The possible future role of antibiotics as treatment of Type 1 Autism?

An article was just released pre-publication on the Journal of Autism and Developmental Disorders. It’s not a report of an empirical study. Instead, it’s a letter to the editor of the journal written by Dr. Hari Manev and Dr. Radmila Manev from the University of Illinois. I never discuss letters to the editor on this blog, but this particular letter caught my attention. In this letter the authors present an interesting speculative suggestion of the possible role of some types of antibiotics in treating a specific type of autism. This is the basic argument:
- A number of studies have identified a mutation in the neurexin gene CNTNAP2. Not all cases of autism are related to this mutation, thus the label of Type 1 Autism was proposed by Dr. Stephan on the article “Unraveling Autism” published on the American Journal of Human Genetics (2008). Type 1 Autism would then refer to cases of autism that also have the gene mutation.
- This mutation results in a premature stop codon resulting in a non-functional CNTNAP2 protein. A stop codon is a genetic sequence that signals the end of the process of creating a protein.
- Some antibiotics, such as gentamicin and PTC124, have been shown to suppress the premature stop condons, thus preventing the specific protein deficits associated with such premature codons.
- It is theoretically possible that such antibiotics may suppress the actions of the premature codon in children with this type of autism, possibly leading to a normalization of the levels of protein related to CNTNAP2.

But would this lead to improved symptoms among children already with a full diagnosis? Or will the treatment only be effective before the CNTNAP2 mutation affects protein synthesis during early development, which would argue for early genetic testing? And of course, this assumes that indeed the CNTNAP2 mutation has a causative role in autism and is not simply a comorbid condition. We should note that none of these medications have been approved or studied as a possible treatment for “type 1” autism. Yet, the basic theoretical foundation is there to guide future research to examine the possible role of antibiotics in treating Type 1 autism.

Executive Functioning in High Functioning Autism

A review of: GILBERT, S., BIRD, G., BRINDLEY, R., FRITH, C., BURGESS, P. (2008). Atypical recruitment of medial prefrontal cortex in autism spectrum disorders: An fMRI study of two executive function tasks. Neuropsychologia DOI: 10.1016/j.neuropsychologia.2008.03.025

Executive functioning is an umbrella term used in clinical neuropsychology and cognitive neurosciences to refer to a series of “higher-order” cognitive processes usually associated with frontal lobe functioning. These include planning, organizing, categorizing, response inhibition, monitoring, multitasking, etc. Research on executive functioning and autism has provided mixed results likely due to differences in the area of executive function measured. In this functional MRI study, the authors used a new test of executive function used to assess for stimulus dependent vs. stimulus independent thoughts. Stimulus dependent refers to cognitive processing (thinking) that is associated with, or dependent on, a specific stimulus that is presented. For example, I may ask you to press the b key when you see a blue square or the r key when you see a red square. For this task the stimulus dependent phase consisted of capital letters presented in alphabetical order. Once a letter was presented, the person had to press one key if the letter contained only straight lines (such as the letter A) and a different key if the letter contained curves (such as the letter B). In the stimulus independent task, the person was presented with one letter and ask to follow the same response pattern (one key if straight lines – another key if curves). However, the second letter presented was random and did not follow the alphabetical order, yet the person was asked to respond based on the next alphabetical letter. For example, assume the first letter was “C”, then the next letter presented was the letter “H” (random) yet the person was asked to respond to the next alphabetical letter starting from the first letter presented (C), thus the next response was based on the characteristics of the letter D, even though the person was seeing the letter H. This task therefore, requires the person to continue to “think” of the characteristics of the letters in alphabetical order, independent of the letters presented (which now are distractors).

In the study the authors examined 15 adults with high functioning autism and 18 typically developing adults that were matched for age (mean 38) and IQ (mean 119). The participants performed the task while undergoing a functional magnetic resonance imaging scan (fMRI). There was no difference in accuracy or response times between the groups. Both groups showed more activation of the lateral frontal and parietal cortex on the more difficult stimulus-independent task. However, the autism group had significantly more activation of specific areas of the medial prefrontal cortex during the easier stimulus dependent condition than the typically developing group (this was interpreted as failure to deactivate these areas). The authors argued that these results suggest an atypical brain organization in HFA with limited deactivation of the rostral prefrontal cortex during easier task compared to typically developing individuals. However, the equivalent performance (both groups did just as well on the task) suggests that the fMRI findings simply reflect different approaches to cognitive performance between the two groups.

Acetaminophen use and Autism.

