Cristiano Termine

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce.

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.

Abstract Headache is one of the most common neurological symptom reported in childhood and adolescence, leading to high levels of school absences and being associated with several comorbid conditions, particularly in neurological, psychiatric and cardiovascular systems. Neurological and psychiatric disorders, that are associated with migraine, are mainly depression, anxiety disorders, epilepsy and sleep disorders, ADHD and Tourette syndrome. It also has been shown an association with atopic disease and cardiovascular disease, especially ischemic stroke and patent foramen ovale (PFO).

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.

Background. Developmental Language Disorder (DLD) is frequent in childhood and may have long-term sequelae. By employing an evidence-based approach, this scoping review aims at identifying (a) early predictors of DLD; (b) the optimal age range for the use of screening and diagnostic tools; (c) effective diagnostic tools in preschool children. Methods. We considered systematic reviews, meta-analyses, and primary observational studies with control groups on predictive, sensitivity and specificity values of screening and diagnostic tools and psycholinguistic measures for the assessment of DLD in preschool children. We identified 37 studies, consisting of 10 systematic reviews and 27 primary studies. Results. Delay in gesture production, receptive and/or expressive vocabulary, syntactic comprehension, or word combination up to 30 months emerged as early predictors of DLD, a family history of DLD appeared to be a major risk factor, and low socioeconomic status and environmental input were reported as risk factors with lower predictive power. Optimal time for screening is suggested between age 2 and 3, for diagnosis around age 4. Because of the high variability of sensitivity and specificity values, joint use of standardized and psycholinguistic measures is suggested to increase diagnostic accuracy. Conclusions. Monitoring risk situations and employing caregivers’ reports, clinical assessment and multiple linguistic measures are fundamental for an early identification of DLD and timely interventions.

An in vivo anatomic study of gray matter volume was performed in a group of familial dyslexic individuals, using an optimized method of voxel-based morphometry.Focal abnormalities in gray matter volume were observed bilaterally in the planum temporale, inferior temporal cortex, and cerebellar nuclei, suggesting that the underlying anatomic abnormalities may be responsible for defective written language acquisition in these subjects.

The aim of this study was to investigate the frequency of reading, writing, and calculation disabilities in children with typical rolandic epilepsy (RE) and healthy control children. We also aimed to define the possible electroclinical markers of specific cognitive dysfunctions in RE. School abilities were evaluated and compared in 20 children (eight males, 12 females; mean age 10y 3mo [SD 1y 7mo]; range 7y 9mo‐12y 9mo) consecutively diagnosed with typical RE, and a group of 21 healthy controls (nine males, 12 females; mean age 10y 4mo [SD 1y 8mo]; range 7y 6mo‐13y 3mo). All the children received standardized neuropsychological tests. For each patient an exhaustive seizure diary was kept and all the sleep electroencephalogram (EEG) recordings were reviewed. Specific difficulties with reading, writing, and calculation (diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition) were found in nine out of 20 children with RE and two out of 21 healthy controls (χ 2 =0.01). The specific learning disabilities in the RE group were correlated with a marked increase in epileptiform discharges during sleep (χ 2 =0.02) and an early onset of epilepsy (χ 2 =0.02). Our findings suggest that seizure onset before age 8 years and epileptiform discharges (more than 50% of the sleep EEG recording) in several tracings over more than a year are relevant markers for identifying patients at risk of developing academic difficulties.

Headache is the most common somatic complaint in children and adolescents. The evaluation should include detailed history of children and adolescents completed by detailed general and neurological examinations. Moreover, the possible role of psychological factors, life events and excessively stressful lifestyle in influencing recurrent headache need to be checked. The choice of laboratory tests rests on the differential diagnosis suggested by the history, the character and temporal pattern of the headache, and the physical and neurological examinations. Subjects who have any signs or symptoms of focal/progressive neurological disturbances should be investigated by neuroimaging techniques. The electroencephalogram and other neurophysiological examinations are of limited value in the routine evaluation of headaches. In a primary headache disorder, headache itself is the illness and headache is not attributed to any other disorder (e.g. migraine, tension-type headache, cluster headache and other trigeminal autonomic cephalgias). In secondary headache disorders, headache is the symptom of identifiable structural, metabolic or other abnormality. Red flags include the first or worst headache ever in the life, recent headache onset, increasing severity or frequency, occipital location, awakening from sleep because of headache, headache occurring exclusively in the morning associated with severe vomiting and headache associated with straining. Thus, the differential diagnosis between primary and secondary headaches rests mainly on clinical criteria. A thorough evaluation of headache in children and adolescents is necessary to make the correct diagnosis and initiate treatment, bearing in mind that children with headache are more likely to experience psychosocial adversity and to grow up with an excess of both headache and other physical and psychiatric symptoms and this creates an important healthcare problem for their future life.

After decades of research, the importance of psychological factors in child and adolescent headache is no longer in doubt. However, it is not clearly understood whether different types of headache are comorbid with specific kinds of psychopathology. To address this issue, we set out to establish whether young patients with migraine do or do not show significant levels of psychopathological symptoms compared with age-matched healthy controls and patients with tension-type headache (TTH).Ten studies were selected on the basis of a widely used psychodiagnostic tool (the Child Behavior Checklist (CBCL)) and by applying rigorous criteria: The studies were compared in a meta-analysis in order to evaluate the presence of Internalizing (mainly anxiety and depression) and Externalizing (mainly behavioral problems) symptoms in different types of headache (and versus healthy controls).Patients with migraine showed more psychopathological symptoms than healthy controls. TTH patients also had more psychopathology than controls, although the difference was more marked in the area of Internalizing disorders. Finally, no differences emerged between migraine and TTH.Psychopathological symptoms affect children with migraine, but also children with TTH. Biological, pathophysiological and clinical links need to be established. Effective treatment of affected children and adolescents is imperative in order to prevent chronic evolution. In this context, the CBCL may be a good screening instrument with a view to developing a tailored clinical approach.

A thorough evaluation of headache in children and adolescents is necessary to make the correct diagnosis and initiate treatment. In part 1 of this article (Özge et al. in J Headache Pain, 2010), we reviewed the diagnosis of headache in children and adolescents. In the present part, we will discuss therapeutic management of primary headaches. An appropriate management requires an individually tailored strategy giving due consideration to both non-pharmacological and pharmacological measures. Non-pharmacological treatments include relaxation training, biofeedback training, cognitive-behavioural therapy, different psychotherapeutic approaches or combinations of these treatments. The data supporting the effectiveness of these therapies are less clear-cut in children than in adults, but that is also true for the data supporting medical treatment. Management of migraine and TTH should include strategies relating to daily living activities, family relationships, school, friends and leisure time activities. In the pharmacological treatment age and gender of children, headache diagnosis, comorbidities and side effects of medication must be considered. The goal of symptomatic treatment should be a quick response with return to normal activity and without relapse. The drug should be taken as early as possible and in the appropriate dosage. Supplementary measures such as rest in a quiet, darkened room is recommended. Pharmaco-prophylaxis is only indicated if lifestyle modification and non-pharmacological prophylaxis alone are not effective. Although many prophylactic medications have been tried in paediatric migraine, there are only a few medications that have been studied in controlled trials. Multidisciplinary treatment is an effective strategy for children and adolescents with improvement of multiple outcome variants including frequency and severity of headache and school days missed because of headache. As a growing problem both children and families should be informed about medication overuse and the children's drug-taking should be checked.

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental condition characterised by multiple motor and phonic tics and associated behavioural problems, carrying a significant burden on patients' lives. Although the term health related-quality of life (HR-QOL) has only been used in recent years, several studies have long addressed the impact of GTS on physical, psychological and social aspects of wellbeing of both children and adults with GTS. We set out to answer the question "Is HR-QOL affected by GTS and, if so, in what domains?" by conducting a systematic literature review of published original studies addressing HR-QOL in both children and adult patients with GTS. This review focuses on the current evidence on the impact of GTS on patients' lives, mainly informed by studies using generic functional impairment and HR-QOL measures from the last decade, and expands on the new opportunities introduced by the recently developed GTS-specific HR-QOL scales (GTS-QOL and GTS-QOL-C&A). Analysis of the first decade of studies specifically addressing HR-QOL in GTS suggests that co-morbid conditions are key factors in determining HR-QOL in young patients, whilst the picture is more complex in adults with GTS. These findings offer some general directions for both current clinical practice and future research.

We report the neuropsychological profile and the pattern of brain activity during reading tasks in a sample of familial dyslexics. We studied our subjects with an in-depth neuropsychological assessment and with functional neuroimaging (fMRI) during word and pseudoword reading and false font string observations (baseline condition). The neuropsychological assessment revealed that familial dyslexia, in both persistent and compensated forms, is often associated with deficits in verbal short-term memory, phonological awareness and automatization abilities. The functional results showed a lack of activation in the posterior areas of the reading network. This study, together with the previously published VBM study (Brambati, S.M., Termine, C., Ruffino, M., Stella, G., Fazio, F., Cappa, S.F. and Perani, D., Regional reductions of gray matter volume in familial dyslexia, Neurology, 63 (2004) 742–5), provides a multiple modality evaluation of familial dyslexia. The neuropsychological assessment showed cognitive deficits associated with dyslexia that persist also in subjects with compensated reading deficit. Both the anatomical and the functional study point out a deficit in the posterior areas of the reading network.

Introduction: Gilles de la Tourette Syndrome (GTS) is a childhood-onset hyperkinetic movement disorder defined by the chronic presence of multiple motor tics and at least one vocal tic and often complicated by co-morbid behavioural problems. The pharmacological treatment of GTS focuses on the modulation of monoaminergic pathways within the cortico-striato-thalamo-cortical circuitry. This paper aims to evaluate the efficacy and safety profiles of pharmacological agents used in the treatment of tics in patients with GTS, in order to provide clinicians with an evidence-based rationale for the pharmacological treatment in GTS. Method: In order to ascertain the best level of evidence, we conducted a systematic literature review to identify double-blind randomised controlled trials of medications in GTS populations. Results: We identified a large number of pharmacological agents as potentially effective in improving tic symptoms. The alpha-2 agonist Clonidine is amongst the agents with the most favourable efficacy-versus-adverse events ratio, especially in patients with co-morbid attention-deficit hyperactivity disorder, although effect sizes vary evidence-based studies. Discussion: Our results are in line with the findings of uncontrolled open-label studies. However, most trials have low statistical power due to the small sample sizes, and newer agents, such as Aripiprazole, have not been formally tested in double-blind randomised controlled trials. Further research should focus on better outcome measures, including Quality of Life instruments.

Background: Gilles de la Tourette syndrome (GTS) is a chronic childhood-onset neuropsychiatric disorder with a significant impact on patients’ health-related quality of life (HR-QOL). Cavanna et al. (Neurology 2008; 71: 1410–1416) developed and validated the first disease-specific HR-QOL assessment tool for adults with GTS (Gilles de la Tourette Syndrome-Quality of Life Scale, GTS-QOL). This paper presents the translation, adaptation and validation of the GTS-QOL for young Italian patients with GTS. Methods: A three-stage process involving 75 patients with GTS recruited through three Departments of Child and Adolescent Neuropsychiatry in Italy led to the development of a 27-item instrument (Gilles de la Tourette Syndrome-Quality of Life Scale in children and adolescents, C&A-GTS-QOL) for the assessment of HR-QOL through a clinician-rated interview for 6–12 year-olds and a self-report questionnaire for 13–18 year-olds. Results: The C&A-GTS-QOL demonstrated satisfactory scaling assumptions and acceptability. Internal consistency reliability was high (Cronbach’s alpha > 0.7) and validity was supported by interscale correlations (range 0.4–0.7), principal-component factor analysis and correlations with other rating scales and clinical variables. Conclusions: The present version of the C&A-GTS-QOL is the first disease-specific HR-QOL tool for Italian young patients with GTS, satisfying criteria for acceptability, reliability and validity.

Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by multiple motor and vocal tics, which commonly presents with multiple behavioral problems, including co-morbid attention-deficit and hyperactivity disorder and obsessivecompulsive disorder.Both tics and co-morbid conditions have been shown to potentially affect patients' health-related quality of life.While TS typically presents in childhood, its manifestations peak in severity during adolescence, a critical period in which affected individuals are exposed to potential stigma from peers.Physical and behavioral manifestations can also contribute to stigma, which subsequently leads to poorer health outcomes, discrimination, and a reduced willingness to seek help.The available evidence suggests that young patients with TS can experience reduced social acceptance from peers and difficulties establishing relationships.There is also evidence that some health care professionals share the unhelpful belief that young patients with TS should be disciplined in order to correct their disruptive behavior, based on the erroneous assumption that tics can be consciously controlled.Studies focussed on self-perception in patients with TS have yielded inconsistent results, with some studies showing problems in the domains of self-concept and self-esteem.Feelings of isolation, loneliness, and experiences of bullying have been reported more consistently.Interventions are required to reduce misconceptions about the condition and thus reduce stigma through targeted education and behavioral interventions.A multi-faceted approach that focuses on educating children, adults, and educators about TS would be beneficial to help alleviate stigma.This can be combined with self-advocacy and tailored psychological therapies for young patients with TS.The present paper reviews the current literature on stigma and self-perception in adolescents with TS in order to inform clinical decisions about management strategies and possible interventions to improve health-related quality of life.

1. A simple method for gauging changes in the output of glucose by the liver has been described. Throughout post-absorption, there are present in hepatic venous blood aperiodic fluctuations in glucose which are reflected throughout the major peripheral arterial tree. Under the influence of the drug, these fluctuations at both sites promptly disappear. The quantitated changing rate of output of glucose by the liver after Orinase (33% fall in 10 minutes) is drastic. A small dose of glucagon by vein immediately reverses this trend with a return in exaggerated form of the normal postabsorptive fluctuatinos. As a corollary one may infer that long use of the drug does not impair liver glycogen deposition. 2. It is suggested that the site of action of Orinase is proximal to the phosphorylase enzyme systems and takes the form of a suppression of glucagon production at source with a resulting reduction of glucose output by the liver. After 70 days of intensive exposure to the drug in the normal dog, acute signs and symptoms of toxicity are present but no histopathologic changes in the liver, kidneys, thyroid, adrenals or pancreas (including alpha-beta cell ratios). 3. No evidence was found to suggest that the drug works by destruction of the alpha cells of the pancreas.

Few controlled studies have considered, in paediatric subjects, associations between Tourette's syndrome (TS) and psychiatric/behavioural disorders. We conducted a case-control study to verify the reproducibility of the few data published on this topic to date.Clinicians' impression (i.e. structured interviews and usual history taking), standardized psychiatric and behavioural rating scales (CBCL, TAI, CDI, CRS-R:L, Y-GTSS, CY-BOCS) were used to investigate these associations in 17 youngsters with TS and in 17 age- and sex-matched controls.The clinician's diagnoses revealed TS alone in 23.5% of the patients (4/17), TS plus attention-deficit/hyperactivity disorder (ADHD) in 11.8% (2/17), TS plus obsessive-compulsive disorder (OCD) in 41.2% (7/17), and TS plus ADHD and OCD in 23.5% (4/17). No control subject presented ADHD and/or OCD. These clinical findings were confirmed by Child Behaviour Check List (CBCL) results. The TS group, compared with the controls, recorded significantly higher CBCL scores in scales relating to the main comorbid conditions. No significant differences emerged on the Children's Depression Inventory or Test Anxiety Inventory.TS patients have a high prevalence of psychiatric and behavioural problems compared with controls. The CBCL is a rapid and useful screening-diagnostic instrument for highlighting the main psychiatric and behavioural problems in TS.

Tourette syndrome (TS) is a neurodevelopmental disorder consisting of multiple motor and one or more vocal/phonic tics. TS is increasingly recognized as a common neuropsychiatric disorder usually diagnosed in early childhood and comorbid neuropsychiatric disorders occur in approximately 90% of patients, with attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) being the most common ones. Moreover, a high prevalence of depression and personality disorders has been reported. Although the mainstream of tic management is represented by pharmacotherapy, different kinds of psychotherapy, along with neurosurgical interventions (especially deep brain stimulation, DBS) play a major role in the treatment of TS. The current diagnostic systems have dictated that TS is a unitary condition. However, recent studies have demonstrated that there may be more than one TS phenotype. In conclusion, it appears that TS probably should no longer be considered merely a motor disorder and, most importantly, that TS is no longer a unitary condition, as it was previously thought. Neurodegenerative Diseases, edited by Shamim I. Ahmad.

Gilles de la Tourette syndrome is a chronic neuropsychiatric disorder that can have a detrimental impact on the health-related quality of life of children with the condition. To date no patient-reported health-related quality of life measures have been developed for children and adolescents in the English language. This study validated the first disease-specific scale for the quantitative assessment of health-related quality of life in 118 children and adolescents with Gilles de la Tourette syndrome (C&A-GTS-QOL) following language adaptation from Italian to English in the United Kingdom. Standard statistical methods were used to test the psychometric properties of the rating scale. Principal component factor analyses led to the identification of six health-related quality of life domains (cognitive, copro-phenomena, psychological, physical, obsessive-compulsive, and activities of daily living), explaining 66.7% of the overall variance. The C&A-GTS-QOL demonstrated satisfactory scaling assumptions and acceptability; validity was supported by interscale correlations (range 0.2-0.7), confirmatory factor analysis, and correlation patterns with other rating scales and clinical variables.

Tourette syndrome (TS) and attention-deficit and hyperactivity disorder (ADHD) are co-morbid neurodevelopmental conditions affecting more commonly male patients. We set out to determine the impact of co-morbid ADHD on cognitive function in male children with TS by conducting a controlled study. Participants included four matched groups of unmedicated children (age range 6–15 years): TS (n=13), TS+ADHD (n=8), ADHD (n=39), healthy controls (n=66). Following clinical assessment, each participant completed a battery of tests from the Wechsler Intelligence Scale for Children-III, the Italian Battery for ADHD, the Tower of London test, the Corsi test, and the Digit Span test. All patient groups reported significantly lower scores than healthy controls across the neuropsychological tests involving executive functions. The TS+ADHD group was the most severely affected, followed by the ADHD group and the TS group, particularly in the tests assessing planning ability, inhibitory function, working memory and visual attention, but not auditory attention. Problems in executive functions are more common in patients with neurodevelopmental disorders than controls. Deficits in planning ability, inhibitory function, working memory and visual attention reported by children with TS appear to be more strongly related to the presence of co-morbid ADHD symptoms than core TS symptoms.

Following school closures due to the SARS-CoV-2 pandemic, for some months, children received only distance learning. The effects of this approach, however, are not clear for children with dyslexia. We conducted a cross-sectional comparison between children with and without dyslexia after the so-called “lockdown” and a comparison between pre- and post-lockdown parameters in children with dyslexia. We recruited sixty-five children with dyslexia (dyslexia group, DG) from an outpatient facility in Pavia (Lombardy, Italy) and fifty-two children without specific learning disabilities as the control group (CG) from summer camps in the same province. We performed neuropsychological tests to explore reading skills and an ad hoc questionnaire to explore how parents and children had experienced the measures taken to reduce spreading of SARS-CoV-2 infection. Between 59 to 63% of children with dyslexia did not reach the average expected increase of reading skills. According to their parents, they also showed greater social isolation and fewer worries about the pandemic and the school’s closure. Our data indicate that children with dyslexia are at increased risk of consequences on their learning potential in case of school closure. They also seem to have a peculiar psychological experience of school closure. Specific interventions should therefore be provided to minimize the risk of negative effects on global development.

Objective.—To assess the evolution of idiopathic headache with early onset and to investigate the influence of early somatic disorders, “life events,” and psychiatric disorders on the onset and the course of headache. We also studied the possible prognostic role of gender, headache diagnosis at onset, and history of headache in family members on the course of headache. We also investigated the applicability of the ICHD‐II criteria to idiopathic headache in preschool children. Methods.—Prospective evaluation of 25 consecutive headache patients referred before the age of 6 years. Headache diagnosis was based on the IHS 1988 criteria, on the ICHD‐II criteria, and on “alternative” clinical criteria [eg, duration less than 1 hour in migraine without aura (MWA), less than 30 minutes in tension‐type headache (TTH)]. All patients were assessed by a structured interview to detect early developmental disorders (eg, feeding difficulties or sleep disorders) and “life events” (eg, parents' separation and others according to DSM‐IV). All patients underwent clinical observations and assessment of psychiatric comorbidity (ICD‐10) by means of interviews and the Child Behaviour Check List. All the above‐mentioned evaluations were performed at recruitment (T0) and at the end of the follow‐up period (T1). Results.—A total of 25 children with headache (12 males; 13 females) were monitored through long‐term clinical follow‐up (mean duration: 4.2 years; range: 2.8 to 6.6 years). The “definite” diagnosis of migraine without aura or TTH at T0 was possible in only 6/25 (24%) and 9/25 patients (36%) applying the IHS 1988 criteria and the ICHD‐II criteria respectively, but in 20/25 (80%) applying the “alternative” clinical criteria. Evaluation of headache at T1 revealed: remission in 16/25 (64%) patients and persistence in 9/25 (36%). At T1, the ICHD‐II diagnosis was possible in 100% of the children with headache persistence (1/9 migraine without aura and 8/9 TTH) and these diagnoses were found to be perfectly concordant with those obtained applying the “alternative criteria.” Early developmental disorders were present in 11/25 children, with a significantly higher prevalence in children with headache persistence compared to children showing headache remission (78% vs. 25%; P < .05). No significant differences were found between patients with headache persistence and patients with headache remission with regard to gender, history of headache in family members, headache diagnosis at onset, psychiatric comorbidity at T0, and with regard to “life events” at both T0 and T1. Conversely, the children presenting psychiatric disorders at T1 were more frequently affected by headache than those without psychiatric disorders (59% vs. 15%; P < .05). Conclusions.—Our results suggest that the ICHD‐II criteria are too restrictive to allow the classification of migraine without aura and TTH in preschool children. Nevertheless, a diagnosis based on these criteria was possible in all the patients with headache persistence at the end of several years' follow‐up. We found a significant association between early somatic disorders and persistence of headache and also between the presence of psychiatric disorders at the end of follow‐up and the persistence of headache. “Life events,” on the other hand, while not showing a statistically significant association with the evolution of the headache, may nevertheless influence the course of the headache in some patients. Our results suggest that environmental and psychological factors play an important role in idiopathic headache with onset in preschool age, and thus that the diagnostic–therapeutic approach must take these factors into account.

Tourette syndrome is a neurodevelopmental disorder characterized by multiple tics and is often associated with comorbid behavioral problems. Research with generic instruments in child populations showed that comorbid disorders can have a greater impact on health-related quality of life than tic severity. This study investigated the usefulness of a newly developed disease-specific instrument, the Gilles de la Tourette Syndrome–Quality of Life Scale for Children and Adolescents (GTS-QOL-C&A), in assessing health-related quality of life in young patients with Tourette syndrome with and without behavioral comorbidity. We recruited 75 patients with Tourette syndrome (60 males; age 12.4 ± 3.2 years). All participants were evaluated by a neuropsychiatrist and completed a standardized psychometric battery, including the GTS-QOL-C&A, Child Depression Inventory, and Multidimensional Anxiety Scale for Children. Forty-two patients (56%) fulfilled diagnostic criteria for at least one comorbidity: obsessive-compulsive disorder (n = 25 patients [33.3%]); attention deficit/hyperactivity disorder (n = 6 patients [8%]); both (n = 11 patients [14.7%]). The GTS-QOL-C&A demonstrated usefulness in differentiating “pure” Tourette syndrome from Tourette syndrome “plus” behavioral problems with regard to health-related quality of life scores for the obsessive-compulsive subscale. In addition to focusing on core tic symptoms, the GTS-QOL-C&A showed sensitivity to the impact of behavioral comorbidities on health-related quality of life and can usefully complement existing nonspecific instruments.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor/phonic tics and a wide spectrum of behavioral problems (e.g., complex tic-like symptoms, attention deficit hyperactivity disorder, and obsessive-compulsive disorder). TS can be a challenging condition even for the specialists, because of the complexity of the clinical picture and the potential adverse effects of the most commonly prescribed medications. Expert opinions and consensus guidelines on the assessment and treatment of tic disorders have recently been published in Europe and Canada. All pharmacological treatment options are mere symptomatic treatments that alleviate, but do not cure, the tics. We still lack evidence of their effects on the natural long-term course and on the prognosis of TS and how these treatments may influence the natural course of brain development. The most commonly prescribed drugs are dopamine antagonists, such as typical (e.g., haloperidol, pimozide) and atypical neuroleptics (e.g., risperidone, aripiprazole), and α-2-adrenoreceptor agonists (e.g., clonidine). However, several studies have investigated the efficacy and tolerability of alternative pharmacological agents that may be efficacious, including the newest atypical antipsychotic agents (e.g., paliperidone, sertindole), tetrabenazine, drugs that modulate acetylcholine (e.g., nicotine) and GABA (e.g., baclofen, levetiracetam), tetrahydrocannabinol, botulinum toxin injections, anticonvulsant drugs (e.g., topiramate, carbamazepine), naloxone, lithium, norepinephrine, steroid 5α reductase, and other neuroactive agents (buspirone, metoclopramide, phytostigmine, and spiradoline mesylate). As regards nonpharmacological interventions, some of the more recent treatments that have been studied include electroconvulsive therapy and repetitive transcranial magnetic stimulation. This review focuses primarily on the efficacy and safety of these emerging treatment strategies in TS.

