Blood lead levels and childhood behaviour

"Blood lead concentrations, even at a mean concentration of 6.4 µg/dL, were associated with increased risk of behavioral problems in Chinese preschool children, including internalizing and pervasive developmental problems". That was the conclusion of the study by Jianghong Liu and colleagues [1] looking at blood lead levels in preschoolers aged 3-5 years resident in Jiangsu province in China. Some associated media accompanying this study can be viewed here including the text: "This research focused on lower blood lead levels than most other studies and adds more evidence that there is no safe lead level".

You lead... @ Wikipedia 

Lead (Pb) is a metal which has appeared before on this blog - quite a few times in fact (see here and see here for example) - all for the wrong reasons. Outside of it's many and varied industrial uses, including helping many of us get from A to B, lead is pretty dangerous stuff if it manages to find itself into the human and animal body in any amount particularly with its neurotoxic effects [2] in mind.

For quite a few years, much of the guidance on exposure to lead had suggested that blood lead levels above 10 μg/dL "should prompt public health actions" [3] albeit not defining "a threshold for the harmful effects of lead". As per that CDC report [3] there has been an increasing realisation that even blood lead levels below 10 microg/dL may have some undesirable effects particularly on infants and young children. Indeed the revised CDC guidance now lists "5 micrograms per deciliter of lead in blood" as the point where concerns should be raised about blood lead levels and action taken.

Back to the Liu paper...

• Looking at spot blood lead levels (BLLs) or even blood lead concentrations for over 1300 youngsters, researchers administered the "Chinese versions of the Child Behavior Checklist and Caregiver-Teacher Report Form" to parents and teachers of participants when children were aged 6 years old.
• Results: the mean (average) BLL for participants was 6.4 µg/dL, although a range of results were reported. Incremental increases in BLLs correlated with an "increase of teacher-reported behavior scores on emotional reactivity, anxiety problems, and pervasive developmental problems". Also: "mean teacher-reported behavior scores increased with blood lead concentrations, particularly for older girls".
• The authors conclude: "continued monitoring of blood lead concentrations, as well as clinical assessments of mental behavior during regular pediatric visits, may be warranted".

Bearing in mind this was a study looking at parent and teacher scoring of Chinese children and not more formal assessment of behavioural (or cognitive) issues, also focused on spot samples rather than multiple samples to assess BLLs, there are some important lessons to be learned from these results. Not least is the continued undesirability of contact with lead and it's potential effects on behaviour. I think back to some of the chatter on lead exposure and crime (see here) taking into account the old 'correlation is not the same as causation' mantra as one potential societal effect.

Reading through some of the other literature in this area, it's not difficult to find supporting information about the detrimental effects of lead exposure particularly in children. The paper by Hou and colleagues [4] (open-access here) pretty much sums it up: "Compared with healthy children, more children with lead poisoning had abnormal behaviors, especially social withdrawal, depression, and atypical body movements, aggressions and destruction". They conclude: "Lead is a neurotoxin with no physiological functions in the human body, the ideal concentration of which in the blood is zero".

Whilst exposure to lead through older formulations of petrol or house paint or plumbing is a declining issue in many areas of the world, I don't think we can be complacent about our situation. Roberts and colleagues [5] commented on this issue in their study (bearing in mind their use of the 10 microg/dL cutoff level). They noted: "Despite a low prevalence of children with EBLL [elevated blood lead levels], parental report suggested that approximately 29% of children had lead-based paint in their home environment". Similar analyses of other areas of lead exposure risk such as dust, soil and water suggest continued monitoring is required as per the study results from Oulhote and colleagues [6].

If there is a take-home message from this post and the Liu results it is that lead exposure can have often pronounced developmental effects on behaviour (and cognition) in infants and children and that even markers of low levels of exposure should be examined with much greater assiduity. Without trying to brush everyone with autism as lead poisoned, such results might also direct much greater research attention when findings of EBLL are noted in cases of autism (see here). Indeed, papers like the one from El-Ansary and colleagues [7] might offer much more information than they have hitherto been given credit for...

----------

[1] Liu J. et al. Blood Lead Concentrations and Children’s Behavioral and Emotional Problems. JAMA Pediatrics. 2014. June 30.