A review of: Schultz, S.T., Klonoff-Cohen, H.S., Wingard, D.L., Akshoomoff, N.A., Macera, C.A., Ming Ji, . (2008). Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: The results of a parent survey. Autism, 12(3), 293-307. DOI: 10.1177/1362361307089518

A study in the latest issue of the journal Autism examined the possible role of acetaminophen use after MMR vaccine and autism. The authors provided an excellent review of the MMR vaccine-autism research, which indicates that although some clinical studies have found a link, most epidemiological studies have failed to find an association between MMR and autism. The authors noted that acetaminophen is commonly used to treat the adverse reaction of MMR vaccinations such a fever and rash. In addition, one study (Alberti et al, 1999) showed that some low functioning children with autism process acetaminophen differently. Thus, the authors proposed a innovative hypothesis: Does acetaminophen use after MMR vaccination increase the risk for Autism?

The authors recruited parents of typically developing children and children with autism via internet advertisement. The total sample included 83 parents completing the survey for children with autism and 80 parents completing the control survey. The surveys included a variety of questions about the child such as age, gender, what medications were used to prevent or treat reactions to the MMR vaccine, including aspirin, acetaminophen, or ibuprofen. The survey of parents of children with autism included additional questions about their children diagnosis such as whether a regression in development was observed.

The authors found that parents of children with autism reported:
- more adverse effects of MMR vaccine, including fever, diarrhea, irritability
- increased presence of concurrent illnesses with MMR vaccine
- more acetaminophen use after the MMR vaccine among children who had a reaction to the vaccine, children who had a regression in development, and those under 5.
- more acetaminophen use between 12 and 18 months of age
No association was found between ibuprofen use and autism.


A few caveats:
The finding that parents of children with autism reported more adverse effects of MMR vaccine or more concurrent illnesses with MMR vaccine is not overly informative. Note that these results were based on parental reports via internet with no possibility of verification of accuracy of such reports. So it is completely plausible to argue that given the extended media coverage of the vaccine-autism link, some parents of children with autism are more attuned to their children histories after vaccination and thus are more likely to remember or report complications. What is informative and actually interesting is that there was a significant difference in reports of acetaminophen use as compared to ibuprofen use. This difference can not easily be explained on the basis of some report bias. The problem is that acetaminophen use was reported much more frequently than ibuprofen use by all parents. So it could be argued that since parents of children with autism were more likely to report complications (even if just a by-product of recall bias), the use of acetaminophen will also appear to be different between the two groups.

Autism and Cerebellar Differences?

Study finds no differences in cerebellar volume in people with autism after controlling for macrocephaly, IQ, and age.

A review of: CLEAVINGER, H.B., BIGLER, E.D., JOHNSON, J.L., LU, J., McMAHON, W., LAINHART, J.E. (2008). Quantitative magnetic resonance image analysis of the cerebellum in macrocephalic and normocephalic children and adults with autism. Journal of the International Neuropsychological Society, 14(03) DOI: 10.1017/S1355617708080594

As I do my weekly literature search on Autism Research for Translating Autism, I noticed a number of forthcoming manuscripts about the role of the cerebellum in Autism. I will likely review some of these new studies and decided to start with Cleavinger et al (2008) MRI examination of cerebellum in children and adults with autism.

The cerebellum is located on the lower back region of the brain and traditionally it has been implicated in the integration of sensory information and the coordination of movement. However, more recent investigations have determined that the cerebellum is also active in various higher-order functions such as language, emotion, and cognition. In the past, studies looking at differences in the cerebellum of people with and without autism have provide mixed results with some showing increased volume in people with autism, while others show no difference, or decreased volume. One possible explanation for these conflicting findings is that people with autism often vary in degree of macrocephaly (large head size) which may affect the results if the samples studied included individuals with and without macrocephaly. To address this question the authors of this study examined 4 groups: a) people with autism and macrocephaly (N=13) b) people without autism and macrocephaly (N=8) c) people with autism and without macrocephaly (N=28) and c) people without autism and without macrocephaly (N=16). In general, after controlling for macrocephaly, age, and IQ, no statistically significant differences in cerebellar volume were found, although a trend was observed in that people with autism who also had macrocephaly showed smaller cerebellar volume as compared to similar macrocephalic individuals without autism. This trend is important because the ‘non-significant’ differences reported here are likely due to the small sample size and unequal group size, which affects the statistical power of the analysis (making it more difficult to show statistical significant differences even when such differences actually exist). But even if the 'non-differences' result is replicated and in fact no differences in cerebellar volume exist between these groups, does this mean that the cerebellum is not implicated in autism? Not at all. Here again I touch the issue of how we should avoid reaching conclusions that go beyond what the data tell us. These results only speak to the size of the cerebellum, suggesting no apparent morphological differences. These results however, do not speak to possible anomalies in the functioning of the cerebellum, which may or may not be present in autism.

A micro history of the recent mercury autism controversy.