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental condition characterised by multiple motor and phonic tics and associated behavioural problems, carrying a significant burden on patients' lives. Although the term health related-quality of life (HR-QOL) has only been used in recent years, several studies have long addressed the impact of GTS on physical, psychological and social aspects of wellbeing of both children and adults with GTS. We set out to answer the question "Is HR-QOL affected by GTS and, if so, in what domains?" by conducting a systematic literature review of published original studies addressing HR-QOL in both children and adult patients with GTS. This review focuses on the current evidence on the impact of GTS on patients' lives, mainly informed by studies using generic functional impairment and HR-QOL measures from the last decade, and expands on the new opportunities introduced by the recently developed GTS-specific HR-QOL scales (GTS-QOL and GTS-QOL-C&A). Analysis of the first decade of studies specifically addressing HR-QOL in GTS suggests that co-morbid conditions are key factors in determining HR-QOL in young patients, whilst the picture is more complex in adults with GTS. These findings offer some general directions for both current clinical practice and future research.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple tics and associated with co-morbid behavioral problems (TS-plus). We investigated the usefulness of self-report versus parent- and teacher-report instruments in assisting the specialist assessment of TS-plus in a child/adolescent population.Twenty-three patients diagnosed with TS (19 males; age 13.9 ± 3.7 years) and 69 matched healthy controls participated in this study. All recruited participants completed a standardized psychometric battery, including the Children's Depression Inventory (CDI), the Self Administrated Psychiatric Scales for Children and Adolescents (SAFA) and the State-Trait Anger Expression Inventory (STAXI). Parents completed the Child Behavior Checklist (CBCL) and Conners' Parent Rating Scales-Revised (CPRS-R). Participants' teachers completed the Conners' Teacher Rating Scales-Revised (CTRS-R). Results were compared with similar data obtained from controls.Nineteen patients (82.6%) fulfilled DSM-IV-TR criteria for at least one co-morbid condition: obsessive-compulsive disorder (OCD, n = 8; 34.8%); attention deficit-hyperactivity disorder (ADHD, n = 6; 26.1%); OCD + ADHD (n = 5; 21.7%). Scores on self-report instruments failed to show any significant differences between TS and controls. Most subscores of the CPRS-R, CTRS-R, and CBCL were significantly higher for the TS group than controls. The TS + OCD subgroup scored significantly higher than the TS-OCD subgroup on the CBCL-Externalizing, Anxious/Depressed and Obsessive-Compulsive subscales.Self-report instruments appear to have limited usefulness in assisting the assessment of the behavioral spectrum of young patients with TS. However, proxy-rated instruments differentiate TS populations from healthy subjects, and the CBCL can add relevant information to the clinical diagnosis of co-morbid OCD.

Background: Osmophobia is frequent in children with migraine (20–35%) but can also occur in up to 14% of cases with tension-type headache (TTH). So far, the prognostic role of this symptom in children with primary headaches has never been evaluated. Methods: A longitudinal prospective study was conducted on 90 young patients with TTH (37 with osmophobia, 53 without osmophobia). We evaluated whether osmophobia could predict the diagnosis transformation from TTH to migraine after a 3-year follow-up. Results and Discussion: In our cases the rate of diagnosis change was significantly greater in cases with osmophobia (62%) than in those without (23%). Osmophobia persisted at a 3-year follow-up in the majority of our cases (85%) and it was found to be one of the major predictors for the development of migraine; other predictors of evolution to migraine were phonophobia, a probable rather than certain diagnosis of TTH and olfactory triggers (p < 0.05). Conclusion: Our data confirm that osmophobia has an important diagnostic and prognostic role in children with primary headaches and should be systematically investigated at diagnosis and during follow-up.

Difficulties in handwriting, such as dysgraphia, impact several aspects of a child's everyday life. Current methodologies for the detection of such difficulties in children have the following three main weaknesses: (1) they are prone to subjective evaluation; (2) they can be administered only when handwriting is mastered, thus delaying the diagnosis and the possible adoption of countermeasures; and (3) they are not always easily accessible to the entire community.This work aims at developing a solution able to: (1) quantitatively measure handwriting features whose alteration is typically seen in children with dysgraphia; (2) enable their study in a preliteracy population; and (3) leverage a standard consumer technology to increase the accessibility of both early screening and longitudinal monitoring of handwriting difficulties.We designed and developed a novel tablet-based app Play Draw Write to assess potential markers of dysgraphia through the quantification of the following three key handwriting laws: isochrony, homothety, and speed-accuracy tradeoff. To extend such an approach to a preliteracy age, the app includes the study of the laws in terms of both word writing and symbol drawing. The app was tested among healthy children with mastered handwriting (third graders) and those at a preliterate age (kindergartners).App testing in 15 primary school children confirmed that the three laws hold on the tablet surface when both writing words and drawing symbols. We found significant speed modulation according to size (P<.001), no relevant changes to fraction time for 67 out of 70 comparisons, and significant regression between movement time and index of difficulty for 44 out of 45 comparisons (P<.05, R2>0.28, 12 degrees of freedom). Importantly, the three laws were verified on symbols among 19 kindergartners. Results from the speed-accuracy exercise showed a significant evolution with age of the global movement time (circle: P=.003, square: P<.001, word: P=.001), the goodness of fit of the regression between movement time and accuracy constraints (square: P<.001, circle: P=.02), and the index of performance (square: P<.001). Our findings show that homothety, isochrony, and speed-accuracy tradeoff principles are present in children even before handwriting acquisition; however, some handwriting-related skills are partially refined with age.The designed app represents a promising solution for the screening of handwriting difficulties, since it allows (1) anticipation of the detection of alteration of handwriting principles at a preliteracy age and (2) provision of broader access to the monitoring of handwriting principles. Such a solution potentially enables the selective strengthening of lacking abilities before they exacerbate and affect the child's whole life.

Tourette syndrome (TS) is a neuropsychiatric disorder in which dopaminergic dysfunction and immune system abnormalities seem to coexist. Using real-time PCR, we determined mRNA expression of dopamine receptors (DRs) D1-5 in peripheral blood lymphocytes (PBLs) from 15 TS patients and 15 sex- and age-matched healthy controls (HCs). DRD5 mRNA levels in cells from TS were higher than in cells from HCs. In TS patients with obsessive-compulsive disorder, DRD5 mRNA levels in PBLs showed a highly positive correlation with the severity of compulsive symptoms. DRD5 mRNA upregulation in PBLs from TS patients may represent a peripheral marker of dopaminergic dysfunction and supports the involvement of the immune system in TS.

PurposeTo study neuropsychological functions in children with idiopathic epilepsy at onset of treatment and after 1 year of therapy and to identify factors associated with cognitive impairment.Methods43 Subjects aged 5.2–16.9 years with newly diagnosed idiopathic epilepsy were enrolled and started treatment with valproate or carbamazepine. At admission and after 12 months, all patients underwent clinical examinations, the Child Behavioural Checklist, EEG and a neuropsychological test battery. The results of each test were correlated to demographic, clinical, electrophysiological and therapeutic variables.ResultsExcept for attention, all neuropsychological functions were normal at admission and after 12 months. An improvement with time was noted for memory (p < 0.05) and logical-executive functions (p < 0.01). Attentive deficit was worse at 12 months (53.5% vs. 32.6%). Low socio-economic level and emotional and behavioural disturbances were the only factors negatively correlated to intelligence, memory and attention. Compared to valproate, carbamazepine was most commonly implicated.DiscussionIdiopathic epilepsy can affect attention, even before starting treatment. Emotional and behavioural difficulties and a low socio-economical status are associated with cognitive impairment.

This study was planned to investigate the diagnostic utility of osmophobia as criterion for migraine without aura (MO) as proposed in the Appendix (A1.1) of the International Classification of Headache Disorders (ICHD-II, 2004).We analysed 1020 patients presenting at 10 Italian juvenile headache centres, 622 affected by migraine (M) and 328 by tension-type headache (TTH); 70 were affected by headache not elsewhere classified (NEC) in ICHD-II. By using a semi-structured questionnaire, the prevalence of osmophobia was 26.9%, significantly higher in M than TTH patients (34.6% vs 14.3%).Osmophobia was correlated with: (i) family history of M and osmophobia; and (ii) other accompanying symptoms of M. By applying these 'new' criteria, we found an agreement with the current criteria for the diagnosis of migraine without aura (MO) in 96.2% of cases; 54.3% of previously unclassifiable patients received a 'new' diagnosis.In conclusion, this study demonstrates that this new approach, proposed in the Appendix (A1.1), appears easy to apply and should improve the diagnostic standard of ICHD-II in young patients too.

Migraine is a neurological disorder characterized by unilateral head pain, nausea and/or vomiting and altered sensory perception (particularly phono- and/or photophobia). It is a common and disabling condition in children and adolescents, just as it is in adults; its origins, pathophysiology and long-term course are still not fully understood. Biological factors are currently held to be crucial in the aetiopathogenesis of primary headaches, such as migraine. In children and adolescents, we hypothesize that for migraine to develop, life events and their psychological processing are fundamental and can act in two different ways: either as a predisposing factor, inducing a chronic state of anxiety or depression (even subclinical), or as a trigger factor, activating a cascade of psychological events which, in turn, activate the biological mechanisms that produce the migraine attack. According to our hypothesis, psychological processing of life events (i.e. how the child perceives and mentally processes them) is the main factor in migraine aetiopathogenesis. This hypothesis has important implications in terms of diagnostic and therapeutic choices for children and adolescents with migraine.

Tourette syndrome is a neurodevelopmental disorder characterized by tics and comorbid behavioral problems. This study compared child- and parent-reported quality of life and everyday functioning. We assessed 75 children with Tourette syndrome, of which 42 (56%) had comorbid conditions (obsessive-compulsive disorder = 25; attention-deficit hyperactivity disorder = 6; both comorbidities = 4). All patients completed psychometric instruments, including the Gilles de la Tourette Syndrome-Quality of Life Scale for Children and Adolescents (child report) and the Child Tourette's Syndrome Impairment Scale (parent report). Data were compared for patients with pure Tourette syndrome, Tourette syndrome + obsessive-compulsive disorder, Tourette syndrome + attention-deficit hyperactivity disorder, and Tourette syndrome + both comorbidities. There were no group differences in quality of life. However, there were differences for total, school, and home activities impairment scores. Children and parents may not share similar views about the impact of Tourette syndrome on functioning. The measurement of health-related quality of life in Tourette syndrome is more complex in children than adults.

Background: Data on clinical presentation of Hemiplegic Migraine (HM) are quite limited in the literature, particularly in the pediatric age. The aim of the present study is to describe in detail the phenotypic features at onset and during the first years of disease of sporadic (SHM) and familial (FHM) pediatric hemiplegic migraine and to review the pertinent literature. Results: Retrospective study of a cohort of children and adolescents diagnosed with hemiplegic migraine, recruited from 11 Italian specialized Juvenile Headache Centers. Forty-six cases (24 females) were collected and divided in two subgroups: 32 SHM (16 females), 14 FHM (8 females). Mean age at onset was 10.5 ± 3.8 y (range: 2-16 y). Mean duration of motor aura was 3.5 h (range: 5 min-48 h). SHM cases experienced more prolonged attacks than FHM cases, with significantly longer duration of both motor aura and of total HM attack. Sensory (65%) and basilar-type auras (63%) were frequently associated to the motor aura, without significant differences between SHM and FHM. At follow-up (mean duration 4.4 years) the mean frequency of attacks was 2.2 per year in the first year after disease onset, higher in FHM than in SHM cases (3.9 vs. 1.5 per year, respectively). A literature review retrieved seven studies, all but one were based on mixed adults and children cohorts. Conclusions: This study represents the first Italian pediatric series of HM ever reported, including both FHM and SHM patients. Our cohort highlights that in the pediatric HM has an heterogeneous clinical onset. Children present fewer non-motor auras as compared to adults and in some cases the first attack is preceded by transient neurological signs and symptoms in early childhood. In SHM cases, attacks were less frequent but more severe and prolonged, while FHM patients had less intense but more frequent attacks and a longer phase of active disease. Differently from previous studies, the majority of our cases, even with early onset and severe attacks, had a favorable clinical evolution.

