T. gondii infection might be "a contributing causal factor for schizophrenia"

T. gondii mentioned in the title of this post refers to Toxoplasma gondii, a parasite with something of a rather interesting profile and history (see here and see here). I've talked quite a bit on this blog about T. gondii and it's various 'associations', but of particular interest has been the suggestion of a 'connection' between T. gondii exposure and risk of psychiatric diagnoses like schizophrenia (see here).

The findings reported by Kristoffer Sølvsten Burgdorf and colleagues [1] (open-access available here) add further evidence to such a 'psychiatric' connection with their conclusion that: "exposure to T. gondii might be a contributing causal factor for developing schizophrenia." Researchers arrived at their conclusion following the examination of an intriguing initiative called the Danish Blood Donor Study (DBDS). Started in 2010, the DBDS includes records for over 100,000 patients and "contains DNA and EDTA plasma samples, consecutive for all donors returning for blood donation after enrolment." That's a lot of data. So: authors "identified all individuals in the DBDS cohort registered with psychiatric disorders, suicidal behavior, or traffic accidents (N=5,953)." Said participants were matched with 'suitable' controls (N=7,101) and stored samples were analysed for "immunoglobulin (IgG) class antibodies against T. gondii and CMV." CMV by the way, refers to cytomegalovirus. Contact with (congenital) CMV has also been talked about on this blog (see here). CMV (exposure) also shares a potential *link*  with "psychiatric disorders, cognitive deficits, suicidal behavior, and traffic accidents."

Results: "Of the 11,546 studied individuals, 2,990 and 7,020 individuals, respectively, tested positive for IgG class antibodies against T. gondii (25·9%) or CMV (60·8%)." Onward: "We found that individuals with a T. gondii infection had increased odds of being diagnosed with schizophrenia disorders compared to those without infection." Because researchers were also able to access other national databases containing details on outcomes like diagnosis of a psychiatric disorder and 'attempting suicide' and cross-reference them with their participants, they were also able to look at "temporality, with pathogen exposure preceding outcome" as a factor. And when they did, that T. gondii exposure - schizophrenia association was described as "even stronger." The other data on T. gondii or CMV exposure in relation to traffic accidents or suicide attempts was not as statistically strong, and indeed nothing showed significance when temporality was taken into consideration in relation to causation. On that basis, I'm gonna leave that part of the results without further comment.

This was a good study. It drew on data from a well-defined group (those Scandinavian databases 'do it' yet again) and was able to take into account the important issue of temporality. It wasn't a perfect study - "We cannot rule out that socio-economic factors could potentially account for part or all of the observed causal effect" - and said nothing about possible mechanism(s) of effect however. That being said, I'm willing to go along with the conclusions made and the need for a lot more investigation in this area linking T. gondii exposure and subsequent risk of mental illness. In particular whether new or existing treatment methods for T. gondii *might* hold the promise of much more...

And whilst on the topic of T.gondii and the specific input from cats on the spread of T. gondii (see here and see here), I'll state here and now that I am not a great believer in the idea of 'cat eradication' as mentioned by some researchers recently [2]. That being said, a toxoplasmosis vaccines for cats (see here) sounds like a really good idea...

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[1] Sølvsten Burgdorf K. et al. Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders. Brain Behav Immun. 2019 Jan 24. pii: S0889-1591(18)30699-8.

[2] de Wit LA. et al. Potential public health benefits from cat eradications on islands. PLoS Negl Trop Dis 13(2): e0007040

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Borna disease virus antibodies and autism: baseline data setting the scene

The findings reported by Tomoyuki Honda and colleagues [1] setting out a baseline prevalence rate of antibodies against bornavirus in children diagnosed with an autism spectrum disorder (ASD) provides the blogging fodder today. Whilst the Honda findings might not exactly sound like 'exciting science' I would perhaps beg to differ...

Although no expert on Borna disease or Borna disease virus (BDV), I am an interested amateur. Borna disease was named after the town of Borna in Germany, where a fatal neurological (encephalitic) disease affected certain livestock including sheep, cattle and horses. The causative agent was found to be BDV. As well as being characterised by a "meningoencephalomyelitis" state, the symptoms of Borna disease also stretch to certain behaviours. This includes stereotypical behaviours (animals travelling in circular movements or standing in peculiar positions and poses) as well as ataxia affecting coordination and balance. Presentation in some animals has led to the name 'Staggering disease' being used.