A commentary on: Aschner, M. (2008). Response to Article by DeSoto and Hitlan on the Rlationship Between Mercury Exposure and Autism. Journal of Child Neurology, 23(4), 463-463. DOI: 10.1177/0883073808314647

DeSoto, M.C., Hitlan, R.T. (2008). Concerning Blood Mercury Levels and Autism: A Need to Clarify. Journal of Child Neurology, 23(4), 463-465. DOI: 10.1177/0883073808314718

The latest issue of the Journal of Child Neurology includes two letters regarding the mercury-autism controversy. For most people familiar with this issue, this summary will not present anything new, but for those interested in knowing the basics of this latest controversy, here is a micro-crash course on the mercury-autism link.

In 2004 authors Ip, Wong, HO, Lee, and Wong, published an article in the Journal of Child Neurology comparing the blood and hair mercury levels of children with and without autism in order to examine if a mercury-autism link existed. The results were as follow:

There was no difference in the mean mercury levels [between the group]. The mean blood mercury levels of the autistic and control groups were 19.53 and 17.68 nmol/L, respectively (P = .15), and the mean hair mercury levels of the autistic and control groups were 2.26 and 2.07 ppm, respectively (P = .79).

The conclusion, which was supposedly inconsistent with the theory that mercury causes autism, shocked some members of the autism community. I said ‘supposedly’ because whether or not the mercury theory is correct, the manner in which the results are presented goes beyond what the data can actually say. Specifically, the authors concluded that:

Thus, the results from our cohort study with similar environmental mercury exposure indicate that there is no causal relationship between mercury as an environmental neurotoxin and autism.

The problem here is that this data only speak to concurrent levels of mercury and autism diagnosis. So it is entirely possible that in some children pre- or post-natal exposure to this toxin results in neurodevelopmental changes leading to autism symptoms. This idea does not imply that mercury levels would remain high in affected children. It only implies that that these children were exposed to this toxin. A similar example would be exposure to alcohol during pregnancy leading to fetal alcohol syndrome (FAS). Children with FAS do not have higher levels of alcohol in their blood than typically developing kids. I am not endorsing the mercury theory, but I am stating that the conclusions as stated by Ip go beyond what their data say.

But back to the Ip et al. (2004) study. In 2007, DeSoto and Hitlan published an article in the Journal of Child Neurology after they found a major mathematical mistake in the original findings reported by Ip. Specifically, they found that the non-significant differences in blood levels reported by Ip was an error and significant differences were actually observed. I did the calculations myself, and yes in fact, the kids with autism had significantly higher mercury levels than the control group (t = 2.6163; df = 135; p>.01).

Then in the latest issue of the Journal of Child Neurology, Dr. Michael Aschner published the following short correspondence:

In a recent article DeSoto and Hitlan1 reanalyzed an original data set, concluding that a relationship exists between blood mercury levels and the diagnosis of autism spectrum disorder (ASD). The conclusion is based on the reanalysis of hair to blood mercury ratios. Hair to mercury concentration ratios while informative need to be considered within the context of a temporal relationship. As elegantly demonstrated by Grandjean and colleagues, mercury levels in the hair reflect a delayed average compared to the blood mercury level averages. That is, mercury hair concentrations at hypothetical time point T reflect blood mercury levels at T minus 1 to 2 months. Chelation therapy and changes in diet and fish consumption (both more likely to occur in the ASD group) in the 2 months preceding the mercury analysis are likely to affect blood, but not hair mercury sample concentrations. The analysis by DeSoto and Hitlan, which presumes that the 2 biomarkers are equally affected, is clearly erroneous. Thus, absent appropriate corrections for the temporal fluctuations in mercury levels, the conclusions should be interpreted with utmost caution and revalidated taking the above issue into account.

This was followed by a response from DeSoto and Hitlan explaining further that their 2007 study addressed directly the error in blood sample Mean differences as reported by Ip et al in 2004. DeSoto and Hitlan re-analyzed Ip's data showing that in fact blood mercury levels in the autistic group were higher than in the control group. This finding, and the original Ip error, had nothing to do with hair-to-blood ratios as described by Dr. Aschner. Dr. Aschner criticism is much more applicable to a separate hair analysis performed by DeSoto and Hitlan showing that the autism group had lower hair mercury levels than expected based on their blood samples, which is inconsistent with the idea that chelation therapy may have affected the blood levels. I explain: blood levels reflect immediate levels of mercury while hair levels reflect levels 1 to 2 month prior to testing. Thus, if blood levels at Time 1 were 20 (I’m using random numbers as example), then hair levels at Time 2 (2 month later) should be 20. If after Time 1 the child undergoes chelation therapy, then theoretically, blood levels at time 2 (2 month later) should be lower than 20 but hair levels should remain 20. Thus at Time 2, blood levels should be lower than hair levels. This was not supported by DeSotos’ analyses. What does this mean? Simply that the differences in blood levels found between the autism and control group are unlikely to have been affected by chelation therapy in the autistic group since the hair-blood analysis was not consistent with what is expected if chelation therapy had occur. WARNING: this is not a statement supporting chelation therapy, it is just a clarification of a possible interpretation of this data.

