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Autonomic symptoms may be local and general clinical manifestations of both epilepsy and migraine caused by the dysfunction of brain areas best known as the central autonomic network. Despite their prevalence, autonomic signs are often misdiagnosed and their treatment is undervalued. This review aims to describe the autonomic manifestations reported during seizures and migraineur attacks according to their presentation, focusing on the role of the central autonomic network (CAN) and on the parasympathetic outflow that often-induced cranial autonomic symptoms (CAS) during migraineur attacks. Further, our purpose is to analyze the pathophysiological meanings and whether their presence influences the prognosis and therapy of these disorders.
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Sistema Nervioso Autónomo , Epilepsia , Trastornos Migrañosos , Humanos , Trastornos Migrañosos/fisiopatología , Epilepsia/fisiopatología , Sistema Nervioso Autónomo/fisiopatologíaRESUMEN
BACKGROUND: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder for which the neurological aspects, particularly headaches, remain poorly understood, despite significantly affecting morbidity. The present study aimed to elucidate the prevalence, characteristics and treatment strategies, as well as explore the pathogenesis of headaches, in SWS. METHODS: Using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed observational studies, case reports and series from eight databases (Cochrane Library, EBSCO, Embase, Medline, PubMed, Science Direct, Scopus and Web of Science), published from 1978 to 2023, to investigate the prevalence, characteristics, medication response and pathogenic theories of headaches in SWS. RESULTS: The review analyzed 48 studies, uncovering headache prevalence between 37% and 71%. Migraine-like headache affected up to 52% of individuals. Prophylactic and acute treatments included non-steroidal anti-inflammatory drugs, triptans and antiepileptic drugs, despite the lack of established guidelines. Life-threatening headaches in SWS are uncommon, typically accompanied by other neurological symptoms. The pathogenesis of headaches in SWS is considered to involve venous congestion and neuronal hyperexcitability linked to leptomeningeal angiomas. CONCLUSIONS: Headaches occur more frequently in individuals with SWS than in the general population. Despite symptoms meeting migraine criteria, these headaches should be considered secondary to vascular conditions. Implementing acute and prophylactic treatment is advised to reduce the impact on patients' lives.
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Cefalea , Síndrome de Sturge-Weber , Síndrome de Sturge-Weber/complicaciones , Síndrome de Sturge-Weber/epidemiología , Humanos , Cefalea/epidemiología , Cefalea/etiologíaRESUMEN
BACKGROUND: The relationship between Helicobacter-pylori(Hp)infection and inflammatory-bowel-disease(IBD) in pediatric-patients remains controversial. We aimed to assess the Hp-infection occurrence in newly-diagnosed pediatric-patients with IBD compared to no-IBD patients. Additionally, we aimed to examine differences in clinical-activity-index(CAI) and endoscopic-severity-score(ESS)between IBD-patients with and without Hp-infection, at baseline and at 1-year-follow-up(FU), after eradication-therapy(ET). METHODS: IBD diagnosis was based on Porto-criteria, and all patients underwent gastroscopy at baseline and 1-year FU. For Crohn's-disease(CD) and ulcerative colitis(UC), IBD-CAI and -ESS were classified using PCDAI/SES-CD and PUCAI/UCEIS, respectively. RESULTS: 76 IBD-patients were included in the study[35 F(46.1%),median-age 12(range 2-17)]. CD and UC were diagnosed in 29(38.2%) and 45(59.2%)patients, respectively, and unclassified-IBD in two(2.6%)patients. Non-IBD patients were 148[71 F(48.0%),median-age 12(range 1-17)]. Hp-infection at baseline was reported in 7(9.2%) and 18(12.2%)IBD and non-IBD patients, respectively(p = 0.5065). The 7 IBD patients with Hp infection were compared to 69 IBD patients without Hp-infection at baseline evaluation, and no significant differences were reported considering CAI and ESS in these two groups. At 1-year FU, after ET, IBD patients with Hp infection improved, both for CAI and ESS, but statistical significance was not reached. CONCLUSION: The occurrence of Hp-infection did not differ between IBD and no-IBD patients. No differences in CAI or ESS were observed at the diagnosis, and after ET no worsening of CAI or ESS was noted at one-year FU, between Hp-positive and -negative IBD patients.
