Downloaded from http://adc.bmj.com/ on December 3, 2017 - Published by group.bmj.com
Archimedes
Towards evidence based medicine for paediatricians Edited by Bob Phillips
Probiotic supplementation in children with autism spectrum disorder SCENARIO A mother of a 4 year old with autism spectrum disorder (ASD) attends the paediatric outpatient clinic. Her son has significant behavioural difficulties, tantrums that are difficult to control, an obsession with spinning wheels and sensory difficulties. She has heard and read about the advantages of probiotic supplementation (PS) in ASD. She wants to know if her son should be given probiotics to improve his behaviour. You wonder if there is any evidence that regular PS improve behaviour in children with ASD. Structured clinical question: In children with proven ASD ( patient), does supplementation with any probiotic microorganism/s (intervention) compared with placebo/none (comparator) improve behaviour (outcome) in the short term? Search strategy and outcome—secondary sources: The Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane library, Issue 2, 2012) was searched in August 2014 and March 2015 using the words ‘probiotic’ and ‘autism’ with no limits. None of the 46 retrieved reviews was relevant. Primary sources: MEDLINE (1966 to March 2015), CINAHL (Cumulative Index of Nursing and allied Health Literature) EMBASE, Science direct, Scirus databases and proceedings of the Paediatric Academic Society Meetings ( published online from 2007), Paediatric Gastroenterology conferences (2007 onwards) and the society of Developmental Behavioural Paediatrics (2006 onwards) were searched in August 2014 and March 2015 using the MeSH words ‘Probio*’ OR ‘Prebio*’ OR ‘Synbio* ‘ OR ‘Oligosacch*’ OR ‘Lactobac*’ OR ‘Bifidobacter*’ AND ‘Autism’ OR ‘Pervasive developmental disorder’ OR ‘Asperger syndrome’ OR ‘Autism spectrum’. No restrictions were applied on language or study design. Autism and probiotics were used as text words to identify more studies. The reference lists of identified articles and key review articles were searched for additional studies. The literature search retrieved 35 abstracts; 31 abstract that did not meet the inclusion criteria were excluded. One doubleblind placebo-controlled crossover trial and three nonrandomised studies were included in the final review.1–4 Results are provided in table 1. Level of evidence was graded based on the Oxford levels of evidence.5
What about mixedupness? The subject of heterogeneity (mixed∼up∼ness) in systematic reviews is tricky. A bit like ‘significance’ you can think about it as both a clinical and statistical concept, and in the same way, you can get results that aren’t always concordant. (Remember the idea of a drug that, for 99.999% sure, reduces your systolic blood pressure by 0.01 mm Hg. It’s a statistical association that’s unlikely to be due to chance, but is clinically irrelevant). The same questions need to be asked of heterogeneity within studies as you do of ‘significance’. Ask first: are they clinically different, and any attempt to add them up is daft, or are they similar enough to try to combine? Then, if they make sense, you should look at if the results look like they are similar, or different, and perhaps have a look at the statistical measures of heterogeneity (which in this setting means ‘more different than you’d expect by chance’). But a quick ‘hold on’ before the answer arrives too simply. What does ‘clinically too mixed up mean’? Remember, the differences between the studies, to make them too heterogenous, should mean that we expect the treatment to actually have a truly different effect in the different study groups. Then if you can explain why they could be different, and why you might be expecting to need to do something different with those groups of patients, you can quite reasonably say that any sort of lumping is the wrong thing to do and you’ll ignore any meta-analytic results that emerge. Because it might not be statistically heterogenous, but it’s clinically too mixed up to make sense. Bob Phillips Correspondence to Dr Bob Phillips, Centre for Reviews and Dissemination, University of York, York YO10 5DD, UK; [email protected] Competing interests None declared. Provenance and peer review Commissioned; internally peer reviewed. Accepted 31 March 2015
▸ http://dx.doi.org/10.1136/archdischild-2014-308002 Arch Dis Child 2015;100:505. doi:10.1136/archdischild-2015-308706