The aim of this study was to investigate the frequency of reading, writing, and calculation disabilities in children with typical rolandic epilepsy (RE) and healthy control children. We also aimed to define the possible electroclinical markers of specific cognitive dysfunctions in RE. School abilities were evaluated and compared in 20 children (eight males, 12 females; mean age 10y 3mo [SD 1y 7mo]; range 7y 9mo-12y 9mo) consecutively diagnosed with typical RE, and a group of 21 healthy controls (nine males, 12 females; mean age 10y 4mo [SD 1y 8mo]; range 7y 6mo-13y 3mo). All the children received standardized neuropsychological tests. For each patient an exhaustive seizure diary was kept and all the sleep electroencephalogram (EEG) recordings were reviewed. Specific difficulties with reading, writing, and calculation (diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition) were found in nine out of 20 children with RE and two out of 21 healthy controls (chi2=0.01). The specific learning disabilities in the RE group were correlated with a marked increase in epileptiform discharges during sleep (chi2=0.02) and an early onset of epilepsy (chi2=0.02). Our findings suggest that seizure onset before age 8 years and epileptiform discharges (more than 50% of the sleep EEG recording) in several tracings over more than a year are relevant markers for identifying patients at risk of developing academic difficulties.

Young patients with Tourette Syndrome (TS) can exhibit poor emotional control and aggression. We explored anger in young patients with TS. Twenty-five patients diagnosed with TS and 41 healthy controls completed the State-Trait Anger Expression Inventory (STAXI). Parents and teachers completed the child behavior checklist and Conners’ Parent/Teacher Rating Scales-Revised. STAXI scores were not significantly different between patients with TS and controls. However, many proxy-rated measures linked to anger and externalizing problems were significantly higher in TS. As proxy-rated instruments revealed more oppositional and aggressive behaviors in young patients with TS, they are important in the multidimensional assessment of TS. These findings offer useful insights into the nature of anger symptoms in young patients with TS and provide a basis for more effective diagnosis and management.

Background: The direct and long-term effects of children's exposure to traumatic events can be seen in a complex continuum, based first of all on the type of trauma. Children's reactions to trauma may have different manifestations from the clinical picture of the PTSD, exhibiting dissociative, somatic, depressive or anxiety symptoms, and/or disruptiveness. Aim: we conducted a cross-sectional study in a psychiatric patients sample to determine the extent to which complex trauma history is associated with disease-related characteristics (diagnosis, dissociative symptoms, somatic symptomatology, impairment degree). Methods: We have enrolled 107 subjects, aged between 12 and 18 years, who consecutively referred for a psychiatric evaluation to the Child Neuropsychiatry Unit of the Del Ponte Hospital in Varese. All subjects underwent a clinical evaluation performed by infantile neuropsychiatrists. The battery of tests that was administered to patients included CGI and CGAS (filled out by the clinician), CBCL (filled out by parents), MMPI-A and TSSC-A (filled out by patients), and Wechsler scale. Results: We found out that 35.5% of subjects had a mood disorder, 23.4% a personality disorder, 13.1% a psychotic disorder, 20.6% a post-traumatic stress disorder, while 26.2% were classified as other diagnostic categories (more frequently ADHD, DOP and conduct disorders). 58.9% of patients had at least one comorbidity. 33.6% of subjects also experienced a complex trauma. In multivariate logistic regression analyses, subgroup fellows were collapsed to compare the single trauma and no trauma versus complex trauma group. Gender, age and affective disorders were generally unrelated to subjects', clinicians', and parents' scores. About subjects' self-assessment (MMPI-A Structural Summary Factors), complex trauma history was a statistically significant contributor to high scores on the Immaturity, Health Concerns, Familial Alienation and Psychoticism Factors, followed by presence of dissociative symptoms (except for Familial Alienation factor). Presence of dissociative symptoms, personality and psychotic disorder diagnosis was related to higher clinician impairment scores (CGI-S > 4). Conclusion: These results reinforce available evidence that in trauma-exposed adolescents, the full burden of trauma, including other psychiatric diagnosis than PTSD (such as affective, personality, and psychotic disorders), dissociative and somatic symptomatology, is substantial and needs appropriate assessment and therapeutic interventions.

We evaluate personality traits, anxiety and depression in a population of paediatric and adolescent patients, correlating personality characteristics with headache and sociodemographic variables. The clinical features of headache include specific personality traits. We report a clinical study of 57 patients (age 8-18 years), divided up as follows: 12 migraine with aura, 29 migraine without aura and 16 tension-type headache. One of Cattel's tests was administered to every patient; the Children's Depression Inventory test was administered to 53 patients and the Test Anxiety Inventory test to 43 subjects. The scores obtained by every patient in each test were correlated with the characteristics of headache and with sociodemographic data. We found that patients affected by idiopathic headache share some personality traits, mainly emotional rigidity and tendency to repress anger and aggression. These traits do not seem to be correlated with sociodemographic data and the duration of headache: we considered these as characteristic of migrainous patients.

The prevalence of tic disorders in children varies from 1% to 29% depending on the characteristics of the study population, the diagnostic criteria, and the study design and methods.To calculate the prevalence of tic disorders among primary school children in Italy.The study population comprised 2347 primary school children from the city of Pavia (pop. 80 073), Northern Italy. Using trained school teachers as the source of cases, all children with motor or vocal tics occurring intermittently and unpredictably out of a background of normal motor activity were accepted. The type, frequency, and circumstances of tic disorders were noted. School performance was correlated to the presence of tics.A total of 68 children (56 boys, 12 girls) aged 6-11 years were identified with tic disorders. The period prevalence was 2.9% (95% CI 2.3 to 3.7). The prevalence was 4.4% in boys and 1.1% in girls, with no detectable trends at age 6-11. Motor tics were present in 46 cases, vocal tics in 6, and motor and vocal tics in 16. Situation related tics were noted in 37 cases. A significant correlation was found between the presence of tic disorders and impaired school performance.Tic disorders are a fairly uncommon but disabling clinical disorder among primary school children from an urban community. The fairly low prevalence of this clinical condition, as compared to other reports, can be explained by the choice of stringent diagnostic criteria and the exclusion of patients with other movement disorders.

Gilles de la Tourette syndrome (GTS) is a chronic childhood-onset neuropsychiatric disorder with a significant impact on patients' health-related quality of life (HR-QOL). Cavanna et al. (Neurology 2008; 71: 1410-1416) developed and validated the first disease-specific HR-QOL assessment tool for adults with GTS (Gilles de la Tourette Syndrome-Quality of Life Scale, GTS-QOL). This paper presents the translation, adaptation and validation of the GTS-QOL for young Italian patients with GTS.A three-stage process involving 75 patients with GTS recruited through three Departments of Child and Adolescent Neuropsychiatry in Italy led to the development of a 27-item instrument (Gilles de la Tourette Syndrome-Quality of Life Scale in children and adolescents, C&A-GTS-QOL) for the assessment of HR-QOL through a clinician-rated interview for 6-12 year-olds and a self-report questionnaire for 13-18 year-olds.The C&A-GTS-QOL demonstrated satisfactory scaling assumptions and acceptability. Internal consistency reliability was high (Cronbach's alpha > 0.7) and validity was supported by interscale correlations (range 0.4-0.7), principal-component factor analysis and correlations with other rating scales and clinical variables.The present version of the C&A-GTS-QOL is the first disease-specific HR-QOL tool for Italian young patients with GTS, satisfying criteria for acceptability, reliability and validity.

Gilles de la Tourette Syndrome (GTS) is a childhood-onset hyperkinetic movement disorder defined by the chronic presence of multiple motor tics and at least one vocal tic and often complicated by co-morbid behavioural problems. The pharmacological treatment of GTS focuses on the modulation of monoaminergic pathways within the cortico-striato-thalamo-cortical circuitry. This paper aims to evaluate the efficacy and safety profiles of pharmacological agents used in the treatment of tics in patients with GTS, in order to provide clinicians with an evidence-based rationale for the pharmacological treatment in GTS.In order to ascertain the best level of evidence, we conducted a systematic literature review to identify double-blind randomised controlled trials of medications in GTS populations.We identified a large number of pharmacological agents as potentially effective in improving tic symptoms. The alpha-2 agonist Clonidine is amongst the agents with the most favourable efficacy-versus-adverse events ratio, especially in patients with co-morbid attention-deficit hyperactivity disorder, although effect sizes vary evidence-based studies.Our results are in line with the findings of uncontrolled open-label studies. However, most trials have low statistical power due to the small sample sizes, and newer agents, such as Aripiprazole, have not been formally tested in double-blind randomised controlled trials. Further research should focus on better outcome measures, including Quality of Life instruments.

We conducted a cross-sectional study to compare the impact of social distancing and lifestyle changes that occurred during Corona Virus Disease 2019 (COVID-19) lockdown on children and adolescents with and without Neurodevelopmental Disorders (NDDs). An online questionnaire was administered in order to investigate the effects of NDD condition, socio-demographic status, familiar/home environment and COVID-19 exposure on their lives during a two months period of social isolation. We used logistic regression, focusing on five endpoints (remote learning, lifestyle, stress/anxiety, sociality, scolding) to define the extent of these effects. Most questions were paired up to parents and children, to verify the occurrence of agreement. 8305 questionnaires were analyzed, 1362 of which completed by NDDs and 6943 by controls. Results showed that the presence of a NDD, compared to controls, had a significant impact on: Remote Learning (i.e. subjects with NDDs experienced more difficulties in attending online classes and studying), Sociality (i.e. subjects with NDDs missed their schoolmates less), Scolding (i.e. subjects with NDDs were scolded more often) and Anxiety (i.e. subjects with NDDs were perceived by their parents as more anxious). Substantial agreement between parents and children arose from questions concerning Remote learning, Lifestyle and Scolding. The current study actually points out that having a NDD gives account for a stronger influence on school performance and on behavioral and psychological aspects, during a two months lockdown. Such results may provide useful information to governments and school authorities on how carrying through supportive strategies for youth affected by NDDs.The online version contains supplementary material available at 10.1007/s12144-021-02321-2.

Although developmental reading disorders (developmental dyslexia) have been mainly associated with auditory-phonological deficits, recent longitudinal and training studies have shown a possible causal role of visuo-attentional skills in reading acquisition. Indeed, visuo-attentional mechanisms could be involved in the orthographic processing of the letter string and the graphemic parsing that precede the grapheme-to-phoneme mapping. Here, we used a simple paper-and-pencil task composed of three labyrinths to measure visuo-spatial attention in a large sample of primary school children (n = 398). In comparison to visual search tasks requiring visual working memory, our labyrinth task mainly measures distributed and focused visuo-spatial attention, also controlling for sensorimotor learning. Compared to typical readers (n = 340), children with reading difficulties (n = 58) showed clear visuo-spatial attention impairments that appear not linked to motor coordination and procedural learning skills implicated in this paper and pencil task. Since visual attention is dysfunctional in about 40% of the children with reading difficulties, an efficient reading remediation program should integrate both auditory-phonological and visuo-attentional interventions.

Handwriting learning delays should be addressed early to prevent their exacerbation and long-lasting consequences on whole children's lives. Ideally, proper training should start even before learning how to write. This work presents a novel method to disclose potential handwriting problems, from a pre-literacy stage, based on drawings instead of words production analysis. Two hundred forty-one kindergartners drew on a tablet, and we computed features known to be distinctive of poor handwriting from symbols drawings. We verified that abnormal features patterns reflected abnormal drawings, and found correspondence in experts' evaluation of the potential risk of developing a learning delay in the graphical sphere. A machine learning model was able to discriminate with 0.75 sensitivity and 0.76 specificity children at risk. Finally, we explained why children were considered at risk by the algorithms to inform teachers on the specific weaknesses that need training. Thanks to this system, early intervention to train specific learning delays will be finally possible.