[2] Lidsky TI. & Schneider JS. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain. 2003; 126: 5-19.

[3] CDC. nterpreting and managing blood lead levels < 10 microg/dL in children and reducing childhood exposures to lead: recommendations of CDC's Advisory Committee on Childhood Lead Poisoning Prevention. MMWR Recomm Rep. 2007 Nov 2;56(RR-8):1-16.

[4] Hou S. et al. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theor Biol Med Model. 2013 Feb 18;10:13.

[5] Roberts JR. et al. Are children still at risk for lead poisoning? Clin Pediatr (Phila). 2013 Feb;52(2):125-30.

[6] Oulhote Y. et al. mplications of different residential lead standards on children's blood lead levels in France: predictions based on a national cross-sectional survey. Int J Hyg Environ Health. 2013 Nov;216(6):743-50.

[7] El-Ansary AK. et al. Relationship between chronic lead toxicity and plasma neurotransmitters in autistic patients from Saudi Arabia. Clin Biochem. 2011 Sep;44(13):1116-20.

----------

Liu, J., Liu, X., Wang, W., McCauley, L., Pinto-Martin, J., Wang, Y., Li, L., Yan, C., & Rogan, W. (2014). Blood Lead Concentrations and Children’s Behavioral and Emotional Problems JAMA Pediatrics DOI: 10.1001/jamapediatrics.2014.332

Organic acids as biomarkers of autism?

Whilst I am always a little cautious about the use of the word 'biomarker' when applied to a heterogeneous condition like autism, even the autisms, I am nevertheless always intrigued at any reasonable prospect reported in the scientific literature. So it was when I read the paper by Joanna Kałużna-Czaplińska and colleagues [1] and their assertion that "there is a significant metabolic difference between autistic and non-autistic children" and onwards that "21 metabolites were identified as potential biomarkers".

Let me expand on this a little...

• This was a small study looking at potential biomarker identification on the basis of the analysis of urine samples via gas chromatography-mass spectrometry (GC-MS). If you want some further background on this technique applied to autism research, have a look at a previous post (see here) where it has been utilised. Overnight urine samples from 14 children (aged 4-10 years) diagnosed with an autism spectrum disorder (ASD) undergoing "rehabilition" (whatever that means) were analysed in comparison to samples from 10 asymptomatic controls.
• Quite a bit of information is included about sample treatment and the analytical method. Each sample result was represented as a TIC (total ion count) and, as is often the case with such methods, data processing was an important part of the analysis. Most compounds were identified by cross-referencing with the NIST mass spectra library and via fragmentation patterns. Principal component analysis (PCA) was "applied to check the dataset structure and assess the variability of the profiles belonging to groups of autistic vs. non-autistic children". 
• Results: as indicated, 21 metabolites were deemed as "potential marker metabolites" some detected in higher quantities in the autism samples, and some lower. Fourteen of these compounds were described as organic acids. Without hopefully breaking any copyright, I've attached a copy of the table included in the paper with all the compounds differing between autism and control samples. The eagle-eyed will also note the big 'H' - homocysteine - to be a part of that list, and as expected, elevations in urinary homocysteine for the autism group as per other work in this area (see here).
• Given the title of this post I'll point out a few organic acids which seemed to be important differentiators between autism and control samples: (i) levels of beta hydroxybutyric acid were elevated in autism sample. This compounds has been talked about previously on this blog with regards to inborn errors of metabolism and autism (see here). (ii) Hydroxybenzoic acid was again elevated and perhaps ties into other findings from this group [2] potentially indicative of intestinal dysbiosis. (iii) Succinic acid levels were also generally elevated, and as the authors point out: "is considered a potential marker for deficiency of CoQ10 and riboflavin in children with autism". Co-enzyme Q10 y'say? I could go on, but won't.
• Various statistical models (PCA) were applied to the datasets which led authors to find: "The group of samples from non-autistic control children [were] more homogeneous than the group from autistic children". Further: "There is a clear distinction between those two groups of samples". ROC analysis looking at the performance of the PCA models was also applied leading authors to conclude that there may be something in their results from a diagnostic point of view.