COMMENTARY We identified four studies exploring the effects of PS in ASD.1–4 All had limitations related to design, sample size, criteria for diagnosis and patient enrolment. No specific information was available on concurrent medications or conditions that may affect gut flora and clinical outcomes during PS. None of the studies was designed or powered to assess significant differences in clinical outcomes or identify adverse effects. Only two studies reported on behavioural effects.2 3 Kaluzna-Czaplinska and Blaszczyk reported that PS improved the ability to carry out orders and concentration, but had no effect on the response to emotions. However, detailed information on the tools used to study these effects was not provided.2 Parrocho et al3 used
questionnaires to study behaviour and reported that PS improved behaviour scores compared with the baseline. Scores for disruptive antisocial behaviour, anxiety problems and communication disturbances were higher in the placebo group. All studies showed changes in gut flora following PS. None of the studies reported any adverse effects.1–4 It has been suggested that healthy gut flora has an effect on brain and behaviour via the ‘gut–brain axis’.6 In a mouse model for autism, PS with Bacteroides fragilis not only corrected the gut permeability and altered the metabolic composition of the body, but ameliorated defects in communicative, stereotypic
Arch Dis Child May 2015 Vol 100 No 5
505
Downloaded from http://adc.bmj.com/ on December 3, 2017 - Published by group.bmj.com
Archimedes Table 1 Study characteristics Study design and level of evidence
Author/year
Study group
Kaluzna-Czaplinska and Blaszczyk 20122
Patients: children with autism (n=22). Intervention: oral supplementation of Lactobacillus acidophilus strain twice daily for 2 months. Controls: self, before the treatment Patients on probiotics (n=19) vs no probiotics (n=38) in a subgroup of patients with ASD Intervention: none:
Parrocho et al 20103
n=62 Intervention: Lactobacillus plantarum WCSF1 for 12 weeks
Double-blind, placebo-controlled, crossover design Level 2
Tomova et al 20154
n=10 Controls: 9 siblings of autism and 10 unrelated controls. Supplements: combination of Lactobacillus, Bifidobacter, and Streptococci, three times a day for 4 months
Cohort study Level 3
Adams et al 20111
Clinical outcomes
Results
Comments
Cohort study Level 3
Level of concentration and ability to carry out order
Improvement in ability to concentrate and carry out orders on probiotic therapy but no difference in behavioural responses to other people’s emotions
Risk of selection and performance bias was high
Case–control study Level 4
1. Outcome- to assess the severity of gastrointestinal symptoms in ASD. 2. Autism symptoms assessed with the ATEC Behaviour scores were assessed using a questionnaire
ATEC scores were not provided for probiotic or the control arm
The type of probiotic organism, dose, duration of supplementation is not provided
Scores for disruptive antisocial behaviour, anxiety problems and communication disturbances were higher in the placebo group CARS and behaviour not studied after probiotic supplementation
Low risk for selection and performance bias in view of blinding. Very high dropout rates
Severity evaluated using CARS
Risk of selection bias high
ASD, autism spectrum disorder; ATEC, Autism Treatment Evaluation Checklist; CARS, Childhood Autism Rating Scale.
anxiety and sensorimotor behaviours.7 However, there are no human studies of similar nature to our knowledge. Overall, there is currently no convincing evidence that PS alter behaviour in children with autism.7–9 A large definitive randomised controlled trial is warranted to assess the effects of PS in patients with ASD.
Provenance and peer review Not commissioned; internally peer reviewed.
Received 2 December 2014 Revised 4 March 2015 Accepted 5 March 2015 Published Online First 25 March 2015
Clinical bottom line
Arch Dis Child 2015;100:505–506. doi:10.1136/archdischild-2014-308002
The current clinical evidence does not support the use of probiotics to modify behaviour in patients with ASD.
REFERENCES 1
2
Ravisha Srinivasjois,1 Shripada Rao,2 Sanjay Patole3 1 Department of Neonatology and Paediatrics, Joondalup Health Campus, Perth, Western Australia, Australia 2 Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, Perth, Western Australia, Australia 3 Department of Neonatal Paediatrics, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
Correspondence to Dr Ravisha Srinivasjois, Department of Paediatrics, Joondalup Health Campus, Suite 204, Specialist Medical Centre, Perth 6027, Australia; [email protected] Contributors RS and SR searched literature and wrote the initial manuscript. SP reviewed the evidence and edited the manuscript. All the authors had equal contribution in the manuscript. Competing interests None.
