ArticlePDF Available

The varied rate of response to dietary intervention in autistic children

Authors:

Abstract and Figures

Exorphins from casein and gluten have been found by HPLC and mass spectroscopy with fragmentation pattern in quickly frozen urine. Removing the proteins that contain these peptides, by dietary intervention has been tried with behavioral effects. We wanted to know how fast such changes take place. Method: Parents and caregivers filled out ATEC scores (Au-tism treatment evaluation checklist) over time so that changes in scores could be registered. Results: In this group of children who all responded to diet the time required for a positive effect was months rather than weeks. Conclusion: Short term interventions are probably a waste of time and money, and at least 3-6 months trials seem to be necessary.
Content may be subject to copyright.
Open Journal of Psychiatry, 2013, 3, 56-60 OJPsych
doi:10.4236/ojpsych.2013.32A009 Published Online April 2013 (http://www.scirp.org/journal/ojpsych/)
The varied rate of response to dietary intervention in
autistic children
Jørgen Klaveness1, Jay Bigam2, Karl L. Reichelt3*
1Greåker, Norway
2Edmonton, Canada
3Department of Pediatric Research, University of Oslo Hospital, Oslo, Norway
Email: *karlr@ulrik.uio.no
Received 4 December 2012; revised 10 January 2013; accepted 19 January 2013
Copyright © 2013 Jørgen Klaveness et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Exorphins from casein and gluten have been found by
HPLC and mass spectroscopy with fragmentation
pattern in quickly frozen urine. Removing the pro-
teins that contain these peptides, by dietary interven-
tion has been tried with behavioral effects. We wanted
to know how fast such changes take place. Method:
Parents and caregivers filled out ATEC scores (Au-
tism treatment evaluation checklist) over time so that
changes in scores could be registered. Results: In this
group of children who all responded to diet the time
required for a positive effect was months rather than
weeks. Conclusion: Short term interventions are pro-
bably a waste of time and money, and at least 3 - 6
months trials seem to be necessary.
Keywords: ATEC-Score; Autism; Casein; Diet; Gluten
1. INTRODUCTION
Exorphins from casein, glutenin and gliadin have been
reported in urine from autistic children [1,2] using HPLC
and spiking with standards. This has now been firmly es-
tablished by the use of mass spectroscopy and fragmen-
tation mass spectroscopy (MS/MS) [3], when precautions
are taken to prevent peptidase activity in the urine by
rapid freezing or adding 1% by volume concentrated ace-
tic acid (In prep). Also antibodies especially of the IgA
type have been found in autism against these same pro-
teins [4-7], as well as expected physiological effects in
animal models [8,9] It is therefore reasonable to remove
the source of these peptides using gluten and casein free
diet (GF/CF).
There are several open and positive reports on gluten
and casein free diet [2,8-14]. Controlled single blind ei-
ther paired or grouped randomly assigned studies [15,16]
have been published. One study was followed up for 4
years [17], to counter placebo effects, which are not very
likely after such a long time. However, trials that turned
out negative so far have employed GF/CF diet for only a
few weeks [18,19]. Due to experiments on semi-chronic
schizophrenic patients, where it took 28 weeks to nor-
malize their peptiduria [20], we suspect that sufficient
time is a major factor when intervening with a GF/CF
diet. This report therefore tries to document the rate of
improvement in a group of children on GF/CF diet. We
did not obtain any negative cases, and the parents would
probably not participate in such cases.
2. PATIENTS AND METHODS
Parents and caregivers who had taken an interest in the
GF/CF diet by joining the GFCFKIDS discussion group
at www.yahoo.com, were encouraged to fill out an online
survey before starting dietary intervention, and at regular
intervals thereafter. The survey was based on the ATEC
(Autism Treatment Evaluation Checklist), developed by
ARI (the Autism Research Institute in San Diego, USA)
and freely available at www.autism.com/atec/index.html.
The ATEC score sheet is considered to have high general
reliability (http:/www.autism.com/arec/report1.html). Pa-
rents or caregivers have used it for several years to report
on the effectiveness of treatment alternatives [21].
The checklist was filled in by the parents and/or care-
givers themselves. Responses to the survey were gath-
ered in a secure database on line (set up by Bigam) and
analyzed by Klaveness. A reasonably high number re-
ported in first time at the start of dieting, before any ef-
fects were known. These conformed to the general pat-
tern and strengthen the data. All the children had an offi-
cial diagnosis within the autism spectrum (DSMIV and
ICD 10).
*Corresponding author.
Published Online April 2013 in SciRes. http://www.scirp.org/journal/ojpsych
J. Klaveness et al. / Open Journal of Psychiatry 3 (2013) 56-60 57
Complience is a problem because gluten and gliadin is
widely used a thickener, to add body to fluids, soups etc.
Also starch sold as gluten free may contain up to 1% by
weight of wheat, which many celiacs tolerate. In short,
we do not know how strict the diets really were. Re-
ported complience is generally very unreliable. Even in a
metabolic ward, strict diet does at times pose problems.
When dietary infringements did take place, the time be-
fore symptoms reappeared, was registered.
Of the original group of 137 children, seven were eli-
minated from the calculations since their age was 1 year
old at the start, and the diagnosis of autism at that age is
uncertain and difficult. The participants all had official
diagnoses of autism covered by ICD-10 registrations
F84.0 and F 84.1.
The age range will be seen from Table 1. Average ±
SD = 4.75 ± 2.49 (n = 130).
Statistics: Instat program was used throughout. When
the collected data did not show normal distribution, non
parametric statistics were used (Mann Whitney U test). If
the distribution was normal, t test was used, but when the
standard deviations differed significantly the Welch cor-
rection for the t-test was employed...