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Colitis Ulcerosa , Infecciones por Helicobacter , Helicobacter pylori , Humanos , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/diagnóstico , Niño , Masculino , Femenino , Adolescente , Estudios Prospectivos , Preescolar , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/microbiología , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/microbiología , Índice de Severidad de la Enfermedad , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/microbiología , Gastroscopía , Estudios de Seguimiento , Antibacterianos/uso terapéuticoRESUMEN
BACKGROUND: Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. METHODS: We enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. RESULTS: We studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. CONCLUSIONS: Our study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.
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Electroencefalografía , Epilepsia , Fenotipo , Humanos , Niño , Masculino , Femenino , Preescolar , Epilepsia/fisiopatología , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Adolescente , Adulto , Adulto JovenRESUMEN
Febrile seizures (FS) are commonly perceived by healthcare professionals as a self-limited condition with a generally 'benign' nature. Nonetheless, they frequently lead to pediatric consultations, and their management can vary depending on the clinical context. For parents and caregivers, witnessing a seizure can be a distressing experience, significantly impacting their quality of life. In this review, we offer an in-depth exploration of FS management, therapeutic interventions, and prognostic factors, with the aim of providing support for physicians and enhancing communication with families. We conducted a comprehensive literature search using the PubMed and Web of Science databases, spanning the past 50 years. The search terms utilized included "febrile seizure," "complex febrile seizure," "simple febrile seizure," in conjunction with "children" or "infant." Only studies published in English or those presenting evidence-based data were included in our assessment. Additionally, we conducted a cross-reference search to identify any additional relevant data sources. Our thorough literature search resulted in a compilation of references, with carefully selected papers thoughtfully integrated into this review.
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Convulsiones Febriles , Humanos , Convulsiones Febriles/terapia , Convulsiones Febriles/diagnóstico , Niño , Lactante , Guías de Práctica Clínica como Asunto , Anticonvulsivantes/uso terapéutico , PronósticoRESUMEN
BACKGROUND: To date, the etiology and risk factors of torticollis are still poorly defined in the pediatric literature. Especially in the Emergency Department (ED) scenario, it is critical to reliably distinguish benign and transient conditions from (potentially) life-threatening disorders. This study describes the clinical characteristics of a large sample of children with torticollis. The aim of our study was to detect epidemiology, etiology and predictive variables associated with a higher risk of life-threatening conditions in acute torticollis. METHODS: We conducted a pediatric retrospective study of acute torticollis over a 13-year period referred to the ED of a tertiary pediatric Hospital. We reported the characteristics in the overall sample and in two subgroups divided according to urgency of the underlying condition. Furthermore, we developed a multivariate model aimed at identifying the main clinical predictors of the need for urgent care. RESULTS: 1409 patients were analyzed (median age 5.7 years, IQR 5.8). A history of trauma was present in 393 patients (27.9%). The symptom most frequently associated with torticollis were pain (83.5%). At least one pathological finding was found in 5.4 to 7.9% of patients undergoing further imaging. Hospitalization was required in 11.1% of cases (median duration 4 days). The most frequent etiologies of torticollis were postural cause (43.1%), traumatic (29.5%), and infective/inflammatory (19.1%). A longer time from onset of torticollis and the presence of headache or vomiting were strongly correlated with an underlying urgent condition, after adjusting for the other clinically and statistically significant variables in the bivariate analysis. CONCLUSION: Our study shows that an urgent condition most commonly occur in patients presenting with history of trauma or headache, vomiting and torticollis for more than 24 h should undergo further diagnostic evaluation and short-term follow-up, restricting invasive or expensive investigations to patients with clinical suspicion of an underlying harmful condition.