The COVID-19 lockdown affected children, especially those with autism spectrum disorder, due to the disruption in rehabilitation and educational activities. We conducted a cross-sectional study of 315 preschool-aged children, 35 of which had autism, to investigate this impact. A questionnaire was administered to explore socio-demographic status, familiar/home environment, and COVID-19 exposure. The clinical features of autistic subjects were also examined. Seven variables were considered to describe the effect of pandemic: Remote learning, Behavior changes, Home activities, Sleep habits, Night awakenings, Physical activity, Information about the virus. The lockdown had a significant impact on Remote learning, Behavior changes, and Information about the virus in participants with autism. Moreover, we found a worsening in repetitive movements, echolalia, restricted interests, and aggressive behaviors.

The long-term course of migraine with aura (MA) has been poorly explored. The present 11-year follow-up study assessed the long-term natural history and possible prognostic factors of MA with onset in childhood or adolescence. Patients were recruited from the original case records of our department, which are specifically designed to report all headache characteristics, aura symptoms and electroencephalogram (EEG) findings. A total of 77 patients (47 females; 30 males) whose records contained detailed descriptions of both headache and aura symptoms apparently meeting the International Classification of Headache Disorders (ICHD)-II criteria for MA (i.e., 1.2.1, 1.2.2, 1.2.6) underwent structured face-to-face follow-up headache interviews, all of which were conducted by the same neurologist, who has particular expertise in this field. A multivariate model (logistic regression analysis) was used to investigate the association between possible prognostic factors and the remission of both aura and headache at follow-up. The results of our study showed that 23.4% of the MA patients were headache-free at follow-up, 44.1% still had MA and 32.5% had a transformed headache diagnosis (i.e., fulfilling the criteria for ICHD-II 1.1. or 2). Patients with basilar-type migraine (1.2.6) showed the highest headache remission rate (38.5%). Our study seems to show that migraine with typical aura (1.2.1–1.2.2) is associated with a favourable evolution of aura symptoms over time (remission of aura in 54.1% of patients). Subjects experiencing only visual aura had a lower remission rate compared with those with visual ± sensory ± aphasic aura symptoms (36.8% vs. 61.5%, p = 0.054). A short headache duration (&lt;12 hrs) and the presence of EEG abnormalities at baseline were the only significant predictors of aura remission at follow-up (odds ratio [OR] = 9.12, 95% confidence interval [CI]: 1.79 ± 46.51, and OR = 4.76, 95% CI: 1.18 ± 19.15, respectively). No significant predictors of headache remission were found. In conclusion, our results suggest that MA shows a favourable course. Further prospective studies with detailed EEG analysis both at baseline and at follow-up are needed in order to confirm the possible prognostic role of EEG abnormalities in MA. That said, it would, in our opinion, be highly premature at present to submit children with MA to EEG examinations for prognostication purposes.

Over the last few years, aripiprazole has been proposed as a potentially useful medication for tics in patients with Tourette syndrome (TS). Aripiprazole has been associated with fewer adverse effects compared with other atypicals; however, little is known about its tolerability profile in the TS population. This study assessed the prevalence and characteristics of adverse effects resulting from the use of aripiprazole in a retrospective chart review of 29 patients with TS. Six patients (20.7%) discontinued aripiprazole because of the severity of specific adverse effects. The most commonly reported adverse effects were sedation ( n = 9, 30%) and sleep problems ( n = 5, 17%). In the majority of cases, adverse effects were not severe. There were no differences in demographic or clinical variables between the patients who did or did not experience adverse effects. The discontinuation rate of 20.7% suggests that aripiprazole is safe and reasonably well tolerated for use in TS. The prevalence of adverse effects appears to increase with treatment duration.

Despite growing interest in psychotherapy in child and adolescent headache, efficacy studies in this research field have focused mainly on cognitive-behavioral therapies. Whereas relaxation and cognitive-behavioral techniques, in particular, have been found to reduce the intensity and frequency of headache in children and adolescents, data on psychodynamic psychotherapy in this population are lacking.Our aim was to explore the effectiveness of a brief psychodynamic psychotherapy program in the treatment of idiopathic headache in childhood and adolescence.Thirty-three newly diagnosed idiopathic headache sufferers aged 6-18 years, consecutively referred to our outpatient services, were randomized to receive either a brief cycle of psychodynamic psychotherapy (eight sessions administered at two-week intervals) or usual care (clinical interview, neurological examination, counselling, symptomatic therapy).The two groups were evaluated at baseline (T0) and at six months (T1) to be assessed for headache characteristics (i.e. frequency, intensity and duration), quality of life (i.e. the EuroQoL score), patient's global health status (i.e. the Clinical Global Impression score), and emotional-behavioral symptoms (i.e. Child Behavior Checklist scores).The two groups were fairly similar with reference to the main demographic and clinical variables. The T0/T1 comparison showed a statistically significant improvement in headache frequency (p = 0.005), intensity (p < 0.001) and duration (p = 0.002), a statistically significant improvement in the CGI score (p = 0.018), and a borderline improvement in the EuroQoL score (p = 0.053) in the group receiving psychotherapy.According to our pilot findings, a brief psychodynamic psychotherapy program may be more effective than usual care in children and adolescents with idiopathic headache.

Little is known about the perceived impact of the COVID-19 pandemic and subsequent lockdown measures on young patients with tic disorders. Previous studies focused on clinician and parent ratings of tic severity, whereas the only international self-report data are available for adult populations. We present the first findings from a case-control study on children and adolescents with tics during lockdown in Italy.We surveyed 49 patients aged 6-18 years and 245 matched controls with a newly developed questionnaire covering socio-demographic and clinical data, as well as lockdown-related changes to daily life activities.About half (53.2%) of the Italian school-age patients who took part in our survey experienced changes in tic severity during lockdown. Perceived increases in tic severity (29.8%) were reported more often than decreases (23.4%). Analogous trends were reported for perceived restlessness and, more significantly, irritability, whereas changes in pain symptoms were less common and were similar in both directions. The presence of tics was associated with increased difficulties with remote learning (p = 0.01), but decreased feelings of missing out on social interactions with schoolmates (p = 0.03).Self-reported data on the impact of COVID-19 lockdown in school-age patients with tic disorders indicate perceived changes in tic severity, as well as restlessness and irritability, in about half of the cases. These findings could guide both clinicians and teachers in the implementation of targeted adjustments in the delivery of care and educational strategies, respectively.

Continuous spikes and waves during slow sleep (CSWS) are a well-known EEG pattern that can be associated with cognitive and behavioural deterioration. We present the long-term clinical, neuropsychological and EEG follow-up of two patients who developed CSWS during childhood. In both the CSWS onset was followed immediately by rapid cognitive and behavioural deterioration. Later the CSWS fragmented or fluctuated and the spike-wave discharges diminished and this was associated with progressive clinical improvement. At the same time bilateral frontal EEG abnormalities appeared awake and in sleep. After the initial period of rapid cognitive and linguistic improvement both patients stabilised. The latest neuropsychological assessment showed a frontal syndrome. The presence of frontal EEG abnormalities superimposed on CSWS, their persistence after CSWS resolution and, in addition, the finding of subtle frontal-type neuropsychological alterations early in recovery may indicate poor long-term outcome.

Myoclonus epilepsy with ragged red fibers (MERRF) is one of the major mitochondrial encephalomyopathies. Its main clinical features are myoclonus epilepsy, ataxia, and myopathy with ragged red fibers. Whereas there is a close correlation between MERRF syndrome and the A8344G mutation of mitochondrial DNA, the reverse is not true. In fact, this mutation is also responsible for various other syndromes, such as Leigh syndrome, spinocerebellar degeneration, atypical Charcot-Marie-Tooth disease, and multiple truncal lipomas. We describe a child with the A8344G mutation of mitochondrial DNA and an unusual clinical, neuroradiologic, and biochemical phenotype, characterized by early-onset, nonprogressive cerebellar ataxia, and subclinical myoclonias in association with bilateral putaminal necrosis on magnetic resonance imaging and a reduction in complex V activity. Our case confirms the existence of a relationship between alteration in adenosine triphosphatase activity and basal ganglia involvement. We recommend that the possibility of a mitochondrial pathology should always be taken into consideration in the presence of bilateral symmetric lesions of the basal ganglia, even when the typical clinical picture is lacking. ( J Child Neurol 2006;21:79—82).

Migraine is a common and disabling condition in children and adolescents. The complexity of migraine on a pathogenetic and clinical level results from the interaction between biological, psychological and environmental factors. Appropriate management requires an individually tailored strategy giving due consideration to both pharmacological and non-pharmacological measures. Ibuprofen (7.5 – 10.0 mg/kg) and acetaminophen (15 mg/kg) are safe and effective, and should be considered for symptomatic treatment. Sumatriptan nasal spray (5 and 20 mg) is also likely to be effective, but at the moment, should be considered for the treatment of adolescents only. With reference to prophylactic drug treatment, the available data suggest that flunarizine (5 mg/day) is likely to be effective and pizotifen and clonidine are likely to be ineffective. The efficacy data regarding propranolol, nimodipine and trazodone are conflicting. Insufficient evidence is available on cyproheptadine, amitriptyline, divalproex sodium, topiramate, levetiracetam, gabapentin or zonisamide. The management of migraine in children needs an individualised therapeutic approach, directed to the whole person of the child, taking into account the developmental perspective and the high rate of psychiatric comorbidities. It is the authors’ opinion that for the prophylaxis of migraine, interventions such as identification and avoidance of trigger factors, regulation of lifestyle, relaxation, biofeedback, cognitive behavioural treatment and psychological or psychotherapeutic interventions (e.g., psychodynamics) could be much more effective than pharmacotherapy.

Clonidine, an alpha-2 adrenergic agonist, has been used to treat Tourette syndrome (TS) for nearly 3 decades. This first-tier medication is especially recommended for children and adolescents with a combination of attention-deficit/hyperactivity disorder and mild tics. Although clonidine is thought to have a low rate of adverse effects (AEs), little is known about its tolerability profile in adult patients with TS.This study investigated the prevalence and characteristics of AEs associated with clonidine through a retrospective chart review. We assessed 36 patients with TS (27 men; mean [SD] age, 24.6 ± 13.9; range, 10-62 years), of whom 32 (88.8%) had comorbid conditions (most common: attention-deficit/hyperactivity disorder, n = 12; obsessive-compulsive disorder, n = 9).Seventeen patients (47.2%) experienced AEs. Eleven patients (30.5%) withdrew clonidine because of the severity of AE (n = 5) or absence (n = 4)/reduction (n = 2) in efficacy. The most commonly reported AEs were sedation and headache. In most cases, AEs were mild and occurred with higher starting doses. In 12 patients (70.6%) who also took other psychotropic medications, cotherapy could have been linked to the appearance of AE.Our findings suggest that clonidine is a safe and well-tolerated medication in the TS population. Adults with TS treated with this medication experience mild and relatively infrequent AE; high starting dose and polytherapy seem to be the only clinically relevant risk factors for AE development.

We describe the long-term follow-up of a patient with bilateral striatal necrosis associated with Mycoplasma pneumoniae infection occurred in adolescence. In the literature there are no longitudinal studies of such a rare condition. Our patient, 4 years after the onset of an acute and reversible akinetic-rigid syndrome, showed a severe obsessive-compulsive disorder, cognitive decline, and a neuropsychological profile characterized by signs of deficient executive functioning. The clinical picture that emerged in our patient is suggestive of a frontosubcortical dementia which might be considered a major long-term sequela of the bilateral selective striatal necrosis and consequent dysfunction of frontostriatal connections.

In Tourette syndrome, motor and phonic tics are associated with a spectrum of psychiatric disorders. As proxy report instruments are commonly used to assess children with Tourette syndrome, we investigated the relationship between child and mother ratings of behavioral problems. We enrolled 28 children with Tourette syndrome (25 males; mean age, 13.9 years) and 61 gender- and age-matched healthy controls (55 males; mean age, 14.7 years). Clinicians completed measures of tic severity, and all children completed the Youth Self-Report version of the Child Behavior Checklist, while their mothers completed the Child Behavior Checklist. In the clinical group, Youth Self-Report scores were significantly lower than mothers’ Child Behavior Checklist scores across the majority of subscales (especially affect and somatization). In contrast, for the control group, mother and child ratings only differed for the externalizing behavior subscales. Clinicians should be aware of these differences between self and mother ratings for specific behavioral problems in Tourette syndrome.

