Diagnosis and Therapy of Infectious Encephalitis in Children: A Ten-Years Retrospective Study.

BACKGROUND: Infectious encephalitis represents a rare but potentially severe clinical condition. However, limited international data are available in pediatric age. METHODS: We conducted a retrospective study to review (a) the clinical presentation; (b) laboratory, radiology, and neurophysiology findings; (c) the correlations between these exams and outcome; and (d) the therapy performed. RESULTS: Fifty-six patients were enrolled [22 female (39.6%), mean age 4.7 years, IQR 0.7-8.7 years], 19.6% presented neurologic sequelae. HSV was the single most frequently isolated pathogen (19.6%), although in most cases, the etiology remained undefined. 41.1% children presented prodromal before the development of neurologic signs. Fever was the most frequent constitutional symptom (83.9% of cases). Cerebrospinal fluid was normal in 48.5% of cases and electroencephalograpy in 24.5% cases. Brain computed tomography scans was normal in 33 (91.7%) cases, while cerebral magnetic resonance imaging (MRI) showed pathologic findings in 62.5% of cases. MRI was the only parameter associated with neurologic sequalae [P = 0.01; OR, 8.1 (95% CI: 1.52-42.84)]. CONCLUSIONS: Pediatric encephalitis is a heterogeneous entity with nonspecific clinical and laboratory findings, with undefined etiologies in most times. MRI can play a primary role, both on a diagnostic and prognostic point-of-view, and its role should be implemented and made more accessible. Further studies are needed to define the exact role and timing of steroids.

Sleep Disorders in Autism Spectrum Disorder Pre-School Children: An Evaluation Using the Sleep Disturbance Scale for Children.

Background and Objectives: Sleep disorders are common in children with Autism Spectrum Disorder (ASD). The aims of this study were to describe the incidence and characteristics of sleep disorders using a questionnaire completed by the caregiver in a sample of preschool-aged children with ASD and to identify possible differences in a control group of peers. Materials and Methods: Sleep disorders were investigated with the Sleep Disturbance Scale for Children (SDSC) in a population of pre-school-aged (3-5 years) ASD children and in a control group. The Autism Diagnostic Observation Schedule-second ed. (ADOS-2) was further used to assess autism symptom severity. A total of 84 children (69 males; mean age 3.9 ± 0.8 years) with a diagnosis of ASD and 84 healthy controls (65 males; mean age of 3.7 ± 0.8 years) that were matched for age and sex were enrolled. Results: ASD children reported significantly higher (pathological) scores than the control group on the SDSC total scores and in some of the factor scores, such as Difficulty in Initiating and Maintaining Sleep (DIMS), disorders of excessive somnolence (DOES), and sleep hyperhidrosis. A total of 18% of ASD children had a pathological SDSC total T-score, and 46% had an abnormal score on at least one sleep factor; DIMS, parasomnias, and DOES showed the highest rates among the sleep factors. Younger children (3 years) reported higher scores in DIMS and sleep hyperhidrosis than older ones (4 and 5 years). No specific correlation was found between ADOS-2 and SDSC scores. Conclusions: Pre-school children with ASD showed a high incidence of sleep disorders with different distributions of specific sleep factors according to their age. We suggest a screening assessment of sleep disorders using the SDSC in these children with a more in-depth evaluation for those reporting pathological scores on the questionnaire.

Spinal Cord Involvement in Adult Mitochondrial Diseases: A Cohort Study.

The central nervous system is metabolically very demanding and consequently vulnerable to defects of the mitochondrial respiratory chain. While the clinical manifestations and the corresponding radiological findings of the brain involvement in mitochondrial diseases (e.g., stroke-like episodes, signal changes of the basal ganglia, cerebral and cerebellar atrophy) are well known, at present there are few data on the spinal-cord abnormalities in these pathologies, in particular in adult subjects. In this study, we present a cross-sectional cohort study on the prevalence and characterization of spinal-cord involvement in adult patients with genetically defined mitochondrial diseases.

Cortical Thickness and Clinical Findings in Prescholar Children With Autism Spectrum Disorder.

