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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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

Does rubella (german measles) cause autism?

Rubella rash @ NHS Choices

"Rubella might still cause autism, even in vaccinated populations."

That was one of the points raised in the '2015 reappraisal' document published by Jill Hutton [1] (open-access) covering a topic that has quite a long history with autism in mind (see here).

Rubella, also called german measles, a previously common childhood disease characterised by a rash, high temperature and cold-like symptoms, has in many parts of the world almost been entirely eradicated as a consequence of vaccination and other health measures. Here in Blighty (UK), our public health agency has even recently announced that it will soon halt screening for rubella in pregnant women as a result of the decline of the disease (see here). That screening was carried out following some potentially pretty serious complications to the unborn child known to be associated with maternal contraction of the disease. Sounds familiar doesn't it?

Anyhow, Hutton takes readers through the main points of the research linking rubella or rather congenital rubella syndrome (CRS) and autism down the years. Stella Chess, the first person to talk about rubella (CRS) and autism [2] (at least in the peer-reviewed domain) gets a pretty big shout-out throughout the article, alongside the overlap between CRS and autism from various different perspectives (behavioural, physiological, genetic). Drawing also on literature around the topic of vaccination and autism (see here), discussions also turn to the quite important group of children with autism who do not seem to display the appropriate immunological response to rubella infection/vaccination as per that discussed by Libbey and colleagues [3] for example. The idea being that antibody titers normally showing whether a vaccination has 'worked' in terms of conferring protection against a disease, were lower or none existent in some children on the autism spectrum and potentially indicates some type of immune dysfunction. Similar things have been talked about in other research papers (see here).

Hutton also discusses an important feature of the literature intersecting with migration and autism (see here) and how some: "Foreign born mothers (from the developing world, without vaccinations) are less likely to be immune or again more likely to be susceptible to rubella" and what potential effect this might have on cases of CRS and autism. During the times I've discussed the topic of autism and migration, I've tended to labour the point about how different foods, different exposures and in particular, different levels of vitamin D *might* be part and parcel of the effect noted in cases (see here). The Hutton discussions have been food for thought for me particularly in light of other findings [4].

"The thought that vaccination has wiped out rubella is falsely reassuring and has managed to wipe out most rubella research, but unfortunately rubella lingers." I was also interested in this statement and how, on the back of those previous findings about how a certain kind of immune system might react, or rather not react, to vaccination (assuming complete vaccine coverage), there may be quite a bit more scope for further research with at least some autism in mind. I know this has the potential to take us back into some quite heated discussions but if we are learning anything about the plural autisms (see here) it is that exposure to viral infection in particular, seems to have some important links to at least some types of autism (see here and see here).

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[1] Hutton J. Does Rubella Cause Autism: A 2015 Reappraisal? Front. Hum. Neurosci. 2016. 1 Feb.

[2] Chess S. Autism in children with congenital rubella. J Autism Child Schizophr. 1971 Jan-Mar;1(1):33-47.

[3] Libbey JE. et al. Are there altered antibody responses to measles, mumps, or rubella viruses in autism? J Neurovirol. 2007 Jun;13(3):252-9.

[4] Bahta L. & Ashkir A. Addressing MMR Vaccine Resistance in Minnesota's Somali Community. Minn Med. 2015 Oct;98(10):33-6.

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Hutton, J. (2016). Does Rubella Cause Autism: A 2015 Reappraisal? Frontiers in Human Neuroscience, 10 DOI: 10.3389/fnhum.2016.00025

Congenital rubella, autism and remote stroke

Case reports. I know they rank pretty low in the order of what counts as objective scientific evidence [1] despite their often interesting findings. That being said, when it comes to a diagnosis like autism, with all its associated heterogeneity and elevated risk of various comorbidity probably better encapsulated in a more 'plural autisms' understanding, case reports can offer something of an important view into the many and varied ways in which someone might arrive on the autism spectrum and their subsequent individual experiences. A focus on the N=1 if you like...

The case report from Jill and George Hutton [2] (open-access) describing how the "diagnosis of congenital rubella was recognized more than ten years after the birth" of their male infant subject and how "congenital rubella is linked to both autism and ischemic brain injury" provides some rather interesting details for science and practice. The paper is open-access but a few pointers might be useful:

• The paper describes a boy delivered at 38 weeks to a "USA born physician at 30 years of age mostly working at a busy, urban, county hospital with a large immigrant population". Mum had been vaccinated against rubella at least once some decades earlier (possibly with a booster 7-8 years before giving birth). "She was non-immune to rubella at her first prenatal visit at 10 weeks gestation" but at delivery showed immunity to rubella suggesting intervening exposure. The authors reported the detail about 'large immigrant population' because of the issue of risk of transmission from those "emigrating from countries with absent or suboptimal national vaccination programs" [3].
• Her son "met all motor milestones, but was delayed in speech and exhibited social anxiety" during early infancy. He had a single seizure at 18 months (febrile seizure). He was eventually diagnosed with autism between 5-7 years old.
• An MRI was fortuitously offered at 10 years old with findings "most consistent with a remote stroke". The authors conclude that: "As causes of stroke were eliminated, the diagnosis of congenital rubella as a unifying diagnosis of autism and stroke became more probable."