Ethics: The data were volunteered from parents and
collected by the parents. (Parent driven effort) .We also
have ethical committee clearance for the study of psy-
chiatric and neurological disorders (S-06270a) for south
eastern Norway.
3. RESULTS
Overall results of collected data can be seen in Table 1.
The difference in ATEC score before and after is highly
significant (unpaired t-test with a p value < 0.001 with
Welch correction for unequal SD, and normal distribu-
tion of data.
The initial score compared to the last score obtained is
statistically very different with a highly significant p
value of 0.001 (n = 130) two tailed. The average de-
crease pr month = 2.9 points. Given the average rate and
comparing this to the average initial score it is obvious
that many months must be necessary for significant im-
provements (Table 1).
In Table 2 we looked at children with ATEC score
less than 50 points before and after intervention, the p
value is <0. 001 and n = 28. For those with ATEC scores
higher than 100 points non-parametric statistics had to be
used. n = 28 and Mann Whitney U = 3.00 and U’ = 781.00
Table 1. Overall changes found.
Item Age at 1st
registration
Initial
score
Last
score
Registration interval
(months)
Numerical decrease
in ATEC score
Percent
decrease
mean 4.75 76.1 41.26 10.01 35.25 41.85
SD 2.49 30.91 21.26 13.38 30.21 26.45
Number 130 130 130 130 130 130
95% Conf Interval lower 4.32 70.79 37.61 7.69 39.06 37.30
95% Conf Interval upper 15 81.43 44.91 12.33 40.45 46.39
Passed normality test No Yes Yes No No Yes
Minimum 2.00 8.00 6.00 0.25 +12 36.00
Maximum 15.00 154.00 103.00 120.00 147.00 96.00
Table 2. Comparing children with ATEC scores > 100 with scores < 50 (The last four columns).
Item Age at start ATEC at start Months on diet ATEC after diet Age at start ATEC at start Months on diet ATEC after diet
Mean 4.84 121.89 17.61 46.37 5.36 37.89 7.56 25.32
SD 3.16 14.64 24.62 25.92 2.68 10.50 5.80 11.66
N = 28 28 28 28 28 28 28 28
95% CI upper 6.96 127.57 27.15 13.0 6.4 41.97 9.81 29.84
95% CI Lower 3.61 116.21 8.06 4..0 4.32 33.82 5.31 20.8
Minimum 2.00 100.00 1.00 7.00 2.00 8.00 0.5 6.0
Maximum 13.00 154.00 120.00 163.00 15.00 50.00 24.0 47.0
Normality No Yes No No No Yes No Yes
Copyright © 2013 SciRes. OJPsych
J. Klaveness et al. / Open Journal of Psychiatry 3 (2013) 56-60
58
and p < 0.0001 (two tailed).
The 28 highest scores on ATEC compared to the 28
lowest scores (Table 2).
Comparing the group scoring higher than 100 with the
group scoring at the start less than 50, the rate of de-
crease was again different. The high scoring group had a
monthly decrease of 4.4 units per month, while the low
scoring group had a monthly decrease of 1.6 points per
month. It is therefore obvious that long observation pe-
riod especially in the high functioning children is a ne-
cessity.
Rate of change per month for the whole group can be
seen in Table 1. The relationship of age to decrease in
rating scale had to be calculated nonparameterically and
the Spearman coefficient r = 0.2482 (corrected for ties)
was very significant and different from zero with a p
value = 0.0059.
The attached figure (Figure 1) compiled by J. Klave-
ness and Bigam show this graphically. The Y axis score
is Rimlands ATEC score and the X axis is the time in-
tervals in months. The parents reported the scores over
the internet. A conference report has been published in
proceedings of that meeting [20].
The best reacts one third of the autistic children (Fig-
ure 1).
Infringements are extremely difficult to detail. How-
ever, the time elapsed after accidentally or intentionally
breaking the diet, and the appearance of symptoms, can
be seen in Table 3. Hyperactivity, aggression and emo-
tional aloofness seemed to be the cardinal symptoms.
Of the total participants 16 did not answer questions
about dietary breaks etc. Those that answered made up
86.7% of the total. We do not know why there are such
large differences (Table 3).
4. DISCUSSION
The respondents are not a random sample of parents or
caregivers. Persons, who think they see changes in their
autistic children, are probably more likely to respond to
the survey and fill out the ATEC score sheet. The figure
cannot tell us anything about those who did not respond
at all, and where the parents may be suspected of not re-
porting in their autistic children’s data. The survey can
therefore not be used to determine the percentage of chil-
dren that will improve on a GF/CF diet, or how much the
average child will improve. It can, however, be used to
make two other predictions, that should be taken into
consideration when future studies are designed.
The first is that if the positive effect of the GF/CF diet
that is reported in this survey is real, it does not seem to
be a very rare phenomenon. It is fully possible that en-
thusiastic parents have over-estimated the effects. The
Table 3. Time elapsed after dietary infringement to noticed
symptoms.
Less than 30 min 14 13%
30 min to 3 hours 34 33%
3 - 12 hours 31 30%
More than 12 hours 25 24%
Total that answered 104 100%
0 5 10 15 20 25
160
140
120
100
80
60
40
Months on diet
ATEC score
Figure 1. The ATEC score is plotted along the ordinate against months on diet along the abscissa.
Copyright © 2013 SciRes. OJPsych
J. Klaveness et al. / Open Journal of Psychiatry 3 (2013) 56-60 59
effect is so strong however, that it would still be highly
significant if divided by a factor of 10. If the diet is help-
ful for some children, the effect ought therefore to be
common enough to be observable in relatively small
study groups.
