Sleep Spindle-Related EEG Connectivity in Children with Attention-Deficit/Hyperactivity Disorder: An Exploratory Study.

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder with known brain abnormalities but no biomarkers to support clinical diagnosis. Recently, EEG analysis methods such as functional connectivity have rekindled interest in using EEG for ADHD diagnosis. Most studies have focused on resting-state EEG, while connectivity during sleep and spindle activity has been underexplored. Here we present the results of a preliminary study exploring spindle-related connectivity as a possible biomarker for ADHD. We compared sensor-space connectivity parameters in eight children with ADHD and nine age/sex-matched healthy controls during sleep, before, during, and after spindle activity in various frequency bands. All connectivity parameters were significantly different between the two groups in the delta and gamma bands, and Principal Component Analysis (PCA) in the gamma band distinguished ADHD from healthy subjects. Cluster coefficient and path length values in the sigma band were also significantly different between epochs, indicating different spindle-related brain activity in ADHD.

A new neurodevelopmental disorder linked to heterozygous variants in UNC79.

PURPOSE: The "NALCN channelosome" is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals with a neurodevelopmental syndrome have been reported with disease causing variants in NALCN and UNC80. However, no pathogenic UNC79 variants have been reported, and in vivo function of UNC79 in humans is largely unknown. METHODS: We used international gene-matching efforts to identify patients harboring ultrarare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology. RESULTS: We found 6 unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features, including mild to moderate intellectual disability and a mild developmental delay, whereas a single patient reportedly had normal cognitive and motor development but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and 4 patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild type. In addition, they have impaired ability in learning and memory. CONCLUSION: Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurologic pathologies.

Haploinsufficiency as a Foreground Pathomechanism of Poirer-Bienvenu Syndrome and Novel Insights Underlying the Phenotypic Continuum of CSNK2B-Associated Disorders.

CSNK2B encodes for the regulatory subunit of the casein kinase II, a serine/threonine kinase that is highly expressed in the brain and implicated in development, neuritogenesis, synaptic transmission and plasticity. De novo variants in this gene have been identified as the cause of the Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) characterized by seizures and variably impaired intellectual development. More than sixty mutations have been described so far. However, data clarifying their functional impact and the possible pathomechanism are still scarce. Recently, a subset of CSNK2B missense variants affecting the Asp32 in the KEN box-like domain were proposed as the cause of a new intellectual disability-craniodigital syndrome (IDCS). In this study, we combined predictive functional and structural analysis and in vitro experiments to investigate the effect of two CSNK2B mutations, p.Leu39Arg and p.Met132LeufsTer110, identified by WES in two children with POBINDS. Our data prove that loss of the CK2beta protein, due to the instability of mutant CSNK2B mRNA and protein, resulting in a reduced amount of CK2 complex and affecting its kinase activity, may underlie the POBINDS phenotype. In addition, the deep reverse phenotyping of the patient carrying p.Leu39Arg, with an analysis of the available literature for individuals with either POBINDS or IDCS and a mutation in the KEN box-like motif, might suggest the existence of a continuous spectrum of CSNK2B-associated phenotypes rather than a sharp distinction between them.

Case report: A relevant misdiagnosis: Photosensitive epilepsy mimicking a blinking tic.

Blinking in children is most frequently a functional and transient symptom. Nonetheless, sometimes it is the first clinical manifestation of a neurological disorder. The differential diagnosis between voluntary actions, tics and other neurological disorders among which seizures may be challenging and misdiagnosis is common. A 6-year-old girl in good health was admitted for a recent history of bilateral eye blinking. Blinking did not interfere with the girl's activities. The patients reported that blinking seemed to be triggered by sunlight exposure and that girl sometimes seemed to be attracted by the sunlight. Ophthalmological diseases had been already excluded. The girl was addressed to our hospital for neurological consultation, as tic disease was considered the most probable hypothesis. Neurological examination was negative. In the field of differential diagnosis of photosensitive abnormal eyelid movements, the hypothesis of seizures was explored and further investigated with a video-EEG recording with light stimulation. This exam demonstrated a photoparoxysmal response (PPR) to intermittent photic stimulation with appearance on EEG of bilateral spike and polyspike waves associated with eyelid jerks. This girl suffers from generalized epilepsy with photosensitivity. Photosensitivity is a common feature of many epilepsy syndromes, mainly occurring in children and adolescents. To control the seizures, it is essential to avoid the triggering stimulus, by wearing specific glasses. Additional antiseizures treatment is often necessary, at first with valproate and levetiracetam, and ethosuximide, lamotrigine, and benzodiazepines as the second choice. Overlapping phenomenology of seizures and movement disorders is well known in paediatric clinical practice. Moreover, epilepsy and movement disorder may coexist, mainly in children. Seizures with semeiology limited to eye motor manifestations may mimic functional blinking, tics, and other motor events frequently observed in childhood. Differentiating seizures from other non-epileptic paroxysmal movements may be challenging and specialist evaluation is needed for proper treatment and prognostic counselling.

TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Safety of Off-Label Pharmacological Treatment in Pediatric Neuropsychiatric Disorders: A Global Perspective From an Observational Study at an Italian Third Level Children's Hospital.

Background: The acquisition of proper and relevant pediatric clinical data is essential to ensure tolerable and effective pediatric drug therapies. In the field of pharmacological treatment of neuropsychiatric disorders, the lack of sufficient high quality scientific evidence for pediatric age results in the frequent need to prescribe off-label drugs. With the aim of improving knowledge about safety profile of off-label drug prescription in children and adolescent with neurological and/or psychiatric disorders, we realized a multidisciplinary pharmacovigilance study. Materials and methods: An observational retrospective study was conducted to assess the safety of off-label pharmacological therapies in patients aged 0-18 years, admitted to the Neuropsychiatry Unit of the Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" between January 2016 and December 2018. Prescription patterns and adverse drug reactions were evaluated by a multidisciplinary team. Results: Overall, 230 patients were enrolled, 48% boys (N = 111), 52% girls (N = 119), average age of 10 years, and a total of 534 prescriptions was analyzed. 54.5% (N = 125) of patients had epilepsy, 37.5% (N = 86) suffered from psychiatric disorders, 8% (N = 19) had other neurological disorders. The prevalence of off-label prescriptions was 32% and 50% of the study population received at least one off-label drug. A total of 106 ADRs was detected: 57% of ADRs were due to drug-drug interactions, 30% were due to off-label prescriptions, 10% were due to overdose and 3% were due to improper use. No significant association between emerged ADRs and off label prescriptions was found (Fisher's exact two-tailed test, p = 1.000). There was significant association between increasing number of administrated drugs and risk of ADRs (OR 1.99; IC95% 1.58-2.5; p = 0.000). Psychiatric disorders were associated with at least three times higher risk to be treated with an off-label drug (OR 3.30; IC95% 2.26-4.83; p = 0.000). Conclusions: This study shows that off-label prescribing in neuropsychiatric disorders does not pose a greater risk of ADRs than on-label prescribing and highlights unmet clinical needs in pediatric neuropsychopharmacology. The multidisciplinary approach can provide important contributions to improve therapeutic path of these already complex pathologies by careful monitoring of therapeutic appropriateness and drug interactions.

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge.

Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype-phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.

Expanding Phenotype of Poirier-Bienvenu Syndrome: New Evidence from an Italian Multicentrical Cohort of Patients.

BACKGROUND: Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) is a rare disease linked to mutations of the CSNK2B gene, which encodes for a subunit of caseinkinase CK2 involved in neuronal growth and synaptic transmission. Its main features include early-onset epilepsy and intellectual disability. Despite the lack of cases described, it appears that POBINDS could manifest with a wide range of phenotypes, possibly related to the different mutations of CSNK2B. METHODS: Our multicentric, retrospective study recruited nine patients with POBINDS, detected using next-generation sequencing panels and whole-exome sequencing. Clinical, laboratory, and neuroimaging data were reported for each patient in order to assess the severity of phenotype, and eventually, a correlation with the type of CSNK2B mutation. RESULTS: We reported nine unrelated patients with heterozygous de novo mutations of the CSNK2B gene. All cases presented epilepsy, and eight patients were associated with a different degree of intellectual disability. Other features detected included endocrinological and vascular abnormalities and dysmorphisms. Genetic analysis revealed six new variants of CSNK2B that have not been reported previously. CONCLUSION: Although it was not possible to assess a genotype-phenotype correlation in our patients, our research further expands the phenotype spectrum of POBINDS patients, identifying new mutations occurring in the CSNK2B gene.

Does a standard triage tool adequately detect the needs of children and adolescents admitted for mental health problem?