506
3
4 5 6 7
8
9
Adams JB, Johansen LJ, Powell LD, et al. Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC Gastroenterol 2011;11:22. Kaluzna-Czaplinska J, Blaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition 2012;28:124–6. Parracho HMRT, Gibson GR, Knott F, et al. A double blind placebo controlled crossover designed probiotic feeding study in children diagnosed with autistic spectrum disorders. Int J Probiotics Prebiotics 2010;5:69–74. Tomova A, Husarova V, Lakatosova S, et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav 2015;138:179–87. OCEBM Levels of Evidence Working Group. The Oxford 2011 levels of evidence. Oxford Centre for Evidence-Based Medicine, 2009. Macfabe D. Autism: metabolism, mitochondria, and the microbiome. Glob Adv Health Med 2013;2:52–66. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155:1451–63. de Theije CG, Wopereis H, Ramadan M, et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun 2014;37:197–206. Gilbert JA, Krajmalnik-Brown R, Porazinska DL, et al. Toward effective probiotics for autism and other neurodevelopmental disorders. Cell 2013;155:1446–8.
Arch Dis Child May 2015 Vol 100 No 5
Downloaded from http://adc.bmj.com/ on December 3, 2017 - Published by group.bmj.com
Probiotic supplementation in children with autism spectrum disorder Ravisha Srinivasjois, Shripada Rao and Sanjay Patole Arch Dis Child 2015 100: 505-506 originally published online March 25, 2015
doi: 10.1136/archdischild-2014-308002 Updated information and services can be found at: http://adc.bmj.com/content/100/5/505.1
These include:
References Email alerting service
Topic Collections
This article cites 8 articles, 0 of which you can access for free at: http://adc.bmj.com/content/100/5/505.1#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections ADC Archimedes (277) Autism (133) Child and adolescent psychiatry (paedatrics) (683) Pervasive developmental disorder (138) Childhood nutrition (712) Childhood nutrition (paediatrics) (396) Asperger syndrome (2) Child health (3922) Stroke (227) Personality disorders (10) Clinical genetics (49)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Archimedes
Towards evidence based medicine for paediatricians Edited by Bob Phillips
Probiotic supplementation in children with autism spectrum disorder SCENARIO A mother of a 4 year old with autism spectrum disorder (ASD) attends the paediatric outpatient clinic. Her son has significant behavioural difficulties, tantrums that are difficult to control, an obsession with spinning wheels and sensory difficulties. She has heard and read about the advantages of probiotic supplementation (PS) in ASD. She wants to know if her son should be given probiotics to improve his behaviour. You wonder if there is any evidence that regular PS improve behaviour in children with ASD. Structured clinical question: In children with proven ASD ( patient), does supplementation with any probiotic microorganism/s (intervention) compared with placebo/none (comparator) improve behaviour (outcome) in the short term? Search strategy and outcome—secondary sources: The Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane library, Issue 2, 2012) was searched in August 2014 and March 2015 using the words ‘probiotic’ and ‘autism’ with no limits. None of the 46 retrieved reviews was relevant. Primary sources: MEDLINE (1966 to March 2015), CINAHL (Cumulative Index of Nursing and allied Health Literature) EMBASE, Science direct, Scirus databases and proceedings of the Paediatric Academic Society Meetings ( published online from 2007), Paediatric Gastroenterology conferences (2007 onwards) and the society of Developmental Behavioural Paediatrics (2006 onwards) were searched in August 2014 and March 2015 using the MeSH words ‘Probio*’ OR ‘Prebio*’ OR ‘Synbio* ‘ OR ‘Oligosacch*’ OR ‘Lactobac*’ OR ‘Bifidobacter*’ AND ‘Autism’ OR ‘Pervasive developmental disorder’ OR ‘Asperger syndrome’ OR ‘Autism spectrum’. No restrictions were applied on language or study design. Autism and probiotics were used as text words to identify more studies. The reference lists of identified articles and key review articles were searched for additional studies. The literature search retrieved 35 abstracts; 31 abstract that did not meet the inclusion criteria were excluded. One doubleblind placebo-controlled crossover trial and three nonrandomised studies were included in the final review.1–4 Results are provided in table 1. Level of evidence was graded based on the Oxford levels of evidence.5