Abstract Background The association of stereotypies and tics is not rare in children with severe autism spectrum disorder (ASD). The differential diagnosis between stereotypies and tics in this patient population can be difficult; however, it could be clinically relevant because of treatment implications. Methods A total of 108 video recordings of repetitive behaviors in young patients with stereotypies in the context of ASD were reviewed by a movement disorders expert and a trainee, in order to assess the prevalence of possible co-morbid tics. The Modified Rush Videotape Rating Scale (MRVS) was used to rate tic frequency and severity. Results Out of 27 patients with stereotypies (24 males; mean age 14 years), 18 (67%) reported possible tics. The most frequently observed tics were eye blinking, shoulder shrugging, neck bending, staring, and throat clearing. The mean MRVS score was 5, indicating mild tic severity. The only significant difference between patients with tics and patients without tics was the total number of stereotypies, which was higher in the subgroup of patients without tics ( p = 0.01). Conclusions Expert review of video-recordings of repetitive behaviors in young patients with ASD and stereotypies suggests the possibility of a relatively high rate of co-morbid tics. These findings need to be integrated with a comprehensive clinical assessment focusing on the diagnostic re-evaluation of heterogeneous motor manifestations.

Headache is a disease that has a high social impact in the paediatric as well as in the adult population, often resulting in a significant reduction in the young patient's quality of life, reflected primarily in a greater number of days off school and increasingly frequent recourse to symptomatic drugs. The idea for this study came from the clinical impression that some paediatric headache patients might benefit more from inpatient than outpatient care.The aim of our study was to compare the effectiveness of hospitalization to outpatient care of patients with newly diagnosed frequent and disabling headache.A pragmatic randomized open-label trial was conducted at the Child Neurology Clinic of the University of Pavia, Italy. Children and adolescents with a 2- to 6-month moderate-to-severe migraine or tension-type headache history were randomized to hospital admission or outpatient assessment and followed for 6 months. The efficacy of the two therapeutic strategies was measured by counting the number of responders in each arm. Other end points included the mean frequency and duration of attacks, the number of drug prescriptions taken to control pain, and the number of patients and physicians expressing satisfaction with treatment.The study population included 27 girls and 23 boys aged 8 through 18 years with migraine (23 cases) or tension-type headache (27 cases). Compared to outpatient assessment, hospital admission was correlated to a significant increase in the number of responders: 0 vs. 44% (1 month), 0 vs. 68% (3 months), and 12 vs. 68% (6 months). The mean frequency and duration of attacks were significantly lower in hospitalized patients (p < 0.0001). Hospitalization was correlated with a significant reduction of patients with severe headache (p < 0.005), a reduction of drug use, and a higher number of satisfied patients and physicians (p < 0.05). Logistic regression analysis confirmed the higher responder rate among hospitalized patients after adjusting for age, sex, diagnosis, and headache characteristics or admission.We think hospitalization reduces the emotional mechanisms that provoke stress in children and often induce or favour headache attacks. If these mechanisms can be interrupted, the management of disease may become easier and with enduring benefits.

Background: To date only three studies, all lacking a control group, have investigated the personality style underlying tic disorders or Tourette’s syndrome (TS), using the projective Rorschach test. Despite the recent controversy about its proper use in clinical practice and research, the Rorschach test may be useful to explore personality organization in TS. The research hypothesis under investigation in this exploratory study was that young TS patients exhibit a peculiar personality organization, with significantly increased indicators of poor emotional control, aggression, anxiety and depression, on the Rorschach test, compared to healthy controls. Methods: We analyed the Rorschach protocols of 17 newly diagnosed paediatric TS patients and 17 age- and sex-matched healthy controls. Results: Compared with the controls young TS patients recorded significantly lower mean percentages of F and F+ responses and a significantly higher number of FM and FC responses, thus showing reduced control of emotions and difficulty in integrating aggressivity. Furthermore, associations emerged between comorbidity with ADHD and increased emotional instability and between severity of tics and of OCD and a pattern of emotional hyper-control and application of rigid defensive mechanisms. Conclusions: These results seem to confirm the existence of a peculiar personality style in young TS patients and may have important implications, both pathogenetic and therapeutic.

Headache and psychopathology (especially anxiety and mood disorders) are comorbid across the life span. The present study is a clinical contribution in the direction of studying the familial recurrence of headache, and the interplay of headache and psychopathology in children.The clinical sample is composed by 130 headache patients (53 boys and 77 girls, age range 8-18), while the control group is composed by 87 healthy subjects from the general population (39 boys and 48 girls, age range 8-18). A structured interview according to International Classification for Headache Disorders-II criteria has been administered to the clinical group; the Child Behavior Checklist (CBCL) and the Self Administrated Psychiatric Scales for Children and Adolescents (SAFA) have been used in order to assess psychopathology in both groups.The recurrence of headache in family members is confirmed by the present study, albeit limited to paternal side, χ2 (4, N.=130)=10.47, P=0.033. Results also showed that scores obtained by the clinical sample in CBCL and SAFA are generally higher than scores obtained by the control group, but without differences between headache sub-types. Finally, internalizing symptoms (anxiety and depression) in children correlate with mothers' point of view, r≥0.23, P<0.05, outlining a specific attunement between headache patients and their mothers.Headache runs in families, with high level of psychological disorders. Mothers are particularly attuned with the psychological needs of their headache children.

Tourette syndrome is a neurodevelopmental disorder characterized by multiple tics and commonly associated with behavioral problems, especially obsessive-compulsive disorder and attention-deficit hyperactivity disorder (ADHD). The presence of specific personality traits has been documented in adult clinical populations with Tourette syndrome but has been underresearched in younger patients. We assessed the personality profiles of 17 male adolescents with Tourette syndrome and 51 age- and gender-matched healthy controls using the Minnesota Multiphasic Personality Inventory-Adolescent version, along with a standardized psychometric battery. All participants scored within the normal range across all Minnesota Multiphasic Personality Inventory-Adolescent version scales. Patients with Tourette syndrome scored significantly higher than healthy controls on the Obsessiveness Content Scale only (P = .046). Our findings indicate that younger male patients with Tourette syndrome do not report abnormal personality traits and have similar personality profiles to healthy peers, with the exception of obsessionality traits, which are likely to be related to the presence of comorbid obsessive compulsive symptoms rather than tics.

Failing to master handwriting, as in the case of Dysgraphia, has negative consequences on children's lives. In early stage of development, Dysgraphia diagnosis is delayed and not easily achievable. Thus, the aim of this work is to propose a valid tool to anticipate Dysgraphia screening at a preliteracy age. We developed a tablet application to analyze characteristics altered in dysgraphic handwriting, such as rhythmical laws (isochrony and homothety), or a collection of kinematic and dynamic parameters (smoothness, pressure, frequency contents). To be suitable for the pre-literacy stage, possible alterations are investigated in symbol drawings. The app is tested on 104 preschoolers, both with normal (n=76) and delayed graphical abilities (n=28), reporting excellent acceptance. Some isochrony alterations were reported only for children with delayed graphical abilities. Moreover, kinematic and dynamic parameters are effective in discriminating between risk and norisk conditions. Indeed, the logistic classification adopted resulted in a 0.819 area under the precision-recall curve. These findings pave the way toward an early screening of future handwriting alteration, starting from a pre-literacy age.

Dysgraphia negatively impacts school-aged children, but its diagnosis is still unsatisfactory. Among its criticalities, it relies on a subjective evaluation of the final product, and it can be delayed as professional consultation might be difficult to be reached. To address these problems, we proposed to leverage two digital tools, a smart ink pen, and a consumer tablet with pen and a custom app, both capable of collecting data about gesture production. The aims of this work are (1) to test usability and acceptance of such tools, (2) to assess their concurrent validity, and (3) to leverage gesture-production features to assess handwriting proficiency. The tools were tested on 52 second and third graders performing a handwriting speed test. It revealed optimal usability (SUS>95) and acceptance. The scores of the speed test were compared to normative data, revealing that they were almost superimposable, even if collection of ad hoc normative data for tablets would allow a safer comparison. Two gesture-production features, the In-air time and the Coefficient of variation of the tilt, showed good discriminatory capabilities between different levels of handwriting maturation. These findings suggest the feasibility of adopting the digital tools for an evaluation of handwriting evolution, both enriched with quantitative information, and potentially administered in a pre-clinical environment (teleconsultation or remote monitoring). This is a first step to discover potential alteration, and achieve a more targeted diagnosis for dysgraphia.

This is a study of two children with neuroradiologically diagnosed dolichobasilar anomaly: in both cases, the diagnosis was based on magnetic resonance imaging and magnetic resonance angiography findings. We examined the first child (R., aged 6 years and 8 months) following four episodes of intense pain in the left orbit, lasting between 10 and 30 min and accompanied by photophobia and vomiting. The second child (S., aged 9 years and 2 months), suffering from Marfan’s syndrome, was examined following recurrent episodes of intense pain that started above the left orbit, moving to the homolateral orbit after a few minutes. These episodes, which lasted between 20 and 30 min, took place mainly at night and were accompanied by phono-photophobia and vomiting. In both cases, the pain attacks can be interpreted as a result of compression of the root of the trigeminal nerve caused by an arterial malformation.

Headache is an extremely frequent symptom in childhood and adolescence, and a common reason for neurological consultation. The prevalence of primary headaches (about 85% in tertiary centers) ranges from 10% to 20% in schoolchildren, and increases with increasing age. No sex difference is apparent until age 11. Female preponderance begins about age 12; during adolescence the female-to-male ratio is about 2:1. A child is not a “little adult” and many developmental and individual factors affect headaches, pertaining to the clinical expression, diagnosis, and therapy of the primary headache. According to this view, several points have to be clarified, beginning by considering the child as a whole as regards his or her development, taking into account neurobiological and psychological maturational processes, familial, social, and environmental factors, and avoiding an adult-focused approach to the disease. It is necessary to find key points in the etiology, pathogenesis, diagnosis, treatment, and outcome of headache in childhood and adolescence.

Confrontation naming tasks are useful in the assessment of children with learning and language disorders.The aims of this study were (1) providing longitudinal data on confrontation naming; (2) investigating the role of socioeconomic status (SES), intelligence, age, and gender in confrontation naming; (3) identifying relationship between confrontation naming and reading abilities (fluency, accuracy, and comprehension).A five-year longitudinal investigation of confrontation naming (i.e., the Boston Naming Test (BNT)) in a nonclinical sample of Italian primary school children was conducted (n = 126), testing them at the end of each school year, to assess nonverbal intelligence, confrontation naming, and reading abilities.Performance on the BNT emerged as a function of IQ and SES. Significant correlations between confrontation naming and reading abilities, especially comprehension, were found; BNT scores correlated better with reading fluency than with reading accuracy.The longitudinal data obtained in this study are discussed with regard to reading abilities, intelligence, age, gender, and socioeconomic status.

The objective of the study was to assess whether a family history of vascular disorders is more common in children and adolescents with migraine than in the general population. Family history of stroke, arterial hypertension, myocardial infarction and diabetes was investigated by history taking in relatives of ambulatory children and young adults with migraine and in a control group. The odds ratios (ORs) with 95% confidence intervals (95% CI) were used as a risk measure. Using univariate and multivariate (logistic regression) analysis, family history was assessed in the whole sample and in subgroups by sex and age, degree of relationship (parents and grandparents vs. relatives), disease type (migraine with and without aura), and type of vascular disorder. The sample included 143 cases (migraine with aura 35, migraine without aura 108) and 164 controls aged 324 years (mean 12 ± 3.8 years). Patients with migraine were at increased risk of vascular disorders in parents and grandparents but not in all relatives. Multivariate analysis indicated family history of stroke as most common only in boys. In conclusion, our study provides some clues to the assumption that migraine and vascular disorders have common pathogenic mechanisms and that genetic susceptibility plays a role in increasing the risk of migraine in the offspring of families with one or more cerebrovascular or cardiovascular conditions.

