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Archive for July, 2013

Susan L. Hyman, M.D.

Professor – Department of Pediatrics, Neurodevelopmental & Behavioral Pediatrics

University of Rochester Medical Center, School of Medicine and Dentistry

Some families come into my office and tell me that they observe that their child with an Autism Spectrum Disorder (ASD) experiences behavioral change with constipation.**  Many families report selective eating and express concern how a limited variety of foods their child is willing to eat might affect their health. Other families don’t associate variability in their child’s behavior with gastrointestinal (GI) symptoms until asked about other signs of discomfort. In this blog I will discuss some of the commonly asked questions I hear from families about these and other potential associations between GI symptoms and ASD.

How often do children with ASD have constipation or other gastrointestinal (GI) symptoms?

The rate of GI symptoms reported by families for their children with ASD is 20-70% depending on the definitions used and the groups studied (Mazurek et al., 2013; Mourisden et al 2013; Wang et al, 2011; Buie et al, 2010; Ibrahim et al. 2009).  The two GI problems that research data consistently report occurring with greater frequency among children and youth with autism are constipation and feeding problems. Medical chart review of children and teens with ASD compared to controls in Olmstead County Minnesota identified that constipation (34% vs 18%) and food refusal (25% vs 16%) were the only two GI problems reported more commonly in the group with ASD (Ibrahim et al., 2009).  Families participating in the Autism Treatment Network registry reported GI symptoms in 24% of the children; with the most common symptoms being constipation in 12% and abdominal discomfort in 11.7% (Mazurek et al., 2013). No difference in stool patterns or consistency was reported for children less than 42 months of age later diagnosed with ASD compared to controls (Sandhu et al., 2012). In this same large prospective study in the UK, children later diagnosed with ASD were reported to be more selective in their eating patterns by 15 months of age, however (Emond et al., 2012).  Even less is known about the GI symptoms of adults with ASD. A longitudinal study of a registry of people with ASD in Denmark found no increase in hospital care for GI disorders compared to the general population, except for disorders of the oral cavity (including dental disease).  While not statistically significant, there was the observation that GI problems may be more common among people with  lower IQ (Mouridsen et al, 2013; Mouridsen et al 2010).

Why is constipation more commonly reported?

The studies of GI symptoms in children with ASD use different definitions so it is difficult to compare them. Some do not define what they consider as constipation. Some report on lifetime prevalence to date of a reported symptom, some report on symptoms within a shorter time frame, some ask about chronic symptoms. Constipation is typically defined as less than 3 stools per week and/or stools that are difficult or painful  to pass. Constipation might be increased in people with ASD because of behavioral stool withholding due to stress or discomfort around having a bowel movement, decreased fluid intake, decreased consumption of fiber, decreased activity, medications used for other purposes that affect intestinal motility, or perhaps primary intestinal problems. To date the research literature has not confirmed that people with autism have abnormal motility or movement of their intestines to cause constipation (Buie et al, 2010). One study did not find an association of constipation with diet or with medication use (Gorrindo et al, 2012).  The typical interventions used for constipation in children can be effective for children with ASD, (Buie 2010) so children with infrequent and difficult to pass stools should  be seen by their health care provider for evaluation and management. Toolkits for families and clinicians regarding constipation management have been developed by both the American Academy of Pediatrics (published in the AAP Autism Toolkit) and  the Autism Treatment Network (online publication).

Why might children with ASD have feeding problems?  

Food selectivity might be related to perseveration or repetitive behaviors, discomfort related to food allergies/intolerances, discomfort related to gastrointestinal reflux, sensory differences, or other behavioral influences. Future postings will discuss feeding behaviors further including behavioral and nutritional suggestions.  While there is not documentation that children with ASD have an increased rate of gastrointestinal reflux, this is a common medical problem and needs to be considered if a child has food refusal, vomiting after meals, belching after meals or signs of chest or abdomen discomfort.

Does the food itself cause GI symptoms?   