The second is that future studies must allow for the
possibility that the helpful effect of the diet is slow to
materialize, and that it could be seen at very different
rates in different children. This is demonstrated by this
report (Figure 1). These data conform to studies on semi-
chronic schizophrenic patients where it took 28 weeks to
completely normalize the urine pattern and levels [20]
though behavioral changes were registered earlier. This
prediction would be equally reasonable since a change in
physiology still demands relearning of social skills. Mor-
phological changes in the brain, for example, need con-
siderable time to be ameliorated. Antibodies against food
proteins have very different rates of decrease, and anti-
bodies to gliadin also have effects on cerebellar Purkinje
cells [22].
A dietary effect is a physiological and biochemical
possibility and probability has been documented [23,24].
We do not know why the variation in improvement is so
great. However there may be problems of compliance es-
pecially in the most severely ill group. Furthermore stud-
ies of those with IgA and or IgG antibody increases [4-7]
indicate that a subgroup show increased protein uptake
from the gut, and we suspect that breaks in the diet takes
more time to recover (preliminary observations). Since
there is a correlation of severity of autism and peptide
levels [25], we may suspect that it takes more time to
correct or ameliorate damaged CNS function. Casomor-
phins cause FOS antigen activation in the CNS [26]
blocked by naloxone, and opioids interfere with brain
maturation [27]. Thus it seems from the collected data
that the higher the initial score the slower the improve-
ment. This is also what is found by Pennessi [14].
5. CONCLUSION
For the members of the internet survey, who reported in
using the ATEC scores, as seen in Figure 1 and Table 1,
it is clear that some show very slow improvement. 14
days interventions are a waste of time, as it takes time to
get used to what is permissible to eat.
REFERENCES
[1] Reichelt, K.l. and Knivsberg, A.-M. (2003) Can the patho-
physiology of autism be explained by the nature and the
discovered urine peptides? Nutritional Neuroscience, 6,
19-28. doi:10.1080/1028415021000042839
[2] Cade, R., Private, Fregly, M., Rowland, N., Sun, Z., Zele,
V., Wagemaker, H. and Edelstein, C. (2000) Autism and
schizophrenia: Intestinal disorders. Nutritional Neurosci-
ence, 3, 57-72.
[3] Reichelt, K.L., Tveiten, D., Knivasberg, A.-M. and Brøn-
stad, G. (2012) Peptides role in autism with emphasis on
exorphins. Microbial Ecology in Health and Disease, 23,
2012. doi:10.3402/mehd.v23i0.18958
[4] Reichelt, K.L., Ekrem, J. and Scott, H. (1990) Gluten,
milk proteins and autism: Dietary intervention effects on
behavior and peptide secretion. Journal of Applied Nutri-
tion, 42, 1-11.
[5] Kawashti, M.I., Amin, O.R. and Rowehy, N.G. (2006)
Possible immunological disorders in autism: Concomitant
autoimmunity and immune tolerance. Egyptian Journal of
Immunology, 13, 99-104.
[6] Traikovski, V., Petichoski, A., Efinska-Mladenovskia, O.,
Trajkov, D., Arsov, T. and Strezova, A. (2008) Higher
plasma concentration of food-specific antibodies in per-
sons with autistic disorder in comparison to their siblings.
Focus on Autism and Other Developmental Disabilities,
23, 176-186. doi:10.1177/1088357608320413
[7] Vojdani, A., O’Bryan, T., Green, J.A., Mc Candless, J.,
Woeller, K.N., Vojdani, E., Nourian, A.A. and Cooper,
E.L. (2004) Immune response to dietary proteins, gliadin
and cerebellar peptides in children with autism. Nutri-
tional Neuroscience, 7, 151-161.
[8] Knivsberg, A.-M., Wiig, K., Lind, G., Nødland, M. and
Reichelt, K.L. (1990) Dietary intervention in autistic syn-
dromes. Brain Dysfunction, 3, 315-327.
[9] Reichelt, K.L., Knivsberg, A.-M., Lind, G. and Nødland,
M. (1991) Probable etiology and possible treatment of
childhood autism. Brain Dysfunction, 4, 308-319.
[10] Lucarelli, S., Frediani, T., Zingoni, A.M., Ferruzzi, F.,
Giardini, O., Quintieri, F., Barbato, M., D’Eufemia, P.
and Cardi, E. (1995) Food allergy and infantile autism.
Panminerva Medica, 37, 137-141.
[11] Kniker, W.T., Andrews, A., Hundley, A. and Garver, C.
(2001) The possible role of intolerance to milk/dairy and
wheat/gluten foods in older children and adults with au-
tism spectrum disorder. An autism odyssey. The Autism
Research Unit, Sunderland University, 183-191.
[12] Whiteley, P., Rodgers, J., Savery, D. and Shattock, P.
(1999) A gluten-free diet as an intervention for autism
and associated spectrum disorders: Preliminary findings.
Autism, 3, 45-65. doi:10.1177/1362361399003001005
[13] Slimak, K.M. (2003) Reduction of autistic traits follow-
ing dietary intervention and elimination of exposure to
environmental substances. Proceedings of International
Symposium on Indoor Air Quality and Health Hazards,
Tokyo, 8-11 January 2003, pp. 206-216.