Although predominantly seen as a disease affecting animals and livestock, there has been a gradual shift towards the idea that Borna disease virus can also infect humans too. Quite a lot of scientific resources have, for example, concluded that BDV might show an important connection to human psychiatric diagnoses/conditions such as schizophrenia [2]. This, on the basis of serological evidence for recent or continued viral exposure. Following on from a previous case report from Honda and colleagues [3] describing antibodies against BDV in a child with autism and her mother, the authors seem to have developed an interest in all-things BDV and autism. There has also been discussion about a BDV rodent model of autism from other research groups [4] including from the now [sadly] non-functioning research tag-team that was Hornig and Lipkin [5].

On this latest research occasion, Honda et al observed a few things. First: "The prevalence of antibodies against bornavirus-specific speckles, N, and P proteins were 22%, 48%, and 33%, respectively, in the ASD children." For discussions on 'Bornavirus-specific speckles, N, and P proteins' I'll refer you to some other work including Honda on the authorship title [6] on the viral nitty-gritty details. Second: "According to our criteria, the prevalence of antibodies against bornaviruses was 7.4% in the ASD children." Bearing in mind a dearth of investigations on the estimated prevalence of Borna virus more generally, particularly in children, and the various ways and means that immunological contact with the virus can be assayed by, that percentage did seem quite high. Other work [6] for example, has talked about a figure of 2% 'exposure' rate in non-clinical populations. I suppose the 'baseline data' from Honda is trying to make in-roads into this prevalence issue.

Obviously, there's a way to go yet on this topic before any sweeping generalisations are made. The impact of viral infection/illness in relation to [some] autism has quite a long peer-reviewed research history; be that the effect of congenital cytomegalovirus (CMV) (see here) or the work looking at rubella and autism (see here) for examples. The more contemporary research base examining various encephalitis conditions also presenting as autism or autistic-like disorder(s) (see here and see here) is also important. With regards to any specific possible connection between Borna disease virus and autism, future work needs to establish lots of things (infection route, exposure characteristics, etc.). We also need to know whether behavioural symptoms/traits are actually 'caused' by such viral exposure or perhaps more generally linked to immune responses as per the whole 'immune system does more than just fight infection' bit. If a link is shown beyond reasonable doubt, there could be some real scientific advances possibilities on the back of what is already emerging [7]. But at the moment, it's still 'a big if'...

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[1] Honda T. et al. Prevalence of antibodies against Borna disease virus proteins in Japanese children with autism spectrum disorder. Microbiol Immunol. 2018 May 22.

[2] Azami M. et al. The association between Borna Disease Virus and schizophrenia: A systematic review and meta-analysis. Asian J Psychiatr. 2018 Apr;34:67-73.

[3] Honda T. et al. Detection of Antibodies against Borna Disease Virus Proteins in an Autistic Child and Her Mother. Jpn J Infect Dis. 2017;70(5):599.

[4] Pletnikov MV. et al. Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virus-infected Lewis rats: a model of autism. Behav Brain Res. 1999 Apr;100(1-2):43-50.

[5] Hornig M. et al. An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12102-7.

[6] Matsumoto Y. et al. Bornavirus Closely Associates and Segregates with Host Chromosomes to Ensure Persistent Intranuclear Infection. Cell Host & Microbe. 2012; 11: 492-503.

[7] Honda T. et al. Neuropathogenesis of persistent infection with Borna disease virus. Uirusu. 2015;65(1):145-54.

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"results suggest that maternal CMV infections may influence ASD symptoms"

CMV infections mentioned in the title of this post - "results suggest that maternal CMV infections may influence ASD [autism spectrum disorder] symptoms" - refers to cytomegalovirus, a beta-herpes virus, that infects quite a percentage of the population, but is typically kept in check by a healthy immune system.

Although not usually a 'problem-causer', CMV infection under certain circumstances can have various unwanted adverse effects. One such circumstance is that of congenital CMV infection, where some infants acquire CMV during the nine months that makes us, and in some cases, it leads to an array of adverse physical and developmental outcomes. You probably won't be surprised to hear that congenital CMV infection has also been *linked* to some instances of autism (see here) and indeed, on more than one peer-reviewed research occasion (see here).