What about mixedupness? The subject of heterogeneity (mixed∼up∼ness) in systematic reviews is tricky. A bit like ‘significance’ you can think about it as both a clinical and statistical concept, and in the same way, you can get results that aren’t always concordant. (Remember the idea of a drug that, for 99.999% sure, reduces your systolic blood pressure by 0.01 mm Hg. It’s a statistical association that’s unlikely to be due to chance, but is clinically irrelevant). The same questions need to be asked of heterogeneity within studies as you do of ‘significance’. Ask first: are they clinically different, and any attempt to add them up is daft, or are they similar enough to try to combine? Then, if they make sense, you should look at if the results look like they are similar, or different, and perhaps have a look at the statistical measures of heterogeneity (which in this setting means ‘more different than you’d expect by chance’). But a quick ‘hold on’ before the answer arrives too simply. What does ‘clinically too mixed up mean’? Remember, the differences between the studies, to make them too heterogenous, should mean that we expect the treatment to actually have a truly different effect in the different study groups. Then if you can explain why they could be different, and why you might be expecting to need to do something different with those groups of patients, you can quite reasonably say that any sort of lumping is the wrong thing to do and you’ll ignore any meta-analytic results that emerge. Because it might not be statistically heterogenous, but it’s clinically too mixed up to make sense. Bob Phillips Correspondence to Dr Bob Phillips, Centre for Reviews and Dissemination, University of York, York YO10 5DD, UK; [email protected] Competing interests None declared. Provenance and peer review Commissioned; internally peer reviewed. Accepted 31 March 2015
▸ http://dx.doi.org/10.1136/archdischild-2014-308002 Arch Dis Child 2015;100:505. doi:10.1136/archdischild-2015-308706
COMMENTARY We identified four studies exploring the effects of PS in ASD.1–4 All had limitations related to design, sample size, criteria for diagnosis and patient enrolment. No specific information was available on concurrent medications or conditions that may affect gut flora and clinical outcomes during PS. None of the studies was designed or powered to assess significant differences in clinical outcomes or identify adverse effects. Only two studies reported on behavioural effects.2 3 Kaluzna-Czaplinska and Blaszczyk reported that PS improved the ability to carry out orders and concentration, but had no effect on the response to emotions. However, detailed information on the tools used to study these effects was not provided.2 Parrocho et al3 used
questionnaires to study behaviour and reported that PS improved behaviour scores compared with the baseline. Scores for disruptive antisocial behaviour, anxiety problems and communication disturbances were higher in the placebo group. All studies showed changes in gut flora following PS. None of the studies reported any adverse effects.1–4 It has been suggested that healthy gut flora has an effect on brain and behaviour via the ‘gut–brain axis’.6 In a mouse model for autism, PS with Bacteroides fragilis not only corrected the gut permeability and altered the metabolic composition of the body, but ameliorated defects in communicative, stereotypic
Arch Dis Child May 2015 Vol 100 No 5
505
Downloaded from http://adc.bmj.com/ on December 3, 2017 - Published by group.bmj.com
Archimedes Table 1 Study characteristics Study design and level of evidence
Author/year
Study group
Kaluzna-Czaplinska and Blaszczyk 20122
Patients: children with autism (n=22). Intervention: oral supplementation of Lactobacillus acidophilus strain twice daily for 2 months. Controls: self, before the treatment Patients on probiotics (n=19) vs no probiotics (n=38) in a subgroup of patients with ASD Intervention: none:
Parrocho et al 20103
n=62 Intervention: Lactobacillus plantarum WCSF1 for 12 weeks
Double-blind, placebo-controlled, crossover design Level 2
Tomova et al 20154
n=10 Controls: 9 siblings of autism and 10 unrelated controls. Supplements: combination of Lactobacillus, Bifidobacter, and Streptococci, three times a day for 4 months
Cohort study Level 3
Adams et al 20111
Clinical outcomes
Results
Comments
Cohort study Level 3
Level of concentration and ability to carry out order
Improvement in ability to concentrate and carry out orders on probiotic therapy but no difference in behavioural responses to other people’s emotions
Risk of selection and performance bias was high
Case–control study Level 4
1. Outcome- to assess the severity of gastrointestinal symptoms in ASD. 2. Autism symptoms assessed with the ATEC Behaviour scores were assessed using a questionnaire
ATEC scores were not provided for probiotic or the control arm
The type of probiotic organism, dose, duration of supplementation is not provided
Scores for disruptive antisocial behaviour, anxiety problems and communication disturbances were higher in the placebo group CARS and behaviour not studied after probiotic supplementation
Low risk for selection and performance bias in view of blinding. Very high dropout rates
Severity evaluated using CARS
Risk of selection bias high
ASD, autism spectrum disorder; ATEC, Autism Treatment Evaluation Checklist; CARS, Childhood Autism Rating Scale.
