Social anxiety in one in four adults with autism

"Twenty-eight percent (14 of 50) of individuals with ASD [autism spectrum disorder] fulfilled the diagnostic criteria for SAD [social anxiety disorder]".

"I am Vulcan, sir. We embrace technicality."

So said the findings reported by Susanne Bejerot and colleagues [1] (open-access) as part of their investigations looking at SAD occurrence among adults diagnosed with ASD. Once again the sometimes very disabling issue of anxiety resurfaces with autism in mind. Before going on, I'm minded to reiterate that SAD in the context of this research/post means social anxiety disorder and not seasonal affective disorder (which also uses the same acronym).

The Bejerot paper is open-access but a few factoids from the study might be in order:

• Drawing on participant data derived from another study by the authors [2] talking about [some] autism as potentially being representative of a "gender defiant disorder", 50 adults diagnosed with autism were compared with 53 asymptomatic controls and 100 participants diagnosed with SAD.
• Various measures were used to ascertain things like autistic traits and the presence of any other psychiatric issues including the Mini International Neuropsychiatric Interview (M.I.N.I.) and the Autism Spectrum Quotient (AQ). When it came to looking at social anxiety and social avoidance, the Liebowitz Social Anxiety Scale Self-Report (LSAS-SR) was used and "SAD diagnosis was established by diagnostic interview using the Structure Clinical Interview for DSM-IV (SCID)".
• Results: those diagnosed with SAD (not comorbid to autism) showed the highest (mean) scores when it came to social anxiety and avoidance based on the LSAS-SR measure. This is probably not an unexpected finding given that they were already diagnosed with SAD. But... the ASD group were not that far behind based on their scores on these parameters and ahead of the asymptomatic controls: "[significantly] higher scores of anxiety and avoidance in ASD relative to subjects in the non-ASD comparison group".
• Then the headline result suggesting that over a quarter of those with autism also fulfilled diagnostic criteria for SAD (based on their M.I.N.I results) and further that: "the 14 individuals that fulfilled the criteria for social anxiety had a higher AQ score... than the rest of the group". This last point potentially ties the two diagnoses (autism and SAD) together as per some recent chatter about intolerance of uncertainty and autism (see here) and with social communication issues specifically in mind, the findings reported by Georgia Halls and colleagues [3] (open-access).

There are some potentially very important points to take from the Bejerot findings specifically in relation to the requirement for further screening as and when a diagnosis of ASD is received. It's an all too common theme these days, that the label 'autism' rarely exists in a diagnostic vacuum both during childhood (see here) and into adulthood (see here for example). Although not exactly making great reading, some of that comorbidity (if that is what it actually is) can for some people on the autism spectrum, lead down some very dark roads indeed (see here). The first step it seems, is screening for said comorbidity in order to start thinking about how such issues can be mitigated and quality of life improved (as and when required).

Just before I leave you to further mull over the Bejerot findings, I'll also draw your attention to a few other details discussed by the authors. They talk about possible "differences in the quality of social anxiety in ASD and SAD" as a function of some of the unique issues which follow a diagnosis of autism. So, social awkwardness is discussed, and the quite sweeping statement that "the ASD group is socially awkward" as being a possible differentiator from the SAD group who: "sense that they are socially incompetent" despite possessing the appropriate skills to socialise. I assume this idea stems from the developmental aspect of autism?

Interestingly too, the authors also suggest that issues with the concept of insight might be something which may help protect some on the autism spectrum from developing social anxiety. The idea being that the realisation of said social awkwardness might promote social anxiety and conversely "individuals with ASD and poor insight may be protected from developing social anxiety". As difficult an issue this might be to think about, the authors draw on other data which proposed that: "either unawareness of, or perhaps being unconcerned with how people perceive them, could be protective factors for social anxiety [in cases of autism]". Certainly there seems to be quite a bit more to do in this area outside of other potentially important work [4]. I wonder also for example, whether the concept of self-monitoring might come into play here too?

Music to close and having seen Bryan Adams last evening, I have something of a new found admiration for some of his music, so here is a classic: Summer of '69.

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[1] Bejerot S. et al. Social anxiety in adult autism spectrum disorder. Psychiatry Research. 2014; 220: 705-707.

[2] Bejerot S. et al. The extreme male brain revisited: gender coherence in adults with autism spectrum disorder. Br J Psychiatr. 2012; 201: 116-23.

[3] Halls G. et al. Social communication deficits: Specific associations with Social Anxiety Disorder. Journal of Affective Disorders. 2015; 172: 38–42.

[4] White SW. et al. Social-cognitive, physiological, and neural mechanisms underlying emotion regulation impairments: understanding anxiety in autism spectrum disorder. Int J Dev Neurosci. 2014 Dec;39:22-36.

