S100B protein and autism continued

"Our findings showing an increase in peripheral concentrations of S100B and TNF-α provide limited support to the hypothesis about the roles of altered immune function and S100B in autism spectrum disorder (ASD)."

So said the findings reported by Selin Aktan Guloksuz and colleagues [1] (open-access available here) continuing some discussions a few years back on a possible role for S100B in relation to at least some autism (see here).

S100B - S100 calcium-binding protein B - is a compound involved in quite a few biological reactions not least "as a biomarker of global glial activity." Elevations of the S100B have been reported in relation to several states including that of [traumatic] brain injury. Outside of some research suggesting that elevations of S100B might also be a feature of diagnoses such as schizophrenia (see here), it has also been the topic of investigations with [some] autism in mind [2] too. The name of the game is elevations in S100B in relation to autism and more.

Based on analyses of fasting blood samples from "40 unmedicated children with autism" (where autism diagnoses were confirmed by study researchers) and 35 asymptomatic control children, researchers measured levels of plasma S100B alongside various markers of immune function (cytokines). Among the suite of cytokines examined, levels of "tumor necrosis factor alpha (TNF-α), interferon gamma, interleukin (IL)-1β, IL-4, IL-6, IL-10, and IL-17A" were included. The idea of using unmedicated children with autism stems from the suggestion that at least one medication used for some autism might have the ability to elevate S100B [3].

Results: as per the opening sentence to this post, levels of S100B and TNF-α were 'different' between the groups (both elevated) and this finding remained "after controlling for age, sex, and BMI [body mass index]." Researchers also reported some results looking at whether ASD symptom presentation might show any 'association' with S100B levels. On this topic they reported that: "Plasma S100B concentrations in children with severe ASD symptoms were higher than in children with mild-moderate ASD symptoms" but when again controlling for age, sex and BMI this association did not hold (significantly). As for the other cytokines outside of TNF-α... nothing came up as significant between the groups. This is interesting in light of recent work (see here) and even Guloksuz et al talk about future "prospective longitudinal studies investigating a broad set of immune markers, both in serum and CSF [cerebrospinal fluid], in large samples" and the pros- and cons of looking in CFS.

Where next for this area of investigation? Well, taking into account the link between S100B and brain injury and what that could mean for cognitive processes for example, I'd be minded to suggest that more study is needed looking at the effect of S100B levels in relation to cognition and autism. Take for example the study results from Chen and colleagues [4] who reported that "serum S100B level was an independent contributor to the global cognitive dysfunctions, particularly for the speed of processing, attention/vigilance, visual learning and reasoning/problem solving subscores" in their cohort of participants with schizophrenia. Might similar correlations be present alongside S100B elevations in relation to autism? I'd also be minded to suggest looking at a possible role for comorbidities potentially accompanying a diagnosis of autism as being important for S100B elevations in light of other research on depression for example [5]. Depression (various types) and autism is very much an important area of overlap (see here for example) and might actually offer at least one way to target elevations in S100B.

There is more to do on this topic.

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[1] Guloksuz SA. et al. Elevated plasma concentrations of S100 calcium-binding protein B and tumor necrosis factor alpha in children with autism spectrum disorders. Rev Bras Psiquiatr. 2017 Jan 12:0.

[2] Al-Ayadhi LY. & Mostafa GA. A lack of association between elevated serum levels of S100B protein and autoimmunity in autistic children. J Neuroinflammation. 2012 Mar 16;9:54.

[3] Quincozes-Santos A. et al. Effect of the atypical neuroleptic risperidone on morphology and S100B secretion in C6 astroglial lineage cells. Mol Cell Biochem. 2008 Jul;314(1-2):59-63.

[4] Chen S. et al. Cognitive dysfunction correlates with elevated serum S100B concentration in drug-free acutely relapsed patients with schizophrenia. Psychiatry Res. 2017 Jan;247:6-11.