The findings reported by Brooke Slawinski and colleagues [1] add to this important area of autism science with their suggestion of a potentially important *correlation* between the presence of CMV infection and scores on one of the premier autism assessment tool, the Social Responsiveness Scale version 2 (SRS-2).

Authors looked for "CMV IgG and HSV2 [herpes simplex virus 2] IgG in serum from the mothers of 82 children whose ASD symptoms were assessed at 3-6 years of age using the Social Responsiveness Scale version 2 (SRS-2)." The presence of IgG antibodies typically indicates past and/or recent exposure to a pathogen (in this case, CMV) with results expressed as seropositivity or seronegativity. Authors observed that those children whose mothers were seropositive for CMV IgG antibodies scored marginally higher on the SRS than those who were seronegative for CMV IgG antibodies. They did not find a similar relationship / correlation when looking at past / recent exposure to HSV2. Ergo, children *potentially exposed* to CMV infection during pregnancy showed a more severe autism presentation than those that weren't, at least in relation to the SRS measured social aspects of autism.

Of course you can see the issues with this work as it stands. Two variables (albeit "robust to several statistical adjustments") have been brought together and a possible 'connection' made. Not for the first time I might add, where one needs to be slightly cautious about making too much of any relationship given the wide array of potentially influencing variables / confounders. There is also an inference in the Slawinski work that a positive results means that maternal CMV infection during pregnancy was present and that "prenatal exposure to maternal infections" plays a role with [some] autism in mind. That is of course, if you assume that infections post-pregnancy might not also play a role in some autism (see here for example)...

The authors sensibly announce that their findings are "being further evaluated in ongoing prospective studies with larger population samples" so there should be more to see on this topic. For now however, I think it's important to stay mindful of the fact that exposure to various infective agents - viral, bacterial and otherwise - seem very much able to influence both physiology and behaviour in a wide variety of contexts including autism. Oh, and response to infection *might* also play a role in behaviour too (see here).

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[1] Slawinski BL. et al. Maternal cytomegalovirus sero-positivity and autism symptoms in children. Am J Reprod Immunol. 2018 Mar 9.

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Congenital cytomegalovirus (CMV) infection and autism continued and meta-analysed

The findings - based on systematic review and meta-analysis - reported by Kaori Maeyama and colleagues [1] make for important reading on the topic of an "association of congenital cytomegalovirus (CMV) infection with autism spectral disorder (ASD)." CMV by the way, is a herpesvirus that can be potentially transmitted during pregnancy from mother to developing child and can, in some instances, lead to various adverse developmental and neurodevelopmental outcomes.

I've talked about CMV and autism a few times already on this blog (see here and see here) including the idea that, outside of any possible *link* with some autism, there may [eventually] be ways and means of protecting against some of the adverse effects of such viral exposure during such a critical period (see here) (with lots more research required).

Maeyama et al concluded that a "high prevalence of congenital CMV infection in ASD cases (OR 11.31, 95% CI 3.07-41.66) was indicated" on the basis of their analysis of the collected research literature published so far. They caution however, that quite a bit more research is required. Not least on how much of a contribution CMV infection might make to the very broad autism spectrum.

As I've said before on this topic, the data so far produced suggest that 'CMV-related autism' (if I can call it that) is likely to be quite a rare occurrence but we don't know for sure. Part of that stems from the fact that I don't think CMV is routinely screened for during pregnancy (at least here in Blighty) and I'm pretty sure that most autism assessments/diagnostic procedures probably won't also ask about or include a screen for CMV exposure either. It's therefore highly likely that we don't yet know the true extent to which CMV infection may/may not be linked to autism.

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[1] Maeyama K. et al. Congenital Cytomegalovirus Infection in Children with Autism Spectrum Disorder: Systematic Review and Meta-Analysis. J Autism Dev Disord. 2017 Nov 28.

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On preventing the deleterious effects of CMV: implications for some autism?

"Anxiety drug may prevent common virus that causes birth defects" went one of the headlines covering the study results published by Sara Ornaghi and colleagues [1].

Continuing a research theme from this group (see here) on how use of some mood stabilising medicines at critical periods might have some important impact on the deleterious effects of cytomegalovirus (CMV) infection, there is quiet optimism that this new research could have big implications for a range of different labels including some autism (see here).

