Seminars in Pediatric Neurology : Advances in the Diagnosis and Treatment of Autism Spectrum Disorder -2 (Septembre 2020)

vendredi 18 septembre 2020

La revue Seminars in Pediatric Neurology propose en septembre 2020 son second volume sur les dernières avancées dans le diagnostic et les traitements proposés dans le TSA.

Advances in the Diagnosis and Treatment of Autism Spectrum Disorder - 2

1. Rashid S, Chugani HT. Evolution of Surgical Management for Intractable Epileptic Spasms. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100581.

The understanding and management of epileptic spasms has considerably evolved since the mid 19th century. The realization that epileptic spasms can be generated from a focal brain lesion played a pivotal role in the development of neurosurgical management for intractable forms of this epilepsy. During pre-surgical planning, the addition of functional FDG PET imaging has further refined the electroencephalographic localization of epileptogenic lesions. In some cases, neurosurgical resection of a focus that is co-localized by the FDG PET scan and electroencephalography can lead to partial or complete reversal of developmental delay along with reduced seizure frequency or seizure freedom. In cases where near-complete hemispheric cortex is implicated in spasm generation, subtotal hemispherectomy has shown encouraging results. Moreover, palliative resection of the major perpetrating focus in carefully chosen patients with bilateral multifocal spasms has also led to favorable outcomes. However, in patients with tuberous sclerosis with high tuber burden, the localizing value of FDG PET imaging may be limited. In such cases, employment of AMT PET technology has become a valuable tool for localization of actively epileptogenic tubers. This article highlights the historic steps in the successful advancements of neurosurgical interventions for the treatment of intractable epileptic spasms.

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2. De Luca F. Endocrinological Abnormalities in Autism. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100582.

A number of chemical messengers, such as various hormones and hormone-like substances, along with neurotransmitters, such as serotonin, dopamine, and norepinephrine, are directly or indirectly linked with the encoding of social behavior via their action at the amygdala, hippocampus, and other related brain structures known to be involved in different aspects of social development. It is thought that any imbalance in the secretion and action of these chemicals may lead to defective or abnormal social behaviors that are the hallmarks of Autism Spectrum Disorders (ASDs). Many of the studies have described an association between ASDs and endocrine dysfunction, but have failed to establish a cause-effect connection between these 2 conditions. All together, the literature regarding the role of endocrine-related factors and ASDs is sparse and remains somewhat preliminary, controversial, and inconclusive. Thus, more research is needed in the future to shed more light on this topic.

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3. James SN, Smith CJ. Early Autism Diagnosis in the Primary Care Setting. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100827.

As the prevalence of autism spectrum disorder (ASD) has increased in recent years, so too has the body of research describing the importance of early diagnosis and early intervention. Unfortunately, a large proportion of children with the disorder do not receive a diagnosis until after their fourth birthday. Various reasons exist for late diagnosis, including limited understanding of nuanced early warning signs and limited knowledge of effective early detection mechanisms among healthcare providers. Since early diagnosis enables access to treatment, and early intensive intervention improves long-term developmental outcomes, early detection by pediatric healthcare providers is critical. This article will review ASD prevalence rates, describe correlates and factors that might influence prevalence estimates, and highlight recent advances in early detection methods and intervention services.

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4. Frye RE. Introduction to Part 2. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100828.

Autism spectrum disorder (ASD) is one of the most challenging neurodevelopmental disorders of our era. Currently the Centers for Disease Control and Prevention reports that the prevalence continues to rise with the current estimate at 1 in 54 children in the United States. Over the last 2 decades research on ASD has increased, particularly in areas focusing on physiological disruptions such as mitochondrial and redox metabolism abnormalities, immune system dysfunction and environmental health, although research focusing on genetics and behavior still predominate the field. Drug treatment trials have provided few “home runs” and many failures. A series of 2 issues of Seminars in Pediatric Neurology provide articles representing the cutting edge of research and clinical care for children with ASD. The first issue contained 3 articles on Advances in Diagnostic Methodology and 3 articles on Cutting Edge Methods for Studying Outcomes. The second issue contains 2 articles on Advances in Early Screening and Diagnosis on the Front Lines and 7 articles on Novel and Cutting-Edge Therapies. The 2 issues will provide significant insight into new and exciting developments in the field as well as provide a framework for understanding the challenges ahead.

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5. Frye RE. Mitochondrial Dysfunction in Autism Spectrum Disorder : Unique Abnormalities and Targeted Treatments. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100829.