[14] Pennesi, C.M. and Klein, C. (2012) Effectiveness of the
gluten-free, casein-free diet for children diagnosed with
autism spectrum disorder: Based on parental report. Nu-
tritional Neuroscience, 15, 85-91.
doi:10.1179/1476830512Y.0000000003
[15] Knivsberg, A.-M., Reichelt, K.L., Høien, T. and Nødland,
M. (2002) A Randomized, controlled study of dietary in-
tervention in autistic syndromes. Nutritional Neurosci-
ence, 5, 251-261. doi:10.1080/10284150290028945
[16] Whiteley, P., Haracopos, D., Knivsberg, A.-M., Reichelt,
Copyright © 2013 SciRes. OJPsych
J. Klaveness et al. / Open Journal of Psychiatry 3 (2013) 56-60
60
K.L., Parlar, S., Jacobsen, J., Seim, A., Pedersen, L.,
Schondel, M. and Shattock, P. (2010) The ScanBrit ran-
domized, controlled, single-blind study of a gluten-and
casein-free dietary intervention for children with autism
spectrum disorders. Nutritional Neuroscience, 13, 87-100.
doi:10.1179/147683010X12611460763922
[17] Knivsberg, A.-M., Reichelt, K.L., Nødland, M. and Høien,
T. (1995) Autistic syndromes and diet: A follow-up study.
Scandinavian Journal of Educational Research, 39, 223-
236.
[18] Johnson, C.R., Handen, B.L., Zimmer, M., Sacco, K. and
Turner, K. (2011) Effects of gluten free/casein free diet in
young children with autism: a pilot study. Journal of De-
velopmental and Physical Disabilities, 23, 213-225.
doi:10.1007/s10882-010-9217-x
[19] Elder, J.H., Shankar, M., Shuster, J., Theriaque, D., Burns,
S. and Sherril, L. (2006) Review of the gluten-free, ca-
sein-free diet in autism: Results of a preliminary double
blind trial. Journal of Autism and Developmental Disor-
ders, 16, 413-420. doi:10.1007/s10803-006-0079-0
[20] Reichelt, K.L., Sagedal, E., Landmark, J., Tshumi-Sang-
vik, B., Eggen, O. and Scott, H. (1990) The effect of a
gluten free diet on glycoprotein associated urinary pep-
tide excretion in schizophrenia. Journal of Orthomolecu-
lar Medicine, 5, 223-239.
[21] Rimland, B. (2003) Parents rating of the behavioral ef-
fects of biomedical interventions. Autism Institute Re-
ports.
[22] Klaveness, J. and Bigam, J. (2002) The GFCF kids diet
survey. In: Building Bridges. The Autism Research Unit
and Autism North Ltd., Sunderland, 77-84.
[23] Hadjivassiliou, M., Boscolo, S., Davies-Jones, G.A.B.,
Grünewald, R.A., Not, T., Sandea, D.S., Simpson, J.E.,
Tongiorgi, E., Williamson, C.A. and Woodroofe, N.M.
(2002) The humeral response in the pathogenesis of glu-
ten ataxia. Neurology, 58, 1221-1226.
doi:10.1212/WNL.58.8.1221
[24] Reichelt, K.L. and Knivsberg, A.-M. (2009) The possibil-
ity and probability of a gut-to-brain connection in autism.
Annals of Clinical Psychiatry, 21, 205-211.
https://www.aacp.com/pdf%2F2104%2F2104ACP_Revie
w1.pdf
[25] Sacco, R., Curatolo, P., Manzi, B., Militerni, R., Bravac-
cio, C., Frolli, A., Lenti, C., Saccani, M., Elia, M., Rei-
chelt, K.L., Pscucci, T., Puglisi-Allegra, S. and Persico,
A.M. (2010) Principal pathogenic components and bio-
logical endophenotypes in autism spectrum disorders. Au-
tism Research, 3, 237-252. doi:10.1002/aur.151
[26] Sun, Z., Cade, R.J., Firefly, M.J. and Privette, R.M. (1999)
Beta casomorphin induces fos-like immunoreactivity in
discrete brain regions relevant to schizophrenia and au-
tism. Autism, 3, 67-83.
doi:10.1177/1362361399003001006
[27] Hauser, K.F., McLaughlin, P.J. and Zagon, I.S. (1989)
Endogenous opioid systems and the regulation of dendri-
tic growth and spine formation. Journal of Comparative
Neurobiology, 281, 13-22. doi:10.1002/cne.902810103
Copyright © 2013 SciRes. OJPsych
... Expressive language, sociability, sensory awareness, and health were assessed by Autism Treatment Evaluation Checklist (ATEC) (Rimland & Edelson, 1999), a measure validated for longitudinal tracking of symptoms and assessing changes in ASD severity (Charman et al., 2004;Klaveness et al., 2013;Magiati et al., 2011;Mahapatra et al., 2018). The expressive language subscale of ATEC consists of 14 items; the sociability subscale contains 20 items; the sensory awareness subscale has 18 items; and the health subscale contains 25 items. ...
... Charman et al. utilized ATEC amongst other measures to test the feasibility of tracking the longitudinal changes in children using caregiver-administered questionnaires and noted differential effects across subscales of ATEC, possibly driven by development-focused vs. symptomfocused subscales that are conflated in the ATEC total score (Charman et al., 2004). Another study assessing the ability of dietary intervention to affect ASD symptoms also utilized ATEC as a primary measure (Klaveness et al., 2013), concluding that it has "high general reliability" coupled with an ease of access. These studies support the effectiveness of ATEC as a tool for longitudinal tracking of symptoms and assessing changes in ASD severity. ...