So: "Valnoctamide (VCD), a neuroactive mood stabilizer with no known teratogenic activity, was recently demonstrated to have anti-CMV potential" was the starting premise for the Ornaghi study. Using mouse models - that's MOUSE models - of CMV infection and whether the anti-CMV potential of VCD could be "translated into an efficacious therapeutic effect to improve CMV-induced adverse neurological outcomes", researchers first looked at survival rates when injected 'low-dose' VCD was used. They reported that compared with those receiving a control substance (not VCD), the mice in receipt of VCD were more likely to survive. As per the media chatter about this study: "They lived longer, their body weight was greater – everything about them looked better" on the basis that congenital CMV infection can, in some cases, prove fatal.

Researchers also assessed whether various 'adverse neurological outcomes' associated with congenital CMV infection might be potentially offset by the use of VCD. They observed that: "VCD during the first 3 weeks of life restored timely acquisition of neurological milestones in neonatal male and female mice and rescued long-term motor and behavioral outcomes in juvenile male mice."

Then to the possible mechanism of effect, and based on the use of "CMV-infected human fetal astrocytes" they observed that "VCD reduced both viral infectivity and replication by blocking viral particle attachment to the cell." In other words, VCD, a medicine typically indicated as a sedative, seemed to possess some quite potent activity in relation to how CMV takes hold in important cells in the brain.

I've already mentioned about how at least some cases of autism might benefit from this work. I say this on the basis that there is a robust evidence base suggesting that congenital CMV infection could very well result in autism (see here). There is a need for quite a bit more investigation in this area in terms of translating mouse findings into human findings (see here) but the promises of this area of work are not to be under-estimated...

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[1] Ornaghi S. et al. Valnoctamide inhibits cytomegalovirus infection in developing brain and attenuates neurobehavioral dysfunctions and brain abnormalities. J Neurosci. 2017. June 19.

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Congenital cytomegalovirus (CMV) infection and autism continued

I wanted to briefly talk about the paper by Francesca Garofoli and colleagues [1] on congenital cytomegalovirus (CMV) infection and autism not because it contains any novel data (see here), but because it reminds us that the potential 'pathways' to a diagnosis of autism are multiple and not necessarily 'pre-programmed' as per the 'it's all genetic' arguments that frequently figure in various domains.

Congenital CMV infection refers to the transmission of CMV - "a common virus that belongs to the herpes family of viruses" - from mother to foetus during pregnancy. The details are still under investigation as to how and why CMV affects a foetus (bearing in mind this is quite a common virus) but autism as a consequence of [some] congenital CMV infection has growing evidence-based support [2].

Garofoli et al included 70 'proven' cases of CMV "congenitally-infected infants" in their study; specifically looking "to correlate congenital cytomegalovirus (CMV) infection with autism spectrum disorder (ASD) and to define its prevalence." They determined that 2 of their 70 strong cohort met criteria for an ASD at the age of 3 years. Two of 70 translated as 2.8% of their cohort and contrasts with [estimated] autism prevalence "in general Italian population (0.66-1.36%)." The figure of 2.8% is also not a million miles away from other estimates of autism suggested via congenital CMV infection [3].

Although 2.8% of the cohort (2/70) might not sound like a lot I'm inclined to suggest that it does prompt quite a lot more additional investigation. Not least is the question: 'why was autism/ASD not diagnosed in the other 68 children?' and onward whether other factors (genetics(!), biology, infection timing, immunologic response, etc) might come into play [4] in relation to the congenital CMV infection - autism association? Taking also into account the estimated prevalence of ASD in Italy, these figures (estimates) do seem to be a little lower than that described in other geographical locations (see here and see here for examples). Indeed, bearing in mind the research evidence already looking at estimated ASD prevalence in Italy [5] it's not unfair to say that 'under-estimation' might be a familiar theme...

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[1] Garofoli F. et al. An Italian Prospective Experience on the Association Between Congenital Cytomegalovirus Infection and Autistic Spectrum Disorder. J Autism Dev Disord. 2017 Mar 3.

[2] Ornoy A. et al. Prenatal factors associated with autism spectrum disorder (ASD). Reprod Toxicol. 2015 Aug 15;56:155-69.

