dressed polaritons.'' The master equation rigorously includes spectral baths for the cavity and vibrational degrees of freedom, as well as a pure dephasing bath for the resonant two-level system, which play a significant role. Employing realistic parameters for gold dimer cavity modes, we investigate the emission spectra in several characteristic strong coupling regimes, leading to extremely rich spectral resonances due to an interplay of phonon-modified polariton states and bath-induced resonances. We also show explicitly the failure of the standard master equation in these quantum nonlinear regimes.

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.

Background Ehlers-Danlos syndrome (EDS) is part of connective tissue disorders and is characterized by skin hyperextensibility, joint hypermobility, easy bruising and other severe manifestations such as epilepsy, pneumothorax, arterial rupture and bowel perforation. In 2017 a new classification was published, indicating major and minor criteria for each form of EDS. Further reports in the past years tried to determine whether or not the absence of lingual frenulum should be included in minor criteria for the diagnosis of EDS, but a consensus has still not been reached. The aim of this study was to assess the clinical relevance of lingual frenulum absence, evaluating its prevalence in a cohort of EDS pediatric patients and comparing it to a group of controls. Methods Patients with Ehlers-Danlos syndrome were observed at our Department of Pediatrics of Policlinico S. Matteo in Pavia, Italy. Each patient underwent clinical examination of the oral cavity, and controls were chosen among patients referred to our Department. Results Thirty-three over 40 patients showed absence of lingual frenulum and 3 of them showed frenulum hypoplasia. Absence or hypoplasia of lingual frenulum showed a prevalence of 90% in our population, whereas only 3/170 controls (1.8%), had lingual frenulum absence. Overall, absence of the lingual frenulum showed a sensibility of 90% and a specificity of 98.2% in our population. Conclusions In agreement with other authors, we believe that the absence of lingual frenulum should be included in the minor diagnostic criteria for Ehlers-Danlos Syndrome.

We introduce a protocol to transfer excitations between two noninteracting qubits via purely dissipative processes (i.e., in the Lindblad master equation there is no coherent interaction between the qubits). The fundamental ingredients are the presence of collective (i.e. nonlocal) dissipation and unbalanced local dissipation rates (the qubits dissipate at different rates). The resulting quantum trajectories show that the measurement backaction changes the system wave function and induces a passage of the excitation from one qubit to the other. While similar phenomena have been witnessed for a non-Markovian environment, here the dissipative quantum state transfer is induced by an update of the observer knowledge of the wave function in the presence of a Markovian (memoryless) environment -- this is a single quantum trajectory effect. Beyond single quantum trajectories and postselection, such an effect can be observed by histogramming the quantum jumps along several realizations at different times. By investigating the effect of the temperature in the presence of unbalanced local dissipation, we demonstrate that, if appropriately switched on and off, the collective dissipator can act as a Maxwell's demon. These effects are a generalized measure equivalent to the standard projective measure description of quantum teleportation and Maxwell's demon. They can be witnessed in state-of-the-art setups given the extreme experimental control in, e.g., superconducting qubits or Rydberg atoms., 11 pages, 5 figures

Zika virus (ZIKV) has been associated with many neurological inflammatory and demyelinating diseases involving both the peripheral and the central nervous system (CNS). The pathogenic mechanisms of ZIKV-related demyelination are yet to be clarified, but the main theories comprise “molecular mimicry” and direct viral cytotoxicity. Guillain-Barre syndrome was the first acquired ZIKV-related peripheral demyelinating disease to be described, presenting mostly as an acute inflammatory demyelinating polyneuropathy. CNS complications related to ZIKV infection include acute transverse myelitis and encephalomyelitis. There is a substantial overlap among the typical arboviral clinical manifestations and other neurotropic virus infections, and coinfection with more than one virus is relatively common. For these reasons, ZIKV-related inflammatory and demyelinating diseases are difficult to characterize in terms of epidemiology, pathology, and clinical presentation. To minimize misinterpretations, RT-PCR performed in blood and other biological materials (i.e., CSF) is now considered the gold standard test to confirm acute ZIKV infection, and it should be performed in any patient with a suspected neurological ZIKV-related disease.