[5] Rajewska-Rager A. & Pawlaczyk M. The role of S100B protein as a potential marker in affective disorders. Psychiatr Pol. 2016;50(4):849-857.

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Guloksuz SA, Abali O, Aktas Cetin E, Bilgic Gazioglu S, Deniz G, Yildirim A, Kawikova I, Guloksuz S, & Leckman JF (2017). Elevated plasma concentrations of S100 calcium-binding protein B and tumor necrosis factor alpha in children with autism spectrum disorders. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) PMID: 28099628

No significant difference in circulating cytokines in autism vs controls?

"As compared with 54 typically developing controls, we found no evidence of differences in the blood profile of immune mediators supportive of active systemic inflammation mechanisms in participants with autism."

That was the unexpected research bottom-line published by Carlos Pardo and colleagues [1] (open-access) examining whether various immune-related chemicals - "cytokines, chemokines, or growth factors in serum and cerebrospinal fluid" - might be linked to autism following longitudinal assessment. By longitudinal I mean that: "Up to four serum samples and up to two CSF samples were obtained from participants, at intervals ranging from 9–24 months, and stored until simultaneous laboratory analysis."

"Participants were drawn from a longitudinal study of autism" we are told, the aim of which was 'to learn more about autism and its subtypes'. Indeed, some of the research attached to this cohort has been previously discussed on this blog (see here) and for example, the suggestion that the horror that is a gluten- and/or casein-free diet used in the context of autism might not be as horrible as many people might think [2]. This time around serum samples were available for over 100 children diagnosed with autism and some 54 not-autism controls. Sixty-seven of the children with autism also provided a cerebrospinal fluid (CSF) sample taken via a lumbar puncture. The authors note: "Ethical constraints prevented lumbar punctures in the TYP [control] group" so make of that what you will.

Bearing in mind that no participants had a history of immunodeficiency or autoimmune disorder (important concepts to some autism) but that "Food, environmental, and seasonal allergies were present in a minority of participants, but were more common in AUT [participants with autism]" the results are interesting. First, when comparing results based on the analysis of CSF samples and serum samples researchers noted that there were "striking differences in the expression of selected cytokines, immune-related growth factors, and chemokines in the CSF compartment compared to the circulating bloodstream compartment." So basically what goes on in serum might not necessarily be the same as that going on in CSF in a biochemical sense.

Next and as per the title and headline of this post: "we found no evidence for major differences in the expression of circulating cytokines and chemokines between children with autism and typically developing controls." This contrasts with quite a bit of other research in the area of immune-related compounds and autism (see here for example) but one has to be a little careful with the wording here, specifically the term 'major differences'. I say that because the authors do report that EGF - epidermal growth factor - did come out as 'different' between the groups (greater in the autism group) for example. EGF has been mentioned before in the context of autism but levels of the stuff have tended to be lower in autism not higher (see here). Puzzling.

This is important work not least because of the cautions highlighted by the authors: "about the lack of relationship between central and peripheral immune markers, signaling that caution should be taken when interpreting the available studies implicating current immune dysfunction in the phenomenology of ASD [autism spectrum disorder], as few have included direct measures of CNS [central nervous system] status." Bearing in mind that there were no CFS comparison samples from controls included in this study (quite a big research flaw by all accounts) it is something else to suggest that if one really wants to see what is going on with immune function and autism, one needs to be looking to a far more invasive sample media. That some of this research group have some 'form' when it comes to the immune system potentially being linked to autism [3] and even more invasive tissue types is also worth noting as further investigations are very carefully merited...

The immune system and autism continues to intrigue.

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[1] Pardo CA. et al. Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study. Molecular Autism. 2017. 8: 1.

[2] Graf-Myles J. et al. Dietary adequacy of children with autism compared with controls and the impact of restricted diet. J Dev Behav Pediatr. 2013 Sep;34(7):449-59.

[3] Vargas DL. et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81.