[3] Engman ML. et al. Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta Paediatr. 2015 Aug;104(8):792-5.

[4] Lombardo MV. et al. Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol. Psychiatr. 2017. March 21.

[5] Ferrante M. et al. Prevalence and age at diagnosis of Autism Spectrum Disorder in south Italy, 2004–2014. Eur J Public Health. 2015; 25 (suppl_3).

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Garofoli F, Lombardi G, Orcesi S, Pisoni C, Mazzucchelli I, Angelini M, Balottin U, & Stronati M (2017). An Italian Prospective Experience on the Association Between Congenital Cytomegalovirus Infection and Autistic Spectrum Disorder. Journal of autism and developmental disorders PMID: 28258350

HSV-2 gestational infection and offspring autism risk

"In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy."

That was the conclusion reached in the paper published by Milada Mahic and colleagues [1] including the research tag-team that is Mady Hornig and Ian 'virus hunter' Lipkin in the list of contributing authors. Having already received some media attention (see here), it doesn't need much more from me but I do want to include a few details and relevant points in this blog entry.

So, the Autism Birth Cohort was the starting point, and "442 mothers of children with ASD... and 464 frequency-matched controls" who all provided plasma samples "(903 samples acquired at midpregnancy and 878 acquired after delivery)." Said samples were analysed for IgG antibodies to ToRCH agents: "Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), and herpes simplex viruses 1 (HSV-1) and 2 (HSV-2)." Some of those viruses and parasites have previously been mentioned with [some] autism in mind (see here and see here and see here).

Results: well, an important detail first: "Because rubella vaccination is part of the routine child vaccination schedule in Norway, almost all individuals had IgG antibodies to rubella virus." Indeed, other authors have speculated that rubella vaccination has actually "prevented substantial numbers" of autism as a knock-on effect of reducing the numbers of cases of congenital rubella syndrome [2]. Vaccination doing more than just saving lives eh?

Next: "Our data suggest that the presence of high levels of anti-HSV-2 antibodies at midpregnancy increases the risk of ASD [autism spectrum disorder] in boys." The authors complemented this finding by some rather neat statistical wizardry whereby odds ratios were calculated based on "four different anti-HSV-2 reference levels (60, 120, 180, and 240 arbitrary units [AU]/ml)." Having said that: "High levels of antibodies, which are typically indicative of recent infection, were found in only a small number of subjects." They also reported "no statistically significant association with risk was found with high levels of HSV-2 antibodies at delivery" and saw nothing significant when it came to the other infections examined. These important points have been picked up in the NHS Choices entry on this study (see here).

These are interesting findings and, as far as I can see, represent something quite novel to the quite vast autism research landscape (assuming you count maternal HSV-2 levels and not antibody levels in actual people diagnosed with autism). The reliance on data from an initiative like the Autism Birth Cohort ensured some rigour in terms of the diagnosis of autism [3] and with the reputations following Drs Hornig and Lipkin, one would have to be pretty brave to question their virus-hunting credentials also with autism in mind [4].

Then to the million-dollar question: how might elevated HSV-2 antibodies during pregnancy affect offspring risk of autism? There is a familiar theme offered by the authors to this question as per statements like: "ASD risk associated with high levels of antibodies to HSV-2 is not specific to HSV-2 but instead reflects the impact of immune activation and inflammation on a vulnerable developing nervous system." I know some people still have a bit of a problem with the idea that something like maternal immune activation (MIA) might up the risk for various offspring outcomes [hint: if an article contains the word 'truth' in the title, step away] but please, stop with the 'it can never happen' generalisations and instead look to the existing peer-reviewed evidence on the topic [5]. Yes, science needs to do more on the topic of MIA and autism but clues are emerging all the time...

Oh, and I'll be coming to research talking about another member of the herpesviruses in relation to autism quite soon on this blog.

To close, operation hardtack and other videos (best viewed in full-screen mode).

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[1] Mahic M. et al. Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere. 2017. Feb 22.

[2] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination - United States, 2001-2010. BMC Public Health. 2011; 11: 340.

[3] Stoltenberg C. et al. The Autism Birth Cohort (ABC): A Paradigm For Gene-Environment-Timing Research. Molecular Psychiatry. 2010;15(7):676-680.

[4] Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS One. 2008 Sep 4;3(9):e3140.

