Disentangling Tourette syndrome heterogeneity through hierarchical ascendant clustering.

AIM: To explore the heterogeneity of Tourette syndrome as part of a neurodevelopmental spectrum. METHOD: Using hierarchical ascendant clustering based on tic symptoms, developmental milestones, and neurodevelopmental comorbidities, we analyzed the heterogeneity of Tourette syndrome phenotypes in a sample of 174 children and adolescents with Tourette syndrome referred to a tertiary university clinic. RESULTS: The model yielded three distinct clusters characterized as follows. In cluster 1, we found many neurodevelopmental comorbidities (including intellectual disabilities, autism spectrum disorder, attention-deficit-hyperactivity disorder [ADHD], and learning disabilities) and academic impairments. In cluster 2, patients had no other neurodevelopmental comorbidities. In cluster 3, patients had higher intelligence, a high frequency of attentional impairment, school problems related to both ADHD and unspecific attention difficulties, and handwriting problems related to the tics themselves. Interestingly, clusters did not differ in terms of family history or anxious-depressive comorbidities. The only other differences that emerged were related to prenatal or perinatal risk factors (more represented in cluster 1) and treatment profiles (higher rates of stimulants in cluster 1). INTERPRETATION: We conclude that from a phenotypical perspective, Tourette syndrome is a heterogeneous syndrome with at least three main clusters that may help in addressing the etiological basis of Tourette syndrome and specific rehabilitative and therapeutic approaches. WHAT THIS PAPER ADDS: The clustering of Tourette syndrome based on comorbidity with other neurodevelopmental conditions reveals three clusters. A group of patients with Tourette syndrome show school difficulties related to non-specific attention and writing problems. Analysing only children and adolescents helps to distinguish between developmental comorbid conditions and coexistent disorders.

Opioid Overdose and Serotonin Syndrome due to Gastric Bezoar in a Woman with Autism and Pica Behaviour.

We are presenting the case of a 38-year-old woman with nonverbal autism and intellectual disability, hospitalized in a neurobehavioural unit because of a pica behaviour for 3 years. During the hospitalization, the patient presented an episode of pain, agitation, restlessness, rhabdomyolysis, coma, tachycardia, hyperthermia, shivering, and diarrhoea. The main hypothesis raised was tramadol overdose because of the immediate antidote response to the injection of naloxone 0,4 mg/mL. Even if we did not exceed the recommended prescription dosage of tramadol, the presence of gastric bezoar slowed the absorption of the drug, and the consequence was an opioid overdose and serotonin syndrome.

Developmental and symptom profiles in early-onset psychosis.

Psychotic disorders in children are more heterogeneous than is captured by categorical diagnoses. In a new cohort of children and adolescents, we evaluated the relationships among age at onset (AAO), clinical symptoms and developmental impairments. Patients with schizophrenia and other "spectrum" psychotic diagnoses (N = 88; AAO 6-17, mean 12.6) were evaluated with diagnostic interviews, a new clinical scale (Lifetime Dimensions of Psychosis Scale-Child and Adolescent), and neuropsychological and medical evaluations. Key findings were replicated in an adult cohort of 2420 cases, including 127 with retrospective AAO<13. Factor and cluster analyses were carried out to identify clinical profiles. Five clinical factors were identified in each cohort: Positive, Bizarre Positive, Negative/Formal Thought Disorder, Depression and Mania. Earlier AAO predicted severity of bizarre positive symptoms in children and of bizarre and other symptoms in adults. Four clinical clusters in the child cohort were characterized by: more severe bizarre positive symptoms (N = 31); negative symptoms (N = 15); premorbid autism spectrum features and developmental delay (N = 12); and depressive symptoms with heterogeneous diagnoses and mild positive/negative symptoms (N = 25). Previous factor-analytic studies of childhood psychosis did not specifically consider bizarre positive symptoms. Here, bizarre positive symptoms emerged as clinical markers of severe, childhood-onset psychosis similar to adult schizophrenia. The four clusters are clinically meaningful and useful for treatment planning and potentially for biological research. Childhood-onset cases are rare and thus difficult to study, but additional, larger cohorts may be useful in dissecting the biological and developmental heterogeneity of psychotic disorders.