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Pardo, C., Farmer, C., Thurm, A., Shebl, F., Ilieva, J., Kalra, S., & Swedo, S. (2017). Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study Molecular Autism, 8 (1) DOI: 10.1186/s13229-016-0115-7

Immune signature in ME/CFS detected in cerebrospinal fluid

The research tag-team that is Mady Hornig and Ian Lipkin are fairly frequently mentioned on this blog. If it's not to do with their studies in autism research (see here for a recent mention) it is with their ground-breaking work looking at chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) in mind (see here for example).

Indeed their latest paper [1] extends some recent findings (see here) on immune involvement in relation to CFS/ME [2] with a focus on examinations in cerebrospinal fluid (CSF).

Based on the analysis of quite a few cytokines - chemical messengers of the immune system - in CSF, researchers compared profiles in 32 'cases' of CFS/ME compared against 40 participants diagnosed with multiple sclerosis (MS) and 19 asymptomatic controls. It's worth noting that their focus on using MS as a control group probably stems from the condition being described as 'autoimmune' in nature and the idea that the body fails to differentiate between 'self' and 'other' when it comes to mounting an immune response. CFS/ME is not normally thought of as an autoimmune condition (yet) but, as I've mentioned before on this blog, there may be mechanisms through which autoimmunity might rear it's head in cases of CFS/ME (see here). I might at this point, also drop in the study by Capelli and colleagues [3] and their findings on: "the possibility that the disease is supported by an as yet unidentified autoimmune reactivity against antigens."

Anyhow, comparing those cytokine profiles across the groups, researchers reported that: "Group-specific differences were found for the majority of analytes." One particular cytokine called eotaxin (or CCL11 - C-C motif chemokine 11) showed a particular link to 'cases', "a chemokine involved in eosinophil recruitment." Eosinophils, by the way, are white blood cells involved in inflammatory processes (see here). Further, network analysis was also undertaken by Hornig et al which added to the sentiment that: "immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity" may be associated with cases of CFS/ME.

These are important results which build upon the previous sentiments of the authors that: (a) CFS/ME present with psychological/behavioural features but underlying biology is of vital importance to the condition, and (b) part of that biology seems to centre on the immune system and immune function, seemingly moderated by the progression of the condition. I say this acknowledging that the immune system is probably not the be-all-and-end-all of CFS/ME (see here).

I should point out that whilst there is some novelty in the results from Hornig and colleagues, though not necessarily because they were based on the analysis of CSF (cerebrospinal fluid) [4] including the recent results presented by Peterson and colleagues [5], this is by no means the first time that immune function has be described as potentially 'problematic' in cases of CFS/ME. Researchers such as Michael Maes have, for quite a while, talked about potential immune involvement among things. The paper from Gordon Broderick and colleagues [6] (open-access) similarly talked about cytokine networks in CFS (that's chronic fatigue syndrome not cerebrospinal fluid) and results that implicated immune function albeit not necessarily in the same direction as those reported in the current study. Oh, and then there is the recent paper from Kate Earl and colleagues [7] too concluding that: "a sub-group of patients with CFS may have low level inflammation." The immune system seems to show some involvement in at least some cases of ME/CFS.

Where next? Well, further efforts are required to independently replicate these results. Assuming that the whole diagnostic issue around CFS/ME can be clarified by something like the proposed SEID rebranding of the condition(s), the idea that objective biological tests might be at some point within reach of CFS/ME is becoming a clearer prospect. I say this acknowledging however that CFS/ME covers quite a bit of diagnostic ground and includes quite a bit of comorbidity too (see here) which is bound to complicate matters. Overlapping symptoms is something that I've always been interested in from the perspective of CFS/ME [8]; more so in light of papers such as the one from Khaiboullina and colleagues [9].