Specific foods can cause GI symptoms based on allergy, food intolerance, or medical conditions that are not specific to ASD. An example is the excess consumption of juice that results in “toddlers diarrhea” in children with and without autism.  Other common medical problems like lactose intolerance, the inability to digest milk sugars, might result in abdominal pain or diarrhea with exposure to milk products. Lactose intolerance runs in families.  It can occur temporarily after a viral diarrheal illness or antibiotic use. If a family or patient identifies discomfort or GI symptoms related to a specific food, further evaluation by an allergist or gastroenterologist may be necessary. If a food group like dairy products are eliminated on a trial basis, other products need to be substituted that can provide the nutrients that would otherwise be found in that food.

What about gluten? 

GI disorders that occur in other people also occur in people with ASD. We do not have evidence at this time that celiac disease is more common among children with ASD then among other children. Although some immune response to gluten that is different from that seen in celiac disease might be found more frequently in children with ASD (Lau et al, 2013). Celiac disease is an immunologic intolerance to the peptide gluten found in food products containing barley, rye and wheat.  The population prevalence of celiac disease is about  1:100, which is fairly common, so celiac disease should be considered in the work up of GI symptoms or poor growth in children with and without ASD.  There is now a blood test that serves as first level test for celiac disease. Many families elect a trial of removal of gluten and/or casein from their child’s diet. The reason they do this is not because of food allergy or celiac disease and is based on individual observations relating diet and behavior. Diet and ASD will also be discussed in future blogs in this series.

Can GI discomfort lead to behavioral symptoms?

Since many individuals with ASD do not report pain in a typical fashion or do not have the language to report discomfort, a change in behavior may be the only clue the family or clinician has that a painful condition is present. GI problems like gastrointestinal reflux or constipation benefit from conventional medical treatment. The family and clinician must be alert for symptoms like belching after meals and air swallowing in addition to the more classic symptoms of gastrointestinal reflux of vomiting after meals or report of heartburn.  Painful conditions in general may lead to behavioral change in people with ASD, so dental pain, headaches, minor injuries, and other general medical conditions need to be considered with an acute change in behavior. GI symptoms have been associated with challenging behaviors like opposition, sleep problems, and  food selectivity (Maennur et al, 2012 ).

Isn’t anxiety associated with GI symptoms?   

Anxiety is associated with abdominal pain in children and youth with and without ASD.  An association between GI symptoms, anxiety and reported sensory symptoms was identified in children participating in the Autism Treatment Network (Mazurek et al, 2013). Anxiety may be more common among people with ASD for biological reasons, because of problems with state dysregulation, or perhaps because they cannot predict what will happen in the environment.  Research needs to be done to determine if treatment of the anxiety improves GI symptoms or if treatment of the GI symptoms improves anxiety.

Are the bacteria and other microbes in the intestines associated with GI symptoms?

There is a lot of interest in the role of the bacteria and yeasts that live in the intestine that aide in both absorption of nutrients and in normal GI functioning.  Current research studies are investigating if there are differences in the patterns of intestinal bacteria in children with ASD (Gondalia et al., 2012; Williams et al, 2011).  Whether probiotic supplements provide benefit to people taking a balanced diet requires further research. They are typically without side effects.

Has research demonstrated other differences in the GI tract in people with ASD?

There are several hypotheses about GI function in people with ASD that have conflicting evidence. Some studies are not of the quality to allow scientific conclusions to be drawn. Theories that are as yet unproven include the hypothesis that people with autism have an alteration in the production of digestive enzymes (Williams et al, 2011, Munasingh et al, 2010), the hypothesis that there is altered microscopic appearance to the intestinal lining (Chen et al, 2011; McDonald, 2007) and the hypothesis that there is a “leaky gut” that allows abnormal absorption of nutrients that produce behavioral change in people with ASD (Buie, 2010). Because the development of intestine and brain are both directed by genes early in fetal life, it is plausible that future research might find genetic or environmental influences that impact the development of both brain and gut.