OPINION article Front. Neurol., 14 August 2018Sec. Headache and Neurogenic Pain Volume 9 - 2018 | https://doi.org/10.3389/fneur.2018.00667

Attention‐deficit/hyperactivity disorder (ADHD) often co‐occurs with reading disability. A cross‐sectional study in an Italian‐speaking, nonclinical sample was conducted in an attempt to document the existence of an early association between reading difficulties (RD) and ADHD behaviours. We recruited a sample of 369 children in their first year at primary school. Of the sample, 8.4% displayed RD; 7.0% had ADHD; 3.5% presented both RD and ADHD behaviours; 50% of the children with ADHD displayed RD; 41.9% of those with RD displayed ADHD behaviours. Low socioeconomic status was associated with a fourfold increased probability of displaying RD (odds ratio = 3.98), but not ADHD behaviours. In this nonclinical sample, we detected an early association between ADHD behaviours and RD. A key role in this association may be played by inattention symptoms, which occurred with significantly increased frequency also in the group presenting only RD.

To investigate the prevalence of mitral valve prolapse (MVP) and abnormalities of haemostasis in children and adolescents with migraine with aura (MA) compared with peers affected by other idiopathic headaches.We recruited 20 MA patients (10 men and 10 women; age range 8-17 years) and 20 sex- and age-matched subjects with other idiopathic headaches. Both groups underwent colour Doppler transthoracic echocardiography to detect MVP and the following laboratory work-up: plasma prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, protein C, protein S, homocysteine, lupus anticoagulant, von Willebrand factor (vWF) ristocetin cofactor activity, immunoglobulins (Ig) G and M anticardiolipin antibodies (aCL). Factor V Leiden, factor II and methylenetetrahydrofolate reductase were investigated (we did not test the entire genes, but screened for specific point mutations).The prevalence of MVP was significantly higher in the MA subjects than in the patients affected by other idiopathic headaches (40% vs 10%; P < 0.05). Moreover, the MA patients showed a higher rate of above-normal IgM aCL titres (45% vs 10%; P < 0.05). Finally, in the group of patients with MVP we found a higher prevalence of aCL in those with MA compared with those affected by other idiopathic headaches.A proportion, at least, of the MA patients showed a more complex phenotype characterized by MVP and/or positive aCL titres. The pathogenetic role of these associations is obscure and larger studies are needed to confirm the usefulness of echocardiographic and laboratory investigations in this area and to identify possible new treatment approaches that might be explored in this group of MA patients.

The management of headaches with juvenile onset presents several problems, related not only to appropriate drug selection but also to the specific features distinguishing headache disorders in children and adolescents: a child is not a "little adult". Many age-related factors influence the clinical expression of headache and these should be taken into account not only in the treatment, but also in the diagnosis, of juvenile headache. Few randomised placebo-controlled clinical trials of acute or preventive drugs have been conducted in paediatric headache patients, and those that have show a high placebo response rate in children (e.g. up to 55% for prophylactic drugs and up to 69% for symptomatic ones). The available data on symptomatic drugs are presented and discussed, focusing, in particular, on mechanisms of action, evidence of efficacy, and tolerability.

Evaluation of any possible behavioural reactions in epileptic patients during vigabatrin treatment.Ten patients with refractory partial epilepsy, previous mental retardation and psychosis or other significant psychiatric morbidity treated with vigabatrin were submitted periodically to specific tests (to quantify any possible change in behavioural parameters) and also to EEG recordings.After 1 year of treatment 5/10 patients became seizure-free, 3/10 of them presented reduction of seizures by over 75%. None of the subjects presented episodes that could be interpreted as psychotic reactions and, moreover, some patients showed a reduction in stereotypies, instability and aggressiveness. In 66% of these patients an improvement in cognitive functions was observed.The onset of side effects can be prevented by a gradual introduction of vigabatrin and by the use of the drug in moderate doses. These data do not confirm the contraindication to treat with vigabatrin patients with a history of psychiatric disturbances.

There are few literature evidences about the intellectual profile of adolescents with headache and no study has used the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV) in patients with a diagnosis of headache according to the ICHD-III-beta. We recruited 30 patients (age 11-14 years; male:female = 1:2) seen for headache in a tertiary center in Northern Italy and 30 healthy controls matched for age and sex, recruited in a public school from the same geographic area. The diagnosis of headache was done according to the ICHD-III criteria (beta version): the case group was composed of 16 patients with migraine and 14 with tension-type headache. Cognitive functioning was assessed using the WISC-IV. Recruited patients with idiopathic headache diagnosis had on average a cognitive function within the normal range. We found no statistically significant differences in the total Intellective Quotient comparing patients with headache and controls; the Working Memory Index was, however, lower in patients with headache (p = 0.012), and in particular, we found a lower Digit Span (p < 0.001). We also found a borderline statistical difference (p = 0.051) between case and controls Verbal Comprehension Index (CVI), which was due to a lower score in the Similarities subtest (p < 0.001). Our results suggest that, although within normal limits, cognitive functioning of adolescents with headache differs from that of healthy peers regarding memory and verbal skills. The Working Memory Index is related to the subject's ability to store new information and keep them in short-term memory, to maintain focused attention and to manipulate them to find solutions. The difference in Similarities is also important because it provides a measure of the level of verbal reasoning and concept formation; it is also a measure of verbal abstract thinking skills relevant for language development, lexical knowledge, auditory comprehension, memory, and ability to discriminate between essential and non-essential characteristics. Our data, in keep with previous findings, suggest the need for further researches to better understand the pathogenesis of these difficulties and obtain ideas for an adequate rehabilitative treatment.

Abstract Although developmental reading disorders (developmental dyslexia) have been mainly associated with auditory-phonological deficits, recent longitudinal and training studies have shown a possible causal role of visuo-attentional skills in reading acquisition. Indeed, visuo-attentional mechanisms could be involved in the orthographic processing of the letter string and the graphemic parsing that precede the grapheme-to-phoneme mapping. Here, we used a simple paper-and-pencil task composed of three labyrinths to measure visuo-spatial attention in a large sample of primary school children (n = 398). In comparison to visual search tasks requiring visual working memory, our labyrinth task mainly measures distributed and focused visuo-spatial attention, also controlling for sensorimotor learning. Compared to typical readers (n = 340), children with reading difficulties (n = 58) showed clear visuo-spatial attention impairments that appear not linked to motor coordination and procedural learning skills implicated in this paper and pencil task. Since visual attention is dysfunctional in about 40% of the children with reading difficulties, an efficient reading remediation program should integrate both auditory-phonological and visuo-attentional interventions.

Summary: Purpose: To study the neuropsychological status of an epileptic patient presenting with epileptic activity triggered by eye closure in a 14‐year follow‐up period. Methods: The patient was studied at 12 and 26 years of age; during this period he underwent periodical clinical evaluations and EEG investigations; brain magnetic resonance imaging (MRI) was performed at 12 years of age. A neuropsychological assessment was carried out both at 12 years of age (T0) and at 26 years of age. At T0 and T1, neuropsychological tests (digits and words span, graphoestesia, reactions time to auditory stimuli, sentences repetition, words repetition, digital gnosis, backward counting [i.e.,100–0]) were performed during video‐EEG monitoring either with eyes closed or with eyes open, to evaluate possible transitory effects related to ongoing epileptic activity. Moreover, at T0 the patient underwent Wechsler Intelligence Scale for Children‐Revised, and at T1 to Wechsler Adult Intelligence Scale‐Revised. Results: EEG recordings showed continuous epileptic activity triggered by eye closure, disappearing only with eyes opening, both at T0 and T1 (in this latter case, anteriorly predominant). The results of neuropsychological assessment during eyes closed as compared to performances with eyes open did not show significant differences, at T0 as well as at T1. Wechsler Intelligence scales showed a deterioration of performances at T1 with respect to T0; in addition, at T1, attention and short‐term memory abnormalities, impairment in facial recognition and block design, and defective results in Continuous Performance Test and Wisconsin Card Sorting Test were observed. Conclusions: Lack of differences between the results of neuropsychological tests performed with eyes closed as compared to the eyes open condition suggests that in our patient epileptic activity did not cause transitory cognitive abnormalities. Deterioration of Wechsler Intelligence Scales in the follow‐up period might be interpreted as the result of a disruption of cognitive processes possibly related to the persistence of a continuous epileptic activity during eye closure over the years. We speculate whether a dysfunction in posterior cortical areas involved in visual processing might be related to the impairment in face recognition and block design tests as well to eye closure sensitivity.

Diagnosis of pervasive developmental disorders (PDDs), and above all diagnosis of the different PDD subtypes, is an ongoing challenge in psychopathology. Application of categorical criteria is complex and problematic in the clinical field where the boundaries dividing some of the PDD entities are blurred, creating particular problems for the clinician. A dimensional clinical approach, considering autistic symptom severity, level of functioning, developmental characteristics and symptoms other than the ones typically observed in autism, may be a more suitable approach in the clinical field and could provide the clinician treating these disorders with empirical guidance. To identify the clinical features that might differentiate the PDD subtypes, we conducted a comparative study in a clinical sample of children affected by autism disorder (AD) or pervasive developmental disorders not otherwise specified (PDD-NOS) and a mini critical review of the available literature addressing clinical and psychopathological differences between the two subtypes. The results of both our study and our literature review seem to show little support for the current PDD subtypes. In such a framework, the most significant element in clinical practice appears to be a deep knowledge of the characteristics of the individual in question. By adopting a broad and multi-faceted perspective, it becomes possible to define the most effective rehabilitation treatment. This applies particularly to the pharmacological treatment, since, to date, no specific therapies for PDDs are known and the choice of pharmacotherapy can be decided only on the basis of the patient’s general profile and specific features. Keywords: Autism, classification, pervasive developmental disorder, pervasive developmental disorder not otherwise specified, pharmacological treatment, subtype.

In recent years, it has become common practice, in the treatment of headache, to use alternative methods, both alone and in association with drug therapies. Alternative therapies would appear to be more indicated in certain subjects: patients opposed to pharmacological treatments, those showing low tolerance of drugs or with a history of drug abuse, and those presenting medical contraindications or poor response to certain drugs. Numerous studies of alternative therapies have been published and here we review the literature data on the topic, considering in particular the accuracy of the various study methods in evaluating the effectiveness of the different therapies and their specificity for the different forms of headache. Specialists involved in the assessment and care of headache patients should strive to increase their knowledge of alternative therapies, so as to be better equipped to guide patients towards safe, economical and potentially effective treatments, rather than useless, costly or dangerous ones.

It is widely known that humans have a tendency to imitate each other and that appropriate modulation of automatic imitative behaviors has a crucial function in social interactions. Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterized by motor and phonic tics. Apart from tics, patients with GTS are often reported to show an abnormal tendency to automatically imitate others' behaviors (i.e., echophenomena), which may be related to a failure in top-down inhibition of imitative response tendencies. The aim of the current study is to explore the top-down inhibitory mechanisms on automatic imitative behaviors in youngsters with GTS. Error rates and reaction times from 32 participants with GTS and 32 controls were collected in response to an automatic imitation task assessing the influence of observed movements displayed in the first-person perspective on congruent and incongruent motor responses. Results showed that participants with GTS had higher error rates than controls, and their responses were faster than those of controls in incompatible stimuli. Our findings provide novel evidence of a key difference between youngsters with GTS and typically developing participants in the ability to effectively control the production of own motor responses to sensory inputs deriving from observed actions.

Although mild-to-moderate intellectual disability is usually considered part of WAGR syndrome (Wilms' tumour (WT), Aniridia, Genital abnormalities, and metal Retardation, due to 11p13 deletion) the neuropsychological profile of the syndrome is little reported in the literature. We report about a 12-year-old boy presenting with WAGR syndrome (WT, right complete aniridia, bilateral cryptorchidism, interstitial deletion involving band 11p13) but with no mental retardation. An in-depth clinical evaluation revealed no behavioural or social problems and the child's neuropsychological profile was found to be within the normal range for all abilities and functions investigated (with the exception of an impulsive cognitive style and some difficulties in academic skills). This case underlines the importance of in-depth neuropsychological evaluation that includes not only IQ measurement, but also examination of attention and academic skills, in order to establish the complete phenotypical profile of WAGR patients, rather than labelling them as learning disabled (i.e. mental retardation).