In some accompanying media about these latest results, Prof. Lipkin also talks about the possibility of therapeutics to eventually come from this stream of work for CFS/ME. Aside from the fact that certain pharmaceutics have already been discussed in the peer-reviewed arena with specific cases of CFS/ME in mind (see here), I'm a little bit cautious about the use of something like human monoclonal antibodies as one possibility. Further safety and efficacy studies are required. Insofar as that specific eotaxin finding (elevated in CFS/ME), I might be minded to suggest that evidence from other conditions on possible pharmaceutics to tackle this specific cytokine might lead to some interesting discussions...

Music to close: Radiohead - Fake Plastic Trees.

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[1] Hornig M. et al. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Molecular Psychiatry. 2015. March 31.

[2] Hornig M. et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Science Advances. 2015; 1: 1: e1400121.

[3] Capelli E. et al. Chronic fatigue syndrome: Features of a population of patients from northern Italy. Int J Immunopathol Pharmacol. 2015 Mar;28(1):53-9.

[4] Natelson BH. et al. Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clin Diagn Lab Immunol. 2005 Jan;12(1):52-5.

[5] Peterson D. et al. Cytokines in the Cerebrospinal Fluids of Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Mediators Inflamm. 2015;2015:929720.

[6] Broderick G. et al. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010 Oct;24(7):1209-17.

[7] Earl K. et al. The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome (CFS). The FASEB Journal. 2015; 29: 1055.34.

[8] Whiteley P. et al. Correlates of Overlapping Fatigue Syndromes. J Nutritional Enviro Med. 2004; 14: 247-259.

[9] Khaiboullina SF. et al. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis. Cytokine. 2015 Mar;72(1):1-8.

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Hornig, M., Gottschalk, G., Peterson, D., Knox, K., Schultz, A., Eddy, M., Che, X., & Lipkin, W. (2015). Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome Molecular Psychiatry DOI: 10.1038/mp.2015.29

Cytokines activating the kynurenine pathway in schizophrenia?

I'm a bit of a fan of tryptophan biochemistry on this blog. This quite remarkable aromatic amino acid and it's off-shoot metabolites, which appear to have no end of biological uses, have taken quite a bit of my blogging time down the years. Most recently was the suggestion that a metabolite slotting in between serotonin (5-HT) and melatonin might require quite a bit more investigation when it comes to at least some cases of autism (see here).

See ya later, President Fartfeathers.

The findings reported by Lilly Schwieler and colleagues [1] (open-access here) add to the scientific interest and their assertion that: "IL-6 [interleukin-6] induces the KYN [kynurenine] pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA [kynurenic acid] in patients with schizophrenia." IL-6 by the way, is a cytokine (chemical messenger of the immune system) which is normally taken to be a pro-inflammatory cytokine (see here). Kynurenine and it's metabolic relations, are yet another set of compounds derived from tryptophan. The kynurenic hypothesis of schizophrenia (see here) hints at some of the research history this compound (and metabolites) has with the condition.

The Schwieler paper is open-access but a few pointers might be in order:

• Looking at a "well-characterized cohort of olanzapine-treated patients with chronic schizophrenia" researchers set about looking at cerebrospinal fluid (CSF) levels of various cytokines compared to a small participant group of asymptomatic controls "free from current signs of psychiatric morbidity or difficulties in social adjustment at the time of sampling".
• Previously measured levels of "tryptophan metabolites of the KYN pathway" were also included in the study bundle. Researchers also looked at a possible 'interplay' between IL-6 and kynurenic acid in human astrocyte cultures. This involved stimulation of said cultures with IL-6 and measuring KYNA using triple quadrupole mass spectrometry.
• Results: "The CSF IL-6 concentration was elevated in patients with chronic schizophrenia compared with controls." No real surprises there considering what has been reported previously in this area of schizophrenia research [2] and the growing idea of inflammation and psychiatry being linked. 
• CSF levels of kynurenine and kynurenic acid were also elevated in the schizophrenia group compared to controls, but no significant differences were noted in the starting material (tryptophan) between the groups. Authors also confirmed that IL-6 did indeed significantly raise levels of kynurenic acid (KYNA) in astrocyte cultures.
• They conclude that "The increased production of KYNA in fetal human astrocytes following exposure of IL-6 shows that this cytokine is able to induce the activity of the KYN pathway." This process may also pertain to schizophrenia.