The interaction between quantized electromagnetic fields in cavities and natural or artificial atoms has played a crucial role in developing our understanding of light-matter interactions and quantum technologies. Recently, new regimes beyond the weak and strong light-matter coupling of cavity-QED have been explored in several settings, wherein the light-matter coupling rate becomes comparable to (ultrastrong coupling) or even exceeds (deep-strong coupling) the photon frequency. These ultrastrong coupling regimes can give rise to new physical effects and applications, and they challenge our understanding of cavity QED; fundamental issues like the proper definition of subsystems, their quantum measurements, the structure of light-matter ground states, and the analysis of time-dependent interactions are subject to gauge ambiguities that lead to even qualitatively distinct predictions. The resolution of these ambiguities is important for understanding and designing next-generation quantum devices that can operate in extreme coupling regimes. Here we discuss and provide solutions to these ambiguities by adopting an approach based on operational procedures involving measurements on the individual light and matter components of the interacting system., A.S., D.Z., and S.H. acknowledge RIKEN for its hospitality, D.Z. acknowledges the support by the Spanish Ministerio de Ciencia, Innovaciòn y Universidades within project MAT2017-88358-C3-1-R, the Aragòn Government project Q-MAD, EU-QUANTERA project SUMO and the Fundaciòn BBVA. F.N. is supported in part by: Nippon Telegraph and Telephone Corporation (NTT) Research, the Japan Science and Technology Agency (JST) [via the Quantum Leap Flagship Program (Q-LEAP) program, the Moonshot R&D Grant No. JPMJMS2061, and the Centers of Research Excellence in Science and Technology (CREST) Grant No. JPMJCR1676], the Japan Society for the Promotion of Science (JSPS) [via the Grants-in-Aid for Scientific Research (KAKENHI) Grant No. JP20H00134 and the JSPS RFBR Grant No. JPJSBP120194828], the Army Research Office (ARO) (Grant No. W911NF-18-1-0358), the Asian Office of Aerospace Research and Development (AOARD) (via Grant No. FA2386-20-1-4069), and the Foundational Questions Institute Fund (FQXi) via Grant No. FQXi-IAF19-06. S.H. acknowledges funding from the Canadian Foundation for Innovation, and the Natural Sciences and Engineering Research Council of Canada. S.S. acknowledges the Army Research Office (ARO) (Grant No. W911NF-19-1-0065).

The quantum Rabi model is a widespread description of the coupling between a two-level system and a quantized single mode of an electromagnetic resonator. Issues about this model's gauge invariance have been raised. These issues become evident when the light-matter interaction reaches the so-called ultrastrong coupling regime. Recently, a modified quantum Rabi model able to provide gauge-invariant physical results (e.g., energy levels, expectation values of observables, quantum probabilities) in any interaction regime was introduced [O. Di Stefano, A. Settineri, V. Macrì, L. Garziano, R. Stassi, S. Savasta, and F. Nori, Nat. Phys. 15, 803 (2019)]. Here we provide an alternative derivation of this result, based on the implementation in two-state systems of the gauge principle, which is the principle from which all the fundamental interactions in quantum field theory are derived. The adopted procedure can be regarded as the two-site version of the general method used to implement the gauge principle in lattice gauge theories. Applying this method, we also obtain the gauge-invariant quantum Rabi model for asymmetric two-state systems, and the multimode gauge-invariant quantum Rabi model beyond the dipole approximation., F.N. is supported in part by: Nippon Telegraph and Telephone Corporation (NTT) Research, the Japan Science and Technology Agency (JST) [via the Quantum Leap Flagship Program (Q-LEAP) program, the Moonshot R&D Grant No. JPMJMS2061, and the Centers of Research Excellence in Science and Technology (CREST) Grant No. JPMJCR1676], the Japan Society for the Promotion of Science (JSPS) [via the Grants-in-Aid for Scientific Research (KAKENHI) Grant No. JP20H00134 and the JSPS – RFBR Grant No. JPJSBP120194828], the Army Research Office (ARO) (Grant No. W911NF-18-1-0358), the Asian Office of Aerospace Research and Development (AOARD) (via Grant No. FA2386-20-1-4069), and the Foundational Questions Institute Fund (FQXi) via Grant No. FQXi-IAF19-06. S.H. acknowledges funding from the Canadian Foundation for Innovation and the Natural Sciences and Engineering Research Council of Canada. S.S. acknowledges the Army Research Office (ARO) (Grant No. W911NF1910065).