[5] Careaga M. et al.  Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol Psychiatry. 2017 Mar 1;81(5):391-401.

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Milada Mahic, Siri Mjaaland, Hege Marie Bøvelstad, Nina Gunnes, Ezra Susser, Michaeline Bresnahan, Anne-Siri Øyen, Bruce Levin, Xiaoyu Che, Deborah Hirtz, Ted Reichborn-Kjennerud, Synnve Schjølberg, Christine Roth, Per Magnus, Camilla Stoltenberg, Pål Surén, Mady Hornig, & W. Ian Lipkin (2017). Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere : 10.1128/mSphere.00016-17

Consider congenital cytomegalovirus infection when it comes to autism

"The finding lends some further support for congenital CMV [cytomegalovirus] being one of the many aetiologies underlying autism spectrum disorder with intellectual disability."

That was the conclusion reached by Mona-Lisa Engman and colleagues [1] from Sweden following their study looking to "evaluate the prevalence of congenital cytomegalovirus infection (CMV) in a representative sample of children with autism spectrum disorder." Carrying some rather distinguished company as part of the authorship list (see here and see here for example), researchers analysed that most important (and under-rated in my opinion) of resources, the newborn dried blood spot (see here), to screen for "CMV DNA using TaqMan-polymerase chain reaction."

"One of the 33 children with autism spectrum disorder and intellectual disability - 3% of that group - had congenital CMV infection." Allowing for the small group included for study and the isolated case of congenital CMV infection detected, the corresponding general population estimate for congenital CMV in Sweden (0.2%) was surpassed leading to the call for "similar studies with much larger samples."

I've talked about congenital CMV infection and autism before on this blog (see here) and how some studies [2] have talked about infection rates quite a bit in excess of that seen in the general population when examining children diagnosed with autism. I've got little more to say on this topic aside from the idea that screening for congenital CMV should perhaps be expanded as and when autism is diagnosed. As per other research from Engman [3] congenital CMV might also carry some specific morphological changes to the brain which could also be included for further inspection, particularly in light of the findings from Erbetta and colleagues [4] covered in a recent post (see here).

And then to mechanisms of effect...

Music: Kate Bush and Army Dreamers. And if you're really interested (as I was), The Kate Bush Story: Running Up That Hill.

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[1] Engman ML. et al. Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta Paediatr. 2015 Apr 21.

[2] Sakamoto A. et al. Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. Brain Dev. 2015 Feb;37(2):200-5.

[3] Engman ML. et al. Congenital cytomegalovirus infection: the impact of cerebral cortical malformations. Acta Paediatr. 2010 Sep;99(9):1344-9.

[4] Erbetta A. et al. Low-Functioning Autism and Nonsyndromic Intellectual Disability: Magnetic Resonance Imaging (MRI) Findings. J Child Neurol. 2015 Apr 20.

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Engman ML, Sundin M, Miniscalco C, Westerlund J, Lewensohn-Fuchs I, Gillberg C, & Fernell E (2015). Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta paediatrica (Oslo, Norway : 1992) PMID: 25900322

Magnetic Resonance Imaging (MRI) findings in severe autism

"The aim of this study was to evaluate the frequency of neuroradiologic abnormalities in low-functioning autistic children compared to Intellectual Quotient and age-matched nonsyndromic children, using the same set of magnetic resonance imaging (MRI) sequences."

Accepting that the term 'low-functioning autism' is not one that I would personally use (indeed I'm not exactly enamoured by the term 'high-functioning' either), the results of the study by Alessandra Erbetta and colleagues [1] are briefly served up for your reading delight today. Mirroring other findings from this group [2], authors reported that: "MRI was rated as abnormal in 44% of autistic and 54% of children with intellectual disability" surveyed. Further: "The main results were mega cisterna magna in autism and hypoplastic corpus callosum in intellectual disability."