Several lines of evidence implicate mitochondria in the pathophysiology of autism spectrum disorder (ASD). In this review, we outline some of the evidence supporting this notion, as well as discuss novel abnormalities in mitochondrial function that appear to be related to ASD, and treatments that both target mitochondria and have evidence of usefulness in the treatment of ASD in clinical trials. A suspicion of the mitochondrion’s involvement in ASD can be traced back to 1985 when lactic acidosis was noted in a subset of children with ASD. A large population-based study in 2007 confirmed this notion and found that a subset of children with ASD (∼4%) could be diagnosed with a definite mitochondrial disease. Further studies suggested that children with ASD and mitochondrial disease may have certain characteristics such as fatigability, gastrointestinal disorders, unusual types of neurodevelopmental regression, seizures/epilepsy, and motor delay. Further research examining biomarkers of mitochondrial dysfunction and electron transport chain activity suggest that abnormalities of mitochondrial function could affect a much higher number of children with ASD, perhaps up to 80%. Recent research has identified a type of dysfunction of mitochondria in which the activity of the electron transport chain is significantly increased. This novel type of mitochondrial dysfunction may be associated with environmental exposures and neurodevelopmental regression. Several treatments that target mitochondria appear to have evidence for use in children with ASD, including cofactors such as L-Carnitine and the ketogenic diet. Although the understanding of the involvement of mitochondria in ASD is evolving, the mitochondrion is clearly a novel molecular target which can be helpful in understanding the etiology of ASD and treatments that may improve function of children with ASD.

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6. Burrell TL, Sharp WG, Criado KK, Berry R, Luevano C, Khan R, Scahill L. Feasibility of a Structured, Multidisciplinary Intervention for Weight Management in Children With Autism Spectrum Disorder. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100830.

Children with autism spectrum disorder (ASD) are at an increased risk for obesity. Although treatments for obesity exist, they do not address unique ASD related characteristics. The current study evaluates a structured multidisciplinary treatment program, the Changing Health in Autism through Nutrition, Getting fit and Expanding (food) variety (CHANGE) program. Ten children (ages 5-12) with ASD who were overweight or obese participated in either CHANGE or parent education program for 16 weeks. CHANGE provided nutrition and behavior management strategies, while the parent education program provided ASD education. BMI-for-age percentile at screening was 92.8% ± 5.2. Ten eligible participants enrolled in the study and 2 (20%) dropped out prior to study completion. Attendance of sessions was moderate (57%) ; however, parental adherence (eg, homework completion, session participation) was high. All participants indicated that they would recommend the interventions to others. Preliminary evidence supports the feasibility of the CHANGE program in children with ASD.

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7. McCarty P, Frye RE. Early Detection and Diagnosis of Autism Spectrum Disorder : Why Is It So Difficult ?. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100831.

Autism spectrum disorder (ASD) affects approximately 2% of children in the United States (US). Therapeutic interventions are most effective if applied early, yet diagnosis often remains delayed, partly because the diagnosis is based on identifying abnormal behaviors that may not emerge until the disorder is well established. Universal screening has been recommended by the America Academy of Pediatrics at 18 and 24 months yet studies show low compliance by pediatricians and the US Preventive Services Task Force does not support universal screening. To better understand the limitations of universal screening this article looks at the performance of screening tests given the prevalence of ASD. Specifically, although the sensitivity and specificity of the Modified Checklist for Autism in Toddlers, Revised with Follow-up, the de facto screening tool, exceeds 90%, the relatively low prevalence of ASD in the general population (∼2%) results in a positive predictive value of about 33%, resulting in only 1 of 3 children identified by the Modified Checklist for Autism in Toddlers, Revised with Follow-up actually having ASD. To mitigate this issue, the America Academy of Pediatrics has recently recommended the use of a Level 2 screener after failing a Level 1 screener, before referring children on for a full comprehensive evaluation for ASD. In this way, a series of screening tools are used to enrich the population of children referred for further evaluation so fewer without an ASD diagnosis are evaluated. We have developed a program to train pediatricians to utilize these instruments as well as learn to diagnose ASD so children can effectively be referred for appropriate services at the front lines. Given the current burden on the medical system with the diagnosis and evaluation of children with ASD, it is important to create efficient systems for screening children which can best identify those most likely to have ASD. Developing methods to identify those children most at risk for developing ASD, either through consideration of medical or family history or through the use of biomarkers, may be helpful in identifying the children that require increased surveillance and those that do not need screening.

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8. Casanova MF, Sokhadze EM, Casanova EL, Li X. Transcranial Magnetic Stimulation in Autism Spectrum Disorders : Neuropathological Underpinnings and Clinical Correlations. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100832.

Despite growing knowledge about autism spectrum disorder (ASD), research findings have not been translated into curative treatment. At present, most therapeutic interventions provide for symptomatic treatment. Outcomes of interventions are judged by subjective endpoints (eg, behavioral assessments) which alongside the highly heterogeneous nature of ASD account for wide variability in the effectiveness of treatments. Transcranial magnetic stimulation (TMS) is one of the first treatments that targets a putative core pathologic feature of autism, specifically the cortical inhibitory imbalance that alters gamma frequency synchronization. Studies show that low frequency TMS over the dorsolateral prefrontal cortex of individuals with ASD decreases the power of gamma activity and increases the difference between gamma responses to target and nontarget stimuli. TMS improves executive function skills related to self-monitoring behaviors and the ability to apply corrective actions. These improvements manifest themselves as a reduction of stimulus bound behaviors and diminished sympathetic arousal. Results become more significant with increasing number of sessions and bear synergism when used along with neurofeedback. When applied at low frequencies in individuals with ASD, TMS appears to be safe and to improve multiple patient-oriented outcomes. Future studies should be conducted in large populations to establish predictors of outcomes (eg, genetic profiling), length of persistence of benefits, and utility of booster sessions.