The term autism spectrum disorder (ASD) includes a wide variability of clinical presentation, and this clinical heterogeneity seems to reflect a still unclear multifactorial etiopathogenesis, encompassing different genetic risk factors and susceptibility to environmental factors. Several studies and many theories recognize as mechanisms of autism a disruption of brain development and maturation time course, suggesting the existence of common neurobiological substrates, such as defective synaptic structure and aberrant brain connectivity. Magnetic resonance imaging (MRI) plays an important role in both assessment of region-specific structural changes and quantification of specific alterations in gray or white matter, which could lead to the identification of an MRI biomarker. In this study, we performed measurement of cortical thickness in a selected well-known group of preschool ASD subjects with the aim of finding correlation between cortical metrics and clinical scores to understand the underlying mechanism of symptoms and to support early clinical diagnosis. Our results confirm that recent brain MRI techniques combined with clinical data can provide some useful information in defining the cerebral regions involved in ASD although large sample studies with homogeneous analytical and multisite approaches are needed.

Mild encephalopathy with reversible splenial lesion associated with echovirus 6 infection: a case report and review of the literature.

BACKGROUND: Mild encephalopathy with reversible splenial lesion (MERS), a clinic-radiological syndrome distinguished by reversible encephalopathy onset, has been increasingly recognized in Caucasian children. CASE: We describe a MERS case in a previously healthy 4-year-old girl admitted to the hospital with abnormal consciousness level, muscle weakness, dysphagia and dysarthria after a 4-day history of diarrhea and fever. Magnetic resonance imaging (MRI) of the brain showed hyperintensity in the corpus callosum splenium. Electroencephalogram was normal and cerebrospinal fluid (CSF) culture negative. The stool sample was positive for Echovirus 6 and serology test confirmed the infection. The child`s condition gradually improved and the MRI, after 15 days, depicted a normal brain. Only a mild speech impairment was persistent at discharge, which disappeared one month later. We performed a literature review about pediatric MERS cases demonstrating that infectious agents have been rarely isolated in CSF. CONCLUSION: MERS has an overall good prognosis independently from the treatment approach; this is confirmed by our case - one of the first reported with an Echovirus 6-related encephalopathy.

Mild encephalitis/encephalopathy with reversible splenial lesion (MERS) in twin sisters with two CD36 frameshift mutations.

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinical radiological syndrome with good prognosis that affects mainly children or young adults. We describe two cases of MERS, associated with echovirus 6 and influenza A infection, in two twin sisters, at the age of 4 years. Genetic analysis was performed; next exome sequencing was performed on twins to disclose the eventual causative gene. Two different frameshift mutations in the CD36 gene [NM_000072] were found in both twins and confirmed by Sanger sequencing. To best of our knowledge, we report an association between CD36 mutation and MERS. We think that this relation between CD36 and inflammation has had a crucial role in the same callosal alteration during viral disease in the twin sister with the same gene mutation.

Attention-deficit/hyperactivity disorder and enuresis: a study about effectiveness of treatment with methylphenidate or desmopressin in a pediatric population.

BACKGROUND: The aim of this study was to evaluate the effectiveness of treatment with methylphenidate or desmopressin (dDAVP) in patients with comorbid attention-deficit/hyperactivity disorder (ADHD) and enuresis. METHODS: We enrolled 103 patients affected by ADHD and 125 patients with monosymptomatic nocturnal enuresis (NE). Data were collected between January 2014 and December 2015. The study was carried out in compliance with the Helsinki Declaration. RESULTS: About children with ADHD, 9/103 (8.7%) were also suffering from NE; of those 8/9 followed treatment with methylphenidate and cognitive behavioral therapy. After 3 months 2/8 (25%, CI 95%: 8-65%) showed improvements, remaining 75% has been increased dosage of methylphenidate. After 6 months a response was achieved in 6/8 (75%, CI 95%: 35-96%) children and 1/8 was lost to follow-up. Furthermore the drug withdrawal showed a recurrence of symptoms both ADHD and NE in 1/7 (14.3%, CI 95%: 0.3-57%) vs. 6/7 (85.7%, CI 95%: 42-99%) that not presented recurrences. About children with NE enrolled at Campus Bio-Medico University it was found that 4/125 (3.8%) children were also suffering from ADHD; 3/4 (75%) treated with dDAVP and motivational therapy, of those 2/3 (66.7%, CI 95%: 9-99%) showed no improvements of symptoms vs. 1/3 (33.3%, CI 95%: 0.8-90%) that showed partial response with a reduction of wet-nights. CONCLUSIONS: It is important the service of recruitment of patients with NE. In fact considering NE in a Child Neuropsychiatry Service where patients belong to a diagnosis of ADHD and NE is an incidental finding, this one is not considered as the addressee of treatment, but the therapy is directed to the neuro-behavioral problem using specific drugs and therapies, which are resolutive in the enuretic disorder.