Obviously the Kałużna-Czaplińska results are preliminary and in need of further independent replication. I note that quite a bit of the other literature in this area of biomarkers tend to use both training and test sets, where training samples provide your initial compounds of interest and test sets do just that, test your biomarker assumptions (see here). This wasn't the case in the current study but still leaves the door open to independent verification. That also the word 'comorbidity' does not seem to be mentioned as part and parcel of the autism group means the questions of how widespread comorbidity was in the autism participant group and whether this might have exerted an effect on the results obtained are unanswered. I might also quibble about the way that peaks in the TIC were assigned a compound name: "Peaks with the similarity index more than 80% were assigned compound names..." but now I'm just nit-picking.

That all being said, I do see some promise in the results obtained by Kałużna-Czaplińska et al. I note in another paper by some of the authors [3] they talk about how probiotic therapy might impact on both some of the behavioural measures of autism and also levels of one of the compounds picked up in their latest analysis, D-arabinitol. Again, I'd like to see more research done on this, alongside their other suggestion on the use of B vitamins (and magnesium) potentially affecting organic acids in cases of paediatric autism [4] talked about in a previous post (see here). The focus on the inner working of the gut, and particularly the trillions of gut bacteria which call us home, potentially being connected to some of these biomarkers, ties in well with an emerging autism research area (see here).

Music to close, and yet again my brood provide the inspiration as Bob Marley is fast becoming a YouTube favourite in our home with the classic One Love. You know you're getting old when your kids start listening to cooler music than you do...

----------

[1] Kałużna-Czaplińska J. et al. Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. Journal of Chromatography B. 2014. Feb 2.

[2] Kałużna-Czaplińska J. Noninvasive urinary organic acids test to assess biochemical and nutritional individuality in autistic children. Clin Biochem. 2011 Jun;44(8-9):686-91.

[3] Kałużna-Czaplińska J. & Błaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition. 2012 Feb;28(2):124-6.

[4] Kałużna-Czaplińska J. et al. B vitamin supplementation reduces excretion of urinary dicarboxylic acids in autistic children. Nutr Res. 2011 Jul;31(7):497-502.

----------

Kałużna-Czaplińska J, Zurawicz E, Struck W, & Markuszewski M (2014). Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences PMID: 24565890

Joint hypermobility, gait and autism

I have already made mention of the paper by Maya Shetreat-Klein and colleagues [1] on this blog as part of a post on the potential usefulness of kata training for at least some people on the autism spectrum (see here). Based on an analysis of 38 children diagnosed with autism spectrum disorder (ASD) and a similar number of asymptomatic controls (all medication free), researchers set about recording "the characteristics of gait and prevalence of toe walking, the range of passive joint mobility, and age at walking" for their groups. They concluded that: "Children with ASDs had significantly greater joint mobility... more gait abnormalities... and on average walked 1.6 months later than their non-autistic peers". Ergo, much greater research focus should be directed to motor issues in cases of autism.

The cliff walk @ Wikipedia 

A few further details from the study might be useful:

• The analysis of movement such as gait and mobility is a science which I won't even pretend to understand. You get terms like goniometer fulcrum which probably makes a lot of sense to those in the know, but to me just sounds like a character from Game of Thrones. Suffice to say however that various measures were used to ascertain passive joint mobility - that is suppleness - across fingers, wrist, elbow and ankle. Gait was also analysed based on participants being "videotaped while walking and running barefoot up and down a hallway in the physician's office for 1-2 min".
• Results: as a group, participants with autism showed significantly greater values for maximum passive joint mobility angles across nearly all measured joints than controls. Taking one example, finger extension (or should that be 'finger metacarpo-phalangeal joint extension angle'), the authors present the very stark differences in angles obtained in histogram form between ASD and control participants. The majority of those with autism able to extend 110 degrees or over; such a feat only noted in 1 of the control participants. I might direct you to a post I wrote a while back on joint hypermobility (see here) which I'll talk about it moment.
• When it came to gait, the authors observed: "toe-walking was significantly more prevalent in children with autism" than controls (33% vs 3% observed on video only). I've talked about toe walking and autism in a previous post (see here) and what it may or may not mean for autism when present. Several other features of gait were also observed; 33% of children with autism were described as apraxic (an inability to execute learned purposeful movements) and 20% were described as clumsy. Both of these issues were not noted in any of the control group participants.