In summary, when people with ASD have GI symptoms they need to be evaluated for the common –and if indicated, uncommon – conditions that produce GI symptoms in other people including anxiety.  With acute behavioral change, all sources of potential discomfort need to be considered.  Children with ASD have increased rates of constipation and feeding problems compared to other children.  Clinical and basic research is required to answer the many questions related to the specific causes and treatments for the GI symptoms of individuals with ASD.

References:

Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, Carr EG, Gershon MD, Hyman SL, Jirapinyo P, Jyonouchi H, Kooros K, Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010 Jan;125 Suppl 1:S1-18. doi: 10.1542/peds.2009-1878C

Buie T, Fuchs GJ 3rd, Furuta GT, Kooros K, Levy J, Lewis JD, Wershil BK, Winter H. Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics. 2010 Jan;125 Suppl 1:S19-29.

Chen B, Girgis S, Elmasry M, El-Matary W Abnormal Gastrointestinal Histopathology in Children With Autism Spectrum Disorders.J Pediatr Gastroenterol Nutr. 2011 Feb 2.

Emond A, Emmett P, Steer C, Golding J. Feeding symptoms, dietary patterns, and growth in young children with autism spectrum disorders. Pediatrics. 2010 Aug;126(2):e337-42.

Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, Austin DW. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res. 2012 Dec;5(6):419-27

Gorrindo P, Williams KC, Lee EB, Walker LS, McGrew SG, Levitt P. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

Ibrahim SH, Voigt RG, Katusic SK, Weaver AL, Barbaresi WJ. Incidence of gastrointestinal symptoms in children with autism: a population-based study. Pediatrics. 2009 Aug;124(2):680-6

Lau NM, Green PH, Taylor AK, Hellberg D, Ajamian M, Tan CZ, Kosofsky BE, Higgins JJ, Rajadhyaksha AM, Alaedini A.Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS One. 2013 Jun 18;8(6):e66155

Macdonald TT, Domizio P.Autistic enterocolitis: is it a histopathological entity?Histopathology. 2007 Feb;50(3):371-9; discussion 380-4.

Maenner MJ, Arneson CL, Levy SE, Kirby RS, Nicholas JS, Durkin MS. Brief report: Association between behavioral features and gastrointestinal problems among children with autism spectrum disorder. J Autism Dev Disord. 2012 Jul;42(7):

Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D, Keefer A, Murray DS, Freedman B, Lowery LA. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013 Jan;41(1):165-76

Mouridsen SE, Isager T, Rich B. Diseases of the gastrointestinal tract in individuals diagnosed as children with atypical autism: a Danish register study based on hospital diagnoses. Autism. 2013 Jan;17(1):55-63.

Mouridsen SE, Rich B, Isager T. A longitudinal study of gastrointestinal diseases in individuals diagnosed with infantile autism as children. Child Care Health Dev. 2010 May;36(3):437-43.

Munasinghe SA, Oliff C, Finn J, Wray JA Digestive enzyme supplementation for autism spectrum disorders: a double-blind randomized controlled trial. J Autism Dev Disord. 2010 Sep;40(9):1131-8

Sandhu B, Steer C, Golding J, Emond A. The early stool patterns of young children with autistic spectrum disorder.Arch Dis Child. 2009 Jul;94(7):497-500.

Wang LW, Tancredi DJ, Thomas DW. The prevalence of gastrointestinal problems in children across the United States with autism spectrum disorders from families with multiple affected members. J Dev Behav Pediatr. 2011 Jun;32(5):351-60.

Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick I, Bennett A, Jabado O, Hirschberg DL, Lipkin WI. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One. 2011;6(9):e24585

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Barbara McElhanon, MD (1) & William G. Sharp, PhD (1, 2)