I was drawn to talk about this paper for various reasons.

First is the continuing association between viral/bacterial exposures during pregnancy and offspring behavioural outcomes (see here). As per the research of people such as Stella Chess, mentioned in the Hutton article, discussing autism presenting in cases of congenital rubella [4] and reporting that "a high rate of autism and a high rate of recovery were observed" there is potentially so much more to see in this area of autism research. In-utero rubella exposure, by the way, is not the only infective agent linked to the presentation of autism for some (see here).

Second were some of the details reported by the Huttons on their young participant and in particular, the idea that congenital rubella may 'unify' the findings of stroke + autism. Pediatric stroke has been looked at with infectious disease in mind before [5]. The research literature in the area of stroke and autism is however not exactly straight-forward. It would be easy to say that stroke had a deleterious effect on the brain which then 'lead' to autism as per other research in this area [6], but this perhaps rather simplifies an all-too-likely more complex relationship. Certainly, I would like to see a little more investigation done on this topic and in particular the delayed manifestations of congenital rubella [7] as and when appropriate to a diagnosis of autism or autism spectrum disorder [8]. If and when this connection is further established, one could also reasonably ask about intervention strategies and whether autistic symptoms could be ameliorated in any way in this group? Remember those words from Chess: "a high rate of recovery was observed"...

Finally, the question is raised about the role of vaccination in preventing congenital rubella and possible knock-on effects for offspring development including autism-related outcomes. In a previous post on the talking point that is vaccination and autism (see here) I discussed some data which suggested that rubella vaccination may very well have "prevented hundreds, and perhaps thousands, of ASD [autism spectrum disorder] cases from 2001 through 2010 in the US." [9] The Hutton paper kinda overlaps with such discussions alongside detailing the issue of waning immunity [10]. I might add that analysis of the biology of individual responses (or not) to rubella vaccination [11] and even transmission from previous vaccinees [12] in light of other data is perhaps also implied in any future work in this area.

What the Hutton paper serves to reiterate is that there may be many potential paths towards a diagnosis of autism or ASD. Receipt of said diagnosis should also perhaps be a starting point for further inquiry rather than an endpoint...

Music: Blur - Out Of Time.

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[1] Nissen T. & Wynn R. The clinical case report: a review of its merits and limitations. BMC Res Notes. 2014 Apr 23;7:264.

[2] Hutton J. & Hutton GJ. Congenital Rubella with Autism and Evidence of a Remote Stroke. J Vaccines Vaccin 2014, 5:6

[3] Fang J. et al. Case report: congenital rubella syndrome: a rare but persistent concern in the United States. J Perinatol. 2013 Nov;33(11):899-902.

[4] Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977 Mar;7(1):69-81.

[5] Salih MA. et al. Infectious and inflammatory disorders of the circulatory system as risk factors for stroke in Saudi children. Saudi Med J. 2006 Mar;27 Suppl 1:S41-52.

[6] Weir K. & Salisbury DM. Acute onset of autistic features following brain damage in a ten-year-old. J Autism Dev Disord. 1980 Jun;10(2):185-91.

[7] Sever JL. et al. Delayed Manifestations of Congenital Rubella. Clin Infect Dis. 1985; 7 (Supplement 1): S164-S169.

[8] Hwang SJ. & Chen YS. Congenital rubella syndrome with autistic disorder. J Chin Med Assoc. 2010 Feb;73(2):104-7.

[9] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination--United States, 2001-2010. BMC Public Health. 2011 May 19;11:340.

[10] Just M. et al. Duration of immunity after rubella vaccination: a long-term study in Switzerland. Rev Infect Dis. 1985 Mar-Apr;7 Suppl 1:S91-4.

[11] Kennedy RB. et al. Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination. Hum Genet. 2014 Nov;133(11):1407-17.

[12] Wilkins J. et al. Transmission of rubella vaccine virus from vaccinees to contacts. Calif Med. 1971 Nov;115(5):16-22.

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George J Hutton, J. (2014). Congenital Rubella with Autism and Evidence of a Remote Stroke Journal of Vaccines & Vaccination, 05 (06) DOI: 10.4172/2157-7560.1000258

Paediatric congenital heart disease and autism risk?