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Bejerot S, Eriksson JM, & Mörtberg E (2014). Social anxiety in adult autism spectrum disorder. Psychiatry research PMID: 25200187

Milk has gotta lotta bottle?

"High milk intake was associated with higher mortality in one cohort of women and in another cohort of men, and with higher fracture incidence in women". Those were some of the conclusions reached in the study by Karl Michaëlsson and colleagues [1] (open-access) looking at milk consumption and "mortality and fractures in women and men". The BBC among other media have covered the study (see here).

Take me out tonight

Based on quite a large participant group (two actually) who completed a food frequency questionnaire among other things, researchers followed over 100,000 people some 10-20 years later to ascertain details on "fracture events" and mortality. For a smaller subgroup, they also reported on: "the urine oxidative stress marker 8-iso-PGF2α, a dominant F2-isoprostane and an ideal standard biomarker of oxidative stress in vivo" on the basis of analysing any connection between: "D-galactose in milk with theoretical influences on processes such as oxidative stress and inflammation". Oh, and a familiar cytokine also gets a mention: interleukin-6.

Authors, with caveats, reported something of a possible connection between milk intake and outcomes: "a dose dependent higher rate of both mortality and fracture in women and a higher rate of mortality in men with milk intake, a pattern not discerned with other dairy products" and "positive associations between milk intake and concentrations of markers for oxidative stress and inflammation". IL-6 levels were also correlated with milk intake (although surprisingly little is made of this association in my opinion bearing in mind some of the other literature in this area [2]). For quite a thorough review of the study and findings, I will refer you to the NHS Choices take on it (see here).

Milk has been something of some interest to this blog down the year based on my preoccupation with diet and [some] autism [3] (see here and see here for examples) and further a possible relationship with other behaviourally-defined conditions (see here). I have tried not to come down too heavy on the white stuff (see here) given that it's not all doom and gloom when it comes to the benefits of milk for quite a few people albeit with the sunshine vitamin/hormone also needing to be considered. As an aside, the recent coverage of the the Caerphilly Cohort Study and their 'roadmap to healthy ageing' (see here) previously also talked about milk products and "a markedly reduced prevalence of the metabolic syndrome" [4], so one has to be slightly cautious about demonising milk generally.

The Michaëlsson results however cannot be readily ignored given the impressive participant size and prospective design of study used. The fact that authors reported findings pertinent to milk consumption but that "intake of fermented milk products such as yogurt and soured milk and cheese were associated with lower rates of fracture and mortality" is also potentially important. I could start going on about how processing might affect lactose / galactose content in some cheeses [5] and yoghurts [6] but this is perhaps fodder for another day. Likewise the findings reported by Ji and colleagues [7] suggesting "people with lactose intolerance, characterised by low consumption of milk and other dairy products, had decreased risks of lung, breast, and ovarian cancers" might also be relevant. I note also that chatter about casein (the protein in milk) content as a function of researchers findings are largely absent from the discussions but are perhaps also potentially relevant in light of the whole A1-A2 milk issue rising in prominence these days (also including mention of oxidative stress too).

Music to close: Lorde - Yellow Flicker Beat.

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[1] Michaëlsson K. et al. Milk intake and risk of mortality and fractures in women and men: cohort studies. BMJ. 2014; 349.

[2] Labonté MÈ. et al. Dairy Product Consumption Has No Impact on Biomarkers of Inflammation among Men and Women with Low-Grade Systemic Inflammation. J Nutr. 2014 Nov;144(11):1760-7.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2014 Oct 14:1-6.

[4] Elwood PC. et al. Milk and dairy consumption, diabetes and the metabolic syndrome: the Caerphilly prospective study. J Epidemiol Community Health. Aug 2007; 61(8): 695–698.

[5] Portnoi PA. & MacDonald A. Determination of the lactose and galactose content of cheese for use in the galactosaemia diet. J Hum Nutr Diet. 2009 Oct;22(5):400-8.

[6] Alm L. Effect of fermentation on lactose, glucose, and galactose content in milk and suitability of fermented milk products for lactose intolerant individuals. J Dairy Sci. 1982 Mar;65(3):346-52.

[7] Ji J. et al. Lactose intolerance and risk of lung, breast and ovarian cancers: aetiological clues from a population-based study in Sweden. Br J Cancer. 2014. October 14.

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Michaelsson, K., Wolk, A., Langenskiold, S., Basu, S., Warensjo Lemming, E., Melhus, H., & Byberg, L. (2014). Milk intake and risk of mortality and fractures in women and men: cohort studies BMJ, 349 (oct27 1) DOI: 10.1136/bmj.g6015

One fifth of schizophrenia cases linked to Toxoplasma gondii?