1 Department of Pediatrics, Emory University School of Medicine (Atlanta, GA), 2Marcus Autism Center (Atlanta, GA)

Background 

Gastrointestinal dysfunction is frequently cited among children with autism spectrum disorders (ASD) and many causal and therapeutic hypotheses of ASD involve the gastrointestinal system (Buie et al., 2010). The importance of the gut in ASD, however, is not thoroughly understood. Multiple aspects of gastrointestinal physiology are being investigated, including possible deviations in the intestinal microbiome (Mulle, Sharp, & Cubells, 2013), gene variants (Campbell, Li, Sutcliffe, Persico, & Levitt, 2008), and intestinal permeability (D’Eufemia et al., 1996). Moreover, interventions such as restricted diets, nutritional supplements, enzymes, and antimicrobial agents are being promoted and implemented, but not founded on a large body of scientific evidence.Many diets target gluten and casein, dietary components first proposed in the 1950’s by Asperger and others to be involved in the emergence and/or maintenance of autistic behaviors (Mahikoa, 1996).This molecular hypothesis proposes that opioid-like peptides, gliadomorphin and casomorphin, escape the intestinal barrier, are absorbed into the blood stream, and subsequently disrupt brain functioning as the body’s immune system attacks these molecules and substances (Reichelt, Knivsberg, Lind, & Nodland, 1991). There is no strong evidence, however, indicating that gluten-free and/or casein-free diets improve autistic symptoms or that individuals with ASD have increased intestinal permeability to support the “opioid excess theory” or “leaky gut hypothesis” (Elder et al., 2006; Millward, Ferriter, Calver, & Connell-Jones, 2008). 

The development of causal and therapeutic hypotheses relating the gastrointestinal system to ASD is driven by many factors including: 1) an apparent increase in the prevalence of  ASD, with approximately 1 in every 88 children currently meeting diagnostic criteria in the United States (CDC, 2012); 2) a level of urgency by primary caregivers and practitioners to determine the etiology of ASD and identify interventions to remediate symptoms; 3) frequent reporting of gastrointestinal symptoms with associated cost burden(Croen et al., 2012); and 4) a fivefold increase in the odds of developing a feeding problem in ASD when compared with peers, often with unknown organic origin (Sharp et al., 2013). Unfortunately, research focusing on gastrointestinal disease in children with ASD has been clouded by Dr. Andrew Wakefield’s now retracted publications naming a new pathologic entity, “autistic enterocolitis” related to the MMR vaccine, as responsible for developmental regression in 12 children (Wakefield, Murch, Anthony, et al., 1998 [Retracted]). The medical community has blamed Wakefield directly and indirectly for causing a decrease in vaccination rates and a re-emergence of once eradicated pediatric diseases. Furthermore, while the nature of the impact on gastrointestinal research in ASD is speculative, this controversy likely averted investigators from dedicating resources to examine the relationship between gastrointestinal symptoms and ASD. 

The Evidence Base

In the last few years, the most cited paper on this topic involved a literature review and consensus report that found “an absence, in general, of high-quality clinical research data” supporting an increased risk of gastrointestinal disorders in ASD and, consequently, children with ASD should be treated to have as many gastrointestinal disorders as their non-ASD peers (Buie et al., 2010).  This conclusion was based on a pool of 11 studies involving a wide degree of methodological variability; only 5 studies involved a comparison groups and there was a extremely wide range of prevalence estimates of gastrointestinal disorders in patients with ASD (range: 9% to 91%).  This article has been cited 26 times in peer-reviewed publications (as of April 2013) and is likely a primary source of guidance for caregivers and healthcare providers faced with these issues, highlighting the need for further research in this area. 

More recently, our research group completed the first comprehensive review and meta-analysis surveying the medical literature in order to identify studies using empirical methods to investigate gastrointestinal symptoms among children with ASD using a comparison group (McElhanon, McCracken & Sharp, 2013 – manuscript in preparation).  We identified a total of 15 studies published between January 1980 and September 2012 involving a total sample of 2215 children with ASD. The results of the meta-analysis suggest children with ASD are at increased risk for gastrointestinal issues. Specifically, our analysis indicated greater levels of general concerns regarding gastrointestinal symptoms reported by parents compared with siblings (roughly an 8 fold increase in the risk) and peers (roughly a 3.5 fold increase in the risk), with areas of specific concern including abdominal pain, constipation, and diarrhea.  The summarized research was based largely on parent report and medical chart reviews and often did not account for variation in diet, behavior problems (e.g., toileting issues), and/or ASD diagnostic status. As a result, conclusions regarding the relationship between these factors and possible gastrointestinal dysfunction are unavailable at this time.       