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Servicio de Urgencia en Hospital , Tortícolis , Humanos , Tortícolis/epidemiología , Tortícolis/etiología , Tortícolis/diagnóstico , Masculino , Femenino , Estudios Retrospectivos , Preescolar , Niño , Factores de Riesgo , Lactante , Hospitalización/estadística & datos numéricos , AdolescenteRESUMEN
OBJECTIVES: To assess ocular microvasculature changes using optical coherence tomography angiography (OCTA) in pediatric patients with inflammatory bowel disease (IBD). METHODS: Patients (aged 6-18 years) with IBD were recruited between September 2021 and May 2023. All eligible participants underwent comprehensive clinical assessment and laboratory investigation. Patients with functional gastrointestinal disorders served as the controls. This study assessed specific IBD phenotypes, disease duration, clinical and endoscopic activity indices, laboratory markers, and medication histories. OCTA was utilized to evaluate ocular microvasculature changes in both groups. RESULTS: A total of 63 children (mean age 12.9 ± 3.3 years) were enrolled, comprising 38 in the IBD group (16 ulcerative colitis, 22 Crohn's disease, and 25 in the control group). Most patients in the IBD group were in remission or had mild-to-moderate disease activity at enrollment. Analysis of the OCTA results revealed significant differences in the choroidal luminal area and total choroidal area between the IBD and control groups. CONCLUSIONS: The study identified distinct ocular microvasculature changes in pediatric IBD patients through OCTA, suggestive of potential systemic endothelial dysfunction. These findings underscore the utility of OCTA in evaluating microvascular alterations associated with pediatric IBD, offering insights into potential systemic complications linked to inflammation in IBD patients.
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Tomografía de Coherencia Óptica , Humanos , Niño , Adolescente , Masculino , Femenino , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/fisiopatología , Microvasos/fisiopatología , Microvasos/diagnóstico por imagen , Microvasos/patología , Estudios de Casos y Controles , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/fisiopatología , Endotelio Vascular/fisiopatología , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/fisiopatologíaRESUMEN
The adaptor protein 4 (AP-4) constitutes a conserved hetero-tetrameric complex within the family of adaptor protein (AP) complex, crucial for the signal-mediated trafficking of integral membrane proteins. Mutations affecting all subunits of the AP-4 complex have been linked to autosomal-recessive cerebral palsy and a complex hereditary spastic paraparesis (HSP) phenotype. Our report details the case of a 14-year-old boy born to consanguineous parents, presenting psychomotor delay, severe intellectual disability, microcephaly, and trigonocephaly. Despite a history of febrile seizures, subsequent years were devoid of seizures, with normal EEG. Exome sequencing revealed pathogenic variants in both the AP4B1 and ERF genes. Significantly, the patient exhibited features associated with AP4B1 mutations, including distinctive traits such as cranial malformations. The ERF gene variant, linked to craniosynostosis, likely contributes to the observed trigonocephaly. This case represents the initial documentation of a concurrent mutation in the AP4B1 and ERF genes, underscoring the critical role of exome analysis in unraveling complex phenotypes. Understanding these complex genotypes offers valuable insights into broader syndromic conditions, facilitating comprehensive patient management.
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Complejo 4 de Proteína Adaptadora , Mutación , Factores de Terminación de Péptidos , Fenotipo , Proteínas Represoras , Humanos , Masculino , Adolescente , Factores de Terminación de Péptidos/genética , Complejo 4 de Proteína Adaptadora/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Secuenciación del Exoma , Microcefalia/genética , Microcefalia/patología , Craneosinostosis/genética , Craneosinostosis/patologíaRESUMEN
OBJECTIVE: This study aimed to evaluate the efficacy and safety of co-micronized palmitoylethanolamide (PEA)/polydatin (PD) in the treatment of abdominal pain symptoms in pediatric patients with irritable bowel syndrome (IBS). METHODS: This was a multicenter trial conducted at three Italian pediatric gastroenterology centers, employing a double-blind, placebo-controlled, parallel-arm design. Participants were ages 10 to 17 y and met Rome IV criteria for pediatric IBS. They were randomly allocated to receive either co-micronized PEA/PD or placebo, administered three times daily in a 1:1 ratio, over a 12-wk period. The study assessed baseline severity using the IBS-Severity Scoring System (IBS-SSS) at enrollment and after 4, 8, and 12 wk of treatment. Abdominal pain frequency was assessed on a scale from 1 to 7 d/wk, while stool consistency was classified using the Bristol Stool Scale (BSS) to categorize various IBS subtypes. The primary outcome was the percentage of patients who achieved complete remission, defined as IBS-SSS score <75 points after 12 wk of therapy. RESULTS: The study involved 70 children with IBS. Of the participants, 34 received co-micronized PEA/PD, and 36 received a placebo. As compared with the placebo group, the co-micronized therapy group had significantly more patients achieving complete remission after 12 wk (P = 0.015), with particular benefit in the IBS-diarrhea subtype (P = 0.01). The treatment group also experienced a significant reduction in abdominal pain intensity and frequency compared with the placebo group. No adverse events were recorded during the study period. CONCLUSIONS: Co-micronized PEA/PD is a safe and effective treatment to treat abdominal pain symptoms in pediatric IBS.