I found the Shetreat-Klein paper to be quite an intriguing read. Not only for the results obtained but because nestled in the paper introduction was reference to some of the original descriptions of autism by Leo Kanner, and how he "commented on the motor deficits in many of his patients". I've talked previously on this blog about how the seminal 1943 paper from Kanner [2] contained so much more than just descriptions of the triad (now dyad) of behaviours which make up the clinical diagnosis of the condition (see here). Aspects which we have perhaps ignored for too long...

The word 'hypotonia' - roughly translated as decreased or low muscle tone - is also a discussion point in the paper: "Our findings that passive joint mobility is on average increased in autism corroborates other studies that report a significantly increased proportion of clinically hypotonic children among those with ASD". Once again, I can't profess to be able to offer any great insight into this issue aside from some light reading around this concept and other uses in the research texts with autism in mind. Hypotonia seems to crop up quite a bit in various case reports detailing often rare genetic conditions with autism as part of presentation. Take for example the paper by Belengeanu and colleagues [3] reporting on a young child presenting with developmental delay and among other things, hypotonia. The paper by Shuvarikov and colleagues [4] talking about a potential HERV (human endogenous retrovirus) mediated genetic deletion with hypotonic features is another example; HERVs are another favourite talking point on this blog (see here).

That all being said, I'd also like to go back to the previous mention of joint hypermobility. Shetreat-Klein et al do talk about whether the descriptions of hyptonia in cases of ASD, or at least "joints with ligamentous laxity", might suggest "a disorder of elastin or collagen". Collagen issues immediately brought my mind back to the condition called Ehlers-Danlos syndrome (EDS), a heritable disorder of connective tissue. One of the primary features of EDS - accepting that there are various different presentations - is hyper-flexible joints. The literature looking at any overlap between autism and EDS is currently sparse, very sparse. I did happen upon the paper by Takei and colleagues [5] (open-access here) detailing a single case where "autistic disorder and EDS were diagnosed" concurrently. Takei et al describe a family history of EDS and as they note: "We speculate that associations exist between connective tissue diseases and autistic disorders, and that connective tissue abnormalities may contribute to autistic symptoms". I do wonder whether this might be an area requiring a little more scientific inspection.

The take home message from this post is that joint mobility and gait issues do seem to be quite apparent across the autism spectrum. Alongside other research in this area, one might start asking further questions about the hows and whys of such findings and whether it may offer further insight into some of the underlying issues potentially associated with at least some of the autisms?

To close, football (soccer). Now knowing that Germany are the 2014 World Cup Champions and this is the first lifting of the Jules Rimet trophy in a reunified Germany, I'm sure David Hasselhoff might have something to say...

----------

[1] Shetreat-Klein M. et al. Abnormalities of joint mobility and gait in children with autism spectrum disorders. Brain Dev. 2014 Feb;36(2):91-6.

[2] Kanner L. Autistic disturbances of affective contact. Nervous Child. 1943; 2: 217-250.

[3] Belengeanu V. et al. A de novo 2.3 Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl. Gene. 2014 Apr 10;539(1):168-72.

[4] Shuvarikov A. et al. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays. Hum Mutat. 2013 Oct;34(10):1415-23.

[5] Takei A. et al. High-functioning autistic disorder with Ehlers-Danlos syndrome. Psychiatry Clin Neurosci. 2011 Oct;65(6):605-6.

----------

Shetreat-Klein M, Shinnar S, & Rapin I (2014). Abnormalities of joint mobility and gait in children with autism spectrum disorders. Brain & development, 36 (2), 91-6 PMID: 22401670

Organic food: meta-analysed

A very quick post to direct you to the paper by Barański and colleagues [1] which is currently making a few headlines and sparking some debate (see here and see here) with their assertions: "the concentrations of a range of antioxidants such as polyphenolics were found to be substantially higher in organic crops/crop-based foods" and "the frequency of occurrence of pesticide residues was found to be four times higher in conventional crops, which also contained significantly higher concentrations of the toxic metal Cd [cadmium]".