I'm not a 'brain man' insofar as having any experience of MRI or the 'neuroradiologic' findings reported by Erbetta on either publication occasion. I do however find the idea that MRI or similar imaging methods might be indicated when someone presents with 'severe' autism (severe as in severely impacting on both clinical presentation and interfering with the acquisition of adaptive skills) as being quite a sensible approach. Mega cisterna magna - significantly enlarged CSF retrocerebellar cisterns in the posterior fossa with normal cerebellar morphology (apparently) - is still the source of some debate as to exactly what such a finding means. Zimmer and colleagues [3], looking through almost 20,000 "consecutive CT/MRI of the brain" found 49 cases of "isolated mega cisterna magna" in their cohort. Despite presenting with "overall normal cognitive functioning" they suggested that such a finding might have some influence on aspects of memory and verbal fluency. I say all this acknowledging that the brain is a mighty complex organ that is also surprisingly flexible in terms of the various duties it performs. A possible link between mega cisterna magna and congential cytomegalovirus (CMV) infection [4] is also intriguing from an autism perspective (see here) as per the recent paper from Engman and colleagues [5].

The MRI results of those with severe autism also need to be compared against the data amassed from those perhaps not falling into that 'severe autism' categorisation. I've previously covered the paper by Roma Vasa and colleagues [6] (open-access) (see this post) who concluded that in 90% of cases of 'high-functioning' autism, there was very little too see from a brain imaging perspective. The more recent paper from Koolschijn et al [7] questioning the idea that autistic traits are specifically linked to brain morphometry adds to the idea that looking for a 'brain signature' for 'all autism' is probably not going to yield too many generalisable results, but rather the focus needs to be on endophenotypes.

Music: Daft Punk - Da Funk.

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[1] Erbetta A. et al. Low-Functioning Autism and Nonsyndromic Intellectual Disability: Magnetic Resonance Imaging (MRI) Findings. J Child Neurol. 2015 Apr 20. pii: 0883073815578523.

[2] Erbetta A. et al. Neuroimaging findings in 41 low-functioning children with autism spectrum disorder: a single-center experience. J Child Neurol. 2014 Dec;29(12):1626-31.

[3] Zimmer EZ. et al. Clinical significance of isolated mega cisterna magna. Arch Gynecol Obstet. 2007 Nov;276(5):487-90.

[4] Dogan Y. et al. Intracranial ultrasound abnormalities and fetal cytomegalovirus infection: report of 8 cases and review of the literature. Fetal Diagn Ther. 2011;30(2):141-9.

[5] Engman ML. et al. Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta Paediatr. 2015 Apr 21.

[6] Vasa RA. et al. Normal rates of neuroradiological findings in children with high functioning autism. J Autism Dev Disord. 2012 Aug;42(8):1662-70.

[7] Koolschijn PC. et al. Are Autistic Traits in the General Population Related to Global and Regional Brain Differences? J Autism Dev Disord. 2015 Apr 7.

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Erbetta A, Bulgheroni S, Contarino VE, Chiapparini L, Esposito S, Annunziata S, & Riva D (2015). Low-Functioning Autism and Nonsyndromic Intellectual Disability: Magnetic Resonance Imaging (MRI) Findings. Journal of child neurology PMID: 25895913

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.

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[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.

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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

Cytomegalovirus and autism

Today I'm talking on the topic of cytomegalovirus infection and autism following the paper by Sakamoto and colleagues [1] and their conclusion on: "the involvement of congenital CMV [cytomegalovirus] infection in a portion of children with ASD [autism spectrum disorder]".

Do you mind?  @ Wikipedia 

Cytomegalovirus (CMV) belongs to a family of viruses called herpesviruses which includes chicken pox and shingles. It is a pretty common virus insofar as an estimated 50-80% of the over 40s in the United States are infected with CMV according to the CDC. The various descriptions of CMV have tended to suggest that for many people, CMV infection seems to have little effect on day-to-day health and wellbeing assuming no presence of any underlying disease or state affecting the immune system for example. As with other herpesviruses however, CMV has the ability to lie dormant (latent) in the body, avoiding detection by the immune system. Reactivation of the virus can occur, as seen with other herpesviruses, notably shingles.

CMV is not however always so benign. Where a woman for example, contracts a CMV infection for the first time during pregnancy or in the months before conception, the infection can spread to the developing foetus, something called congenital CMV infection. This can often have serious consequences for offspring health and development. Seroprevalence rates for CMV in pregnant women have been estimated to be quite high particularly when ethnicity is taken into account [2].