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Amidas , Etanolaminas , Glucósidos , Síndrome del Colon Irritable , Ácidos Palmíticos , Estilbenos , Humanos , Niño , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/tratamiento farmacológico , Diarrea/tratamiento farmacológico , Resultado del Tratamiento , Dolor Abdominal/tratamiento farmacológico , Dolor Abdominal/etiología , Respuesta Patológica Completa , Método Doble CiegoRESUMEN
BACKGROUND: Pediatric chronic intestinal pseudo-obstruction (PIPO) is a rare disease characterized by symptoms and radiological signs suggestive of intestinal obstruction, in the absence of lumen-occluding lesions. It results from an extremely severe impairment of propulsive motility. The intestinal endocrine system (IES) jointly with the enteric nervous system (ENS) regulates secreto-motor functions via different hormones and bioactive messengers/neurotransmitters. The neurotransmitter 5-hydroxytryptamine (5-HT) (or serotonin) is linked to intestinal peristalsis and secretory reflexes. Gut microbiota and its interplay with ENS affect 5-HT synthesis, release, and the subsequent serotonin receptor activation. To date, the interplay between 5-HT and gut microbiota in PIPO remains largely unclear. This study aimed to assess correlations between mucosa associated microbiota (MAM), intestinal serotonin-related genes expression in PIPO. To this purpose, biopsies of the colon, ileum and duodenum have been collected from 7 PIPO patients, and 7 age-/sex-matched healthy controls. After DNA extraction, the MAM was assessed by next generation sequencing (NGS) of the V3-V4 region of the bacterial RNA 16 S, on an Illumina Miseq platform. The expression of genes implicated in serotoninergic pathway (TPH1, SLC6A4, 5-HTR3 and 5-HTR4) was established by qPCR, and correlations with MAM and clinical parameters of PIPO have been evaluated. RESULTS: Our results revealed that PIPO patients exhibit a MAM with a different composition and with dysbiosis, i.e. with a lower biodiversity and fewer less connected species with a greater number of non-synergistic relationships, compared to controls. qPCR results revealed modifications in the expression of serotonin-related intestinal genes in PIPO patients, when compared to controls. Correlation analysis do not reveal any kind of connection. CONCLUSIONS: For the first time, we report in PIPO patients a specific MAM associated to underlying pathology and an altered intestinal serotonin pathway. A possible dysfunction of the serotonin pathway, possibly related to or triggered by an altered microbiota, may contribute to dysmotility in PIPO patients. The results of our pilot study provide the basis for new biomarkers and innovative therapies targeting the microbiota or serotonin pathways in PIPO patients.
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Microbioma Gastrointestinal , Seudoobstrucción Intestinal , Humanos , Niño , Serotonina/metabolismo , Proyectos Piloto , Intestinos , Seudoobstrucción Intestinal/genética , Seudoobstrucción Intestinal/diagnóstico , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Different conditions may underlie gastrointestinal bleeding (GIB) in children. The estimated prevalence of GIB in children is 6.4%, with spontaneous resolution in approximately 80% of cases. Nonetheless, the initial approach plays a pivotal role in determining the prognosis. The priority is the stabilization of hemodynamic status, followed by a systematic diagnostic approach. GIB can originate from either upper or lower gastrointestinal tract, leading to a broad differential diagnosis in infants and children. This includes benign and self-limiting disorders, alongside serious conditions necessitating immediate treatment. We performed a nonsystematic review of the literature, in order to describe the variety of conditions responsible for GIB in pediatric patients and to outline diagnostic pathways according to patients' age, suspected site of bleeding and type of bleeding which can help pediatricians in clinical practice. Diagnostic modalities may include esophagogastroduodenoscopy and colonoscopy, abdominal ultrasonography or computed tomography and, when necessary, magnetic resonance imaging. In this review, we critically assess these procedures, emphasizing their respective advantages and limitations concerning specific clinical scenarios.