Lead by researchers based at Nafferton Farm affiliated to Newcastle University, the literature review and meta-analysis looked at over 300 studies looking at "the composition of crops and foods". According to the BBC website, Carlo Leifert who headed the review said: "This study demonstrates that choosing food produced according to organic standards can lead to increased intake of nutritionally desirable antioxidants and reduced exposure to toxic heavy metals".

I've had the pleasure of visiting Nafferton Farm once or twice and chatting to Carlo and his team about some of the work going on. It is a lovely part of the world and some great science is being done and reported in the peer-reviewed press [2]. Appreciating that there are still some significant gaps in the science about organic vs. conventional farming methods and their impact on food in terms of yields and nutritional quality, I do think that this latest (and largest) review is something which should not be ignored...

-----------

[1] Barański M. et al. Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses. Br J Nutr. 2014 Jun 26:1-18.

[2] Stergiadis S. et al. Improving the fatty acid profile of winter milk from housed cows with contrasting feeding regimes by oilseed supplementation. Food Chem. 2014 Dec 1;164:293-300.

----------

Barański M, Srednicka-Tober D, Volakakis N, Seal C, Sanderson R, Stewart GB, Benbrook C, Biavati B, Markellou E, Giotis C, Gromadzka-Ostrowska J, Rembiałkowska E, Skwarło-Sońta K, Tahvonen R, Janovská D, Niggli U, Nicot P, & Leifert C (2014). Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses. The British journal of nutrition, 1-18 PMID: 24968103

Maternal C-Reactive Protein (CRP) and offspring schizophrenia

A big quote to start this post: "This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implications for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders".

Ophelia @ Wikipedia 

The source for this quote was the paper by Sarah Canetta and colleagues [1] based on an analysis of serum samples from mums for C-reactive protein (CRP) as part of the Finnish Prenatal Study of Schizophrenia cohort under the leadership (well, grant holding) of Prof. Alan Brown. Some media interest in this paper can be seen here.

Regular readers of this blog might have heard me talk about some of Prof. Brown's previous research, again with CRP in mind but with an autism research slant (see here). I'll come back to some of that work shortly alongside some more recent research [2] in that area.

In this latest paper, archived maternal serum samples related to nearly 800 people (offspring) diagnosed with schizophrenia or schizo-affective disorder were assayed for CRP and results compared with maternal CRP levels related to a similarly sized asymptomatic control group. "Increasing maternal C-reactive protein levels, classified as a continuous variable, were significantly associated with schizophrenia in offspring (adjusted odds ratio=1.31, 95% confidence interval=1.10-1.56)". Even after controlling for confounders including a parental "history of psychiatric disorders" results remained significant. Ergo, one marker of inflammation present and elevated in spot sera samples of mums may have some implications for subsequent development of offspring.

Having recently heard the sad news about the death of Paul Patterson (see his obituary here) my first thoughts turned to his valuable contributions to this area and the proposed maternal immune activation hypothesis of schizophrenia and autism [3] (open-access here). You'll note that Prof. Brown was the co-author on that last citation with Prof. Patterson, giving you a feel for how such research connections might fit together.

My second thought was slightly more of a critical one with the realisation that CRP whilst a good marker of the acute-phase response linked to inflammation [4] may not necessarily present the whole picture when measured in a spot sample fashion or without reference to the multitude of other compounds reactive to an inflammatory status. Think cytokines for example (see here). I note also in the latest paper that maternal levels of CRP were the focus, and not specifically CRP levels in offspring with and without a diagnosis of schizophrenia. It would be interesting to see how the two measurements might correlate (or not). That being said, and as I've reported before, there is quite a body of evidence suggestive of on-going issues with CRP in at least a proportion of people on the schizophrenia spectrum. Inflammation and psychiatry seem to have some common ground (see here).

Going back to the CRP work with autism in mind, I do think there is a pattern emerging from the available peer-reviewed evidence suggestive that inflammation (excess inflammation or elevated markers of inflammation?) during critical periods of pregnancy might have some connection with later offspring outcomes. The processes potentially relevant to any association are still the source of some speculation, as are the various ways that inflammation might come about: air pollution (see here), maternal obesity (see here), etc. Take yer pick, accepting that genetics and/or epigenetics are probably also going to play a role. What remains to be seen is how the idea of mitigating inflammation - however one goes about doing this - during those critical periods of pregnancy may impact on offspring risk of developmental or psychiatric outcomes. Indeed, as the paper from Patterson and Brown [3] concluded: "It has been suggested that the overall decline in bacterial illnesses due to antibiotic therapy and the initiation of immunization programs may be at least partially responsible for the reduction in the incidence of schizophrenia in certain countries in the last several decades". Does this mean such strategies have already impacted on some of the prevalence figures?