In line with conclusions by Buie et al. (2010), our results suggests, at a minimum, parents and health care providers should be educated about possible underlying gastrointestinal problems in children with ASD. Children suspected of possible gastrointestinal issues should then be screened accordingly. With this in mind, one difficulty in identifying and studying gastrointestinal dysfunction in ASD is that individuals often present with limited verbal communication and their symptom presentation may be atypical compared with peers (Buie et al., 2010). For example, aggression and irritability without clear environmental influence (i.e., antecedents or consequences) may be the only indication of an underlying gastrointestinal problem. This highlights the need to promote greater awareness in the ASD community regarding possible gastrointestinal concerns in this population. Clinical and research activities would also benefit from an ASD-specific gastrointestinal screening instrument which, combined with increased awareness in the ASD community, would promote early detection and intervention.

In addition to better screening and early treatment, special considerations must be addressed when developing treatment plans for children with autism. For example, Furuta et al. (2012) published details on managing constipation in children with ASD. Of note, the guidelines are the same as the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition for all constipated children, with added details such as the expert opinion that children with ASD may not like the taste of magnesium citrate(Glenn et al., 2010). Moving forward, ongoing research is required to elucidate the role of the gut in autistic characteristics, including whether certain phenotypes of children with autism do have different gastrointestinal physiology which could, as an example, respond to dietary changes. In addition, standardized clinical screening of gastrointestinal symptoms in patients should be pursued to promote early intervention and, thus, the best standard of care.

References

Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater J, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125(suppl 1):S1-18

Mulle JG, Sharp WG, Cubells JF. The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep. 2013;15(2):337. doi: 10.1007/s11920-012-0337-0. Epub 2013 Feb 15

Campbell DB, Li C, Sutcliffe JS, Persico AM,  Levitt P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res. 2008; 1: 159–168. doi: 10.1002/aur.27

D’Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagiiini M, Cardi E, Giardini 0. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996;85:1076-9. Stockholm. ISSN 0803-5253

Kulani Mahikoa, Gastrointestinal Illness in Autism: An Interview with Tim Buie, M.D. Autism Advocate 5th edition 2006

Reichelt KL, Knivsberg A-M, Lind G, Nodland M. Probable etiology and possible treatment of childhood autism. Brain Dysfunct. 1991; 4: 308-19

Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L. The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord. 2006;  36 (3): 413–20

Millward C, Ferriter M, Calver SJ, Connell-Jones GG. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD003498. DOI: 10.1002/14651858.CD003498.pub3

Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders — autism and developmental disabilities monitoring network, 14 sites, United States, 2008. Morbidity and Mortality Weekly Report. Vol. 61, March 30, 2012. Available online: http://www.cdc.gov/ncbddd/autism/documents/ADDM-2012-Community-Report.pdf

Croen LA, Najjar DV, Ray GT, Lotspeich L, Bernal P. A comparison of health care utilization and costs of children with and without autism spectrum disorders in a large group-model heath plan. Pediatrics. 2006; 118(4): e1203 – e1211

Sharp WG, Berry RC, McCracken C, Nuhu NN, Marvel E, Saulnier CA, Klin A, Jones W,  Jaquess DL. Feeding Problems and Nutrient Intake in Children with Autism Spectrum Disorders: A Meta-analysis and Comprehensive Review of the Literature. J Autism Dev Disord. 2013; DOI 10.1007/s10803-013-1771-5. Epub 2013 Feb 1

Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, nonspecific colitis, and pervasive developmental disorder in children. Lancet. 1998; 351(9103): 637-641

McElhanon, BO, McCracken C, Sharp WG.Gastrointestinal Disorder in Children with Autism Spectrum Disorders: A meta-analysis and comprehensive review of the literature. Oral presentation at Mead-Johnson North American Pediatric Gastroenterology, Hepatology and Nutrition 3rd Year Fellows’ Research Conference.  Scottsdale, Arizona, 2013, February.