Aside from the limitations already pointed out by the authors in terms of some analytical issues and the spot sampling methodology employed, I might also point out that whilst participants with schizophrenia were all taking olanzapine (and other meds in some cases), the asymptomatic controls were "free from medication for at least 1 month". Granted olanzapine is not generally thought to directly impact on levels of IL-6 for example [3] but one can't discount that other, more indirect effects might come into play. Indeed, I'm going to be talking about olanzapine, gut bacteria and weight gain (see here) early in the New Year.

I'd like to introduce the paper by Johansson and colleagues [4] at this point, and their observations related to kynurenic acid and related metabolites in "cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals." Looking at cells specifically from participants (with all their biological heterogeneity), they similarly concluded that there was an "increase in ratio between neurotoxic 3-HK [3-hydroxykynurenine] and neuroinhibitory/neuroprotective KYNA following exposure to cytokines" in the bipolar and schizophrenia groups compared to controls. The 3-HK finding might be of even greater interest to schizophrenia given the suggestion of a link with redox modulation [5] and the idea that oxidative stress might be a factor to the condition [6].

What's more to say on this topic? Well, not much more aside from the fact that there may be a complicated relationship between immune function - immune signalling - and amino acid biochemistry which may very well impinge on presented behaviour. Such links also offer some interesting prospects for potential intervention too...

And to some music: Lower Than Atlantis - Here We Go.

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[1] Schwieler L. et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. J Psychiatry Neurosci. 2014 Dec 2;39(6):140126.

[2] Kunz M. et al. Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr. 2011 Sep;33(3):268-74.

[3] Hori H. et al. Effects of olanzapine on plasma levels of catecholamine metabolites, cytokines, and brain-derived neurotrophic factor in schizophrenic patients. Int Clin Psychopharmacol. 2007 Jan;22(1):21-7.

[4] Johansson AS. et al. Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine. J Psychiatr Res. 2013 Nov;47(11):1815-23.

[5] Colín-González AL. et al. The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum. Brain Res. 2014 Nov 17;1589:1-14.

[6] Flatow J. et al. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013 Sep 15;74(6):400-9.

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Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, Finn A, Bhat M, Samuelsson M, Lundberg K, Dahl ML, Sellgren C, Schuppe-Koistinen I, Svensson C, Erhardt S, & Engberg G (2014). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. Journal of psychiatry & neuroscience : JPN, 39 (6) PMID: 25455350

The gut-brain axis and schizophrenia

A micropost to direct your attention to the recent paper by Katlyn Nemani and colleagues [1] titled: 'Schizophrenia and the gut-brain axis'. Mentioning words like that, I couldn't resist offering a little exposure to this review and opinion piece, drawing on what seems to be some renewed research interest in work started by pioneers such as the late Curt Dohan [2].

The usual triad of gastrointestinal (GI) variables - gut barrier, gut bacteria and gut immune function - are mentioned in the article, concluding that: "A significant subgroup of patients may benefit from the initiation of a gluten and casein-free diet" among other things. Not a million miles away from related suggestions when it comes to something like the autism spectrum disorders (ASDs) (see here) bearing in mind the concept of overlapping spectrums (see here) and the [plural] schizophrenias.