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Colonoscopía , Hemorragia Gastrointestinal , Lactante , Humanos , Niño , Diagnóstico Diferencial , PediatrasRESUMEN
Cases of association between celiac disease and wheat allergy have been described in the literature. However, to date, no reported cases have linked celiac disease with wheat food protein-induced enterocolitis syndrome (FPIES). We report a case of this association. A child diagnosed with celiac disease at the age of 2 years, following a gluten-free diet, experienced uncontrollable vomiting, and subsequent hypotension within 2 h of accidental ingestion of wheat flour. As a result, the child required hospitalization for fluid therapy. A similar episode occurred when the child turned 5 y, again resulting from accidental gluten ingestion. This time, the symptoms included vomiting, hypotension, and a loss of consciousness, leading to hospitalization for rehydration treatment. After this second episode, on suspicion of FPIES, the patient was referred to the pediatric allergists, who confirmed the diagnosis. To our knowledge, this is the first case of an association between celiac disease and FPIES. It has been hypothesized that exclusion diets in food-allergic children may lead to an increase in specific immunoglobulin E levels for those foods and, consequently, the risk of anaphylaxis. However, FPIES is not an immunoglobulin E-mediated condition. Hence, further investigations are warranted to elucidate the underlying mechanisms linking these 2 disorders.
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Enfermedad Celíaca , Enterocolitis , Hipersensibilidad a los Alimentos , Hipotensión , Humanos , Niño , Lactante , Preescolar , Hipersensibilidad a los Alimentos/complicaciones , Enfermedad Celíaca/complicaciones , Harina/efectos adversos , Triticum/efectos adversos , Enterocolitis/terapia , Enterocolitis/complicaciones , Alérgenos , Vómitos/complicaciones , Inmunoglobulina E , Hipotensión/complicaciones , Proteínas en la Dieta/efectos adversosRESUMEN
BACKGROUND AND OBJECTIVES: Movement disorders (MDs) are underrecognized in the developmental and epileptic encephalopathies (DEEs). There are now more than 800 genes implicated in causing the DEEs; relatively few of these rare genetic diseases are known to be associated with MDs. We identified patients with genetic DEEs who had MDs, classified the nature of their MDs, and asked whether specific patterns correlated with the underlying mechanism. METHODS: We classified the type of MDs associated with specific genetic DEEs in a large international cohort of patients and analyzed whether specific patterns of MDs reflected the underlying biological dysfunction. RESULTS: Our cohort comprised 77 patients with a genetic DEE with a median age of 9 (range 1-38) years. Stereotypies (37/77, 48%) and dystonia (34/77, 44%) were the most frequent MDs, followed by chorea (18/77, 23%), myoclonus (14/77, 18%), ataxia (9/77, 12%), tremor (7/77, 9%), and hypokinesia (6/77, 8%). In 47% of patients, a combination of MDs was seen. The MDs were first observed at a median age of 18 months (range day 2-35 years). Dystonia was more likely to be observed in nonambulatory patients, while ataxia was less likely. In 46% of patients, therapy was initiated with medication (34/77, 44%), deep brain stimulation (1/77, 1%), or intrathecal baclofen (1/77, 1%). We found that patients with channelopathies or synaptic vesicle trafficking defects were more likely to experience dystonia; whereas, stereotypies were most frequent in individuals with transcriptional defects. DISCUSSION: MDs are often underrecognized in patients with genetic DEEs, but recognition is critical for the management of these complex neurologic diseases. Distinguishing MDs from epileptic seizures is important in tailoring patient treatment. Understanding which MDs occur with different biological mechanisms will inform early diagnosis and management.
