Effect of melatonin on sleep quality and EEG features in childhood epilepsy: a possible non-conventional treatment.

Background: Sleep and epilepsy are characterized by a bidirectional relationship. Indeed, epilepsy predisposes to the development of sleep disorders, while sleep deprivation may exacerbate epilepsy. In addition, antiseizure medication can disrupt normal sleep architecture. Therefore, adequate sleep hygiene could lead to improvement in seizure control. The present study aimed to evaluate the effect of melatonin on seizure frequency, EEG tracing, and sleep in children with focal idiopathic epilepsy. Methods: This observation study evaluated the effect of 4 mg oral melatonin in ameliorating sleep-wake cycle, seizure frequency, and EEG features in children with focal idiopathic epilepsy of infancy. Twenty children were enrolled from September 2020 to August 2021. The study consisted of serial controls at enrollment (t0), at 3 months (t1), and at 6 months (t2) including neurological examination, questionnaire about sleep disturbances (CSHQ), and EEG. Results: A significant improvement in sleep quality and daytime sleepiness was observed after melatonin supplementation. Furthermore, we observed a noteworthy improvement in EEG tracing at t2 that exhibited a significant correlation with improvements in CSHQ scores. Conclusion: The studies conducted so far to evaluate the effect of melatonin in persons with epilepsy do not lead to definitive conclusions. Despite the small population sample and the study design, we report sleep and EEG improvement after melatonin administration in our cohort. Larger studies are needed to further study the neuroprotective and anticonvulsant properties of melatonin.

Expanding the genetic and clinical characteristics of Protocadherin 19 gene mutations.

BACKGROUND: PCDH19-related epilepsy is a rare X-linked type of epilepsy caused by genomic variants of the Protocadherin 19 (PCDH19) gene. The clinical characteristics of PCDH19-related epilepsy are epileptic and non-epileptic symptoms with highly variable severity among patients. CASE PRESENTATION: We present a case of a 4-year old female with PCDH19-related epilepsycaused by new variants in the PCDH19 gene. Our patient was admitted for the first time at the age of 12 months for seizure clusters arising under condition of apyrexia. The electroencephalography (EEG) showed frontal paroxysmal activity. The genetic analysis identified the two variants c.1006G > A (p.Val336Met) and c.1014C > A (p.Asp338Glu) in the gene PCDH19. The patient was treated with Carbamazepine and Clonazepam achieving the disappearance of seizures. During the follow-up, the neurological examination was persistently normal with neither cognitive impairment nor behavior disturbances. From 2 years of age EEG controls were persistently normal. CONCLUSION: This patient presents two novel variants of the PCDH19 gene associated with a mild form of epilepsy with normal cognitive development with an apparently better prognosis. According to our experience, the dual therapy with Carbamazepine and Clonazepam has led to a good control of seizures.

Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review.

Rett Syndrome (RTT) is a rare and severe X-linked developmental brain disorder that occurs primarily in females, with a ratio of 1:10.000. De novo mutations in the Methyl-CpG Binding protein 2 (MECP2) gene on the long arm of X chromosome are responsible for more than 95% cases of classical Rett. In the remaining cases (atypical Rett), other genes are involved such as the cyclin-dependent kinase-like 5 (CDKL5) and the forkhead box G1 (FOXG1). Duplications of the MECP2 locus cause MECP2 duplication syndrome (MDS) which concerns about 1% of male patients with intellectual disability. Sleep disorders are common in individuals with intellectual disability, while the prevalence in children is between 16 and 42%. Over 80% of individuals affected by RTT show sleep problems, with a higher prevalence in the first 7 years of life and some degree of variability in correlation to age and genotype. Abnormalities in circadian rhythm and loss of glutamate homeostasis play a key role in the development of these disorders. Sleep disorders, epilepsy, gastrointestinal problems characterize CDKL5 Deficiency Disorder (CDD). Sleep impairment is an area of overlap between RTT and MECP2 duplication syndrome along with epilepsy, regression and others. Sleep dysfunction and epilepsy are deeply linked. Sleep deprivation could be an aggravating factor of epilepsy and anti-comitial therapy could interfere in sleep structure. Epilepsy prevalence in atypical Rett syndrome with severe clinical phenotype is higher than in classical Rett syndrome. However, RTT present a significant lifetime risk of epilepsy too. Sleep disturbances impact on child's development and patients' families and the evidence for its management is still limited. The aim of this review is to analyze pathophysiology, clinical features, the impact on other comorbidities and the management of sleep disorders in Rett syndrome and Rett-related syndrome.

Temporal Lobe Epilepsy and Psychiatric Comorbidity.