I'm also minded to hat-tip another research team including Emily Severance and colleagues who are going great guns when it comes to the whole GI-food link in cases of schizophrenia and beyond (see here for my recent discussion of some of her work). Another of her quite recent papers [3] on cerebrospinal fluid (CSF) levels of antibody response to wheat gluten and bovine milk in first-episode schizophrenia represents another master-class of research in this area. Their suggestion of potential evidence for a leaky blood-CSF barrier is something else which might stimulate further research in this area including some mention for the molecular handyperson that is melatonin among other things to "protect against blood-brain barrier and choroid plexus pathologies". Such findings might also be relevant for other CSF issues reported with schizophrenia in mind (see here).

And whilst we're talking all-things biological membrane permeability and schizophrenia, I'll also link to the paper by Julio-Pieper and colleagues [4] (open-access) reviewing some of the evidence on the 'controversial association' between intestinal barrier dysfunction and various conditions (also covering some of the literature with autism in mind too). Mainstream here we come?

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[1] Nemani K. et al. Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Sep 17. pii: S0278-5846(14)00168-7

[2] Dohan FC. Cereals and schizophrenia data and hypothesis. Acta Psychiatrica Scandinavica. 1966; 42: 125–152.

[3] Severance EG. et al. IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia. Brain Behav Immun. 2014 Sep 17. pii: S0889-1591(14)00462-0.

[4] Julio-Pieper M. et al. Review article: intestinal barrier dysfunction and central nervous system disorders - a controversial association. Aliment Pharmacol Ther. 2014 Sep 28.

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Nemani, K., Ghomi, R., McCormick, B., & Fan, X. (2014). Schizophrenia and the gut–brain axis Progress in Neuro-Psychopharmacology and Biological Psychiatry DOI: 10.1016/j.pnpbp.2014.08.018

Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis and autistic regression

Regression as part of the presentation of autism is still a topic which has the ability to create discussion and fuel controversy. I've talked about it a few times on this blog (see here and here) and how, after a bit of a laboured start, modern day autism research has finally come around to acknowledging that regression can occur in cases of autism.

Fire @ Wikipedia  

The cause(s) of regression associated with autism has been where a lot of the debate has been had over the years. I've talked for example, about how vitamin B12 deficiency has been associated with cases of Childhood Disintegrative Disorder (CDD) (see here). This being one of the less 'controversial' theories put forward for regression in autism or in an autistic-like presentation as per other papers analysing factors such as thimerosal (thiomersal) exposure* and that-which-should-not-be-mentioned**.

What I take from the collection of literature on this topic is that (a) autism is probably better defined as the autisms insofar as the regression being present or not for example, and (b) there probably isn't just one factor influencing regression where and when it occurs in relation to those autisms. Oh and (c) getting to the bottom of the causes of regression in cases of autism is a mighty difficult task.

For today's post I'm talking about the paper by Ori Scott and colleagues*** describing a case report of a child where anti-N-methyl-D-Aspartate (NMDA) receptor encephalitis was suspected "as the cause of autistic regression".

From the top, anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis is an autoimmune condition whereby a person generates antibodies against self, in particular, antibodies that target NMDA receptors in the brain. As per the paper by Florance and colleagues**** (open-access here) the presentation of the anti-NMDA receptor encephalitis in children and adolescents is not wholly dissimilar from that in adults including behaviour and personality changes albeit including "temper tantrums, behavioral change, agitation, aggression, and progressive speech deterioration as initial symptoms". For those more interested in the adult presentation of the condition, the book 'Brain on Fire' by Susannah Cahalan is probably a good starting point.

Scott and colleagues chart the clinical course of a young boy following "an upper respiratory tract infection" into what would eventually "fit the diagnostic criteria for autistic spectrum disorder". Said anti-NMDA receptor antibodies were detected in cerebrospinal fluid (CSF) and treatment with "intravenous immunoglobulins and steroids" brought about a resolution of some of the behavioural issues. I might add that this is not the first time that anti-NMDA receptor encephalitis has been mentioned with autism in mind***** including that cross-over with CDD.