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9. Mostafavi M, Gaitanis J. Autism Spectrum Disorder and Medical Cannabis : Review and Clinical Experience. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100833.

Autism spectrum disorder (ASD) is a multifactorial, pervasive neurodevelopmental disorder defined by the core symptoms of significant impairment in social interaction and communication as well as restricted, repetitive patterns of behavior. In addition to these core behaviors, persons with ASD frequently have associated noncore behavioral disturbance (ie, self-injury, aggression), as well as several medical comorbidities. Currently, no effective treatment exists for the core symptoms of ASD. This review reports the available preclinical and clinical data regarding the use of cannabis and cannabidiol in the treatment of core symptoms, noncore symptoms and comorbidities associated with ASD. Additionally, we describe our clinical experience working with children and young adults with ASD who have used cannabis or cannabidiol. At present, preclinical and clinical data suggest a potential for therapeutic benefit among some persons with ASD and that it is overall well tolerated. Further research is required to better identify patients who may benefit from treatment without adverse effects.

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10. Beversdorf DQ. The Role of the Noradrenergic System in Autism Spectrum Disorders, Implications for Treatment. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100834.

Autism spectrum disorder (ASD) is frequently associated with anxiety and hyperarousal. While the pathological changes in the noradrenergic system in ASD are not entirely clear, a number of functional indices of the sympathetic/parasympathetic balance are altered in individuals with ASD, often with a high degree of inter-individual variability. The neuropsychopharmacological effects of α2 agonists and β-adrenergic antagonists make agents targeting these receptors of particular interest. α2 agonists have shown beneficial effects for attention deficit hyperactivity disorder (ADHD) and in other domains in individuals with ASD, but effects on core ASD symptoms are less clear. Case series and single dose psychopharmacological challenges suggest that treatment with β-adrenergic antagonists has beneficial effects on language and social domains. Additionally, psychophysiological markers and premorbid anxiety may predict response to these medications. As a result, β-adrenergic antagonists are currently being utilized in a clinical trial for improving core symptoms as well as anxiety in individuals with ASD.

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11. Frye RE, Rossignol DA, Scahill L, McDougle CJ, Huberman H, Quadros EV. Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100835.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that currently has no approved medical therapy to address core symptoms or underling pathophysiological processes. Several compounds are under development that address both underlying pathophysiological abnormalities and core ASD symptoms. This article reviews one of these treatments, d,l-leucovorin calcium (also known as folinic acid) for treatment of folate pathway abnormalities in children with ASD. Folate is a water-soluble B vitamin that is essential for normal neurodevelopment and abnormalities in the folate and related pathways have been identified in children with ASD. One of these abnormalities involves a partial blockage in the ability of folate to be transported into the brain utilizing the primary transport mechanism, the folate receptor alpha. Autoantibodies which interfere with the function of the folate receptor alpha called folate receptor alpha autoantibodies have been identified in 58%-76% of children with ASD and independent studies have demonstrated that blood titers of these autoantibodies correlate with folate levels in the cerebrospinal fluid. Most significantly, case-series, open-label, and single and double-blind placebo-controlled studies suggest that d,l-leucovorin, a reduced folate that can bypass the blockage at the folate receptor alpha by using the reduced folate carrier, an alternate pathway, can substantially improve particular symptoms in children with ASD, especially those positive for folate receptor alpha autoantibodies. This article reviews the current evidence for treating core and associated symptoms and underlying pathophysiological mechanisms in children with ASD with d,l-leucovorin.

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12. Thom RP, McDougle CJ. Immune Modulatory Treatments for Autism Spectrum Disorder. Seminars in Pediatric Neurology ;2020 (2020/10/01/) ;35:100836.

Several lines of evidence from family history studies, immunogenetics, maternal immune activation, neuroinflammation, and systemic inflammation support an immune subtype of autism spectrum disorder (ASD). Current Food and Drug Administration-approved medications for ASD do not address the underlying pathophysiology of ASD, have not consistently been shown to address the core symptoms of ASD, and are currently only approved for treating irritability in children and adolescents. In this article, we review the immune modulatory effects of the 2 currently Food and Drug Administration-approved treatments for ASD. We then provide an overview of current data on emerging treatments for ASD from multiple fields of medicine with immune modulatory effects. Although further research is needed to more clearly establish the efficacy and safety of immune modulatory treatments, early data on repurposing medications used to treat systemic inflammation for ASD demonstrate potential benefit and further research is warranted.

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