IL-17/IL-10 double-producing T cells: new link between infections, immunosuppression and acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases. In particular, the severe infections occurring in these patients before or during any treatment suggest an intrinsic alteration of the immune system. In this respect, IL-17-producing T helper (Th17) besides playing a key role in regulating inflammatory response, tumor growth and autoimmune diseases, have been shown to protect against bacterial and fungal pathogens. However, the role of Th17 cells in AML has not yet been clarified. METHODS: T cell frequencies were assessed by flow cytometry in the peripheral blood of 30 newly diagnosed AML patients and 30 age-matched healthy volunteers. Cytokine production was determined before and after culture of T cells with either Candida Albicans or AML blasts. Statistical analyses were carried out using the paired and unpaired two-tailed Student's t tests and confirmed with the non parametric Wilcoxon signed-rank test. RESULTS: A strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors. In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation. To address the role of AML blasts in inducing Th17 alterations, CD4+ cells from healthy donors were co-cultured with CD33+ blasts: data obtained showed that AML blasts induce in healthy donors levels of IL-10-producing Th17 cells similar to those observed in patients. CONCLUSIONS: In AML patients altered Th17 cells actively cause an immunosuppressive state that may promote infections and probably tumor escape. Th17 cells could thus represent a new target to improve AML immunotherapy.

Protracted late infantile ceroid lipofuscinosis due to TPP1 mutations: Clinical, molecular and biochemical characterization in three sibs.

OBJECTIVE: This work investigated the molecular cause responsible for a late-onset parkinsonism-dystonia phenotype in three Italian siblings, and clinically characterize this condition. METHODS: Extensive neurophysiological and neuroradiological exams were performed on the three sibs. Most frequent late-onset metabolic diseases were ruled out through laboratory and biochemical analyses. A whole exome sequencing (WES) approach was used to identify the molecular cause underlying this condition. RESULTS AND CONCLUSIONS: Peculiar neurologic phenotype was characterized by dystonia-parkinsonism, cognitive impairment, gait ataxia and apraxia, pyramidal signs. WES analysis allowed the identification of a compound heterozygosity for two nucleotide substitutions (c.1340G>A, p.R447H; c.790C>T, p.Q264X) affecting the TPP1 gene in the three affected siblings. Biochemical analyses demonstrated abrogated TPP1 catalytic activity in primary skin fibroblasts, but revealed residual activity in leukocytes. Our findings document that late infantile neuronal ceroid lipofuscinosis (CLN2), which is caused by TPP1 gene mutations, should be considered in the differential diagnosis of autosomal recessive dystonia-parkinsonism syndromes. The availability of enzyme replacement therapy and other therapeutic approaches for ceroid lipofuscinoses emphasizes the value of reaching an early diagnosis in patients with atypical and milder presentation of these disorders.

Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus.

Both active and passive immunization strategies against Staphylococcus aureus have thus far failed to show efficacy in humans. With the attempt to develop an effective S. aureus vaccine, we selected five conserved antigens known to have different roles in S. aureus pathogenesis. They include the secreted factors α-hemolysin (Hla), ess extracellular A (EsxA), and ess extracellular B (EsxB) and the two surface proteins ferric hydroxamate uptake D2 and conserved staphylococcal antigen 1A. The combined vaccine antigens formulated with aluminum hydroxide induced antibodies with opsonophagocytic and functional activities and provided consistent protection in four mouse models when challenged with a panel of epidemiologically relevant S. aureus strains. The importance of antibodies in protection was demonstrated by passive transfer experiments. Furthermore, when formulated with a toll-like receptor 7-dependent (TLR7) agonist recently designed and developed in our laboratories (SMIP.7-10) adsorbed to alum, the five antigens provided close to 100% protection against four different staphylococcal strains. The new formulation induced not only high antibody titers but also a Th1 skewed immune response as judged by antibody isotype and cytokine profiles. In addition, low frequencies of IL-17-secreting T cells were also observed. Altogether, our data demonstrate that the rational selection of mixtures of conserved antigens combined with Th1/Th17 adjuvants can lead to promising vaccine formulations against S. aureus.

Headache Following Occipital Brain Lesion: A Case of Migraine Triggered by Occipital Spikes?