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Encefalopatías , Distonía , Trastornos Distónicos , Trastornos del Movimiento , Humanos , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Recién Nacido , Distonía/genética , Trastornos del Movimiento/genética , Temblor , Trastornos Distónicos/genética , Ataxia , Encefalopatías/genéticaRESUMEN
Introduction: Hypnic headache (HH) is a primary headache, and it is considered a rare condition in children. The underlying mechanisms of HH are not yet fully understood. This systematic review aims to provide a comprehensive description of the clinical features of all published cases of pediatric HH. It will also discuss the differences in headache features between children and adults, the increased diagnostic sensitivity of the new diagnostic criteria (ICHD-3), potential pathophysiological hypotheses explaining the higher incidence in adults, differential diagnoses, and therapeutic options for children. Methods: A systematic search was conducted to identify and analyze articles reporting cases of HH in patients under the age of 18. The search was performed in major medical databases including Cochrane Library, EBSCO, Embase, Medline, PubMed, Science Direct, Scopus, and Web of Science. The search covered the period from 1988 to April 2023. Relevant studies were screened for eligibility, and data extraction was performed using a standardized approach. Results: Seven children with HH were included in the analysis. The mean age of onset for headache attacks was 10 ± 4.3 years (range 3-15 years). The average time from the start of headaches to diagnosis was 15.8 ± 25.0 months (range 1-60 months). Headache features in children differed from those observed in adult HH patients. Children experienced throbbing/pulsating pain, while adults reported dull/pressure-like pain. Children also had lower frequency and shorter duration of attacks compared to adults. The use of ICHD-3 criteria appeared to be more sensitive and inclusive for diagnosing HH in children compared to the previous ICHD-2 criteria. The association of headache attacks with sleep suggests that HH may be a primary disorder with a chronobiological origin. Hypothalamic dysfunction and melatonin dysregulation, which are more prevalent in older individuals, could potentially explain the higher incidence of HH in adults. Other primary headaches and secondary causes should be ruled out. Melatonin prophylactic therapy may be considered for pediatric patients. Discussion: Further evaluation of the clinical features of HH in children is needed. The development of specific diagnostic criteria for pediatric cases could improve diagnostic rates and enhance the management of children with HH.
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The clinical phenotype of Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) has been delineated but neuroimaging features have not been systematically analyzed. We studied brain magnetic resonance imaging (MRI) scans in a cohort of CDD patients and reviewed age at seizure onset, seizure semiology, head circumference. Thirty-five brain MRI from 22 unrelated patients were included. The median age at study entry was 13.4 years. In 14/22 patients (85.7%), MRI in the first year of life was unremarkable in all but two. In 11/22, we performed MRI after 24 months of age (range 2.5-23 years). In 8 out of 11 (72.7%), MRI showed supratentorial atrophy and in six cerebellar atrophy. Quantitative analysis detected volumetric reduction of the whole brain (-17.7%, P-value = 0.014), including both white matter (-25.7%, P-value = 0.005) and cortical gray matter (-9.1%, P-value = 0.098), with a reduction of surface area (-18.0%, P-value = 0.032), mainly involving the temporal regions, correlated with the head circumference (ρ = 0.79, P-value = 0.109). Both the qualitative structural assessment and the quantitative analysis detected brain volume reduction involving the gray and white matter. These neuroimaging findings may be related to either progressive changes due to CDD pathogenesis, or to the extreme severity of epilepsy, or both. Larger prospective studies are needed to clarify the bases for the structural changes we observed.
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Espasmos Infantiles , Humanos , Espasmos Infantiles/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Convulsiones/patología , Atrofia/patología , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
The relationship between migraines and allergies is controversial. Though they are epidemiologically linked, the underlying pathophysiological connection between them remains unclear. Migraines and allergic disorders have various underlying genetic and biological causes. As per the literature, these conditions are epidemiologically linked, and some common pathophysiological pathways have been hypothesized. The histaminergic system may be the clue to understanding the correlation among these diseases. As a neurotransmitter in the central nervous system with a vasodilatory effect, histamine has a well-documented influence on the allergic response and could be involved in the pathophysiology of migraines. Histamine may influence hypothalamic activity, which may play a major role in migraines or may simply influence their severity. In both cases, antihistamine drugs could prove useful. This review examines whether the histaminergic system, particularly H3 and H4 receptors, may provide a mechanistic link between the pathophysiology of migraines and allergic disorders, two common and debilitating conditions. Identifying their connection could help identify novel therapeutic strategies.