Autism and COVID-19: A Case Series in a Neurodevelopmental Unit.

BACKGROUND: COVID-19 has become pandemic and can impact individuals with autism as well. Here, we report a case series admitted to a neurobehavioral unit dedicated to challenging behaviors in patients with autism. METHODS: We describe 16 patients (mean age 20.8 years; range 12-43 years; 76% male) with autism hospitalized between March 2020 and mid-April 2020 for challenging behaviors, for which COVID-19 disease has been suspected and who needed both psychiatric and medical care. A close cooperation with the Infectious and Tropical Diseases Department was organized to limit viral spread and training sessions (e.g., hygiene, clinical COVID-19 monitoring, virus testing) were given to staff members. RESULTS: Most patients had severe autism and severe/moderate intellectual disability. Eleven patients were already in the unit when it was hit by the pandemic, and five were admitted from the community. Based on a virus search via reverse transcriptase polymerase chain reaction (RT-PCR) or serology at the 2-month follow-up, we had 11 confirmed COVID-19 cases. The main COVID-19 symptoms included benign upper respiratory infection signs (N = 9, 81.8%), diarrhea (N = 7, 63.6%), fatigue (N = 7, 63.6%), and respiratory signs (N = 5, 45.5%), including one patient who needed oxygen therapy. Three patients remained asymptomatic and COVID-19-free (including two under immunosuppressive treatments). Among the symptomatic patients, five showed atypical behaviors that we understood as idiosyncratic manifestations (e.g., irrepressible licking behavior). On day 14, only one patient with respiratory dysfunction still had a positive RT-PCR SARS-CoV-2 test. CONCLUSIONS: Organizing a COVID+ unit for patients with autism is realistic and requires close collaboration with infectologists. We believe that this initiative should be promoted to limit both the spread of the virus and the ostracism of patients with autism and challenging behaviors.

Incidence of adverse events in antipsychotic-naïve children and adolescents treated with antipsychotic drugs: Results of a multicenter naturalistic study (ETAPE).

The main objective of ETAPE study was to determine the incidence of adverse events (AEs) potentially related to antipsychotic (AP) during a 12-months observational study of naturalistic treatment. ETAPE is a naturalistic prospective multicenter study conducted between April 2013 and May 2016. 200 patients were included. The mean age was 12 ± 3 years, with 73.6% being males. Patients presented a significant clinical improvement over time. At baseline, 92% of patients received a second generation AP, 74% AP monotherapy and 79.5% off-label AP prescriptions. Clinical diagnoses were heterogeneous including psychosis, anxiety, mood and neurodevelopmental disorders. The overall AE incidence rate was 11.52 AEs per person-years. Among AEs potentially attributable to AP, 15.4% were neuromotor, 14.8% gastroenterological, 12.2% metabolic and 11.8% general symptoms. Weight and body mass index increased significantly. More than half of AE appeared during the first 3 months, but onset of AE was noted all over follow-up. The presence of AEs was stable over time. ETAPE study highlights a high incidence rate of AE in children treated with AP. A careful and continuous clinical and biological monitoring is required to adapt treatment decisions based on benefice-risk-analysis. Moreover, additional research is warranted, also in regard of high proportion of off-label prescriptions.

An overview of medical risk factors for childhood psychosis: Implications for research and treatment.