Article
Full-text available
The effect associated with the presence of seizures in 2 to 5-year-old autistic children was investigated in the largest and the longest observational study to-date. Parents assessed the development of 8461 children quarterly for three years on five orthogonal subscales: combinatorial receptive language, expressive language, sociability, sensory awareness, and health. Seizures were reported in 958 children (11%). In order to investigate the effect of seizures, children with seizures were matched to those with no seizures using propensity score based on age, gender, expressive language, receptive language, sociability, sensory awareness, and health at the 1st evaluation. The number of matched participants was 955 in each group. Children with no seizures developed faster compared to matched children with seizures in all subscales. On an annualized basis, participants with no seizures improved their receptive language 1.5-times faster than those with seizures; expressive language: 1.3-times faster; sociability: 2.3-times faster; sensory awareness: 6.2-times faster; and health: 20.0-times faster. This study confirms a high prevalence of seizures in ASD children and informs on the effect of seizures on children’s longitudinal developmental trajectories.
... Expressive language, sociability, sensory awareness, and health were assessed by Autism Treatment Evaluation Checklist (ATEC) (Rimland & Edelson, 1999), a measure validated for longitudinal tracking of symptoms and assessing changes in ASD severity (Charman et al., 2004;Klaveness et al., 2013;Magiati et al., 2011;Mahapatra, Khokhlovich, et al., 2018). The expressive language subscale of ATEC consists of 14 items; the sociability subscale contains 20 items; the sensory awareness subscale has 18 items; and the health subscale contains 25 items. ...
... In contrast, another popular ASD assessment tool, Autism Diagnostic Observation Schedule or ADOS, (Lord et al., 2000) has only been validated as a diagnostic tool. Various studies confirmed the validity and reliability of ATEC (Al Backer, 2016;Geier et al., 2013;Jarusiewicz, 2002) and several trials confirmed ATEC's ability to longitudinally measure changes in participant performance (Charman et al., 2004;Klaveness et al., 2013;Magiati et al., 2011;Mahapatra, Khokhlovich, et al., 2018). Whitehouse et al. used ATEC as a primary outcome measure for a randomized controlled trial of their iPad-based intervention for ASD, named "Therapy . ...
Preprint
Full-text available
The effect of pretend play in 2 to 5-year-old children with ASD was investigated in the largest and the longest observational study to-date. Parents assessed the development of 7,069 children quarterly for three years on five subscales: combinatorial receptive language, expressive language, sociability, sensory awareness, and health. Pretend play was associated with superior developmental trajectories: 1.9-fold faster improvement of combinatorial receptive language (p<0.0001), 1.4-fold faster improvement of expressive language (p<0.0001), and 1.3-fold faster improvement of sensory awareness (p=0.0009). Pretend play had little effect on sociability and health. The strong association of pretend play with combinatorial receptive language remained significant even when controlling for expressive language. Similarly, the effect of pretend play on expressive language remained significant even when controlling for combinatorial receptive language. The effect of pretend play on combinatorial receptive language (but not on the expressive language) was stronger than the effects of seizures, sleep problems or high-TV exposure. The strong effect of pretend-play supports earlier studies indicating that it is an important stepping stone for language acquisition, particularly, the acquisition of combinatorial language.
... ; https://doi.org/10. 1101 confirmed the validity and reliability of ATEC (Geier et al., 2013;Jarusiewicz, 2002) and several trials confirmed ATEC's ability to longitudinally measure changes in participant performance (Charman et al., 2004;Klaveness et al., 2013;Magiati et al., 2011;Mahapatra, Khokhlovich, et al., 2018). Moreover, ATEC has been used as a primary outcome measure for a randomized controlled trial of iPad-based intervention for ASD, named "Therapy Outcomes By You" or TOBY, and it was noted that ATEC possesses an "internal consistency and adequate predictive validity" (Whitehouse et al., 2017). ...
Preprint
Full-text available
The effect of joint engagement in 2- to 6-year-old children with ASD was investigated in the largest and the longest observational study to-date. Parents assessed the development of 12081 children quarterly for three years on five subscales: receptive language, expressive language, sociability, sensory awareness, and health. Longer duration of time spent with an adult actively involved in the same activity was associated with improved trajectory of receptive language, expressive language, and sensory awareness. On the annualized basis, the high-joint-engagement group (3 hours or more of joint engagement per day) improved their combinatorial receptive language 1.4-times faster ( p =0.0019), expressive language 1.5-times faster (p<0.0001), and sensory awareness 1.5-times faster ( p =0.0248) than the low-joint-engagement group (1 hour or less joint engagement per day). The difference in the sociability and the health scores at the end of 3-year study was insignificant. This study confirms the importance of ASD children spending more time with adults actively involved in the same activity and highlights the need to include joint engagement as a target for intervention with this population. Lay summary Parents of 2- to 6-year-old children with ASD assessed the development of 12081 children quarterly for three years. Longer duration of time spent with an adult actively involved in the same activity was associated with improved developmental trajectory. This study confirms the importance of ASD children spending more time with adults actively involved in the same activity and highlights the need to include joint engagement as a target for intervention with this population.
... In contrast, another popular ASD assessment tool, Autism Diagnostic Observation Schedule or ADOS, (Lord et al., 2000) has only been validated as a diagnostic tool. Various studies confirmed the validity and reliability of ATEC (Geier et al., 2013;Jarusiewicz, 2002) and several trials confirmed ATEC's ability to longitudinally measure changes in participant performance (Charman et al., 2004;Klaveness et al., 2013;Magiati et al., 2011;Mahapatra, Khokhlovich, et al., 2018). Moreover, ATEC has been used as a primary outcome measure for a randomized controlled trial of iPad-based intervention for ASD, named "Therapy Outcomes By You" or TOBY, and it was noted that ATEC possesses an "internal consistency and adequate predictive validity" (Whitehouse et al., 2017). ...
