Cannabidiol: metabolism and clinical efficacy in epileptic patients.

INTRODUCTION: The landscape of epilepsy treatment has undergone a significant transformation with the emergence of cannabidiol as a potential therapeutic agent. Epidiolex, a pharmaceutical formulation of highly purified CBD, garnered significant attention not just for its therapeutic potential but also for being the first cannabis-derived medication to obtain approval from regulatory bodies. AREA COVERED: In this narrative review the authors explore the intricate landscape of CBD as an antiseizure medication, deepening into its pharmacological mechanisms and clinical trials involving various epileptic encephalopathies. This exploration serves as a comprehensive guide, shedding light on a compound that holds promise for individuals contending with the significant challenges of drug-resistant epilepsy. EXPERT OPINION: Rigorous studies highlight cannabidiol's efficacy, safety profile, and potential cognitive benefits, warranting further exploration for its approval in various drug-resistant epilepsy forms. As a promising therapeutic option, cannabidiol not only demonstrates efficacy in seizure control but also holds the potential for broader enhancements in the quality of life, especially for patients with epileptic encephalopathies.

Current Overview of CDKL-5 Deficiency Disorder Treatment.

CDKL5 deficiency disorder (CDD) is a complex of clinical symptoms resulting from the presence of non-functional or absent CDKL5 protein, a serine-threonine kinase involved in neural maturation and synaptogenesis [...].

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.

The impact of anti-seizure medications on electroencephalogram (EEG) results.

INTRODUCTION: Despite recent advances in neuroimaging and genetics, electroencephalography (EEG) continues to play a central role in the diagnosis and management of epilepsy. One application of EEG is called pharmaco-EEG. This technique is highly sensitive in detecting the effects of drugs on brain functioning and shows potential in predicting the efficacy and tolerability of anti-seizure medications (ASMs). AREAS COVERED: In this narrative review, the authors discuss the most salient data concerning the effects of different ASMs on EEG. The authors aim to provide a clear and concise overview of the current state of research in this area, while also identifying opportunities for future investigation. EXPERT OPINION: To date, pharmaco-EEG does not appear to be clinically reliable for predicting treatment response in epilepsy, as the literature is limited by underreporting of negative results, a lack of controls in many studies and insufficient direct replication of previous findings. Future research should focus on controlled interventional studies, which are currently lacking.

Clinical spectrum and currently available treatment of type I interferonopathy Aicardi-Goutières syndrome.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a genetically determined disorder with a variable phenotype. Since the original description of AGS, advances in gene sequencing techniques have resulted in a significant broadening of the phenotypic spectrum associated with AGS genes, and new clinical pictures have emerged beyond the classic presentation. The aim of this review is to provide a comprehensive analysis of the clinical spectrum of AGS and report currently available treatments and new immunosuppressive strategies. DATA SOURCES: Literature reviews and original research articles were collected from databases, including PubMed and ClinicalTrials.gov. Relevant articles about AGS were included. RESULTS: The involvement of the nervous system certainly represents the major cause of mortality and morbidity in AGS patients. However, other clinical manifestations, such as chilblains, hepatosplenomegaly, and hematological disturbances, may lead to the diagnosis and considerably impact the prognosis and overall quality of life of these patients. Therapeutic approaches of AGS are limited to interventions aimed at specific symptoms and the management of multiple comorbidities. However, advances in understanding the pathogenesis of AGS could open new and more effective therapies. CONCLUSIONS: The over-activation of innate immunity due to upregulated interferon production plays a critical role in AGS, leading to multi-organ damage with the main involvement of the central nervous system. To date, there is no specific and effective treatment for AGS. New drugs specifically targeting the interferon pathway may bring new hope to AGS patients.

Epilepsy and Cognitive Impairment in Childhood and Adolescence: A Mini-Review.

Managing epilepsy in people with an intellectual disability remains a therapeutic challenge and must take into account additional issues such as diagnostic difficulties and frequent drug resistance. Advances in genomic technologies improved our understanding of epilepsy and raised the possibility to develop patients-tailored treatments acting on the key molecular mechanisms involved in the development of the disease. In addition to conventional antiseizure medications (ASMs), ketogenic diet, hormone therapy and epilepsy surgery play an important role, especially in cases of drugresistance. This review aims to provide a comprehensive overview of the mainfactors influencing cognition in children and adolescents with epilepsy and the main therapeutic options available for the epilepsies associated with intellectual disability.

Clinical and electroencephalographic features of epilepsy in patients with triple X syndrome: A case series.

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 amenorrhea, 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, electroencephalogram 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 epilepsy 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.

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.

Improving Therapy of Pharmacoresistant Epilepsies: The Role of Fenfluramine.