Does this mean that vaccines cause autism? Not at all. Again, although we would like to think that data can give us the entire story, data speak in morphemes rather than words, or sentences. This data only indicate that this particular group of children with autism had higher mercury levels than typically developing children. This could mean many things, such as that the children with autism have difficulty processing mercury or that the children with autism were exposed to higher levels of mercury, and these explanations in turn, may or may not have anything to do with the symptoms observed in children with autism, both in terms of symptom presentation, severity, or causes. These data simply do not give us that information.

More recent articles about the Autism and Mercury controversy and the Autism and Vaccines controversy can be found here.

Autism and Cholesterol: A possible link?

Low levels of cholesterol associated with autism-like symptoms in Smith-Lemli-Opitz Syndrome.

A review of: Aneja, A., Tierney, E. (2008). Autism: The role of cholesterol in treatment. International Review of Psychiatry, 20(2), 165-170. DOI: 10.1080/09540260801889062

The Smith-Lemli-Opitz Syndrome (SLOS) is a genetic disorder characterized by alterations in the processing of cholesterol. Specifically, people with this disorder do not produce enough cholesterol resulting in a variety of morphological, physiological, and behavioral symptoms. Of interest to autism researchers is that people with SLOS have many of the same symptoms that characterize autism spectrum disorders, including language impairments and stereotyped behaviors. How is cholesterol related to ASDs within and outside the SLOS syndrome? In this article, Aneka and Tierney (2008) present a succinct summary and conceptualization of the possible role of cholesterol in the phenomenology of Autism. The authors reviewed the physiological mechanisms by which low levels of cholesterol may play a role in the behavioral phenotype found in kids with SLOS. The following mechanisms were discussed:
1. Cholesterol is necessary for normal embryonic and fetal development.
2. Cholesterol is a precursor of neuroactive steroids (possibly affecting anxiety)
3. Cholesterol is required for the growth of myelin membranes (affecting brain maturation).
4. Cholesterol can be a modulator in oxytocin receptor functioning (Oxytocin plays an important role in social behaviors).
5.Cholesterol is a modulator of the ligand binding activity and G-protein coupling of the serotonin1A (5-HT1A) receptor (affecting serotonin neuron development).

An examination of these factors is beyond the scope of this review, but they represent a sensible theory regarding the possible mechanisms by which low levels of cholesterol may lead to many of the behavioral symptoms present in autism. The authors then discussed the implication of these findings for assessment and possible treatment interventions. First, most comprehensive evaluations of autism may include genetic and laboratory testing, including testing for fragile X, heavy metals, etc. The authors stated that biochemical testing can be utilized to assess for low level of cholesterol (actually low levels relative to another compound - 7DHC). In my experience, requesting this test within a neuropsychological evaluation is not common. Actually I don’t remember ever conducting an evaluation of someone who had been recommended this test by anyone (neurologist, pediatricians, psychologist, etc). Finally, the authors reviewed previous studies that have examined the effectiveness of cholesterol supplementation in children with SLOS. Previous studies have found that children with SLOS that receive cholesterol supplementation show a reduction of autistic behaviors, irritability, attention problems, and improved affect.

Should cholesterol testing become a part of the standard assessment procedures of children with Autism?

Brain Differences in Autism 2: Fusiform Gyrus

A review of: van Kooten, I.A., Palmen, S.J., von Cappeln, P., Steinbusch, H.W., Korr, H., Heinsen, H., Hof, P.R., van Engeland, H., Schmitz, C. (2008). Neurons in the fusiform gyrus are fewer and smaller in autism. Brain DOI: 10.1093/brain/awn033

The fusiform gyrus is an area of the temporal lobes of the brain that has been extensively associated to people’s ability to recognize faces. The authors of this paper proposed that abnormalities in the fusiform gyrus may explain some social deficits in Autism. Although people with autism can correctly complete face processing tasks, the authors noted that people with autism display reduced activation of the fusiform gyrus during these tasks. This alteration could be responsible for atypical behaviors such as reduced eye contact. To examine the underlying hypothesis further, the authors examined the post-mortem brains of 7 children and adults with autism as compared to 10 matched controls. They found significantly reduced neuron density and total neuron number in areas of the fusiform gyrus but not in other cortical areas. The authors presented a very interesting alternative interpretation. Although the reduced neural density and number in the fusiform gyrus could reflect neurodevelopmental impairments in the fusiform itself resulting in specific functional impairments, it is also possible that this atrophy is related to ‘loss of targets’ to which the fusiform gyrus projects. That is, the fusiform gyrus sends neural projections to the amygdale, which play an important role in monitoring eye gaze and other social behaviors. Thus, is the finding of reduced neural density and total number of the fusiform gyrus a reflection of dysfunction of this area of the brain, or simply a byproduct of alterations in other related areas such as the amygdale?