Preprint
Full-text available
The effect of sleep problems in 2- to 5-year-old children with ASD was investigated in the largest and the longest observational study to-date. Parents assessed the development of 7069 children quarterly for three years on five orthogonal subscales: receptive language, expressive language, sociability, sensory awareness, and health. Moderate and severe sleep problems were reported in 13% of children. Children with no sleep problems developed faster compared to matched children with sleep problems in all subscales. The greatest difference in trajectories was detected in the health subscale. When controlling for the health score (in addition to each subscale score at baseline as well as gender and severity), the effect of sleep problems decreased in all subscales except the combinatorial receptive language subscale (where the effect of sleep problems was increased), suggesting that sleep problems affect combinatorial language acquisition irrespective of the overall health. This study confirms a high prevalence of sleep problems in ASD children and points to the need for more systematic research as an initial step in developing treatment strategies.
... In contrast, another popular ASD assessment tool, Autism Diagnostic Observation Schedule or ADOS [20], has only been validated as a diagnostic tool. Various studies have confirmed the validity and reliability of ATEC [21][22][23], and several trials confirmed ATEC's ability to longitudinally measure changes in participant performance [19,[24][25][26]. Whitehouse et al. used ATEC as a primary outcome measure for a randomized controlled trial of their iPad-based intervention for ASD, named "Therapy Outcomes By You" or TOBY, and noted ATEC's "internal consistency and adequate predictive validity" [27]. ...
Article
Full-text available
The effect of passive video and television watching duration on 2- to 5-year-old children with autism was investigated in the largest and the longest observational study to date. Parents assessed the development of 3227 children quarterly for three years. Longer video and television watching were associated with better development of expressive language but significantly impeded development of complex language comprehension. On an annualized basis, low TV users (low quartile: 40 min or less of videos and television per day) improved their language comprehension 1.4 times faster than high TV users (high quartile: 2 h or more of videos and television per day). This difference was statistically significant. At the same time, high TV users improved their expressive language 1.3 times faster than low TV users. This difference was not statistically significant. No effect of video and television watching duration on sociability, cognition, or health was detected.
... In contrast, another popular ASD assessment tool, ADOS, [27] has only been validated as a diagnostic tool. Various studies confirmed the validity and reliability of ATEC [28][29][30] and several trials confirmed ATEC's ability to longitudinally measure changes in participant performance [21,[31][32][33]. Whitehouse et al. used ATEC as a primary outcome measure for a randomized controlled trial of their iPad-based intervention for ASD named TOBY, and noted ATEC's "internal consistency and adequate predictive validity" [34]. ...
Article
Full-text available
Prefrontal synthesis (PFS) is defined as the ability to juxtapose mental visuospatial objects at will. Paralysis of PFS may be responsible for the lack of comprehension of spatial prepositions, semantically-reversible sentences, and recursive sentences observed in 30 to 40% of individuals with autism spectrum disorder (ASD). In this report we present data from a three-year-long clinical trial of 6454 ASD children age 2 to 12 years, which were administered a PFS-targeting intervention. Tablet-based verbal and nonverbal exercises emphasizing mental-juxtaposition-of-objects were organized into an application called Mental Imagery Therapy for Autism (MITA). The test group included participants who completed more than one thousand exercises and made no more than one error per exercise. The control group was selected from the rest of participants by a matching procedure. Each test group participant was matched to the control group participant by age, gender, expressive language, receptive language, sociability, cognitive awareness, and health score at first evaluation using propensity score analysis. The test group showed a 2.2-fold improvement in receptive language score vs. control group (p < 0.0001) and a 1.4-fold improvement in expressive language (p = 0.0144). No statistically significant change was detected in other subscales not targeted by the exercises. These findings show that language acquisition improves after training PFS and that a further investigation of the PFS-targeting intervention in a randomized controlled study is warranted.
Article
The effect of sleep problems in 2- to 5-year-old autistic children was investigated in the largest and the longest observational study to-date. Parents assessed the development of 8540 children quarterly for three years on five orthogonal subscales: combinatorial receptive language, expressive language, sociability, sensory awareness, and health. 57% of caregivers reported no sleep problems, 31% reported mild sleep problems, 10% reported moderate sleep problems, and 2% reported severe sleep problems. In order to investigate the effect of sleep problems, children with moderate and severe sleep problems (N = 651) were matched to those with no sleep problems using a propensity score based on age, gender, expressive language, combinatorial receptive language, sociability, sensory awareness, and health at the 1st evaluation. There were 643 matched participants in each group. Children with no sleep problems developed faster compared to matched children with sleep problems in all subscales. The greatest difference in trajectories was detected in the health subscale. When controlling for the health score (in addition to each subscale score at baseline as well as gender and ASD severity), the effect of sleep problems decreased in all subscales except the combinatorial receptive language subscale (where the effect of sleep problems was increased), suggesting that sleep problems affect combinatorial language acquisition regardless of the overall health. This study confirms a high prevalence of sleep problems in autistic children and provides information on the effect of sleep problems on various aspects of children’s development.