Dysgraphia is a learning disability that causes handwritten production below expectations. Its diagnosis is delayed until the completion of handwriting development. To allow a preventive training program, abilities not directly related to handwriting should be evaluated, and one of them is visual perception. To investigate the role of visual perception in handwriting skills, we gamified standard clinical visual perception tests to be played while wearing an eye tracker at three difficulty levels. Then, we identified children at risk of dysgraphia through the means of a handwriting speed test. Five machine learning models were constructed to predict if the child was at risk, using the CatBoost algorithm with Nested Cross-Validation, with combinations of game performance, eye-tracking, and drawing data as predictors. A total of 53 children participated in the study. The machine learning models obtained good results, particularly with game performances as predictors (F1 score: 0.77 train, 0.71 test). SHAP explainer was used to identify the most impactful features. The game reached an excellent usability score (89.4 ± 9.6). These results are promising to suggest a new tool for dysgraphia early screening based on visual perception skills.

Although developmental dyslexia have been mainly associated with auditory-phonological deficits, recent longitudinal and training studies have shown a possible causal role of visuo-attentional skills in reading acquisition. Indeed, visuo-attentional mechanisms could be involved in the orthographic processing of the letter string and the graphemic parsing that precede the grapheme-to-phoneme mapping. Here, we used a simple paper-and-pencil task composed of three labyrinths to measure visuo-spatial attention in a large sample of primary school children (n= 398). In comparison to visual search tasks requiring visual working memory, our labyrinth task mainly measures distributed and focused visuo-spatial attention, also controlling for sensorimotor learning. Compared to typical readers (n= 340), children with reading difficulties (n= 58) showed clear visuo-spatial attention impairments not linked to motor coordination and procedural learning skills. Since visual attention is dysfunctional in about 40% of the children with reading difficulties, an efficient reading remediation program should integrate both auditory-phonological and visuo-attentional interventions.

Dyslexia is a Specific Learning Disorder (SLD) characterized by subpar reading abilities in terms of accuracy and/or speed. Dyslexia can have a lifelong negative impact on academic and day-to-day life. However, early identification and subsequent training can help dyslexic children overcome their reading difficulties. For instance, tachistoscopic reading, a technique that involves presenting words for a brief period, has been shown to improve reading speed. Technological tools, such as serious games, can also be useful, and governments encourage their use to enhance the management of SLDs. In this study, we investigated the efficacy of a serious game called Tachistoscopio in improving reading speed in children. The game began with a short calibration process, followed by the presentation of a word for a brief duration. The user was then asked to write the word. We tested it on children, carrying out the pictorial system usability scale to assess usability and investigating the effect of class and gender through Mann-Whitney U tests. We determined it had excellent usability and could effectively adapt to users’ abilities, as third graders performed significantly better than second graders (p&lt;0.001). Following the success of this preliminary phase, 36 second-grade children, split into two groups, participated in a training study: 18 children underwent a three-week training phase with the game, while the remaining 18 children served as the control group. Before the training, we assessed all children’s reading abilities using standardized word reading and vocabulary tests. The training involved four 20-item sessions per week. We then collected the reading performance of both groups again and used Mann-Whitney and interval estimates to test for statistically significant difference between the reading speed increments in the two groups. Their confidence intervals did not overlap (training: [0.11; 0.33], control: [-0.10; 0.05]), which suggests a significant difference between them. These findings suggest that Tachistoscopio may be an effective intervention tool for improving reading speed in dyslexic children.

Abstract Although the pharmacological therapy of ADHD has been widely studied, little has been done to compare the different therapeutic approaches (e.g., drug therapy vs. psychological treatments) and even less has been done to compare the outcome of the therapy between centers. This multicenter observational study aims to assess between-center variation in functional outcome of ADHD patients one year after the diagnosis, according to the treatment received. We used the Regional ADHD Registry data on 1429 patients enrolled in 16 ADHD centers in the 2011–2022 period. To evaluate the effectiveness of the therapy we used a generalized linear mixed model with the center as the random effect, including patient condition at diagnosis and center characteristics, weighting by the inverse of the propensity score of the treatment received by the patient. Between-center variation was expressed as the relative difference in odds-ratios between the observed and the expected number of patients whose condition improved, using the Clinical Global Impressions—Improvement Scale (CGI-I), and the relative 95% CI. Patients who received combined treatment were significantly more likely to improve compared to other treatment groups (65.5% vs 54.4% for methylphenidate alone, 53.4% for psychological treatment alone, or 40.5% for no therapy). Adjusted for patients and center characteristics, the log-odds ratio ranged from 0.85 (0.29–1.55 95% CI) to − 0.64 (− 1.17–− 0.18 95% CI). The mean expected probability of improvement after one year of therapy for an average patient with ADHD for each center was 47.7% in a center at the 25th percentile and 61.2% in a center at the 75th percentile of the outcome distribution after adjustments. The wide between-center variation in patient functional improvement one year after the diagnosis of ADHD could be largely explained by center-specific therapeutic approaches or attitudes. More careful and stringent work is needed to reduce differences in responses between centers, as could formal and periodic audit programs within and between centers.

Early screening of handwriting difficulties is key to start remediation activities that help distinguishing between a simple delay and dysgraphia. Technology is fundamental in this process, as also claimed by guidelines for dysgraphia diagnosis: it allows to implement artificial intelligence techniques to help in the discrimination of the difficulty. To this end, a serious game was leveraged to assess handwriting laws altered in dysgraphia starting from symbols drawing. 66 first and second graders were longitudinally tested both with the serious game and with a handwriting proficiency test. Objective features computed from the game were tested to understand if they significantly differed between children at risk and not at risk of dysgraphia, according to a standardized clinical test used to assess handwriting. Then, machine learning models were leveraged to predict the risk and understand the areas of difficulty. On average, 62% of the features significantly differ between risk levels for first graders, whilst only 35% for second graders, thus revealing a better sensitivity in younger children. This is encouraging for an early observation. As for machine learning, a Logistic classifier was able to predict risk with an area under the precision-recall curve of 0.84 for the risk class and 0.98 for the non-risk class. The results of this study could be a valid help for an artificial intelligence-enhanced screening of dysgraphia.

Previous studies have identified areas of cognitive weakness in children diagnosed with Specific Learning Disorder (SLD), in the areas of working memory and processing speed in particular. In adulthood, this literature is still scant, and no studies have compared the cognitive profile of university students with dyslexia (DD) with that of students with Mixed-type SLD.Thus, in this study, the WAIS-IV was used to examine the cognitive functioning of three groups of university students: students with DD, with Mixed-type SLD, and typical students. Statistical analyses were performed to examine differences in WAIS-IV FSIQ, main, and additional indexes and subtests.The results showed strengths in perceptual reasoning and good verbal comprehension abilities in both the DD and Mixed-type SLD group, with weaknesses in working memory and processing speed, leading to a pattern of a better General Ability Index (GAI) than Cognitive Proficiency Index (CPI) in both clinical groups. Thus, discrepancies between GAI and CPI, well documented in children with SLD, still manifest in adulthood in university students. Our findings also revealed worse cognitive performance in university students with mixed learning disorder relative to students with only a reading deficit.The cognitive features and distinctive subtest profiles that emerged should guide the assessment and the definitions of intervention programs, special educational needs, and strategies of compensation.

The diagnosis of Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) can be challenging due to limited accessibility and subjective assessments. Autistic individuals often present difficulties in emotional regulation, emotion recognition and imitation, and in maintaining focus. Emotional expressions and attention are thus hallmarks of ASD and ADHD and can be analyzed to identify these conditions. In this study, we developed and validated a serious game that integrates emotion recognition and attention tracking as a novel tool for identification of ASD and ADHD. Leveraging the TrueDepth camera capabilities, our game provides a cost-effective and user-friendly alternative to current face-tracking technologies. We compared the accuracy of emotion recognition using Euclidean distance with calibrated reference expressions and a calibration-free system based on a machine learning model using Random Forest. We also identified children at risk of ADHD using the Bells test and constructed a machine learning model, utilizing Support Vector Machine and Leave-One-Out Cross Validation, trained on attention data and game data to predict this risk. Our game was tested on 20 adults to validate the emotion recognition system, and then on 17 children of the primary school to assess usability and test the constructed models. The emotion recognition system achieved an accuracy of 0.78 for adults and 0.45 for children, while the machine learning model predicted seven emotions in children with an accuracy of 0.50, suggesting the potential for eliminating the need for calibration. The model also obtained good results in predicting valence and arousal values. The attention model showed excellent validation scores (accuracy: 0.94), indicating the possibility of extending it to a larger cohort. The System Usability Score was excellent (85.0), and children found the game enjoyable, making it a promising tool for ASD and ADHD identification.

In the present dataset, each row represents a subject. For each subject, there are the ID the gender the class the results in the BVSCO-2 test their position over or under the BVSCO-2 threshold ("prove sopra soglia" represents the number of exercises in which the subject was over the thresold, and "sopra soglia generale" is 1 when a subject is over the threshold in all of the exercises, and 0 otherwise) the features extracted from the game described in the article (times and errors) the features extracted from the data produced by drawing with the Apple Pencil the features extracted from the eye tracker.

In the present dataset, each row represents a subject. For each subject, there are the ID the gender the class the results in the BVSCO-2 test their position over or under the BVSCO-2 threshold ("prove sopra soglia" represents the number of exercises in which the subject was over the thresold, and "sopra soglia generale" is 1 when a subject is over the threshold in all of the exercises, and 0 otherwise) the features extracted from the game described in the article (times and errors) the features extracted from the data produced by drawing with the Apple Pencil the features extracted from the eye tracker.

Abstract Background The level of language development reached in pre‐school age is considered the most reliable predictor of reading acquisition. In normally developing children, learning to read is strongly related to early language skills, and in particular to phonological processing abilities. In dyslexic children, reading abilities seem to show a correlation with phonological awareness. Methods A group of 65 children (aged 5–6 years) were recruited and submitted to an in‐depth neuropsychological assessment [i.e. metaphonological skills, intelligence, verbal short‐term memory (VSTM) and other aspects of receptive and expressive language]. We were able to identify 14 children with significant metaphonological difficulties (MD): 11 children with exclusively MD, and the other three children with specific language impairment. This study compares the neuropsychological profile obtained from children with MD with that of a peer group without any language impairment (N). Results The performances of the MD were within the normal ability range in almost all the administered tests but significantly lower compared with those of their peers without language impairment (N) in some items of the intelligence scale (Wechsler Preschool and Primary Scale of Intelligence) and in the tests of VSTM and of receptive/expressive language. Nevertheless, there were not statistically significant differences between MD and N in output phonology. Conclusions In pre‐school age, in a group of non‐clinical children, with a range of abilities, those with MD appear to be at the lower end of the normal range in many other verbal skills. These children could be considered at‐risk for possible subsequent difficulties learning to read and thus need to be identified and to warrant prompt treatment.

Headache affects many children and adolescent causing disability. Many studies underline the role of psychological factors in children’s headache. A recent review [1] questioned the existence of psychological difficulties in migraine children, concluding that they don’t exhibit neither more psychological dysfunctions nor more psychiatric comorbidity then healthy controls. It is not clear how psychological factors effect on different kinds of headache. We wanted to clarify if there is a difference in the influence of psychological factors on migraine compared to healthy subjects and tension-type headache (TTH).

Angelman Syndrome (AS) is due to the loss of function of the single UBE3A gene, mapping to chromosome 15q11-q13 and encoding the E6AP ubiquitin ligase. Expression of UBE3A is subject to genomic imprinting which is restricted to the brain, where only the maternal allele is transcribed. AS pathogenetic mechanisms include deletion of the maternal 15q11-13 chromosomal region, chromosome 15 paternal uniparental disomy (UPD), Imprinting Defects (ImpD) leading to silencing of the maternal allele and intragenic mutations of the maternal UBE3A allele. From our AS cohort we sorted out for detailed clinical-molecular characterization six mosaic cases, five with ImpD epimutations and one with patUPD15. This latter case referred for intellectual disability and fortuitously solved by SNP array, is, to our knowledge, the unique patient reported with mosaic patUPD of this imprinted region. Somatic epimutation mosaicism represents a challenge for both clinical and molecular diagnostics. The described patients, referred to our center either for uncertain AS or simply for intellectual disability, could be molecularly characterized by applying a multi-method approach including Methylation-Sensitive PCR and MS-MLPA without a strict cut off. The percentage of normal cells detected ranged up to 40%. We confirm the mild phenotype reported in mosaic AS ImpD and provide a detailed analysis of IQ. Mild mental retardation, with significant difficulties in language expression, but only mildly impaired performance skills, together with pathognomonic EEG, is a cue not to overlook in mosaic AS patients. Mosaic epimutations should be searched also in patients with minor AS features and presenting only with intellectual disability.