Epilepsy is among the most common neurological chronic disorders, with a prevalence of 0.5-1%. Despite the introduction of new antiepileptic drugs during recent years, about one third of the epileptic population remain drug-resistant. Hence, especially in the pediatric population limited by different pharmacokinetics and pharmacodynamics and by ethical and regulatory issues it is needed to identify new therapeutic resources. New molecules initially used with other therapeutic indications, such as fenfluramine, are being considered for the treatment of pharmacoresistant epilepsies, including Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). Drug-refractory seizures are a hallmark of both these conditions and their treatment remains a major challenge. Fenfluramine is an amphetamine derivative that was previously approved as a weight loss drug and later withdrawn when major cardiac adverse events were reported. However, a new role of fenfluramine has emerged in recent years. Indeed, fenfluramine has proved to be a promising antiepileptic drug with a favorable risk-benefit profile for the treatment of DS, LGS and possibly other drug-resistant epileptic syndromes. The mechanism by which fenfluramine provide an antiepileptic action is not fully understood but it seems to go beyond its pro-serotoninergic activity. This review aims to provide a comprehensive analysis of the literature, including ongoing trials, regarding the efficacy and safety of fenfluramine as adjunctive treatment of pharmacoresistant epilepsies.

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.

Corrigendum: Improving therapy of pharmacoresistant epilepsies: The role of fenfluramine.

[This corrects the article DOI: 10.3389/fphar.2022.832929.].

The Vitamin D Role in Preventing Primary Headache in Adult and Pediatric Population.

Headache is among the main neurological disorders with a great impact on both adults and children. The diagnosis of primary headache and proper management is often delayed with a great impact on work productivity and overall quality of life. Chronic headache often requires prophylactic therapy to reduce the frequency and severity of the attacks and the use of abortive medications. Besides the use of several classes of drugs, another treatment modality is the use of Nutraceuticals. Some studies have suggested a possible role of vitamin D in headache prophylaxis. Indeed, vitamin D is involved in several pathways of brain development, neuroprotection and neurotransmission. Moreover, there is data suggesting a close relationship between primary headache and vitamin D deficiency, both in children and in adults. To date, a few studies have evaluated the effect of vitamin D on headaches. The aim of this review is to summarize the data collected on headache prophylaxis with vitamin D comparing the effects of vitamin D in pediatric and adult populations.

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.

Case Report: Remdesivir and Convalescent Plasma in a Newly Acute B Lymphoblastic Leukemia Diagnosis With Concomitant Sars-CoV-2 Infection.

Introduction: The spread of Covid-19 has worsened the prognosis of oncology patients, interrupting or delaying life-saving therapies and contextually increasing the risk of severe SARS-CoV-2 infections. Acute lymphoblastic leukemia (ALL) is the most frequent cancer in pediatric age and the management of this disease with concomitant SARS-COV-2 infection represents a challenging situation. Case presentation: We present the case of a 6-year-old female newly diagnosed with ALL during a documented SARS-CoV-2 infection. Our patient was admitted 20 days after SARS-CoV-2 detection for evening-rise fever. Laboratory testing showed severe neutropenia while chest x-ray detected moderate pulmonary involvement. Acute lymphoblastic leukemia diagnosis was made through morphological and molecular analysis on bone marrow aspirate. Given the stability of the blood count and clinical conditions, antiviral therapy with Remdesivir and Convalescent Plasma was started before antileukemic treatment, obtaining a rapid resolution of the infection. Conclusion: In our experience, the treatment with Remdesivir and Convalescent Plasma led to a rapid resolution of Sars-Cov-2 infection. Our case did not present any adverse event to the therapy. Thus, this treatment could be considered in patients with malignancies, in order to accelerate the resolution of the infection and begin immunosuppressive treatment safely. Further studies are required to confirm this hypothesis.

The Pharmacoresistant Epilepsy: An Overview on Existant and New Emerging Therapies.

Epilepsy is one of the most common neurological chronic disorders, with an estimated prevalence of 0. 5 - 1%. Currently, treatment options for epilepsy are predominantly based on the administration of symptomatic therapy. Most patients are able to achieve seizure freedom by the first two appropriate drug trials. Thus, patients who cannot reach a satisfactory response after that are defined as pharmacoresistant. However, despite the availability of more than 20 antiseizure medications (ASMs), about one-third of epilepsies remain drug-resistant. The heterogeneity of seizures and epilepsies, the coexistence of comorbidities, and the broad spectrum of efficacy, safety, and tolerability related to the ASMs, make the management of these patients actually challenging. In this review, we analyze the most relevant clinical and pathogenetic issues related to drug-resistant epilepsy, and then we discuss the current evidence about the use of available ASMs and the alternative non-pharmacological approaches.

Noncontact Body Temperature Measurement: Uncertainty Evaluation and Screening Decision Rule to Prevent the Spread of COVID-19.