Most focal seizures originate in the temporal lobe and are commonly divided into mesial and lateral temporal epilepsy, depending upon the neuronal circuitry involved. The hallmark features of the mesial temporal epilepsy are aura, unconsciousness, and automatisms. Symptoms often overlap with the lateral temporal epilepsy. However, the latter present a less evident psychomotor arrest, frequent clones and dystonic postures, and common focal to bilateral tonic-clonic seizures. Sclerosis of the hippocampus is the most frequent cause of temporal lobe epilepsy (TLE). TLE is among all epilepsies the most frequently associated with psychiatric comorbidity. Anxiety, depression, and interictal dysphoria are recurrent psychiatric disorders in pediatric patients with TLE. In addition, these alterations are often combined with cognitive, learning, and behavioral impairment. These comorbidities occur more frequently in TLE with hippocampal sclerosis and with pharmacoresistance. According to the bidirectional hypothesis, the close relationship between TLE and psychiatric features should lead to considering common pathophysiology underlying these disorders. Psychiatric comorbidities considerably reduce the quality of life of these children and their families. Thus, early detection and appropriate management and therapeutic strategies could improve the prognosis of these patients. The aim of this review is to analyze TLE correlation with psychiatric disorders and its underlying conditions.

The Broad Clinical Spectrum of Epilepsies Associated With Protocadherin 19 Gene Mutation.

Protocadherin 19 (PCDH19) gene is one of the most common genes involved in epilepsy syndromes. According to literature data PCDH19 is among the 6 genes most involved in genetic epilepsies. PCDH19 is located on chromosome Xq22.1 and is involved in neuronal connections and signal transduction. The most frequent clinical expression of PCDH19 mutation is epilepsy and mental retardation limited to female (EFMR) characterized by epileptic and non-epileptic symptoms affecting mainly females. However, the phenotypic spectrum of these mutations is considerably variable from genetic epilepsy with febrile seizure plus to epileptic encephalopathies. The peculiar exclusive involvement of females seems to be caused by a cellular interference in heterozygosity, however, affected mosaic-males have been reported. Seizure types range from focal seizure to generalized tonic-clonic, tonic, atonic, absences, and myoclonic jerks. Treatment of PCDH19-related epilepsy is limited by drug resistance and by the absence of specific treatment indications. However, seizures become less severe with adolescence and some patients may even become seizure-free. Non-epileptic symptoms represent the main disabilities of adult patients with PCDH19 mutation. This review aims to analyze the highly variable phenotypic expression of PCDH19 gene mutation associated with epilepsy.

Effects of probiotic administration on immune responses of children and adolescents with type 1 diabetes to a quadrivalent inactivated influenza vaccine.

This study was planned to evaluate whether a 3-month treatment with Lactobacillus rhamnosus GG (LGG) can modify immune system functions in children and adolescents with type 1 diabetes (T1D), leading to an increased immune response to an injectable quadrivalent inactivated influenza vaccine (QIV). A total of 87 pediatric patients with T1D were screened, although 34 patients in the Probiotic group and 30 in the Control group accepted to be vaccinated with QIV and completed the study. Vaccine immunogenicity and safety and the inflammatory cytokine response were studied. Results showed that QIV was immunogenic and safe in T1D pediatric patients and pre-administration of LGG for three months did not substantially modify the QIV humoral immunity. The combination of QIV and LGG reduced inflammatory responses (i.e., IFN-γ, IL17A, IL-17F, IL-6, and TNF-α) from activated PBMCs of pediatric patients with T1D, without dampening the production of seroprotective antibodies. In conclusion, QIV is associated with an adequate immunogenicity in children and adolescents with T1D in presence of a good safety profile. Although a systematic administration of LGG did not result in an improvement of humoral responses to an influenza vaccine, the probiotic did induce important anti-inflammatory effects.

Linear Growth in Children and Adolescents with Type 1 Diabetes Mellitus.

Ensuring normal linear growth is one of the major therapeutic aims in the management of type one diabetes mellitus (T1DM) in children and adolescents. Many studies in the literature have shown that pediatric patients with T1DM frequently present some abnormalities in their growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis compared to their healthy peers. Data on the growth of T1DM children and adolescents are still discordant: Some studies have reported that T1DM populations, especially those whose diabetes began in early childhood, are taller than healthy pediatric populations at diagnosis, while other studies have not found any difference. Moreover, many reports have highlighted a growth impairment in T1DM patients of prepubertal and pubertal age, and this impairment seems to be influenced by suboptimal glycemic control and disease duration. However, the most recent data showed that children treated with modern intensive insulin therapies reach a normal final adult height. This narrative review aims to provide current knowledge regarding linear growth in children and adolescents with T1DM. Currently, the choice of the most appropriate therapeutic regimen to achieve a good insulin level and the best metabolic control for each patient, together with the regular measurement of growth parameters, remains the most important available tool for a pediatric diabetologist. Nevertheless, since new technologies are the therapy of choice in young children, especially those of pre-school age, it would be of great interest to evaluate their effects on the growth pattern of children with T1DM.

