Psychiatric comorbidity in post H1N1 vaccination narcolespy?

I can imagine that the paper by Atilla Szakács and colleagues [1] is likely to draw some rather differing opinions about potential importance based on their subject matter and methods/participant numbers looking at the frequency of psychiatric comorbidity among those with narcolepsy including narcolepsy post H1N1 vaccination. The fact that autism - "pervasive developmental disorder not otherwise specified (i.e., atypical autism)" - is mentioned as one of the comorbidity in the post-vaccination narcolepsy group, albeit only present in some 3% of the 31 participants (one person by my reckoning), potentially moves us into some contentious territory.

I can't go back to yesterday because
I was a different person then.

That being said, the finding that nearly half of the post-vaccination narcolepsy cases presented with some kind of psychiatric comorbidity and the lion's share of that comorbidity was represented by a diagnosis of attention-deficit hyperactivity disorder (ADHD) (~30%) is perhaps the bigger headline from this study. Or is it?

OK, it might be worthwhile taking this one step at a time. The report by the European Centre for Disease Prevention and Control (ECDC) [2] provides a good overview on the correlation between the use of the Pandemrix influenza vaccine and risk of narcolepsy in children and adolescents based on European data. The paper by Miller and colleagues [3] put a UK perspective on this, concluding that: "The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland". These findings and others suggested that there may be quite a bit more to see when it came to any relationship and, as a result, the door was opened to possible compensation as a vaccine-damage case (see the BBC report on this here). But, and it is an important point, other studies in other parts of the world have not reported a similar connection [4] and indeed, whether influenza infection (including 2009 H1N1 infection) itself could have been a risk factor for narcolepsy [5] has been discussed in the peer-reviewed literature.

The hows and whys of any relationship between the H1N1 influenza vaccine and [some] narcolepsy are still under discussion. The hypocretins have been the source of quite a bit of speculation [6] although the research road linking processes related to these compounds and the possible effects of vaccination has not run so smoothly (see here). Autoimmunity, or rather some of the genetics of autoimmunity, has also been highlighted as being a potentially revealing mechanism of involvement [7] perhaps shadowing some recent work in an unrelated area (see here). Indeed, another publication from Szakács and colleagues [8] hinted as much: "All patients in the postvaccination group were positive for human leukocyte antigen (HLA)-DQB1*0602".

Insofar as narcolepsy not related to vaccine administration, there is already a body of work to suggest quite a few comorbidities might already be elevated in risk following a diagnosis. The paper by Ohayon [9] detailed various somatic and psychiatric/behavioural issues to be over-represented alongside a diagnosis of narcolepsy. Of particular note to the psychiatric side of things were reports that: "major depressive disorder (MDD)... and social anxiety disorder" affected around 20% of people with the diagnosis. Both these conditions were noted in the Szakács study. Modestino & Winchester [10], based on the use of "a retrospective self-report questionnaire indicating the presence of childhood ADHD symptomatology in adults" suggested that "childhood ADHD symptomatology history among adult narcoleptics is common". Ideas about mis-diagnosis of ADHD covering for a condition like narcolepsy have also been suggested elsewhere (see here).

I will reiterate that the Szakács study only looked at 38 children and adolescents, and 31 of those participants fitted that post-vaccination narcolepsy criteria. This is a very small study where even the authors highlight that this means little can be conclusively taken from their findings. Insofar as that autism - atypical autism - finding, it is not beyond the realms of statistical possibility that such detection of a single case is entirely a fluke finding or indeed, something that might be expected given the increasing prevalence rate/estimates (see here). Indeed, I'll draw your attention to an earlier report on this matter [11].

The ADHD findings ("29% had attention deficit hyperactivity disorder (ADHD) inattentive type") are a little more difficult to explain away taking account of my previous chatter on the sample size of the Szakács paper. I've talked before on this blog about the paediatric ADHD prevalence figures/estimates (see here) and their hovering between 5-8% in the general population based on the collected work so far published in this area. Diagnoses like autism do seem to carry a greater risk of ADHD (see here) but given that only one case of autism was detected in the Szakács sample, I don't think we can say that this factor accounts for the results reported.

I draw back from suggesting that ADHD (in any or all its forms) is definitely related to narcolepsy post 2009 H1N1 vaccination or indeed natural infection on the strength of the current data and small (unevenly distributed) participant groups. What however the Szakács findings do perhaps impress, is the need for greater scrutiny of this possible variable; if anything else, to potentially highlight any possible mechanisms of response and possibly offer some further insights into the underlying genetics and biochemistry of [at least some] ADHD.

I close with the official (UK) advice on flu vaccination (see here).

Music: Wild Honey by Hugh Laurie (House).

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[1] Szakács A. et al. Psychiatric Comorbidity and Cognitive Profile in Children With Narcolepsy With or Without Association to the H1N1 Influenza Vaccination. Sleep. 2014 Oct 17. pii: sp-00241-14.

[2] European Centre for Disease Prevention and Control. Narcolepsy in association with pandemic
influenza vaccination (a multi-country European epidemiological investigation) Stockholm: ECDC; September 2012.

[3] Miller E. et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ. 2013 Feb 26;346:f794.

[4] Duffy J. et al. Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States. Neurology. 2014 Oct 15. pii: 10.1212/WNL.0000000000000987.

[5] Han F. et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011; 70: 410–417.

[6] Hungs M. & Mignot E. Hypocretin/orexin, sleep and narcolepsy. BioEssays. 2001; 23: 397-408.

[7] Mahlios J. et al. The autoimmune basis of narcolepsy. Curr Opin Neurobiol. 2013 Oct;23(5):767-73.

[8] Szakács A. et al. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology. 2013 Apr 2;80(14):1315-21.

[9] Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013 Jun;14(6):488-92.

[10] Modestino EJ. & Winchester J. A retrospective survey of childhood ADHD symptomatology among adult narcoleptics. J Atten Disord. 2013 Oct;17(7):574-82.

[11] Cohen BI. Possible connection between autism, narcolepsy and multiple sclerosis. Autism. 1998; 2: 425-427.

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Szakács A, Hallböök T, Tideman P, Darin N, & Wentz E (2014). Psychiatric Comorbidity and Cognitive Profile in Children With Narcolepsy With or Without Association to the H1N1 Influenza Vaccination. Sleep PMID: 25325473