anxiety and sensorimotor behaviours.7 However, there are no human studies of similar nature to our knowledge. Overall, there is currently no convincing evidence that PS alter behaviour in children with autism.7–9 A large definitive randomised controlled trial is warranted to assess the effects of PS in patients with ASD.
Provenance and peer review Not commissioned; internally peer reviewed.
Received 2 December 2014 Revised 4 March 2015 Accepted 5 March 2015 Published Online First 25 March 2015
Clinical bottom line
Arch Dis Child 2015;100:505–506. doi:10.1136/archdischild-2014-308002
The current clinical evidence does not support the use of probiotics to modify behaviour in patients with ASD.
REFERENCES 1
2
Ravisha Srinivasjois,1 Shripada Rao,2 Sanjay Patole3 1 Department of Neonatology and Paediatrics, Joondalup Health Campus, Perth, Western Australia, Australia 2 Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, Perth, Western Australia, Australia 3 Department of Neonatal Paediatrics, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
Correspondence to Dr Ravisha Srinivasjois, Department of Paediatrics, Joondalup Health Campus, Suite 204, Specialist Medical Centre, Perth 6027, Australia; [email protected] Contributors RS and SR searched literature and wrote the initial manuscript. SP reviewed the evidence and edited the manuscript. All the authors had equal contribution in the manuscript. Competing interests None.
506
3
4 5 6 7
8
9
Adams JB, Johansen LJ, Powell LD, et al. Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC Gastroenterol 2011;11:22. Kaluzna-Czaplinska J, Blaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition 2012;28:124–6. Parracho HMRT, Gibson GR, Knott F, et al. A double blind placebo controlled crossover designed probiotic feeding study in children diagnosed with autistic spectrum disorders. Int J Probiotics Prebiotics 2010;5:69–74. Tomova A, Husarova V, Lakatosova S, et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav 2015;138:179–87. OCEBM Levels of Evidence Working Group. The Oxford 2011 levels of evidence. Oxford Centre for Evidence-Based Medicine, 2009. Macfabe D. Autism: metabolism, mitochondria, and the microbiome. Glob Adv Health Med 2013;2:52–66. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155:1451–63. de Theije CG, Wopereis H, Ramadan M, et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun 2014;37:197–206. Gilbert JA, Krajmalnik-Brown R, Porazinska DL, et al. Toward effective probiotics for autism and other neurodevelopmental disorders. Cell 2013;155:1446–8.
Arch Dis Child May 2015 Vol 100 No 5
Downloaded from http://adc.bmj.com/ on December 3, 2017 - Published by group.bmj.com
Probiotic supplementation in children with autism spectrum disorder Ravisha Srinivasjois, Shripada Rao and Sanjay Patole Arch Dis Child 2015 100: 505-506 originally published online March 25, 2015
doi: 10.1136/archdischild-2014-308002 Updated information and services can be found at: http://adc.bmj.com/content/100/5/505.1
These include:
References Email alerting service
Topic Collections
This article cites 8 articles, 0 of which you can access for free at: http://adc.bmj.com/content/100/5/505.1#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections ADC Archimedes (277) Autism (133) Child and adolescent psychiatry (paedatrics) (683) Pervasive developmental disorder (138) Childhood nutrition (712) Childhood nutrition (paediatrics) (396) Asperger syndrome (2) Child health (3922) Stroke (227) Personality disorders (10) Clinical genetics (49)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