"The PAF [population attributable fraction] for schizophrenia in those exposed to T. gondii is tentatively 21.4%". That was the headline conclusion made by Prof. Gary Smith [1] in his modelling analysis estimating what percentage of cases of schizophrenia might involve the protozoan Toxoplasma gondii. Some of the accompanying media about this potentially very important finding can be found here and here.

You don't need to study scaring, you just do it.

Although no expert on the PAF - defined as [2]: "the proportional reduction in average disease risk over a specified time interval that would be achieved by eliminating the exposure(s) of interest from the population while distributions of other risk factors in the population remain unchanged" - the author seems to have undertaken some nifty statistical analysis to calculate how many cases of schizophrenia might not occur if T. gondii infection wasn't present.

For those who might not be up to speed with this area, there is quite a bit of evidence to suggest that T. gondii infection (or history of infection) may well tie into the presentation of schizophrenia [3]. The evidence is not altogether straight-forward in this area [4] including some potential involvement for food (see a previous post), but there is certainly something more to see in this area of investigation and perhaps further in psychiatry. As I write this post, yet another study has found evidence of a possible link with schizophrenia in mind [5] and a meta-analysis [6]  has reported: "An increased seroprevalence of T. gondii IgM in patients with acute psychosis". I'll be coming back to that last paper in a subsequent post.

Prof. Smith has quite sensibly called for quite a bit more inspection of the possible connection between T. gondii infection and schizophrenia over and above just "ridiculing the idea of a connection". In the press release about his study he notes: "In other words, we ask, if you could stop infections with this parasite, how many cases could you prevent?” Smith said. “Over a lifetime, we found that you could prevent one-fifth of all cases. That, to me, is significant."

Knowing what we are starting to know about schizophrenia, it's direct and indirect impact on a person and the all-important possibility of plurality issues, I would have to agree that some priority be given to this line of thought albeit in conjunction with other factors undoubtedly moderating any relationship.

And since we're on the topic of organisms potentially affecting human behaviour, I'll draw your attention to a recent paper by Robert Yolken and colleagues [7] (a veteran of the T. gondii - schizophrenia research correlation) on Chlorovirus ATCV-1 and cognitive functions...

Music to close: Marina and the Diamonds with Primadonna.

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[1] Smith G. Estimating the population attributable fraction for schizophrenia when Toxoplasma gondii is assumed absent in human populations. Preventive Veterinary Medicine. 2014. October 23.

[2] Rockhill B. et al. Use and misuse of population attributable fractions. Am J Public Health. 1998 January; 88(1): 15–19.

[3] Torrey EF. et al. Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull. 2012 May;38(3):642-7.

[4] Li Y. et al. Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel. Schizophr Res. 2013 Dec;151(1-3):36-42.

[5] Khademvatan S. et al. Toxoplasma gondii Exposure and the Risk of Schizophrenia. Jundishapur Journal of Microbiology. 2014 November; 7(11): e12776.

[6] Monroe JM. et al. Meta-Analysis of Anti-Toxoplasma gondii IgM Antibodies in Acute Psychosis. Schizophr Bull. 2014 Nov 9. pii: sbu159.

[7] Yolken RH. et al. Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice. Proc Natl Acad Sci U S A. 2014 Oct 27. pii: 201418895.

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Smith, G. (2014). Estimating the population attributable fraction for schizophrenia when Toxoplasma gondii is assumed absent in human populations Preventive Veterinary Medicine DOI: 10.1016/j.prevetmed.2014.10.009

More gluten sensitivity and schizophrenia

Dude means a regular sort of person...

"Our study in 100 people with schizophrenia compared to 100 matched controls replicates a higher prevalence of gluten sensitivity and higher mean antigliadin IgG antibody levels [in] schizophrenia".

So said one of the conclusions of the paper by Jessica Jackson and colleagues [1] as the results further stack up implicating immune function and diet in relation to at least some cases of schizophrenia. That being said, researchers did not find any "robust clinical profile" which differentiated those with antibodies from those without on the basis of symptom presentation, so it seems the only way to determine possible gluten sensitivity is to do some blood work.

I'd only be repeating myself (see here) if I went on discussing the Jackson results in any great detail. That such findings, alongside quite a lot more focus on the gut-brain axis (see here and see here) in relation to at least some schizophrenia (the schizophrenias?) are becoming all too frequent these days in the peer-reviewed research literature is deserving of some real action now. Indeed, a recent Nature piece said as much with the title: Gut–brain link grabs neuroscientists (perhaps only missing out on what exactly has been grabbed).