----------

[1] Canetta S. et al. Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort. Am J Psychiatry. 2014 Jun 27. doi: 10.1176/appi.ajp.2014.13121579.

[2] Brown AS. et al. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014 Feb;19(2):259-64.

[3] Brown AS. & Patterson PH. Maternal infection and schizophrenia: implications for prevention. Schizophr Bull. 2011 Mar;37(2):284-90.

----------

Canetta, S., Sourander, A., Surcel, H., Hinkka-Yli-Salomäki, S., Leiviskä, J., Kellendonk, C., McKeague, I., & Brown, A. (2014). Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort American Journal of Psychiatry DOI: 10.1176/appi.ajp.2014.13121579

Viral exposure and autism

A whole slew of articles published by Ivan Gentile and colleagues based at the University of Naples (Italy) brought me to writing this post looking at some of the literature on viral exposures and autism. Viruses, in case you didn't know, are some of nature's survivors, infecting host cells and reproducing, onwards hopeful of finding more (un)willing cells/organisms to infect. Humankind have developed various biological defence mechanisms against the viral (and bacterial) onslaught that we all face as part of daily life, part of which is the production of antibodies. Antibodies are all about identification, action and memory and form the basis for why we vaccinate against various disease causing viruses. Sometimes antibodies also take part in a process called neutralisation which is all about rendering a virus ineffective when it comes to infectivity.

A founder of virology @ Wikipedia 

I've talked previously on this blog about viruses and their possible connection to some cases of autism (see here for example). I've also discussed how traces of the viruses of yesteryear (many, many yesteryears) can still be found in our genome and how such fossil viruses may, in some cases, still impact on our health and wellbeing (see here and see here). But enough of all this idle chatter...

The specific papers under discussion today include:

• Prevalence and Titre of Antibodies to Cytomegalovirus and Epstein-Barr Virus in Patients with Autism Spectrum Disorder [1]
• Exposure to Varicella Zoster Virus Is Higher in Children with Autism Spectrum Disorder than in Healthy Controls. Results from a Case-control Study [2]
• Prevalence of Herpes Simplex Virus 1 and 2 Antibodies in Patients with Autism Spectrum Disorders [3]

Let's call them paper 1, paper 2 and paper 3 respectively for convenience.

All were published in the journal In Vivo and follow some history looking at viral infections and autism by this research group [4] including those most contentious of viral infections when it comes to autism: measles, mumps and rubella [5]. I might also add that some speculations from this group looking at linking genetic predisposition, vitamin D deficiency and infection potentially correlating with a "a deranged immune response" with some autism in mind [6] might not be as outlandish as once thought. Indeed, that review paper [6] is probably one of the best I've read in a long time drawing on the available data on immune function and autism bearing in mind the emerging vitamin D story (see here).

Anyhow:

• Papers 1-3 all relied on the same participant groups, that is: 54 children diagnosed with an autism spectrum disorder (ASD) and 46 asymptomatic controls. 
• Exposure (seropositivity) rates and antibody titer levels to Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) (paper 1), Varicella Zoster Virus (VZV) (paper 2) and Herpes Simplex Virus 1 (HSV1) and Herpes Simplex Virus 2 (HSV2) (paper 3) were measured and compared between groups.
• Paper 3 detailing the findings on HSV1 and HSV2 concluded: "Seropositivity rate and levels of anti-HSV1/2 were not dissimilar between cases and controls". In other words, nothing to see there in this cohort.
• Paper 1 looking at CMV and EBV came to a similar conclusion as that of paper 3, although the authors note: "considering only patients with ASD, those seropositive for CMV tended to test worse to the major severity scales than the seronegative ones". With my recent interest in CMV and autism (see here), I'm intrigued...
• Paper 2 provides something of a more 'positive' result with it's analysis of VZV, the virus linked to chickenpox and shingles, in connection to the autism grouping. Authors concluded: "The exposure rate and titer of anti-VZV antibodies were significantly higher in children with ASD compared to controls (59% vs. 39% and 694 mIU/ml vs. 94 mIU/ml, respectively)". Further: "exposure to VZV was found to be independently associated with ASD".