OBJECTIVE: Psychotic disorders in childhood and early adolescence often progress to chronic schizophrenia, but in many cases there are diagnosable medical and genetic causes or risk factors. We reviewed our clinical experience and the relevant literature to identify these factors and to define their clinical features, appropriate work-up and treatment. METHOD: We reviewed the results of comprehensive medical evaluations of 160 psychotic children and adolescents in our center. We also searched the Medline database (January 1994 to December 2015) with the following keywords and combinations: early onset schizophrenia, childhood onset schizophrenia, early onset psychosis, first episode psychosis, inborn errors of metabolism (IEM), genetic syndrome, copy number variants, autoimmune disorders, endocrine diseases, nutritional deficiencies, central nervous system infections, movement disorders, and epilepsy. RESULTS: In our center, 12.5% of cases had medical disorders likely to be contributing to psychosis. Based on 66 relevant papers and our experience, we describe the clinical features of multiple genetic syndromes, IEM, and autoimmune, neurological, endocrinological and nutritional disorders that increase the risk of psychotic disorders in childhood and adolescence. We propose an algorithm for systematic laboratory evaluation, informed by clinical examination, emphasizing common and/or treatable factors. CONCLUSIONS: In children and early adolescents with psychotic disorders, systematic medical work-up is warranted to identify medical and genetic factors. Not every rare cause can be worked up, thus careful clinical examinations are required to detect medical, neurological and genetic signs. Comprehensive medical evaluation can detect treatable diseases among cases of early-onset psychosis.

Hormonal Risk Factors for Osteoporosis: Different Profile Among Antipsychotics.

Objectives: Osteoporosis is a major risk factor for fracture and treatment is mainly preventive. Patients with severe psychiatric condition and treated with antipsychotics are at risk for vitamin D deficiency and iatrogenic hyperprolactinemia, two serious risk factors of osteoporosis. We aim to determine whether all antipsychotics are similar regarding the risk of osteoporosis in young patients. Methods: From January 2009 to March 2015, we determined the vitamin D blood level (VDBL) among 484 inpatients and from January 2012 to March 2015, we determined the prolactin blood level (PBL) among 205 inpatients. We systematically recorded well-documented risk factors (e.g., age, gender, ethnic origin, body mass index, or season) and suspected risk factors (e.g., disease type or antipsychotic treatment). Results: Up to 89% of the inpatients had a VDBL under the recommended threshold. Up to 60% of the inpatients had hyperprolactinemia. The multivariate model found a significant effect on VDBL for seasonality (higher VDBL in summer), ethnicity (lower VDBL in Black individuals), and treatment exposure. The multivariate model found a significant effect on PBL for gender and treatment exposure. In both models, aripiprazole had a safer profile compared with other antipsychotics. Conclusion: Because adolescence is a period of bone construction and a critical window of opportunity for maximizing bone mass, we recommend vitamin D supplementation in young patients with severe mental condition. It could be interesting to reconsider to regularly monitor PBL among youth patients treated with antipsychotic, with the exception of aripiprazole.

Catatonia in Children and Adolescents: A High Rate of Genetic Conditions.

Pediatric catatonia is a rare and severe neuropsychiatric syndrome. We previously reported, in 58 children and adolescents with catatonia, a high prevalence (up to 20%) of medical conditions, some of which have specific treatments.1 Here we extend the cohort inclusion and report the first systematic molecular genetic data for this syndrome. Among the 89 patients consecutively admitted for catatonia (according to the pediatric catatonia rating scale)2 between 1993 and 2014, we identify 51 patients (57.3%) who had genetic laboratory testing, of whom 37 had single nucleotide polymorphism (SNP) microarray tests for CNVs and 14 had routine genetic explorations (karyotyping and searches for specific chromosomal abnormalities by fluorescence in situ hybridization [FISH]) or a specific diagnosis test based on clinical history. To assess the causality of observed genetic findings in each patient, we used a causality assessment score (CAUS)3 including 5 causality-support criteria on a 3-point scale (0 = absent; 1 = moderate; 2 = high): the existence of similar cases in the literature; the presence of a clinical contributing factor; the presence of a biological contributing factor; the presence of other paraclinical symptoms; and response to a specific treatment related to the suspected genetic or medical condition.