The need to measure body temperature contactless and quickly during the COVID-19 pandemic emergency has led to the widespread use of infrared thermometers, thermal imaging cameras and thermal scanners as an alternative to the traditional contact clinical thermometers. However, limits and issues of noncontact temperature measurement devices are not well known and technical-scientific literature itself sometimes provides conflicting reference values on the body and skin temperature of healthy subjects. To limit the risk of contagion, national authorities have set the obligation to measure body temperature of workers at the entrance to the workplace. In this paper, the authors analyze noncontact body temperature measurement issues from both clinical and metrological points of view with the aim to (i) improve body temperature measurements accuracy; (ii) estimate the uncertainty of body temperature measurement on the field; (iii) propose a screening decision rule for the prevention of the spread of COVID-19. The approach adopted in this paper takes into account both the traditional instrumental uncertainty sources and clinical-medical ones related to the subjectivity of the measurand. A proper screening protocol for body temperature measurement considering the role of uncertainty is essential to correctly choose the threshold temperature value and measurement method to access critical places during COVID-19 pandemic emergency.

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.

Intestinal lymphangiectasia in a 3-month-old girl: A case report of Hennekam syndrome caused by CCBE1 mutation.

RATIONAL: Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation and rupture of intestinal lymphatic channels leading to protein-losing enteropathy. IL is classified as primary and secondary types. PATIENT CONCERNS: A 3-month-old girl born at term from vaginal delivery with an APGAR score of 10/10 and birth weight of 4.310 g (>97° percentile) was admitted to our hospital because of increasing abdominal tenderness and diarrhea. At first examination, she presented an abdominal circumference of 60 cm, edema of the lower extremities and vulva, and facial dysmorphisms (hypertelorism, flat nasal bridge, flat mid-face). DIAGNOSIS: Once admitted, ultrasonography showed a large amount of ascites, while blood laboratory investigations revealed severe hypoproteinemia, hypoalbuminemia and hypogammaglobulinemia. Lymphoscintigraphy with 99m-Tc-nanocolloid demonstrated abnormal leakage of the tracer in the abdomen as evidence of IL. To detect a possible secondary, exams were performed and demonstrated positive antibody titres for CMV-IgM and IgG in blood and CMV-DNA positivity in blood, urine, saliva, maternal milk, and gastric and duodenal biopsies. Genetic investigations identified the genomic variant c.472C>T of the CCBE1 gene, coding for a protein variant (p.Arg158Cys), in homozygosity. INTERVENTIONS: Total parenteral nutrition was started and continued for a total of 18 days, then gradually bridged by enteral nutrition with a special formula. In addition, antiviral therapy for CMV infection was added first with intravenous ganciclovir for 14 days, resulting in the disappearance of blood viral load after 7 days of therapy and then with valganciclovir per os for another 30 days. OUTCOMES: The clinical course of the child gradually improved. A few days after starting treatments, lower extremities and vulvar edema disappeared, and abdominal circumference gradually decreased to a stable value of 38 cm, without any ultrasonographic signs of ascites left. Moreover, serum albumin and IgG rose to normal values after 3 months (4.3 g/dL and 501 mg/dL, respectively). LESSONS: This case suggests that in presence of IL both primary and secondary causes should be evaluated. On the other hand, genetic diagnosis is crucial not only for diagnosis but also for prognosis in HS. Life expectancy and quality could deeply vary among different gene mutations and protein variants of the same gene. Further studies and case reports are needed to better understand the clinical meaning of these genetic results and the role of CMV as trigger of IL.

Autism Spectrum Disorders and the Gut Microbiota.

In recent years, there has been an emerging interest in the possible role of the gut microbiota as a co-factor in the development of autism spectrum disorders (ASDs), as many studies have highlighted the bidirectional communication between the gut and brain (the so-called "gut-brain axis"). Accumulating evidence has shown a link between alterations in the composition of the gut microbiota and both gastrointestinal and neurobehavioural symptoms in children with ASD. The aim of this narrative review was to analyse the current knowledge about dysbiosis and gastrointestinal (GI) disorders in ASD and assess the current evidence for the role of probiotics and other non-pharmacological approaches in the treatment of children with ASD. Analysis of the literature showed that gut dysbiosis in ASD has been widely demonstrated; however, there is no single distinctive profile of the composition of the microbiota in people with ASD. Gut dysbiosis could contribute to the low-grade systemic inflammatory state reported in patients with GI comorbidities. The administration of probiotics (mostly a mixture of Bifidobacteria, Streptococci and Lactobacilli) is the most promising treatment for neurobehavioural symptoms and bowel dysfunction, but clinical trials are still limited and heterogeneous. Well-designed, randomized, placebo-controlled clinical trials are required to validate the effectiveness of probiotics in the treatment of ASD and to identify the appropriate strains, dose, and timing of treatment.