Brain Differences in children with Autism: White Matter – Gray Matter

A review of: BONILHA, L., CENDES, F., RORDEN, C., ECKERT, M., DALGALARRONDO, P., LI, L., STEINER, C. (2008). Gray and white matter imbalance – Typical structural abnormality underlying classic autism?. Brain and Development DOI: 10.1016/j.braindev.2007.11.006

The authors of this study discussed the relative inconsistent results from studies trying to examine brain differences in children with and without Autism. For example, although many post-mortem studies have found brain differences, the differences they find vary significantly between studies. The same is true of studies using imaging techniques such as MRI. However, the most consistent finding is an overall larger brain volume in children with autism, leading some researchers to propose deficits in cell pruning as a possible cause of autism (more of this below). In this study the authors used MRI (Magnetic Resonance Imaging) to compare 12 children with Autism (average age 12) to 16 matched typically developing children. The results showed that children with autism had increased generalized bilateral gray matter. Specifically increased gray matter was observed in the cingulated gyrus, caudate, cerebellum, claustrum, cuneus, fusiform gyrus, inferior, middle and superior frontal gyri, inferior and superior temporal gyri, inferior and superior parietal lobules, pre and post-central gyrus, precuneus, putamen, thalamus, insula and occipital cortex. The results also showed decreased generalized bilateral white matter in the cuneus, medial and superior frontal gyri, pre- and post-central gyri, inferior parietal lobule, supramarginal gyrus, cingulote gyrus, middle occipital gyrus, parahippocampal gyrus, and the middle and superior temporal gyri. The authors concluded that their data provides strong evidence for increased gray matter and reduced white matter in children with autism when compared to typically developing kids. Similar results have been used as evidence of the cell pruning theory of autism. This theory indicates that children with autism have an atypical brain development process during early infancy. Specifically, during a typical post-natal period, there is considerable removal of connections between cells in the brain leading to more efficiency in cell connectivity and cell communication. Researchers argue that abnormal brain growth during early development in autism is due to limited pruning of such synaptic connections.

More evidence against the Leaky Gut theory of Autism?

A review of: Cass, H., Gringras, P., March, J., McKendrick, I., O'Hare, A.E., Owen, L., Pollin, C. (2008). Absence of urinary opioid peptides in children with Autism. Archives of Disease in Childhood DOI: 10.1136/adc.2006.114389

Should parents of children with autism stop purchasing commercially available test of opioid-peptides?

In this previous POST I reviewed a simple study that examined the intestinal system of children with autism in order to test specific hypotheses related to the “Leaky Gut” theory. As is mentioned before, this theory suggests that children with autism have increased permeability of their intestinal track leading to faster absorption of peptides which could disrupt neural development during the early stages of life. However, the Robertson et al. (2008) article did not find evidence that would support the Leaky Gut theory. In this similar study, the authors compared 68 males with autism between 4 and 11 years of age to 202 typically developing males of similar ages. Autism was diagnosed via ADI-R based on ICD-10 diagnostic criteria. Only 6 of the children with autism were on special diets (gluten free or gluten and casein free). The researchers compared the levels of putative opioid peptides in the urine of all participating children. There was no significant difference between the peptide levels of children with autism when compared to typically developing children. The authors concluded that, given this apparent normative absorption and processing of peptides in children with autism, the presence of high opioid -peptides should not be used as a marker for autism or as an estimate of the possible effectiveness of gluten free diets. The researchers also indicated that previous studies showing high levels of opioid peptides in children with autism prior to the start of a gluten free diet (See for example Knivsberg et al 2002), have not been replicated mostly because of possible inadequate methods used in previous studies. The authors feel strongly that “Children with autism should not be subjected to investigation of urinary opioid peptides or their parents to the expense of the assays which are still widely advertised on the internet by commercial laboratories around the world”.

UPDATE: After I reviewed this study I received several emails from parents with different perspectives on the Gluten Free diet issue. I want to briefly note two things. The data from the Cass article do not directly address the issue of effectiveness of the gluten free diets or the issue of the use of peptide tests to predict treatment effectiveness (despite their strong statement against such tests). Their data simply fails to find support for one of the underlying assumptions of the Leaky Gut theory.

Someone also pointed me to what seems to be the only clinical controlled study of these treatments:

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

In this study, the authors also failed to find statistical evidence for improvement in children exposed to the gluten free diet for 12 weeks. However, this 2006 study was very preliminary with an extremely small sample size. There is no doubt that additional research is needed to help clarify the possible effectiveness of these diets.

“Leaky Gut” revisited: Intestinal problems in children with autism.