BACKGROUND: the visits to the paediatric emergency department for mental problems are increasing exponentially, but the emergency department team in not ready enough to manage them, due to the lack of adequate training. This study aimed to evaluate how the Italian Society of Paediatric Emergency Medicine and Urgency triage system was able to estimate urgency in patients accessing the paediatric emergency department for a mental health problem. METHODS: We conducted a retrospective study at the emergency department of the Institute for Maternal and Child Health, IRCCS Burlo garofolo of Trieste (Italy), from December 2015 to April 2017. During the study period, we identified all the patients undergoing an urgent psychiatric consultation. We collected demographic variables, triage code, diagnosis, and outcomes of each patient. Subsequently, we have assigned a degree of psychiatric urgency, based on Gail and Rosenn's classificationwhich is a specific tool to evaluate psychiatric urgency. The primary study outcome was the comparison between the degree of urgency assigned using the triage system and the Gail and Rosenn's classification. RESULTS: In this series, 567 patients underwent an urgent psychiatric consultation, and 280 of them received a diagnosis of a mental health problem. The degree of urgency assigned at the triage was: emergency for 5 cases (2%), urgency for 96 (34%) and non-urgency for 179 (64%). Instead, the degree assigned with GRC was: emergency for 95 cases (34%), urgency for 112 (42%) and non-urgency for 73 (26%). The number of patients, detected as emergency and urgency by the two tools, was significantly different (p = 0.0001). CONCLUSIONS: In this study, we demonstrated that the Italian Society of Paediatric Emergency Medicine and Urgency triage system underestimated the urgency of patients with mental health problems compared to a specific tool to assess the degree of psychiatric urgency.

High-school students and self-injurious thoughts and behaviours: clues of emotion dysregulation.

BACKGROUND: Suicide attempts and self-harm in adolescence are a major public health concern: they are among the main causes of disability-adjusted life-years worldwide, with severe long-term health consequences in terms of mental illness and psychiatric hospitalisation and a significantly increased risk of suicide. Several studies recently focused on the hypothesis that adolescents may be particularly vulnerable to emotional dysregulation and on the relation between problems with emotion regulation and suicidal and self-harming behaviours. Italian epidemiological data about prevalence of these behaviours at the community level are lacking. Our study aimed to estimate the prevalence of self-injurious thoughts and behaviours (SITBs) in a representative sample of community adolescents, and to examine the association between SITBs and the emotional and behavioural profiles. METHODS: Anonymous self-report questionnaires were completed by 1507 students aged 11-18 years from 24 high schools in the North-eastern Italian region of Friuli Venezia Giulia. Information was collected on SITBs, on the socio-environmental context, and on the psychological profile ('Achenbach's YSR questionnaire 11-18, Multidimensional Test of Self-harm and Multi-Attitude Suicide Tendency Scale). RESULTS: Overall, 11.1% of adolescents reported self-harming behaviours without suicide ideation or attempts, 6.4% declared having thought to suicide without acting a suicide attempt or self-harm, 1.4% declared having attempted suicide and really thought to take away their life. Access to health services following a suicide thought, a self-harming behaviour or suicide attempt was infrequent, particularly for suicide ideation. At the YSR, all the SITBs groups reported high scores in almost all scales, with the most evident differences in the self-harming groups in which adolescents reported significantly higher scores in all scales, both internalising and externalising. An emotion dysregulation profile was found in almost all the groups. CONCLUSIONS: This study provides us with an estimate of the prevalence of SITBs in the adolescent population and confirms the importance of further investigating the association between SITBs and emotion dysregulation. The naturalistic setting of community studies appears to be useful for studies in this field, and it allows to approach the onerous and often neglected issue of adolescent suicidality.

Description of a peculiar alternating ictal electroclinical pattern in a young boy with a novel SPATA5 mutation.

Heterozygous variants in the SPATA5 gene have recently been described to be associated with epileptic encephalopathy. As of 2019, 37 patients have been described in the published literature. We report a patient with a novel autosomal recessive pathogenic variant in SPATA5 and a clinical phenotype consistent with SPATA5 syndrome, including severe neurological impairment, intellectual disability (ID), generalized intractable epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. The epileptic clinical features were characterized by infantile spasms associated with seizures with a complex ocular movement; a predominant involvement of the posterior cerebral area and cortical visual impairment were also noticed. This phenotype is highlighted with a review of the literature showing other patients with SPATA5-related disease. This report aims to contribute to further understanding phenotype/genotype correlations, which are fundamental for the interpretation of data made available by exome sequencing for the diagnosis of epileptic encephalopathies. [Published with video sequence].

Epileptic encephalopathy with microcephaly in a patient with asparagine synthetase deficiency: a video-EEG report.

Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder caused by mutations in the asparagine synthetase gene. It is characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. A decrease in asparagine in CSF or plasma guides subsequent investigations in some cases, but normal values are described in other cases. Therefore, reaching a diagnosis is challenging and relies on exome sequencing. We report the case of a child with progressive microcephaly, irritability, startle reflexes, and jitteriness since birth. Focal clonic and myoclonic seizures, status epilepticus, and infantile spasms appeared in the first months of life. At first, the EEG showed multifocal epileptic activity which later turned into modified hypsarrhythmia and discontinuous activity. Brain MRI showed brain atrophy, a simplified gyral pattern, and poor myelination. Plasma asparagine levels were normal. Due to remote parental consanguinity, a study of contiguous regions of runs of homozygosity was performed, showing a 5-Mb region (chr7:95629078-100679007) including the asparagine synthetase gene. The molecular analysis of this gene led to identification of a novel homozygous missense mutation, c.761G>T(p.Gly254Val), in our patient. The peculiar electroclinical phenotype may lead to diagnostic suspicion and molecular analysis which may benefit genetic counselling. [Published with video sequence].

Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study.

OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

Adolescent Admissions to Emergency Departments for Self-Injurious Thoughts and Behaviors.

The objective of the present study was to describe the incidence and the characteristics of Self-Injurious Thoughts and Behaviors (SITBs), among adolescents aged 11-18 admitted, over a two year period, to all the Emergency Departments of a Region of North-eastern Italy through a comprehensive analysis of medical records. A two-step search was performed in the regional ED electronic database. First, we identified the cases that had been clearly diagnosed as SITBs by an Emergency Department physician. Secondly, suspect cases were detected through a keyword search of the database, and the medical records of these cases were hand screened to identify SITBs. The mean annual incidence rate of SITBs was 90 per 100,000 adolescents aged 11-18 years. Events were more frequent in females. Drug poisoning was the most frequently adopted method (54%). In 42% of cases a diagnosis of SITB was not explicitly reported by the physician. In 65% of cases adolescents were discharged within hours of admission. Only 9% of patients started a psychiatric assessment and treatment program during hospital stay. This research confirms the high incidence of SITBs among adolescents and highlights the difficulty in their proper diagnosis and management. Such difficulty is confirmed by the fact that only a few patients, even among those with a clear diagnosis, were sent for psychiatric assessment. Correct identification and management of SITB patients needs to be improved, since SITBs are an important public health problem in adolescence and one of the main risk factors for suicide.

Diagnostic criteria currently proposed for "ictal epileptic headache": Perspectives on strengths, weaknesses and pitfalls.

PURPOSE: When we published the diagnostic criteria for "ictal epileptic headache" in 2012, we deliberately and consciously chose to adopt restrictive criteria that probably underestimate the phenomenon, rather than spread panic among patients and physicians who are reluctant to accept this entity. METHODS: Here we discuss four intriguing clinical cases to highlight why we believe, to this day, that it is necessary to follow these restrictive diagnostic criteria. CONCLUSIONS: EEG is not recommended as a routine examination for children diagnosed with headache, but it is mandatory and must be carried out promptly in cases of prolonged headache that does not respond to antimigraine drugs, if epilepsy is suspected or has been diagnosed previously. This is not a marginal or irrelevant question because possible isolated, non-motor, ictal manifestations should be taken into account before declaring that an epileptic patient is "seizure free" so as to ensure that any decision taken to suspend anticonvulsant therapy is safe.

Paediatric anti-N-methyl-D-aspartate receptor encephalitis: The first Italian multicenter case series.

BACKGROUND: Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis. METHODS: To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres. RESULTS: Mean age at onset was 8 years (range 3-17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had mRS 0-1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month. CONCLUSIONS: Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender.

Involuntary movements after correction of vitamin B12 deficiency: a video-case report.

Involuntary movements can appear before and after initiation of vitamin B12 treatment. The pathogenesis of involuntary movements in vitamin B12 deficiency and their relationship with cobalamin injection remain unclear due to a lack of video-EEG documentation making the electroclinical correlation difficult to ascertain. Here, we report video-EEG and neuroimaging findings of an 11-month-old girl with vitamin B12 deficiency, who acutely developed involuntary movements a few days after initiation of vitamin B12 treatment with normal vitamin plasmatic levels. Abnormal movements were a combination of tremor and myoclonus involving the face, mouth, and left arm, which disappeared after discontinuation of therapy. [Published with video sequences].