Article
Autism spectrum disorders (ASD) are defined as neurodevelopmental disorders, which are highly variable in nature and do not form a uniform picture, either in terms of symptomatology or depth of the disturbance. Diagnosis of ASD is made for children who show signs of impairment in social interaction, communication and cognitive skills. The exact cause of autism spectrum disorders has not been determined to date. Although there is no cure for ASD, a variety interventions have been proposed. The most commonly used restrictive dietary intervention is the gluten-free casein-free diet (GFCF), which is based on the opioid excess theory. This paper summarizes and discusses research on the core elements of the opioid excess theory in ASD: increased levels of opioid peptides in body fluids in ASD patients, increased intestinal permeability, altered peptidase activity and the effectiveness of GFCF diet in alleviating symptoms of ASD. Furthermore, we discuss the difficulties and their causes in conducting research with ASD patients. The assumptions of the opioid excess theory have neither been definitively confirmed nor disproved. Research in this area should continue, taking into account the highest possible quality standards and the specific needs and abilities of patients with ASD and their families.
Preprint
Full-text available
Imagination exercises administered by caregivers were investigated in a three-year-long observational trial of 3,540 children with autism aged 2-12 years. Tablet-based verbal and nonverbal exercises modeled on language therapy and emphasizing mental-juxtaposition-of-objects were organized into an application called Mental Imagery Therapy for Autism (MITA). MITA-exposed children were matched to the ‘Treatment-as-Usual’ participants (TaU, N=5,222) by age, gender, language, sociability, cognitive awareness, health, and ASD severity at baseline. Both younger (2-5 years-of-age) and older children (5-12 YOA) in MITA and TaU groups improved their symptoms over time, but younger MITA-exposed children showed 2.3-fold improvement in language score at the end of the trial vs. TaU group. There was no difference between MITA and TaU in the older children group, supporting Lenneberg’s critical period hypothesis.
Article
Currently, there is a need in Saudi Arabia to grope the general development of children with Autism Spectrum Disorder (ASD). However, no measures are currently available in Saudi Arabia to assess the general development in children with ASD. The present study thus aimed to explore the psychometric properties of the Autism Treatment Evaluation Checklist (ATEC), in order to adapt it for use in Saudi Arabia. A cohort of 363 children with ASD from four age groups from Riyadh participated in the study. Teachers completed the ATEC to rate children’s behavior. The psychometric properties measured included normality of data, content validity, internal consistency, and construct validity. Content validity was established by presenting the checklist to high-qualified referees with 90 % as the minimum agreement level. Internal consistency was established by computing correlations among items and their subscales and among subscales and the total score. Construct validity was established using exploratory factorial analysis for the ATEC subscales and exploring the correlations between the ATEC and the educational stage of the participants. The reliability of the ATEC was established by Cronbach’s Alpha and split-half methods. Data revealed that the ATEC is quite valid and reliable and thus may be used in a Saudi cultural context. Our findings indicate that the Saudi version of the ATEC tested in this study may be used to identify the extent to which children with ASD benefit from the interventions offered to them in their special education programs.
Article
Full-text available
Based on their urinary glycoprotein-peptide-complex patterns, 19 children with autistic syndromes were treated with either gluten-free and milk-reduced, or milk-free and gluten-reduced diets. Before treatment 5 of 15 fully studied patients had increased levels of antibodies to casein or gluten. We demonstrated a decrease in urinary peptide secretion in response to diet. Improvement was found in some behaviors, and a decrease in epileptic seizures was noted.
Article
Full-text available
Specific IgA, IgG, and IgE antibodies to food antigens in 35 participants with autistic disorder and 21 of their siblings in the Republic of Macedonia were examined. Statistically significant higher plasma concentration of IgA antibodies against alpha-lactalbumin, beta-lactoglobulin, casein, and gliadin were found in the children with autistic disorder. Plasma concentrations of IgG antibodies against alpha-lactalbumin, beta-lactoglobulin, and casein in participants with autistic disorder were significantly higher. IgE-specific antibodies (alpha-lactalbumin, beta-lactoglobulin, casein, and gluten), as well as plasma concentration of total IgE, also were statistically significantly higher in the participants with autistic disorder. Gender differences were found for select IgA, IgG, and IgE (but not for total IgE) food-specific antibodies (kU/L) in the participants with autistic disorder and their siblings.
Article
Full-text available
The nature of the peptides found increased in urine from autism needs verification of their structure, especially those that show opioid activity. The peptides were separated on reverse phase C-18 HPLC in Trifluoroacetic acid-acetonitril gradients. Peaks eluting where synthetic opioids appear, and peaks that are common to most autistic children were analyzed by mass spectrometry and fragmentation pattern on a quadropole mass-spectrometer. We could demonstrate exorphins in the urine from autistic children, and their length varied from one patient to the next. Exorphins are found in urine of autistic children and may account for their symptoms.
Article
Full-text available
Dietary intervention was applied to 15 subjects with autistic syndromes, with pathological urine patterns, and increased levels of peptides found in their twenty‐four‐hour urine samples. The peptides, some of which are probably derived from gluten and casein, are thought to have a negative pharmacological effect on attention, brain maturation, social interaction and learning. Our hypothesis was that a diet without these proteins would facilitate learning. Social behaviour, as well as cognitive and communicative skills, were assessed before diet. The subjects were closely followed for a year, after which their urine was retested blind, and the assessment of behaviors and skills was repeated. Further retesting was made four years after the onset of dietary intervention. Normalization of urine patterns and peptide levels was found after one year. Likewise, a decrease in odd behaviour and an improvement in the use of social, cognitive and communicative skills were registered. This positive development continued through the next three years, though at a lower rate. These promising results encourage further research on the effect of dietary intervention.