Title: Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study.
Source:Robertson, M.A., Sigalet, D.L., Holst, J.J., Meddings, J.B., Wood, J., Sharkey, K.A. (2008). Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-007-0482-1

One of the many theories that have been proposed to explain possible causes of autism is the "leaky-gut, opioid-excess" theory. This theory suggests that children with autism have increased permeability of their intestinal track leading to faster absorption of peptides which could disrupt neural development during the early stages of life. To test this theory, the authors measured intestinal permeability in a group of 14 children with autism (diagnosed via DSM-IV criteria by a developmental pediatrician), 7 typically developing siblings of these children, and 8 typically developing additional children. They tested the leaky gut theory in two ways. First they observed the levels of a hormone (GLP-2) in response to feeding, which is believed to control satiation. Low levels of this hormone could lead to, or reflect, dysregulated peptide absorption. Second, intestinal permeability was assessed via a differential sugar-absorption test. They used different types of sugars that have different molecular weights. In a normal intestinal system, sugars with small molecular weight will pass through the walls easily as compared to heavy sugars, leading to high levels of the small sugars in urine. However, in a highly permeable intestinal system, the ratio of these two sugars in urine will change as the sugars with large molecular weights pass through the intestinal barrier at a higher rate. Results: The authors found no differences between any of the 3 groups of children in GLP-2 response to feeding or the ratio of sugars in urine. The authors concluded that in this small sample of children with autism there was no evidence of increased intestinal permeability as hypothesized in the ‘leaky-gut’ hypothesis.

Side note: I always thought "Developmental Pediatrician" was a completely redundant label, and comparable to 'heart cardiologist' or 'eye ophthalmologist'. Although sadly, my experience with some pediatricians does suggest that some really don't know anything about human development.

Clonidine and Sleep problems in children with Autism

Title:Use of clonidine in children with autism spectrum disorders.
Source:MING, X. (2008). Use of clonidine in children with autism spectrum disorders. Brain and Development DOI: 10.1016/j.braindev.2007.12.007

In this study the authors wanted to evaluate the effectiveness of clonidine in the treatment of insomnia and other behavioral difficulties in children with autism spectrum disorder. The researchers evaluated 19 children with a diagnosis of ASDs obtained via ADI and ADOS. The researchers assessed sleep and behavioral problems as reported by the parents before and during the initiation of the treatment. Seventeen of the 19 children had sleep difficulties including prolonged sleep initiation and or difficulty maintaining sleep. All children with difficulty falling asleep (16) were able to fall asleep faster after taking the medication. In addition 16 of 17 children with sleep maintenance problems had a reduction in the frequency of awakening during the nights. The authors concluded that clonidine was effective in managing sleep difficulties in this sample of children with ASDs. However, the authors also correctly noted some major limitations of this study. This was an open label retrospective study. Open label means that all participants knew which medication they were taking. Under ideal conditions, such as in a randomized double-blind placebo study, both the clinicians and the patients are blind to what medication (or placebo) they are taking, which greatly increases our ability to reach conclusions about the true effects of the medication. In an open label study, there is always the possibility that the results are not due to the actual effect of the medication but to a ‘placebo’ effect.

Autism, Monkeys, and Maternal Antibodies

Title: Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism
Authors: Loren A. Martin, Paul Ashwood, Daniel Braunschweig, Maricel Cabanlit, Judy Van de Water and David G. Amaral
Source: In press. Journal Brain, Behavior, and Immunity

You can find a more complete description and review of this paper based on the press coverage here. Thus, I’ll limit this to a micro summary and a few related thoughts. The researchers wanted to experimentally test the hypothesis that exposure to maternal neuronal antibodies (IgG) during the PREnatal period could be one of the causes of at least some variants of Autism. To test this hypothesis the researchers exposed 4 prenatal rhesus monkeys with IgG taken from human mothers who had multiple children with ASD. They also exposed 5 prenatal monkeys with IgG taken from human mothers who did not have any children with Autism. Once the monkeys were born, these two groups were also compared to monkeys that had not been exposed to any antibodies. The researchers found that the monkeys that had been exposed to the antibodies of human mothers of children with autism engaged in much higher levels of unique whole-body stereotypic behaviors and less social contact with familiar peers, than did the monkeys exposed to IgG of mothers of typically developing kids or monkeys not exposed to any antibodies. Furthermore, these stereotypic behaviors increased when the monkeys were exposed to novel environments or peers. As I understand how controversial this paper will be for some people, I want to say that the authors are very clear and explicit in stating that this is NOT an animal model of autism. That is, they did not intent to say that they were able to “cause” autism in these monkeys via exposure to IgG. Instead, their data presents some evidence that exposure to IgG before birth leads to unique patterns of stereotypic behaviors, similar to those observed in some children with ASD. This is a very small preliminary study, but the results are fascinating in that it will guide future research to explore exposure to IgG as a potential cause (one of many) of ASD.

Diminished Cingulate Respose in Children with High Functioning Autism: A possible neural marker?