The Sakamoto paper adds to quite a long history of research looking at a possible connection between congenital CMV infection and the presentation of autism (see here). Examining blood and/or tissue samples (yes, including those gold mines of information, the neonatal bloodspots) for 27 children diagnosed with ASD, researchers went looking for the DNA of CMV, that is the genetic blueprint of the virus. DNA was preferable to the presence of just antibodies to the virus, which could be there purely because maternal antibodies to CMV will to some extent be reflected in newborn infants. "CMV DNA was detected in two (7.4%) of the 27 children" researchers reported, and interestingly, aside from the presentation of autism, none of the more classical indicators of congenital CMV infection were observed in these children such as hearing loss or epilepsy (see here).

Whilst one has to be a little bit careful in saying that congenital CMV infection 'causes' autism, I do find the association to be a potentially important one. I note from some of the earlier work in this area, specifically that of Gene Stubbs [3] there was a recommendation that: "Physicians who find autistic symptoms in very young children might include cytomegalovirus in their differential to document the presence or absence of a correlation". Likewise the paper by Markowitz [4] similarly hinted "that congenital viral infection may be an important cause of infantile autism". In that case there was also some discussion that "over time improvement was noted" in behavioural presentation in line with what would be expected from an infection-based model of symptoms.

From a cold, objective science perspective, cases of congenital CMV infection with autism presentation also offer a potentially valuable insight into mechanism and intervention. Yamashita and colleagues [5] talked about "subependymal cysts and the later development of AD [autistic disorder]" as one research avenue. Whether such features directly link to the presence of autism or autistic behaviours or other presentation talked about in the case reports discussed by the authors is not yet known. Similarly, Engman and colleagues [6] talked about cerebral cortical malformations being more frequently detected in cases of congenital CMV infection. Various directions for autism research are provided.

The question of 'treating' congenital CMV infection also arises, and what effect this might have on the presentation of autism or autistic traits. I note another paper from Stubbs and colleagues [7] talked about the use of "Transfer factor immunotherapy" in one child to "improve his specific immunocompetence to cytomegalovirus thereby either containing the effects of the virus or eradicating the virus". I'm not making any recommendations or anything about this course of action particularly when one considers some of the history of transfer factor and autism, but following a pattern of treatment of the condition where autism is not mentioned [8] the use of something like an anti-viral might be an area in need of further research investigations, particularly where circulating anti-CMV antibodies persist [9]. As Binstock [10] noted: "immune impairments and atypical infections may be treatable" when it comes to autism, as they might be when it comes to other conditions and other viral infections (again with no medical or clinical advice given or intended).

Music to close. The North-East of England is really pulling in the acts this year. The Kings of Leon play Newcastle this evening, and so I leave you with perhaps their most famous song to date about something being on fire... socks perhaps?

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[1] 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.

[2] Pembrey L. et al. Seroprevalence of cytomegalovirus, Epstein Barr virus and varicella zoster virus among pregnant women in Bradford: a cohort study. PLoS One. 2013 Nov 27;8(11):e81881.

[3] Stubbs EG. Autistic symptoms in a child with congenital cytomegalovirus infection. J Autism Child Schizophr. 1978 Mar;8(1):37-43.

[4] Markowitz PI. Autism in a child with congenital cytomegalovirus infection. J Autism Dev Disord. 1983 Sep;13(3):249-53.

[5] Yamashita Y. et al. Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord. 2003 Aug;33(4):455-9.

[6] Engman ML. et al. Congenital cytomegalovirus infection: the impact of cerebral cortical malformations. Acta Paediatr. 2010 Sep;99(9):1344-9.

[7] Stubbs EG. et al. Transfer factor immunotherapy of an autistic child with congenital cytomegalovirus. J Autism Dev Disord. 1980 Dec;10(4):451-8.

[8] Lombardi G. et al. Congenital cytomegalovirus infection: treatment, sequelae and follow-up. J Matern Fetal Neonatal Med. 2010 Oct;23 Suppl 3:45-8.

[9] Kawashti MI. et al. Possible immunological disorders in autism: concomitant autoimmunity and immune tolerance. Egypt J Immunol. 2006;13(1):99-104.

[10] Binstock T. Intra-monocyte pathogens delineate autism subgroups. Med Hypotheses. 2001 Apr;56(4):523-31.

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Sakamoto A, Moriuchi H, Matsuzaki J, Motoyama K, & Moriuchi M (2014). Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. Brain & development PMID: 24768169