This study describes the case of an 8-year-old boy who developed a genuine migraine after the surgical excision, from the right occipital lobe, of brain abscesses due to selective infestation of the cerebrum by Entamoeba histolytica. After the surgical treatment, the boy presented daily headaches with typical migraine features, including right-side parieto-temporal pain, nausea, vomiting, and photophobia. Electroencephalography (EEG) showed epileptiform discharges in the right occipital lobe, although he never presented seizures. Clinical and neurophysiological observations were performed, including video-EEG and polygraphic recordings. EEG showed "interictal" epileptiform discharges in the right occipital lobe. A prolonged video-EEG recording performed before, during, and after an acute attack ruled out ictal or postictal migraine. In this boy, an occipital lesion caused occipital epileptiform EEG discharges without seizures, probably prevented by the treatment. We speculate that occipital spikes, in turn, could have caused a chronic headache with features of migraine without aura. Occipital epileptiform discharges, even in absence of seizures, may trigger a genuine migraine, probably by means of either the trigeminovascular or brainstem system.

Rapid eye movement sleep behavior disorder: a window on the emotional world of Parkinson disease.

STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is a parasomnia characterized by motor activity during sleep with dream mentation. Aggressiveness has been considered a peculiar feature of dreams associated with RBD, despite normal score in aggressiveness scales during wakefulness. We aimed to measure daytime aggressiveness and analyze dream contents in a population of patients with Parkinson disease (PD) with and without RBD. DESIGN: This is a single-center prospective observational study; it concerns the description of the clinical features of a medical disorder in a case series. SETTING: The study was performed in the Department of Neurosciences of the Catholic University in Rome, Italy. PATIENTS: Three groups of subjects were enrolled: patients with PD plus RBD, patients with PD without RBD, and healthy controls. INTERVENTIONS: The diagnosis of RBD was determined clinically and confirmed by means of overnight, laboratory-based video-polysomnography. For the evaluation of diurnal aggressiveness, the Buss-Perry Aggression Questionnaire (BPAQ) was used. The content of dreams was evaluated by means of the methods of Hall and Van De Castle. MEASUREMENTS AND RESULTS: Patients with PD without RBD displayed higher levels of anger, and verbal and physical aggressiveness than patients with PD and RBD and controls. Patients with PD and RBD and controls did not differ in hostility. CONCLUSIONS: It can be hypothesized that a noradrenergic impairment at the level of the locus coeruleus could, at the same time, explain the presence of RBD, as well as the reduction of diurnal aggressiveness. This finding also suggests a role for REM sleep in regulating homeostasis of emotional brain function.

Rivastigmine for refractory REM behavior disorder in mild cognitive impairment.

BACKGROUND: Mild Cognitive Impairment (MCI) and REM Behavior Disorder (RBD) are both associated with a degeneration of ponto-medullary cholinergic pathways. METHODS: We conducted a placebo-controlled, cross-over pilot trial of Rivastigmine (RVT) in 25 consecutive patients with MCI, who presented RBD refractory to conventional first-line treatments (melatonin up to 5 mg/day and clonazepam up to 2 mg/day). RESULTS: RVT treatment was followed by a significant reduction of RBD episodes when compared with placebo. CONCLUSIONS: Our data suggest that, in MCI patients with RBD resistant to conventional therapies (muscle relaxants benzodiazepines or melatonin,) treatment with RVT may induce a reduction in the frequency of RBD episodes compared to placebo.

Increased levels of neurotrophins in the cerebrospinal fluid of children with Epstein-Barr virus meningoencephalitis.

OBJECTIVE: The aim of this study was to evaluate the expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the cerebrospinal fluid (CSF) of children with Epstein-Barr virus (EBV)-induced meningoencephalitis (ME) in order to establish a possible correlation with laboratory findings and neurological manifestations. METHODS: A prospective observational clinical study was performed on 10 children with viral ME, five of them with EBV-induced ME. As controls, we used CSF samples collected from children admitted with febrile seizures. Neurotrophin levels were measured using an enzyme immunoassay. RESULTS: Significantly higher levels of BDNF and NGF were detected in all patients with viral ME compared to controls. Moreover, in patients with EBV-induced ME, the neurotrophin levels were higher than in those with other viral ME. Of note, in children with EBV-induced ME, we found a significant correlation between neurotrophic factor levels and the number of lymphocytes in the CSF (p<0.001). In these patients we also found a significant correlation between BDNF expression and the blood platelet count (p<0.001). Interestingly, two patients with EBV-induced ME showed a correlation between neurotrophin increase and persistent brain abnormalities, such as prolonged alteration of mental status, psychomotor agitation, and athetosis. CONCLUSIONS: Viral ME induces an early and strong increased biosynthesis of neurotrophic factors. This neurotrophin over-expression is likely to play a key role in the mechanisms of neuronal inflammation and in the severity of brain damage, particularly in EBV-induced ME.