Sylvie Tordjman

Epilepsy in Autism is Associated with Intellectual Disability and Gender: Evidence from a Meta-Analysis

BACKGROUND The association between epilepsy and autism is consistently reported, with a wide range of prevalence rates. This may be attributed to the heterogeneity of the samples with respect to age, comorbidity, sex, and intellectual disability (ID). We aimed to compare the prevalence of epilepsy 1) among autistic patients with ID versus autistic patients without ID and 2) among male versus female autistic patients. METHODS We reviewed all data available from published reports (1963-2006) on autism and epilepsy and conducted a meta-analysis of 10 and 14 studies, respectively, to assess the relative risk (RR) of epilepsy in autism according to ID and gender. The pooled groups included 2112 (627 with IQ > or = 70, 1485 with IQ < 70) and 1530 (1191 male, 339 female) patients, respectively. RESULTS There was a strong discrepancy in relative risk (RR) according to IQ, with more autistic patients with ID having epilepsy (RR = .555; 95% confidence interval [CI]: .42-.73; p < .001). The pooled prevalence of epilepsy was 21.5% in autistic subjects with ID versus 8% in autistic subjects without ID. There was a strong discrepancy in RR according to sex, favoring comorbidity of epilepsy in autistic girls (RR = .549; 95% CI: .45-.66; p < .001). The male:female ratio of autism comorbid with epilepsy was close to 2:1 whereas the male:female ratio of autism without epilepsy was 3.5:1. CONCLUSIONS The results of this meta-analysis indicate that risk for epilepsy in autism is a function of ID severity and distinguishes autism associated with epilepsy as a subgroup of autism by its male-female ratio.

Prenatal depression, prenatal anxiety, and spontaneous preterm birth: a prospective cohort study among women with early and regular care.

Objective: This article investigates the effects of antenatal depression and anxiety on spontaneous preterm birth resulting either from preterm labor or preterm premature rupture of membranes. Methods: We conducted a prospective cohort study of 681 women with singleton pregnancies consecutively recruited between 20 and 28 weeks of gestation in the Obstetrics Department of the French University Hospital of Caen. Most were of European ethnic origin and received early and regular antenatal care. The assessment of gestational age was based on ultrasound examination (occurring before 13 weeks of gestation for 94.9% of the women). Depression and anxiety were assessed using self-administered questionnaires: the Edinburgh Postnatal Depression Scale and the Spielberger State-Trait Anxiety Inventory. Logistic regression analysis, controlling for sociodemographic factors (e.g., maternal age, occupation) and obstetric factors (e.g., previous preterm birth, cervical or vaginal infection), provided adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Spontaneous preterm birth occurred in 31 women (4.8%). The rate of spontaneous preterm birth was significantly higher among women with high depression scores (9.7%) as opposed to other women (4.0%) even after adjustment for potential confounding factors (adjusted OR = 3.3, 95% CI = 1.2–9.2, p = .020). Anxiety was not significantly associated with the outcome. There were no significant interaction effects between psychological and biomedical factors. Conclusions: These findings provide evidence that antenatal depression is significantly associated with spontaneous preterm birth in a population of European women receiving early and regular care. CRH = corticotropin-releasing hormone; EPDS = Edinburgh Postnatal Depression Scale; STAI-Y = State-Trait Anxiety Inventory; BMI = body mass index; HPA = hypothalamic–pituitary–adrenocortical; ACTH = adrenocorticotropin hormone.

Nocturnal Excretion of 6-Sulphatoxymelatonin in Children and Adolescents with Autistic Disorder

BACKGROUND Many studies in autistic disorder report sleep problems and altered circadian rhythms, suggesting abnormalities in melatonin physiology. Additionally, melatonin, a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. METHODS Nocturnal urinary excretion of 6-sulphatoxymelatonin was measured by radioimmunoassay in groups of children and adolescents with autistic disorder (n = 49) and normal control individuals (n = 88) matched on age, sex, and Tanner stage of puberty. RESULTS Nocturnal 6-sulphatoxymelatonin excretion rate was significantly and substantially lower in patients with autism than in normal controls (mean +/- SEM, .75 +/- .11 vs. 1.80 +/- .17 microg/hr, p =.0001), and was significantly negatively correlated with severity of autistic impairments in verbal communication and play (p < .05). CONCLUSIONS These findings indicate clearly that nocturnal production of melatonin is reduced in autism. Further research is warranted in order to understand the mechanisms underlying the lower melatonin production, to assess the impact of altered melatonin on the pathophysiology and behavioral expression of autistic disorder, and to determine the utility of melatonin administration in individuals with autism.