"Children aged 2-17 with CHD [congenital heart disease] were more likely than those without CHD to have had a diagnosis of autism spectrum disorder (crude OR, 4.6; 95% CI, 1.9-11.0) or intellectual disability (Crude OR, 9.1; 95% CI, 5.4-15.4)".

The traveller @ Wikipedia 

That was a key conclusion reported in the study by Hilda Razzaghi and colleagues [1] based on their analysis of data from "the 1997-2011 National Health Interview Survey", a US initiative which aims to provide "information on the health of the U.S. civilian noninstitutionalized population through confidential interviews conducted in households" (see here).

I have to say that I was pretty interested in these findings (even though this is not the first time that neurodevelopmental outcomes have been tied to CHD); a view it seems, that was shared by the authors of the paper, bearing in mind the very wide confidence intervals (CIs) detailed for both conditions and the reliance on second-hand reporting over actual independent screening results. I can't readily offer any one 'smoking gun' explanation for the findings specifically in relation to the autism spectrum but will draw your attention to some discussion about the potential causes of congenital heart disease provided by the NHS Choices websites and how they might tie in.

So: various genetic conditions including Down's syndrome are linked to CHD [2] and the net seems to be closing in on some of the underlying genetics around the association [3]. Although still in need of quite a bit more study, there is a growing appreciation that a diagnosis of autism / autistic traits can coexist alongside a diagnosis of Down's syndrome (see here). As per a recent conversation (thanks Marilyn), one also wonders how this autism - Down's syndrome link might also play out with regards to other areas of the autism research landscape such as dietary effects for example...

Next up is maternal diabetes. As per the NHS Choices entry: "It is estimated that 3 to 6% of women with diabetes who become pregnant will give birth to a baby with a heart defect". Autism and maternal diabetes is an interesting topic which has again cropped up in the autism research literature [4]. If you want my take on the Xu meta-analysis paper and related literature, look no further...

After that is a role for alcohol consumption during pregnancy and mention of the condition called foetal alcohol syndrome (FAS). I have talked about FAS and foetal alcohol spectrum disorder (FASD) before on this blog in the context of autism (see here) but can't readily conclude that the links are overly strong between FAS/FASD and autism presentation.

"A rubella infection can cause multiple birth defects, including congenital heart disease". An interesting association given the history of rubella and autism based to quite a large extent on the work from Stella Chess [5]. I don't know enough about the rate of rubella infection in pregnant women to make any informed statement about how this risk factor might tie into both CHD and autism but the numbers of non-immune women do seem to be quite alarming here in the UK [6].

Influenza during pregnancy? "Women who get flu during the first trimester (three months) of pregnancy are twice as likely to give birth to a baby with congenital heart disease than the general population" according to the NHS Choices website. Regular readers of this blog might already know that I tend to talk quite a bit about how infection - immune system response to infection - during pregnancy seems to have some link to subsequent offspring psychology and development (see here). The link is not altogether straight forward with autism in mind and potentially better related to concepts like fever or fever control [7] but still, there might be more to do here.

The final links - certain medications taken during pregnancy, phenylketonuria (PKU) and exposure to organic solvents during pregnancy - have also, to various extents, been linked to autism (see here and see here for example).

I may very well just be plucking at straws trying to link the causes of CHD with some of the suspected 'causes' of autism (some autism at least) but it strikes me that if one was to further pursue the findings reported by Razzaghi et al those would be the places to start (assuming some shared effect). As per the reports of other physiological findings potentially manifesting alongside a diagnosis of autism (see here), some additional screening of children on the autism spectrum where one or more of the correlates of CHD are suspected might be indicated.

Peter Gabriel and Kate Bush with a beautiful song to close: Don't Give Up.

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[1] Razzaghi H. et al. Long Term Outcomes in Children with Congenital Heart Disease: National Health Interview Survey. J Pediatr. 2014 Oct 8. pii: S0022-3476(14)00820-8.

[2] Laursen HB. Congenital heart disease in Down's syndrome. Br Heart J. Jan 1976; 38(1): 32–38.

[3] Ramachandran D. et al. Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genet Med. 2014 Oct 23. doi: 10.1038/gim.2014.144.

[4] Xu G. et al. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord. 2014 Apr;44(4):766-75.

[5] Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977 Mar;7(1):69-81.

[6] Skidmore S. et al. Is the MMR vaccination programme failing to protect women against rubella infection? Epidemiol Infect. 2014 May;142(5):1114-7.

[7] Zerbo O. et al. Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study. J Autism Dev Disord. 2013 Jan;43(1):25-33.

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Razzaghi H, Oster M, & Reefhuis J (2014). Long Term Outcomes in Children with Congenital Heart Disease: National Health Interview Survey. The Journal of pediatrics PMID: 25304924