We do have to be a little bit careful when it comes to these studies on the basis of their small participant numbers and the applicability of results to other groups whether in age or geography. As per some previous chatter about the other Gentile paper on MMR antibodies and autism (see here) not every study agreed with their findings [7]. Likewise, these latest results say nothing about 'causation' in terms of autistic presentation outside what is already suspected with something like CMV and autism in mind [8]. Correlation is not the same as causation, as if you needed telling.

That all being said I do think there is more to do in this area. There is some research history when it comes viral infection and autism as per the review by Libbey and colleagues [9] and in amongst that literature is mention of varicella [10] including "cases of autism associated with postnatal varicella encephalitis" [11]. The quite stark disparity in mean antibody titers to VZV between autism and control groups suggests that something might be afoot outside of just some healthy immunity to something like chicken pox.

----------

[1] Gentile I. et al. Prevalence and Titre of Antibodies to Cytomegalovirus and Epstein-Barr Virus in Patients with Autism Spectrum Disorder. In Vivo. 2014 07-08;28(4):621-626.

[2] Gentile I. et al. Exposure to Varicella Zoster Virus Is Higher in Children with Autism Spectrum Disorder than in Healthy Controls. Results from a Case-control Study.  In Vivo. 2014 07-08;28(4):627-631.

[3] Gentile I. et al. Prevalence of Herpes Simplex Virus 1 and 2 Antibodies in Patients with Autism Spectrum Disorders. In Vivo. 2014 07-08;28(4):667-671.

[4] Gentile I. et al. Prevalence of HHV-6 and HHV-8 antibodies in patients with autism spectrum disorders. In Vivo. 2013 Nov-Dec;27(6):843-9.

[5] Gentile I. et al. Response to measles-mumps-rubella vaccine in children with autism spectrum disorders. In Vivo. 2013 May-Jun;27(3):377-82.

[6] Gentile I. et al. Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together. Med Hypotheses. 2013 Jul;81(1):26-35.

[7] Singh VK. et al. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci. 2002 Jul-Aug;9(4):359-64.

[8] Sakamoto A. et al. Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. Brain Dev. 2014 Apr 22. pii: S0387-7604(14)00094-1.

[9] Libbey JE. et al. Autistic disorder and viral infections. J Neurovirol. 2005 Feb;11(1):1-10.

[10] Deykin EY. & MacMahon B. Viral exposure and autism. Am J Epidemiol. 1979 Jun;109(6):628-38

[11] Knobloch H. & Pasamanick B. Some etiologic and prognostic factors in early infantile autism and psychosis. Pediatrics. 1975 Feb;55(2):182-91.

----------

Gentile I, Zappulo E, Bonavolta R, Maresca R, Messana T, Buonomo AR, Portella G, Sorrentino R, Settimi A, Pascotto A, Borgia G, & Bravaccio C (2014). Prevalence and Titre of Antibodies to Cytomegalovirus and Epstein-Barr Virus in Patients with Autism Spectrum Disorder. In vivo (Athens, Greece), 28 (4), 621-626 PMID: 24982232


Gentile I, Zappulo E, Bonavolta R, Maresca R, Riccio MP, Buonomo AR, Portella G, Settimi A, Pascotto A, Borgia G, & Bravaccio C (2014). Exposure to Varicella Zoster Virus Is Higher in Children with Autism Spectrum Disorder than in Healthy Controls. Results from a Case-control Study. In vivo (Athens, Greece), 28 (4), 627-631 PMID: 24982233


Gentile I, Zappulo E, Bonavolta R, Maresca R, Riccio MP, Buonomo AR, Portella G, Vallefuoco L, Settimi A, Pascotto A, Borgia G, & Bravaccio C (2014). Prevalence of Herpes Simplex Virus 1 and 2 Antibodies in Patients with Autism Spectrum Disorders. In vivo (Athens, Greece), 28 (4), 667-671 PMID: 24982239