Environmental Factors Associated With Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disorder that leads to progressive pancreatic ß-cell destruction and culminates in absolute insulin deficiency and stable hyperglycaemia. It is very likely that environmental factors play a role in triggering islet autoimmunity. Knowing whether they have true relevance in favoring T1D development is essential for the effective prevention of the disease. Moreover, prevention could be obtained directly interfering with the development of autoimmunity through autoantigen-based immunotherapy. In this narrative review, the present possibilities for the prevention of T1D are discussed. Presently, interventions to prevent T1D are generally made in subjects in whom autoimmunity is already activated and autoantibodies against pancreatic cell components have been detected. Practically, the goal is to slow down the immune process by preserving the normal structure of the pancreatic islets for as long as possible. Unfortunately, presently methods able to avoid the risk of autoimmune activation are not available. Elimination of environmental factors associated with T1D development, reverse of epigenetic modifications that favor initiation of autoimmunity in subjects exposed to environmental factors and use of autoantigen-based immunotherapy are possible approaches, although for all these measures definitive conclusions cannot be drawn. However, the road is traced and it is possible that in a not so distant future an effective prevention of the disease to all the subjects at risk can be offered.

Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives.

BACKGROUND: Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, neurological signs, and other abnormalities. Two causative genes (WFS1 and WFS2) have been identified. The transmission of the disease takes place in an autosomal recessive mode but autosomal dominant mutations responsible for WS-related disorders have been described. Prognosis is poor, death occurs at the median age of 39 years with a major cause represented by respiratory failure as a consequence of brain stem atrophy and neurodegeneration. The aim of this narrative review is to focus on etiology, pathogenesis and natural history of WS for an adequate patient management and for the discussion of future therapeutic interventions. MAIN BODY: WS requires a multidisciplinary approach in order to be successfully treated. A prompt diagnosis decreases morbidity and mortality through prevention and treatment of complications. Being a monogenic pathology, WS represents a perfect model to study the mechanisms of ER stress and how this condition leads to cell death, in comparison with other prevalent diseases in which multiple factors interact to produce the disease manifestations. WS is also an important disease prototype to identify drugs and molecules associated with ER homeostasis. Evidence indicates that specific metabolic diseases (type 1 and type 2 diabetes), neurodegenerative diseases, atherosclerosis, inflammatory pathologies and also cancer are closely related to ER dysfunction. CONCLUSIONS: Therapeutic strategies in WS are based on drug repurposing (i.e., investigation of approved drugs for novel therapeutic indications) with the aim to stop the progression of the disease by reducing the endoplasmic reticulum stress. An extensive understanding of WS from pathophysiology to therapy is fundamental and more studies are necessary to better manage this devastating disease and guarantee the patients a better quality of life and longer life expectancy.

Complex Investigation of a Pediatric Haematological Case: Haemophagocytic Syndrome Associated with Visceral Leishmaniasis and Epstein⁻Barr (EBV) Co-Infection.

BACKGROUND: Visceral leishmaniasis (VL) is an anthropozoonosis caused by an intracellular parasite belonging to the genus Leishmania. In the Mediterranean region, L. donovani and L. infantum are responsible for VL and dogs are the main reservoir. Haemophagocytic lymphohistiocytosis (HLH) represents a complication of VL and consists of unrestrained activation and proliferation of lymphocytes and macrophages, leading to uncontrolled immune activation. Haemophagocytic lymphohistiocytosis may also develop during viral infection, and Epstein⁻Barr virus (EBV) infection is one of the main HLH causes. Macrophage haemophagocytosis in the bone marrow aspirate is pathognomonic. CASE PRESENTATION: The case involves a 19-month-old male infant presenting with a high persistent fever with a fluctuating pattern, pancytopaenia, hepatosplenomegaly, and a high triglyceride level. Initial investigations showed an EBV infection. Considering the persistent signs and symptoms, bone marrow aspiration was performed and confirmed the suspicion of HLH. In addition, the presence of Leishmania infection was shown. The patient was treated with liposomal amphotericin B and had complete resolution of his symptoms. CONCLUSION: Diagnosis of VL represents a demanding challenge in endemic and non-endemic areas. Our case demonstrates that leishmaniasis should always be considered in the differential diagnosis in patients presenting with hepatosplenomegaly and cytopaenia with a persistent fever, even in cases of infectious mononucleosis. Moreover, the execution of bone marrow aspiration should not be delayed in order to diagnose and treat at an early stage the potential occurrence of VL, especially if complicated with HLH.