Taking into account the Scott paper and the writings of Cahalan, I get the impression that luck played a big role in the resolution of both cases. As per the Grauniad (sorry, Guardian) write-up of her book "Cahalan is never in any doubt about the extent of her luck: the luck in finding a sensitive doctor who listened to her, and took her case on its own merits". One can perhaps see that other medics might have not offered a similar diagnosis to the one she was eventually given and upon which treatment was commenced.

The Scott paper also brings into sharp focus how, when presented with cases of "autistic regression", it may be worthwhile undertaking some pretty detailed medical examination to determine whether the source of the regression might just fall into the jurisdiction of something like anti-NMDA receptor encephalitis. This accepting that getting a sample of CSF is not the nicest of procedures although as per other case studies, a full medical work-up is indicated****** (open-access).

That there also may be a medical reason for such a regression to occur is another lesson for autism research as and when it is confronted by children presenting with a fairly rapid regression into autism or autistic-like symptoms. It for example, strikes me that there is a growing respect for anti-NMDA receptor encephalitis when it comes to the presentation of something like delerium******* or even some cases of schizophrenia******** (open-access here) even without seizures being present. So when such a regression occurs in younger children, are they any less deserving of such medical consideration too? Exactly how the Scott report might play into the blanket 'autism is a lifelong condition' is another consideration.

Finally, I have to point out that the Scott paper was a case report and before anyone gets too carried away, does not necessarily mean that every case of regression in autism is due to this factor. That being said, the use of something like IVIg as the chosen treatment method for anti-NMDA receptor encephalitis is not necessarily a stranger to autism research (see here). The use of steroids as immunosuppressive agents, indicated for certain autoimmune conditions, might also offer some clues about certain parts of those autisms (see here) too bearing in mind my caveat on this blog about not giving medical or clinical advice.

Some music to close this post I think. Oasis and Don't Look Back in Anger. "Please [Mr McGee], don't make me angry, you wouldn't like me when I'm angry" (he says hiding behind the sofa).

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* Kern JK. et al. Thimerosal exposure and the role of sulfation chemistry and thiol availability in autism. Int J Environ Res Public Health. 2013 Aug 20;10(8):3771-800.

** Richler J. et al. Is there a 'regressive phenotype' of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):299-316.

*** Scott O. et al. Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler. J Child Neurol. 2013 Oct 3. [Epub ahead of print]

**** Florance NR. et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009 Jul;66(1):11-8.

***** Creten C. et al. Anti-NMDA-receptor encephalitis: a new axis-III disorder in the differential diagnosis of childhood disintegrative disorder, early onset schizophrenia and late onset autism. Tijdschr Psychiatr. 2012;54(5):475-9.

****** Chapman MR. & Vause HE. Anti-NMDA Receptor Encephalitis: Diagnosis, Psychiatric Presentation, and Treatment. Am J Psychaitry. 2011; 168: 245-251.

******* Punja M. et al. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: an etiology worth considering in the differential diagnosis of delirium. Clin Toxicol (Phila). 2013 Sep;51(8):794-7.

******** Tsutsui K. et al. Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. BMC Psychiatry. 2012 May 8;12:37.

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Scott O, Richer L, Forbes K, Sonnenberg L, Currie A, Eliyashevska M, Goez HR. (2013). Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler Journal of Child Neurology DOI: 10.1177/0883073813501875

Schizophrenia, central canal and particles?

Canals, we have quite a few of them here in Blighty. People cruise them on their canal boats to slowly take in the rich countryside and reminisce over their important role in our Industrial past. Venice has also quite a few canals, as was wrongly believed about Mars quite a few years ago.

Canals not camels @ Wikipedia 

A very different kind of canal is the topic of today's post, the central canal, an important part of our body given that it houses cerebrospinal fluid (CSF), the stuff our brains float around in. Just as a matter of interest, you might be interested to read about the lateral ventricles ("the chambers that hold cerebrospinal fluid") of Temple Grandin's brain as per some quite recent news.