Title: Self Responses along Cingulate Cortex Reveal Quantitative Neural Phenotype for High-Functioning Autism
Authors: Pearl H. Chiu, M. Amin Kayali, Kenneth T. Kishida, Damon Tomlin, Laura G. Klinger, Mark R. Klinger and P. Read Montague
Source: Neuron 57, 463–473, February 7, 2008

I first heard about this article at the Autism Vox, which led to an interesting discussion on the difficulty in applying findings from basic science into the creation of diagnostic tools. This was a very interesting piece, but as I mentioned on the Autism Vox discussion, I think we are far from the creation of an FMRI test of autism (see the Autism Vox discussion). In summary, the researchers examined 16 adolescents with high functioning autism and 20 typically developing adolescents in their responses to a computer game called the Multi-round Trust Game. In this game the children received computer money (points) from another player in the form of an investment. During the transaction, the investment increased, so the receiving child obtained more than what the “investor” actually sent. Then the receiving child must decide how much of what he received should be returned to the investor. The key finding was that both groups of kids (Children with autism and typically developing) looked the same, in regards to their brain activation as seen on an fMRI, when the “Other” person was making a decision. The authors refer to this as the “Other Response”. However, when the children were making their own responses (called “Self Response”) the children with Autism lack a particular activation in the Cingulate Cortex (located deep in the center of the brain and usually activated during some social interactions including TofM tasks). This pattern of response was similar to the pattern presented by typically developing kids when playing against a computer instead of an actual person. The conclusion from the authors is that these children with autism may be “impaired in the capacity to represent the social intend of their OWN behavior” while understanding the actions of other (but not necessarily the intentions of others).

Commentary: Here is where the logic gets fussy. Since the two groups of children had a similar response patterns to the “Other” response, the authors argued that such “other” response must refer to a representation of the simple actions of others, but not the “intentions” of others. So the lack of cingulate cortex activation during “self” responses are interpreted as a diminished capacity to understand you own social “intentions” (or I interpret this that as “consequences”) and this is used to explain why children with autism have difficulty on theory of mind tasks. The authors argued that if you can’t represent your own social intentions, it will be difficult to represent the social intentions of others. Now, the problem is that in this game there was no difference between the two groups of kids when the “Other” was responding. Why? If children with autism have difficulty representing the social intentions of others, you would expected to see a difference between these two groups, unless you assume that 1) the typically developing kids also had problems representing the social intentions of others OR 2) during this game there was no need to represent the social intentions of others. In conclusion, what this study clearly shows is reduced Cingulate Cortex activation during “self” responses, suggesting that children with autism have a different brain activation pattern when performing actions that have social intentions, or consequences on someone else. Here is a review from MIT.

Autism and Mercury: The Pediatrics thimerosal study

Title: Mercury Levels in Newborns and Infants After Receipt of Thimerosal-Containing Vaccines
Authors: Michael E. Pichichero, MDa, Angela Gentile, MDb, Norberto Giglio, MDb, Veronica Umido, MDb, Thomas Clarkson, PhDc, Elsa Cernichiari, MSc, Grazyna Zareba, PhDc, Carlos Gotelli, PhDd, Mariano Gotelli, PhDd, Lihan Yan, MSe and John Treanor, MDa
Source: PEDIATRICS Vol. 121 No. 2 February 2008, pp. e208-e214

The famous Thimerosal study from the American Academy of Pediatrics journal finally was released this morning. This short review could not possibly do justice to the major controversy about mercury and autism, so I will limit the commentary to the results of THIS STUDY ONLY. Given that Thimerosal is commonly used in vaccines in other countries outside of the US and Europe, the researchers teamed with a research group in Argentina to examine how infants and toddlers process Thimerosal when injected as part of their standard vaccination procedures. The researchers examined newborns, 2 month old babies, and 6 month old babies. The infants received a birth dosage of BCG and HBV vaccines that contained 32.5 ug of mercury (ethyl mercury). The 2-months-olds received the first dosage of diphtheria-tetanus-whole-cell pertusis and Hib, the first dosage of polio, and the second dosage of HBV, providing a total of about 40-50 ug of mercury. Finally the 6-month-olds received the additional dosage of diphtheria-tetanus-whole-cell pertusis, Hib, and HBV for a total mercury intake also between 40-50 ug. Then the researchers examined mercury levels in the blood, stool, and urine 1, 3, 5, 11, 21, and 30 days after the vaccinations. The 1/2 life of mercury was found to be 3.7 days in new born, 2 days for 2-month olds, and 2.2 days for 6-months olds. Blood mercury levels returned to baseline by day 11 after the vaccination. The 1/2 life refers to the time it takes for the drug to reach 1/2 of its original value (max in the first cycle). Why is this significant? Because part of the argument against the use of Thimerosal in vaccines was based on the effect of Methylmercury in adults. Methylmercury has a 1/2 life of about 50 Days with studies reporting as long as 180 days! This long 1/2 life of Methylmercury means that the person is exposed to levels of mercury for extended periods of times (weeks), which has many potential side effects. The argument made by the authors of this study is that the 1/2 life of Ethyl Mercury as found in children is only about 3 days, significantly reducing the exposure to mercury in these babies. Now, the authors correctly state that this study does not address the "toxicity" of thimerosal, so it could be argued that exposure to ethyl mercury even for a short period of time (3-4 days)could be enough to cause maturational changes in the brain leading to permanent impairments.