Flash Glucose Monitoring: A Review of the Literature with a Special Focus on Type 1 Diabetes.

In people with type 1 diabetes mellitus (T1DM), obtaining good glycemic control is essential to reduce the risk of acute and chronic complications. Frequent glucose monitoring allows the adjustment of insulin therapy to improve metabolic control with near-normal blood glucose concentrations. The recent development of innovative technological devices for the management of T1DM provides new opportunities for patients and health care professionals to improve glycemic control and quality of life. Currently, in addition to traditional self-monitoring of blood glucose (SMBG) through a glucometer, there are new strategies to measure glucose levels, including the detection of interstitial glucose through Continuous Glucose Monitoring (iCGM) or Flash Glucose Monitoring (FGM). In this review, we analyze current evidence on the efficacy and safety of FGM, with a special focus on T1DM. FGM is an effective tool with great potential for the management of T1DM both in the pediatric and adult population that can help patients to improve metabolic control and quality of life. Although FGM might not be included in the development of an artificial pancreas and some models of iCGM are more accurate than FGM and preferable in some specific situations, FGM represents a cheaper and valid alternative for selected patients. In fact, FGM provides significantly more data than the intermittent results obtained by SMBG, which may not capture intervals of extreme variability or nocturnal events. With the help of a log related to insulin doses, meal intake, physical activity and stress factors, people can achieve the full benefits of FGM and work together with health care professionals to act upon the information provided by the sensor. The graphs and trends available with FGM better allow an understanding of how different factors (e.g., physical activity, diet) impact glycemic control, consequently motivating patients to take charge of their health.

Efficacy and safety of the artificial pancreas in the paediatric population with type 1 diabetes.

BACKGROUND: Type 1 diabetes (DM1) is one of the most common chronic diseases in childhood and requires life-long insulin therapy and continuous health care support. An artificial pancreas (AP) or closed-loop system (CLS) have been developed with the aim of improving metabolic control without increasing the risk of hypoglycaemia in patients with DM1. As the impact of APs have been studied mainly in adults, the aim of this review is to evaluate the efficacy and safety of the AP in the paediatric population with DM1. MAIN BODY: The real advantage of a CLS compared to last-generation sensor-augmented pumps is the gradual modulation of basal insulin infusion in response to glycaemic variations (towards both hyperglycaemia and hypoglycaemia), which has the aim of improving the proportion of time spent in the target glucose range and reducing the mean glucose level without increasing the risk of hypoglycaemia. Some recent studies demonstrated that also in children and adolescents an AP is able to reduce the frequency of hypoglycaemic events, an important limiting factor in reaching good metabolic control, particularly overnight. However, the advantages of the AP in reducing hyperglycaemia, increasing the time spent in the target glycaemic range and thus reducing glycated haemoglobin are less clear and require more clinical trials in the paediatric population, in particular in younger children. CONCLUSIONS: Although the first results from bi-hormonal CLS are promising, long-term, head-to-head studies will have to prove their superiority over insulin-only approaches. More technological progress, the availability of more fast-acting insulin, further developments of algorithms that could improve glycaemic control after meals and physical activity are the most important challenges in reaching an optimal metabolic control with the use of the AP in children and adolescents.

Carbohydrate Counting in Children and Adolescents with Type 1 Diabetes.

Carbohydrate counting (CC) is a meal-planning tool for patients with type 1 diabetes (T1D) treated with a basal bolus insulin regimen by means of multiple daily injections or continuous subcutaneous insulin infusion. It is based on an awareness of foods that contain carbohydrates and their effect on blood glucose. The bolus insulin dose needed is obtained from the total amount of carbohydrates consumed at each meal and the insulin-to-carbohydrate ratio. Evidence suggests that CC may have positive effects on metabolic control and on reducing glycosylated haemoglobin concentration (HbA1c). Moreover, CC might reduce the frequency of hypoglycaemia. In addition, with CC the flexibility of meals and snacks allows children and teenagers to manage their T1D more effectively within their own lifestyles. CC and the bolus calculator can have possible beneficial effects in improving post-meal glucose, with a higher percentage of values within the target. Moreover, CC might be integrated with the counting of fat and protein to more accurately calculate the insulin bolus. In conclusion, in children and adolescents with T1D, CC may have a positive effect on metabolic control, might reduce hypoglycaemia events, improves quality of life, and seems to do so without influencing body mass index; however, more high-quality clinical trials are needed to confirm this positive impact.