Anyway, I'm no expert on the central canal and CSF, but someone close to me has advised me that it's a very important system and not to be tampered with too much as per the cautions which follow intrathecal compounding and administration of drugs, including baclofen, a previous resident on this blog.

I don't know if it specifically relevant but the recent outbreak of fungal meningitis in the United States thought due to contaminated epidural steroid injections might also serve as a reminder of how delicate this region of the body really is.

As a diagnostic medium, CSF is also pretty useful. And whilst getting to CSF is quite invasive (lumbar puncture), there have been more than a few suggestions of some potentially important CSF findings in cases of autism.

With all this in mind, I was very interested in the findings reported by Johansson and colleagues* (open-access) on the presence of microscopic particles detected in quite a few samples of CSF from people diagnosed with schizophrenia, schizoaffective disorder or bipolar disorder. Interested because particles like this really ought not to be in CSF, which is a sterile environment, given the juicy medium of glucose and protein that would be more than conducive for pathogen growth.

Back to those microscopic particles, this is not the first time that such an observation has been reported. Wetterberg and colleagues** reported on micrometre sized particles in quite a few CSF samples from participants with schizophrenia (compared with only 2/38 controls). Båve and colleagues*** similarly reported on spherical and thread-like particles being present in CSF samples in over 75% of their cohort diagnosed with bipolar disorder (compared with no such findings in controls).

A few points from the Johansson paper:

• One hundred and two participants in total; 65 healthy controls, 21 monozygotic and 16 dizygotic twins variably diagnosed with schizophrenia, schizoaffective disorder or bipolar disorder.
• Blood and CSF samples were collected. The CSF samples were collected in such a way that two samples were available for examination by scanning electron microscopy (SEM) post-sample size exclusion filtering and coating.
• Results: well, the particles were detected and "strongly associated with schizophrenia and bipolar disorder" whereas being comparatively rarely detected in controls. Being a co-twin seemed to be an important factor; that and the fact that medication status, alcohol abuse, anxiety disorders, body mass index (BMI) and inflammatory markers were not seemingly associated with findings.

So, what are these particles and what do they potentially represent? Good question and at the moment, its more speculation than fact. In true Bruce Forsyth fashion (its a Brit thing), higher than a protein, lower than a cell (you get nothing for a pair... not in this game) size-wise.

A long quote from the authors: "The mainly spherical form points to a high lipid content of the particles, which may reflect an intense apoptosis of lipid rich cell membranes not being cleared rapidly enough by the immune mechanism in the central nervous system". Issues with apoptosis (programmed cell death) eh? Makes you wonder whether they might want to look as those executioner molecules, the caspases in these cohorts. OK, the literature already has to some degree as per articles like this one and this one with some potentially relevant findings reported.

I've a feeling that this won't be the last time we hear about peculiar microscopic particles in CSF. The question is outside of the cases of schizophrenia, bipolar disorder and indeed amyotrophic lateral sclerosis (ALS) examined, whether the hole gets any deeper for particles in CSF?

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* Johansson V. et al. Microscopic particles in two fractions of fresh cerebrospinal fluid in twins with schizophrenia or bipolar disorder and in healthy controls. PLoS One. 2012 ;7: e45994.

** Wetterberg L. et al. Micrometer-sized particles in cerebrospinal fluid (CSF) in patients with schizophrenia. Neurosci Lett. 2002; 329: 91-95.

*** Båve U. et al. Micrometer-sized thread-like and/or spherical particles in the first fraction of cerebrospinal fluid in patients with bipolar disorder. Bipolar Disord. 2010; 12: 298-305.

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Johansson V, Nybom R, Wetterberg L, Hultman CM, Cannon TD, Johansson AG, Ekman CJ, & Landén M (2012). Microscopic particles in two fractions of fresh cerebrospinal fluid in twins with schizophrenia or bipolar disorder and in healthy controls. PloS one, 7 (9) PMID: 23049916