Furuta, et al. Management of constipation in children and adolescents with autism spectrum disorders. Pediatrics. 2012; 130;S98

Glenn T. Furuta, Kent Williams, Koorosh Kooros, Ajay Kaul, Rebecca Panzer, Daniel L. Coury and George Fuchs. Management of Constipation in Children and Adolescents with Autism Spectrum Disorders. Pediatrics 2012;130;S98

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Beth A. Malow, MD, MS

Professor of Neurology and Pediatrics, Burry Chair in Cognitive Childhood Development, Vanderbilt University, Nashville, TN

            Vanderbilt Kennedy Center for Human Development, Nashville TN

Sleep is an essential component of a healthy life, like food and oxygen.  When we don’t sleep well, we feel irritable and have difficulty concentrating. With this in mind, imagine how a child on the autism spectrum feels and behaves without sleep (and how their sleep-deprived caregivers feel)!

Given how common sleep problems are, and how profoundly they affect children and their families,  it is timely to consider what we already know and what the future holds in our understanding of sleep in autism spectrum disorders (ASD).

What we’ve learned so far:  Sleep problems are common in children with ASD,  have many causes, and affect child and family functioning.  

Sleep problems are common in children with autism spectrum disorders (ASD) — ranging from 50-80% (Couturier et al., 2005; Krakowiak et al., 2008; Souders et al., 2009; Goldman et al. 2011), with similar rates across all ages and cognitive levels.  Insomnia, defined as difficulty falling asleep or staying asleep, is the most common sleep problem. Causes (Reynolds and Malow, 2011) range from medical conditions (e.g., gastrointestinal disorders, seizures, sleep apnea, attention deficit disorder, anxiety) and the medications used to treat these conditions (e.g., stimulants, antidepressants) to behavioral factors unique to the child with autism (for example, sensory sensitivities, difficulty transitioning to bedtime activities). Children, regardless of language abilities, may not understand parents expectations about sleep. Parents, in turn, may be too overwhelmed by other priorities and stressors to put a sleep plan in place. Proper identification of the causes of sleep difficulties in children with ASD is critical to successful treatment.

Behavioral and pharmacological treatments that improve sleep positively affect daytime functioning in the child and family (as reviewed in Malow et al., 2012) and may minimize the need for medications that target behavioral symptoms. For example, in 80 children receiving sleep education delivered by their parents (Malow et al., 2013), improvements in anxiety, attention, repetitive behavior, pediatric quality of life, and parenting sense of competence were also observed. While improving sleep does not necessarily change the core features of ASD, addressing  sleep concerns may ameliorate co-occurring medical conditions such as epilepsy or anxiety.  A well-rested child may also be more engaged in therapies that improve social interactions, and his well-rested parents may be empowered to advocate more effectively for his needs.

What we need to learn: What therapies for sleep are effective? Can we predict which treatments will work for subgroups of children?

We still have much more to learn about which therapies are effective for sleep in children with ASD. In particular, we need to understand the impact of treating co-occurring medical and psychiatric conditions (e.g., gastrointestinal disorders, anxiety) on sleep-onset and sleep-maintenance insomnia. For example, insomnia, anxiety, and GI disturbances may coexist in the same child, but whether one causes or contributes to the other coexisting conditions is unresolved. An alternative possibility is that insomnia, anxiety, and GI disturbance share an underlying mechanism. One possible mechanism may be autonomic dysfunction (Kushki, 2013), with sympathetic hyperarousal and parasympathetic underarousal.

While behavioral treatments for sleep have shown promise in ASD and other neurodevelopmental disorders (Malow et al., 2013; Weiskop et al., 2005 and others reviewed in Vriend, 2011), determining  subgroups of children who are most responsive to these therapies are needed. For example, children with short sleep duration and frequent night wakings (in whom medical causes of sleep disturbance have been excluded), or those with limited verbal skills, may have a differing treatment response to behavioral interventions than children with sleep onset delay. This differing response may result from biological causes, or alternatively, a poorer response to the intervention. In those requiring medications, we need to determine which medicines are safe and effective for a variety of sleep problems (sleep onset delay, night wakings). Supplemental melatonin has been studied to a greater extent than any other medication for sleep in ASD, but large well-controlled studies have been limited (Rossignol, 2011). Genetic factors, including those related to melatonin synthesis, may also be important (Melke, 2008) in determining which child may respond to a specific therapy.