Tourette syndrome and other neurodevelopmental disorders: a comprehensive review.

Gilles de la Tourette syndrome (TS) is a complex developmental neuropsychiatric condition in which motor manifestations are often accompanied by comorbid conditions that impact the patient's quality of life. In the DSM-5, TS belongs to the "neurodevelopmental disorders" group, together with other neurodevelopmental conditions, frequently co-occurring. In this study, we searched the PubMed database using a combination of keywords associating TS and all neurodevelopmental diagnoses. From 1009 original reports, we identified 36 studies addressing TS and neurodevelopmental comorbidities. The available evidence suggests the following: (1) neurodevelopmental comorbidities in TS are the rule, rather than the exception; (2) attention deficit/hyperactivity disorder (ADHD) is the most frequent; (3) there is a continuum from a simple (TS + ADHD or/and learning disorder) to a more complex phenotype (TS + autism spectrum disorder). We conclude that a prompt diagnosis and a detailed description of TS comorbidities are necessary not only to understand the aetiological basis of neurodevelopmental disorders but also to address specific rehabilitative and therapeutic approaches.

Incidence of adverse events in antipsychotic-naïve children and adolescents treated with antipsychotic drugs: a French multicentre naturalistic study protocol (ETAPE).

INTRODUCTION: In France, over recent years, the prescription rate of antipsychotic (AP) remained stable in children and adolescents. Prescription of second-generation antipsychotics increased, whereas prescription of first-generation antipsychotics decreased. Off-label prescriptions are very frequent in this population. Adverse events (AEs) in youth treated with AP are common and may be severe. AEs have hitherto been poorly monitored in naturalistic studies independent from industry. METHOD AND ANALYSIS: We describe a French prospective multicentre study in an AP-naïve paediatric population named Etude de la Tolérance des AntiPsychotique chez l'Enfant (ETAPE). The study started in April 2013. So far, 200 patients have been included. The inclusion criteria are: male or female inpatients aged from 6 to 18 years, treated with an AP drug for less than 28 days, never been treated or having received AP for less than 3 months, discontinued at least 6 months prior to inclusion. These assessments of AE are performed at inclusion, as well as at 3, 6, 9 and 12 months after the introduction of the AP. The monitoring period will end in May 2016. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee 'Sud Méditerrané V' (number 12.082) and by the French National Agency for Medicines and Health Products Safety (number 2012-004546-15). All patients and their parents signed informed consent on enrolment in the study. We will submit the results of the study to relevant journals and offer national and international presentations. This study will enable better characterisation of the prescription of AP drugs. The results will further help to develop quality standards and recommendations for monitoring AE during the prescription of AP. TRIAL REGISTRATION NUMBER: NCT02007928.

Facial, vocal and cross-modal emotion processing in early-onset schizophrenia spectrum disorders.

Recognition of emotional expressions plays an essential role in children's healthy development. Anomalies in these skills may result in empathy deficits, social interaction difficulties and premorbid emotional problems in children and adolescents with schizophrenia. Twenty-six subjects with early onset schizophrenia spectrum (EOSS) disorders and twenty-eight matched healthy controls (HC) were instructed to identify five basic emotions and a neutral expression. The assessment entailed presenting visual, auditory and congruent cross-modal stimuli. Using a generalized linear mixed model, we found no significant association for handedness, age or gender. However, significant associations emerged for emotion type, perception modality, and group. EOSS patients performed worse than HC in uni- and cross-modal emotional tasks with a specific negative emotion processing impairment pattern. There was no relationship between emotion identification scores and positive or negative symptoms, self-reported empathy traits or a positive history of developmental disorders. However, we found a significant association between emotional identification scores and nonverbal communication impairments. We conclude that cumulative dysfunctions in both nonverbal communication and emotion processing contribute to the social vulnerability and morbidity found in youths who display EOSS disorder.