Role of the serotonin transporter gene in the behavioral expression of autism

The promoter polymorphism of the serotonin transporter gene (HTT, locus SLC6A4) is of special interest in autism given the well-replicated platelet hyperserotonemia of autism, treatment effects of serotonin reuptake inhibitors, and the role of serotonin in limbic functioning and neurodevelopment. Parent-offspring transmission of the long (l) and short (s) alleles of the deletion/insertion polymorphism in the HTT promoter region was examined in families of 71 children with autism using the transmission test for linkage disequilibrium (TDT). Transmission of HTT promoter alleles did not differ between probands with autism and their unaffected siblings. However, allelic transmission in probands was dependent upon severity of impairments in the social and communication domains, with greater s allele transmission in severely impaired individuals and greater l transmission in mild/moderately impaired individuals. This relationship between HTT promoter alleles and severity of autistic impairment was also seen when ratings of social and communication behaviors were compared across genotypes. The data indicate that HTT promoter alleles by themselves do not convey risk for autism, but, rather, modify the severity of autistic behaviors in the social and communication domains. The results require replication and, given the size of the groups and subgroups examined, must be considered still preliminary. The results suggest that future research on the genetics of autism should carefully assess each of the major behavioral domains and seriously consider the possible role of modifying loci.

Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia

The well-replicated platelet hyperserotonemia of autism has stimulated interest in serotonin (5-HT) in autism. We have examined the effects of the serotonin transporter gene (5-HTT, locus SLC6A4) promoter polymorphism (5-HTTLPR) on platelet 5-HT physiology in autism. Platelet 5-HT uptake rates and affinities (Vmax and Km), uptake site densities (Bmax) and 5-HT levels were examined in 31 French individuals with autism genotyped with respect to the 5-HTTLPR. Platelet 5-HT uptake and 5-HT levels were measured using HPLC; uptake sites were determined by radioligand binding. A 1.5-fold increased rate (Vmax) of platelet 5-HT uptake was observed in ll genotype individuals compared to those with ls and ss genotypes (Mann– Whitney U-test, P = 0.022). However, no significant relationship was observed between genotype and uptake site density (U-test, P = 0.51). Although median levels of platelet 5-HT in platelet-rich plasma were higher in the ll group, only trend level significance was observed (U-test, P= 0.069); platelet 5-HT content measured in whole blood was similar across genotypes. Uptake rates were well correlated with Bmax values (r = 0.66, P = 0.002); correlations between uptake and platelet 5-HT levels and between Bmax values and 5-HT levels were somewhat lower. While 5-HTTLPR alleles had an appreciable effect on platelet 5-HT uptake rates, effects on 5-HT levels and uptake site density were smaller or absent. Based on these preliminary data and prior studies of allele frequencies, we conclude that the 5-HTTLPR is not a major determinant of the group mean platelet serotonin elevation seen in autism. However, a role for increased uptake in the hyperserotonemia of autism can not be ruled out. In addition, it appears that studies of platelet 5-HT measures in autism and other disorders should take account of the effects of 5-HTTLPR genotype on 5-HT uptake

Pain Reactivity and Plasma β-Endorphin in Children and Adolescents with Autistic Disorder

Background Reports of reduced pain sensitivity in autism have prompted opioid theories of autism and have practical care ramifications. Our objective was to examine behavioral and physiological pain responses, plasma β-endorphin levels and their relationship in a large group of individuals with autism. Methodology/Principal Findings The study was conducted on 73 children and adolescents with autism and 115 normal individuals matched for age, sex and pubertal stage. Behavioral pain reactivity of individuals with autism was assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and child psychiatrist during blood drawing), and compared to controls during venepuncture. Plasma β-endorphin concentrations were measured by radioimmunoassay. A high proportion of individuals with autism displayed absent or reduced behavioral pain reactivity at home (68.6%), at day-care (34.2%) and during venepuncture (55.6%). Despite their high rate of absent behavioral pain reactivity during venepuncture (41.3 vs. 8.7% of controls, P<0.0001), individuals with autism displayed a significantly increased heart rate in response to venepuncture (P<0.05). Moreover, this response (Δ heart rate) was significantly greater than for controls (mean±SEM; 6.4±2.5 vs. 1.3±0.8 beats/min, P<0.05). Plasma β-endorphin levels were higher in the autistic group (P<0.001) and were positively associated with autism severity (P<0.001) and heart rate before or after venepuncture (P<0.05), but not with behavioral pain reactivity. Conclusions/Significance The greater heart rate response to venepuncture and the elevated plasma β-endorphin found in individuals with autism reflect enhanced physiological and biological stress responses that are dissociated from observable emotional and behavioral reactions. The results suggest strongly that prior reports of reduced pain sensitivity in autism are related to a different mode of pain expression rather than to an insensitivity or endogenous analgesia, and do not support opioid theories of autism. Clinical care practice and hypotheses regarding underlying mechanisms need to assume that children with autism are sensitive to pain.

Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms

Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD.

Are Patients With Schizophrenia Insensitive to Pain? A Reconsideration of the Question

ObjectivesTo review the scientific literature regarding pain and schizophrenia, examine the empirical basis for the reported pain insensitivity of schizophrenia, and to emphasize the distinction between behavioral responses to pain or self-reported pain and physiologic response to painful stimuli. MethodsA Medline/Oldmedline search was conducted through 2006 using the key words schizophrenia and psychosis combined with pain and related terms designated by the International Association for the Study of Pain. Out of 431 articles initially identified, 57 were considered relevant and classified in 4 groups: case reports (n=9), clinical studies (n=23), experimental research (n=20), and review articles (n=5). ResultsCase reports and clinical studies reported reduced pain reactivity in patients with schizophrenia compared with healthy controls or other psychiatric patients. Similarly, experimental studies using self-report measures of pain reactivity generally reported higher pain perception thresholds in patients with schizophrenia. However, the only experimental study using a neurophysiologic measure of pain reactivity (the nociceptive RIII reflex) demonstrated a normal pain threshold in schizophrenia. DiscussionReview of clinical and experimental data indicates that in most situations behavioral pain reactivity and self-reported responses to pain are reduced in schizophrenia. However, there is little or no physiologic evidence supporting pain insensitivity in schizophrenia. It can be suggested that the widely accepted notion of reduced pain sensitivity in schizophrenia is related more to a different mode of pain expression than to a real endogenous analgesia. Further studies are required and potential directions for future research are proposed to clarify this issue.

Effects of prenatal stress on fetal and child development: A critical literature review

Many studies have examined effects of prenatal stress on pregnancy and fetal development, especially on prematurity and birthweight, and more recently long-term effects on child behavioral and emotional development. These studies are reviewed and their limitations are discussed with regard to definitions (including the concepts of stress and anxiety), stress measurements, samples, and control for confounds such as depression. It appears necessary to assess individual stress reactivity prospectively and separately at each trimester of pregnancy, to discriminate chronic from acute stress, and to take into consideration moderator variables such as past life events, sociocultural factors, predictability, social support and coping strategies. Furthermore, it might be useful to examine simultaneously, during but also after pregnancy, stress, anxiety and depression in order to understand better their relationships and to evaluate their specific effects on pregnancy and child development. Finally, further research could benefit from an integrated psychological and biological approach studying together subjective perceived stress and objective physiological stress responses in pregnant women, and their effects on fetal and child development as well as on mother-infant interactions.

Autism as a Disorder of Biological and Behavioral Rhythms: Toward New Therapeutic Perspectives

There is a growing interest in the role of biological and behavioral rhythms in typical and atypical development. Recent studies in cognitive and developmental psychology have highlighted the importance of rhythmicity and synchrony of motor, emotional, and interpersonal rhythms in early development of social communication. The synchronization of rhythms allows tuning and adaptation to the external environment. The role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of the circadian clocks network suggests that this hormone might be also involved in the synchrony of motor, emotional, and interpersonal rhythms. Autism provides a challenging model of physiological and behavioral rhythm disturbances and their possible effects on the development of social communication impairments and repetitive behaviors and interests. This article situates autism as a disorder of biological and behavioral rhythms and reviews the recent literature on the role of rhythmicity and synchrony of rhythms in child development. Finally, the hypothesis is developed that an integrated approach focusing on biological, motor, emotional, and interpersonal rhythms may open interesting therapeutic perspectives for children with autism. More specifically, promising avenues are discussed for potential therapeutic benefits in autism spectrum disorder of melatonin combined with developmental behavioral interventions that emphasize synchrony, such as the Early Start Denver Model.