This authorship group have previously described preliminary results based on the use of a gluten-free diet in cases of schizophrenia [2] (open-access) but a large comprehensive trial is still lacking at the time of writing. Indeed one has to go back to 1986 and the days of Billy Ocean talking about The Tough Gettin' Going and the results published by Vlissides and colleagues [3] to see how long such a trial has been awaited (assuming we don't count the even earlier writings of the late Curt Dohan on this topic).

Oh and that a gluten-free diet might not be the only research direction to take is another potentially important point...

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[1] Jackson J. et al. Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. Schizophrenia Research. 2014. 11 October.

[2] Jackson J. et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophr Res. 2012 Sep;140(1-3):262-3.

[3] Vlissides DN. et al. A double-blind gluten-free/gluten-load controlled trial in a secure ward population. Br J Psychiatry. 1986 Apr;148:447-52.

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Jackson J, Eaton W, Cascella N, Fasano A, Santora D, Sullivan K, Feldman S, Raley H, McMahon RP, Carpenter WT Jr, Demyanovich H, & Kelly DL (2014). Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. Schizophrenia research PMID: 25311778

An inflammatory autism subtype?

The paper from Harumi Jyonouchi and colleagues [1] (open-access) continues a theme from this author with their suggestion of "an imbalance in the production of inflammatory (IL-1ß and IL-6) and counterregulatory (IL-10) cytokines by ‘flare’ ASD-IS [autism spectrum disorder - inflammatory subtype] monocytes".

Panic on the streets of Birmingham...

'Flare' ASD-IS in this case refers to a coding given to a small participant group (n=24) who were: "defined as those with a history of fluctuating behavioral symptoms following immune insults (mainly microbial infection)" and who experienced: "worsening behavioral symptoms following immune insults, despite the resolution of acute conditions such as viral syndrome (that is, the resolution of other infectious symptoms if associated with a microbial infection, lack of fever, and no other acute physical symptoms associated with immune insults)".

Innate immune system functions (yes, cytokines again) were measured in flare ASD-IS and compared with results from other groups: (i) controls with autism with a history of "non-IgE mediated food allergy (NFA)" (n=20), (ii) ASD/non-NFA controls (n=20), and (iii) "three groups of non-ASD controls (non-ASD/NFA subjects (N =16), those diagnosed with pediatric acute onset-neuropsychiatric syndrome (PANS, N =18), and normal controls without NFA or PANS (N =16))". For those unfamiliar with the term PANS - pediatric acute onset-neuropsychiatric syndrome - this is a term originating from PANDAS (see here) and denotes an important condition bridging the link between infection and psychiatric symptomatology [2]. As if you needed telling...

Authors concluded that: "‘Flare’ ASD-IS PB Mo [peripheral blood monocytes] produced higher amounts of inflammatory cytokines (IL-1β and IL-6) without stimuli than ‘non-flare’ ASD-IS cells". They concluded that their findings: "support parental impression of worsening behavioral symptoms in the ‘flare’ state following immune insults" on the basis of the immune findings also linking in with behavioural descriptions at the time of sample collections.

Whilst including relatively small participant groups, it is the spread of presentations (not just based on diagnosis) which makes this paper stand out. I note that the authors also report that their results may: "indicate a possibility that monocytes from ASD-IS children also have intrinsic defects in regulatory mechanisms of IL-10 production". This is again, potentially important. Although there is still some misconception that cytokines are binary in function (either pro-inflammatory or anti-inflammatory) when the emerging data are suggesting it is very much more complicated than that (see here), the authors are hinting that inflammation with regards to autism may actually be down to issues with the opposing anti-inflammatory response over and above an upregulated pro-inflammatory response. Sort of like a fire tender not carrying enough water to put out a blaze. Indeed, work from this research team had previously hinted as much [3] (see also my previous post on this paper) as have other studies [4].

I am looking forward to seeing this research independently followed-up and reported on to further characterise those people with autism who such results are potentially relevant to. Whether gastrointestinal (GI) symptoms and dietary intervention might also be important factors [5] in such immune responses, also offers some potentially tantalising options for intervention...

Music to close: Rhapsody In Blue.

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[1] Jyonouchi H. et al. Cytokine profiles byperipheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an
inflammatory subtype? Journal of Neuroinflammation. 2014, 11:187

[2] Chang K. et al. Clinical Evaluation of Youth with Pediatric Acute Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2014 Oct 17.

[3] Jyonouchi H. et al. Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study. J Neuroinflammation. 2012 Jan 7;9:4.

[4] Estes ML. & McAllister AK. Alterations in Immune Cells and Mediators in the Brain: It's Not Always Neuroinflammation! Brain Pathol. 2014 Nov;24(6):623-30.

[5] Jyonouchi H. et al. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85.

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Jyonouchi H, Geng L, & Davidow AL (2014). Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype? Journal of neuroinflammation, 11 (1) PMID: 25344730

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