Article
Full-text available
Suggests that increased levels of a group of urinary peptides in autistic syndromes indicate that the genetic disposition could be a defect of peptidases. The quantity of peptides excreted and the effect of diet point to casein and gluten as possible etiological factors. This is confirmed by the increased frequency of elevated immunoglobulin A antibodies against these proteins. The isolation of immunoreactive bovine casomorphins in urine and dialysis fluid also point to a dietary cause. A follow-up over more than 2 yrs of 30 children (aged 3–17 yrs) on diet for these disorders shows further improvements in those who remained on diet, and regression in those who abandoned diet. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
We examined Dohan's hypothesis that schizophrenia is associated with the absorption of “exorphins” contained in gluten and casein. In addition, because of the work of Reichelt et al. (Reichelt, K.L., Saelid, G., Lindback, J. and Orbeck, H. (1986) Biological Psychiatry 21:1279–1290) and Rodriguez et al. (Rodriguez, Trav, A.L., Barreiro Marin, R, Galvez, Borrero, I.M., del Olmo Romero-Nieva, F. and Diaz Alvarez, A. (1994) Journal of Nervous and Mental Disease Aug; 182(8): 478–479), we carried out similar studies on a group of children with autism. In both syndromes we found similar patterns of peptide containing peaks (Ninhydrin positive) after molecular screening with Sephadex G-15.Immunoglobulin assay of IgA and IgG against gliadin and casein in serum was done. High titer IgG antibodies to gliadin were found in 87% of autistic and 86% of schizophrenic patients and high titer IgG antibodies to bovine casein were found in 90% of autistic and in 93% of schizophrenic patients. High titer IgA antibodies to glu...
Article
We examined Dohan's hypothesis that schizophrenia is associated with the absorption of "exorphins" contained in gluten and casein. In addition, because of the work of Reichelt et al. (Reichelt, K.L., Saelid, G., Lindback, J. and Orbeck, H. (1986) Biological Psychiatry 21:1279-1290) and Rodriguez et al. (Rodriguez, Trav, A.L., Barreiro Marin, P., Galvez, Borrero, I.M., del Olmo Romero-Nieva, F. and Diaz Alvarez, A. (1994) Journal of Nervous and Mental Disease Aug; 182(8): 478-479), we carried out similar studies on a group of children with autism. In both syndromes we found similar patterns of peptide containing peaks (Ninhydrin positive) after molecular screening with Sephadex G-15. Immunoglobulin assay of IgA and IgG against glia-din and casein in serum was done. High titer IgG antibodies to gliadin were found in 87% of autistic and 86% of schizophrenic patients and high titer IgG antibodies to bovine casein were found in 90% of autistic and in 93% of schizophrenic patients. High titer IgA antibodies to gluten or casein were found in 30% of children with autism while in schizophrenic patients 86% had elevated IgA antibodies to gluten and 67% to casein; some normal children and adults have these antibodies but only in trace amounts. When schizophrenic patients were treated with dialysis or a gluten-casein free diet, or both (Cade, R., Wagemaker, H., Privette, R.M., Fregly, M., Rogers, J. and Orlando, J. (1990) Psychiatry: A World Prespective 1: 494-500) peptiduria and Brief Psychiatric Rating Scores fell while abnormal behavior diminished. A gluten-casein free diet was accompanied by improvement in 81% of autistic children within 3 months in most of the behavior categories. Our data provide support for the proposal that many patients with schizophrenia or autism suffer due to absorption of exorphins formed in the intestine from incomplete digestion of gluten and casein.
Article
Effects of environmental exposure were isolated and studied in 49 autistic children. Elimination of food-related reactions entirely allowed effects of environmental chemicals to be thoroughly studied indefinitely in the absence of food-related symptoms. Initially unaffected by social contexts, the autistic subjects acted out the ways they were affected by their environment without the altering effects of societal influences; and severity of the adverse effects made observation and study easier. There was a strong correlation (P<.000) between environmental exposure levels and autistic symptoms and behaviors. There appeared to be nothing inherently wrong with autistic children studied. Based on the results of the present study, a broad spectrum of severe and chronic autistic symptoms appear to be environmentally based, apparently caused by chronic exposure to volatile organic compounds, and appear to be fully reversible in the proper environment.
Article
The induction of Fos-like immunoreactivity (FLI) was used to determine the brain localization affected by b-casomorphin-7 (b-CM7). Peripheral administration of human b-CM7 at different doses (5, 10 and 30 mg/kg, IV for 1 hour) to rats induced moderate to strong FLI in discrete brain regions including the nucleus accumbens, caudate putamen, ventral tegmental and median raphe nucleus, and orbitofrontal, prefrontal, parietal, temporal, occipital and entorhinal cortex. All of the above areas have been shown to be altered either functionally or anatomically in patients with schizophrenia, and most have been shown to be functionally abnormal in autism. Some of these brain areas are originators or components of dopaminergic, serotoninergic and GABA-ergic pathways, suggesting that b-CM7 can affect the function of all of these systems. The role of some other affected areas in emotional and motivated behavior, social adaptation, hallucinations and delusions suggests that b-CM7, which was found in high concentration in the CSF, blood and urine of patients with either schizophrenia or autism, may be relevant to schizophrenia and autism. Induction of FLI in the above brain areas by a moderate dose (10 mg/kg) of b-CM7 was attenuated significantly, or blocked, by pretreatment with naloxone (2 mg/kg, IP). It is concluded that human b-CM7 can cross the blood-brain barrier, activate opioid receptors and affect brain regions similar to those affected by schizophrenia and autism.
Article
Dietary intervention was tried in 15 autistic children (aged 6–22 yrs) according to the urinary peptide pattern used for classification. Improvement was noted in tests for autistic behavior and several educational measures (e.g., Illinois Test of Psycholinguistic Abilities and Progressive Matrices). A normalization of the urinary peptide secretion was also noted. An etiologic model is presented. (PsycINFO Database Record (c) 2012 APA, all rights reserved)