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The subtle interplay between the inter-molecular interactions established by catechol with the surrounding solvent and the intra-molecular hydrogen bond (HB) characterizing its conformational dynamics is investigated through a multi-level computational approach. First, quantum mechanical (QM) calculations are employed to accurately characterize both large portions of the catechol's potential energy surface and the interaction energy with neighboring solvent molecules. The acquired information is thereafter exploited to develop a QM derived force-field (QMD-FF), in turn employed in molecular dynamics (MD) simulations based on classical mechanics. The reliability of the QMD-FF is further validated through a comparison with the outcomes of ab initio molecular dynamics, also purposely carried out in this work. In agreement with recent experimental findings, the MD results reveal remarkable differences in the conformational behavior of isolated and solvated catechol, as well as among the investigated solvents, namely water, acetonitrile or cyclohexane. The rather strong intramolecular HB, settled between the vicinal phenolic groups and maintained in the gas phase, loses stability when catechol is solvated in polar solvents, and is definitively lost in protic solvents such as water. In fact, the internal energy increase associated with the rotation of one hydroxyl group and the breaking of the internal HB is well compensated by the intermolecular HB network available when both phenolic hydrogens point toward the surrounding solvent. In such a case, catechol is stabilized in a chelating conformation, which in turn could be very effective in water removal and surface anchoring. Besides unraveling the role of the different contributors that govern catechol's conformational dynamics, the QMD-FF developed in this work could be in future employed to model larger catechol containing molecules, due to its accuracy to reliably model both internal flexibility and solvent effects, while exploiting MD computational benefits to include more complex players as for instance surfaces, ions or biomolecules.
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Simulación de Dinámica Molecular , Agua , Solventes/química , Enlace de Hidrógeno , Reproducibilidad de los Resultados , Agua/química , CatecolesRESUMEN
Complex genomic rearrangements (CGRs) are structural variants arising from two or more chromosomal breaks, which are challenging to characterize by conventional or molecular cytogenetic analysis (karyotype and FISH). The integrated approach of standard and genomic techniques, including optical genome mapping (OGM) and genome sequencing, is crucial for disclosing and characterizing cryptic chromosomal rearrangements at high resolutions. We report on a patient with a complex developmental and epileptic encephalopathy in which karyotype analysis showed a de novo balanced translocation involving the long arms of chromosomes 2 and 18. Microarray analysis detected a 194 Kb microdeletion at 2q24.3 involving the SCN2A gene, which was considered the likely translocation breakpoint on chromosome 2. However, OGM redefined the translocation breakpoints by disclosing a paracentric inversion at 2q24.3 disrupting SCN1A. This combined genomic high-resolution approach allowed a fine characterization of the CGR, which involves two different chromosomes with four breakpoints. The patient's phenotype resulted from the concomitant loss of function of SCN1A and SCN2A.
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Encefalopatías , Aberraciones Cromosómicas , Humanos , Cariotipificación , Translocación Genética , Inversión Cromosómica , Cariotipo , Genómica , Canal de Sodio Activado por Voltaje NAV1.2/genética , Canal de Sodio Activado por Voltaje NAV1.1RESUMEN
Quinidine (QND) is an old antimalarial drug that was used in the early 20th century as an antiarrhythmic agent. Currently, QND is receiving attention for its use in epilepsy of infancy with migrating focal seizures (EIMFS) due to potassium sodium-activated channel subfamily T member 1 (KCNT1) genetic variants. Here, we report the application of Therapeutic Drug Monitoring (TDM) in pediatric patients carrying KCNT1 genetic variants and orally treated with QND for developmental and epileptic encephalopathies (DEE). We measured plasma levels of QND and its metabolite hydroquinidine (H-QND) by using a validated method based on liquid chromatography coupled with mass spectrometry (LC-MS/MS). Three pediatric patients (median age 4.125 years, IQR 2.375-4.125) received increasing doses of QND. Cardiac toxicity was monitored at every dose change. Reduction in seizure frequency ranged from 50 to 90%. Our results show that QND is a promising drug for pediatric patients with DEE due to KCNT1 genetic variants. Although QND blood levels were significantly lower than the therapeutic range as an anti-arrhythmic drug, patients showed a significant improvement in seizure burden. These data underlie the utility of TDM for QND not only to monitor its toxic effects but also to evaluate possible drug-drug interactions.