Another subgroup of  individuals with ASDs worthy of study are adolescents and young adults. My colleagues at Vanderbilt are studying sleep patterns this population at baseline (Dr. Suzanne Goldman, funding from Autism Speaks), and with behavioral treatment (Dr. Whitney Loring, funding from Organization for Autism Research).

The area of sleep and autism is ripe for continued research, in terms of causes, treatments, and overlap with many other areas, ranging from medical co-occurring conditions to genetic and other biological markers to treatment trials. Being vigilant (pun intended) to the role of sleep in autism research has high potential to advance our knowledge of autism subtypes as well as our toolbox for real world treatments that impact people with ASD and their families.

 

References

Couturier JL, Speechley KN, Steele M, Norman R, Stringer B, Nicolson R. (2005) Parental perception of sleep problems in children of normal intelligence with pervasive developmental disorders: prevalence, severity, and pattern. J Am Acad Child Adolesc Psychiatry 44: 815-822.

Goldman SE, Surdyka K, Cuevas R, Adkins K, Wang L, Malow BA. (2009) Defining the sleep phenotype in children with autism. Dev Neuropsychol. 34(5), 560-73.

Kushki A, Drumm E, Pla Mobarak MTanel NDupuis AChau T, Anagnostou E. Investigating the autonomic nervous system response to anxiety in children with autism spectrum disorders. PLoS One. 2013;8(4):e59730. doi: 10.1371/journal.pone.0059730. Epub 2013 Apr 5.

Krakowiak P, Goodlin-Jones B, Hertz-Picciotto I, Croen LA, Hansen RL. (2008) Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population-based study. J Sleep Res. 17(2):197-206.

Malow BA, Byars K, Johnson K, Weiss S, Bernal P, Goldman SE, Panzer R, Coury D, Glaze DG. A practice pathway for the identification, evaluation and management of insomnia in children and adolescents with autism spectrum disorders. Pediatrics. 2012;130 Suppl 2:S106-24.

Malow BA, Adkins KW, Reynolds A, Weiss SK, Loh A, Fawkes D, Katz T, Goldman SE, Madduri N, Hundley R, Clemons T. Parent-Based Sleep Education for Children with Autism Spectrum Disorders. J Autism Dev Disord. 2013 Jun 11.

Melke J, Goubran Botros H, Chaste P, Betancur C, Nygren G, Anckarsater H, Rastam M, Stahlberg O, Gillberg IC, Delorme R, Chabane N, Mouren-Simeoni MC, Fauchereau F, Durand C M, Chevalier F, Drouot X, Collet C, Launay JM, Leboyer M, Gillberg C, Bourgeron T. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry 2008; 13(1):90-98

Reynolds AM, Malow BA. Sleep in Children with Autism Spectrum Disorders. In: Owens J, Mindell JA, Eds. Pediatric Clinics of North America 2011; 58(3):685-98.

Rossignol D, Frye R. Melatonin in autism spectrum disorders: a systemic review and meta-analysis. Developmental Medicine & Child Neurology 2011; 53(9), 783-792.

Souders MC, Mason TB, Valladares O, et al. Sleep behaviors and sleep quality in children with autism spectrum disorders.  SLEEP 2009;32:1566-1578.

Vriend, J. L., Corkum, P. V., Moon, E. C., & Smith, I. M. (2011). Behavioral interventions for sleep problems in children with autism spectrum disorders: Current findings and future directions. Journal of Pediatric Psychology, 36(9), 1017–1029.

Weiskop S, Richdale A, Matthews J. Behavioural treatment to reduce sleep problems in children with autism or fragile X syndrome. Dev Med Child Neurol. 2005;47(2):94-104.

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