Background The recent COVID-19 pandemic pointed out new burdens for researchers on mental health and that evidence-based (EB) studies on vulnerable populations are timely needed. The present paper aims at analysing the impact of suspicious of SARS-COV-2 infection in a cohort of parents presented at 3 major hospitals (spread between north and center of Italy) during the Italian COVID-19 pandemic phase 1. Methods Participants of the present cross-sectional, multicenter study were parental couples of children suspected to have COVID-19 who underwent testing with nasopharyngeal swabbing. All subjects were assessed by means of the: Impact of Event Scale-Revised (IES-R), Generalized Anxiety Disorder 7-Item (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) in order to evaluate Post-traumatic stress (PTSS), anxiety, and depressive symptoms, respectively. Outcomes Results evidenced that parents whose children tested positive for COVID-19 were more prone to developing PTSS, anxiety and depressive symptoms. The same results emerged for parents who had quarantined as opposed to those who had not. Moreover, patients who suffered economic damage showed a higher prevalence of anxiety and depressive symptoms, whereas PTSS was more common among unemployed subjects and among mothers. Interpretation This study identified a mental health strain represented by parenting a child who tested positive for SARS-CoV-2 infection. Further EB research is needed to develop evidence-driven strategies to reduce adverse psychological impacts and related psychiatric symptoms in caregivers of COVID-19 infected children during the next phases of the pandemic.

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.

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.

Background: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the central nervous system (CNS), whose pathogenesis is still debated. It occurs more frequently in children, and the first neurological symptoms usually appear between 2 and 4 weeks after a trigger event, such as an infection or vaccination. Several viral agents have been related to the development of ADEM, while bacteria and parasites are less frequently involved. Severe Streptococcus pneumoniae infection has been rarely described as a trigger for CNS demyelination in particularly predisposed subjects.Case presentation: A 10 year old girl was evaluated for headache, fever and vomit. CSF analysis revealed pleocytosis and presence of S. pneumoniae antigen, and proper antibiotic therapy for bacterial meningitis was started, with rapid improvement. A breach in the right frontal bone, due to a car accident occurring the previous year, was considered the gateway for pneumococcal infection. Three days after admission, the girl developed drowsiness, altered speech and left hemiparesis. Brain MRI showed multiple T2-hyperintense bilateral lesions in the supratentorial white matter, and ADEM was diagnosed. Considering the underlying bacterial meningitis, intravenous immunoglobulins were preferred to steroid therapy, and the patient progressively recovered. However, due to recurrence of encephalopathic symptoms after 11 days, high-dose intravenous steroid therapy was performed. The neurological outcome was favourable, with complete regression of the white matter lesions after 4 months and absence of relapses over a follow-up period of 2 years.Conclusions: Occurrence of ADEM following pneumococcal meningitis is rare, and very few cases have been described in children. It should be suspected in case of persistence, recurrence or onset of new symptoms despite adequate antimicrobial treatment, relying on brain MRI for a thorough differential diagnosis. High level of surveillance is mandatory in patients with predisposing factors to invasive pneumococcal disease. In some cases, acute demyelination can occur few days after the onset of meningitis; pathogenetic mechanisms are not yet fully clarified and the choice of the correct therapeutic approach can be challenging.

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. (www.actabiomedica.it)

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. (www.actabiomedica.it)

BACKGROUND The Ehlers-Danlos Syndrome (EDS) is a rare disorder affecting the connective tissue. EDS patients may suffer of proprioception and balance impairment but all the studies dealing with such symptoms have been addressed to adult subjects. The Study of such impairment in younger patients may lead to a better awareness of own motor abilities and to a focused rehabilitative intervention. Therefore, our work aims to assess the occurrence of these alterations in a pediatric cohort of EDS patients. METHODS The Research was designed as a cross-sectional study with a matching control group and performed on a pediatric cohort of 12 subjects with Ehlers-Danlos Syndrome (Classic and Hypermobility type) and on 12 healthy controls, during a follow-up visit at the Department of Pediatrics and at the Rehabilitation Unit of the Foundation IRCCS Policlinico San Matteo, in Pavia from April 2015 to October 2015. A square forceplatform was used to obtain the CoP (center of pressure) displacement during quiet standing during an open and a closed eyes trials. The comparisons between EDS and control group were performed using a t-test for independent data. P

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 (P