Autism and Fevers: First scientific evidence of improved functioning during fever episodes.

Title: Behaviors Associated with fevers in children with Autism Spectrum Disorders
Authors: Curran, L., Newchaffer, C., Lee, L., Crawford, S., Johnston, M., Zimmerman, A.
Source: Pediatrics 120, 2007.

This article was published in the January issue of Pediatrics by a team at Johns Hopkins University. The study attempted to examine a unique observation commonly reported by parents and clinicians: children with autism seem to improve when they have fevers, especially in regards to their social behaviors. The authors followed about 100 children with autism. During the duration of the study 40 of these children developed a fever. These 40 children were then compared with other children with autism of similar ages but who did not develop a fever during the same time. The authors found that during the episodes of fever the parents reported a significant improvement in irritability, hyperactivity, stereotypy, and inappropriate speech. This was not simply the result of the kids being so sick they couldn’t move, since these children also experienced less lethargy! Unfortunately all improvements were temporary, and ended after the children no longer had a fever. This is the first study to show empirically a phenomenon that parents and clinicians have been reporting. Unfortunately, currently there is no cohesive theory that would explain how or why kids with ASD improve during episodes of fever. We need to wait for more specific research to could show the possible mechanism by which fever temporarily helps to improve these behaviors.

Autism and Vaccines: The California Thimerosal Study

Title: Continuing Increases in Autism Reported
to California’s Developmental Services System
Authors: Robert Schechter, MD, MSc; Judith K. Grether, PhD
Source: Arch Gen Psychiatry. 2008;65(1):19-24

While we wait for the release of the new Academy of Pediatrics study on Thimerosal (see last blog entry), I thought this recent article from the Archives of General Psychiatry was worth reviewing, especially given the current controversy regarding ABC “Eli Stone” episode. This study was simple and elegant. It follows a straightforward logic. If the use of Thimerosal in vaccines has a causal role in the development of autism, the elimination of Thimerosal in vaccines should result in a drop in the rates of autism, or at the very least, a pause in the accelerated increase of these rates. To test this hypothesis the authors reviewed the rates of autism in the State of California from 1995 to 2007. The found a consistent increase in rates during these 11 years without any indication of a slowdown or a drop in autism rates. One particular finding is worth mentioning. The rates of autism in 3 to 5 year old kids increased from 3 to 4.1 per 1000 live births from 2004 to 2007, which represented a higher increase than those observed for all other developmental disabilities. This is of major importance because during this same period all but trace amounts of Thimerosal had been eliminated from vaccines in the State of California. If the link between Thimerosal and autism were "causal" and strong, the rates of autism during the 2004-2007 year should have dropped. Instead these rates increased. Now, although strong, this is far from conclusive evidence, since people could argue that rates continued to increase because of vaccinated babies moving to California or that such trace amounts of Thimerosal were enough to continue the increase in autism. But this last hypothesis will likely be answered by the Pediatrics article due to come out next week.

UPDATE: I found an interesting post at Autism in New Brunswick about a University of Kentucky professor’s (Dr. Boyd Haley) skepticism of this research based on the idea that mercury exposure continued after thimerosal was supposedly removed from vaccines in California (see the press story here). The difficulty with Dr. Haley's argument is that I can't find any reliable data showing that the levels of mercury in vaccines continued to be higher than trace amounts after Thimerosal was taken out of vaccines. At least I can’t find any published studies in scientific journals of such effect. It is difficult to believe that after Thimerosal was removed there was not a reduction in mercury exposure. Arguing that mercury exposure remained stable implies that either Thimerosal was not actually removed, that the new non-Thimerosal vaccines were so delayed to reach Drs offices as to not affect the overall mercury exposure, or that somehow these children continued to be exposed to mercury through a difference source. Otherwise, the most rational conclusion is to assume that mercury exposure was significantly reduced after Thimerosal was pulled from the market and therefore a parallel reduction in new cases with autism is expected. Sadly this didn't happen.

American Academy of Pediatrics Study on Thimerosal and Autism

It seems that due to the ABC decision to air the court drama "Eli Stone", the American Academy of Pediatrics released one study from their February journal issue a week early. This study apparently contradicts the theory that Thimerosal is linked to autism. Here is the link to the news release. I just checked our university online journals and the issue is not available yet. I suspect they made the issue available mostly to the press. As soon as I obtain a copy of the study I will post my commentary and summary as usual.

UPDATE: As of today (1/31 at 10:45am) the study has still not been made public. See the ABC news about the controversy here.

UPDATE: I finally reviewed the article HERE.