"PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS"

There were a few rather familiar aspects to the study results published by Maria Roma and colleagues [1] investigating health-related quality of life (HRQOL) in relation to myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

Familiar because HRQOL was found to be "substantially lower in an ambulatory population of adolescents and young adults with ME/CFS than for healthy controls in North America" in the Roma study, in keeping with other studies looking at this important parameter (see here). Familiar also because PEM - post-exertional malaise - was found to be something really quite important to ME / CFS, again in line with other findings (see here for example). But don't think that the Roma findings aren't important, they are. Indeed, with mention of something called orthostatic intolerance in the context of CFS / ME, they provide some further directions for investigation.

So: "We enrolled 55 consecutive ME/CFS patients (46 F) aged 10–23 years." They all "satisfied the 1994 International Chronic Fatigue Syndrome Study Group criteria" (also called the Fukuda criteria). Importantly too: "Individuals with primary depression who were referred by psychiatrists for evaluation of chronic fatigue were excluded, but those who had developed depression sometime after the onset of ME/CFS were included." See those words 'developed depression... after the onset of ME/CFS'. Control participants (n=55) - asymptomatic and in good health - were also included for study. Quite a large battery of questionnaires and schedules were delivered to participants covering HRQOL and quite a bit more including fatigue and depression. Researchers also asked a few questions about "the type of onset for ME/CFS" as well as items pertinent to the IOM (United States Institute of Medicine) criteria for ME/CFS. Lots to see.

And indeed, the results were pretty revealing. Yes, HRQOL was lower - significantly lower - in the ME/CFS group, as talk about a percentage of those with ME/CFS having to change from regular schooling "to part-time schooling... [or] home tutoring" tells you everything you need to know (yet again). Also: "A novel finding of this study is the correlation of impairment in HRQOL with the frequency of PEM, at least for an ambulatory population with ME/CFS." PEM, or 'payback' as another study categorised it as (see here), is starting to get the clinical and research attention that it truly deserves. Researchers specifically mention how "as the frequency of PEM increased, the mean PedsQL [Pediatric Quality of Life Inventory] score fell and the mean FDI [Functional Disability Inventory] score increased, consistent with a significant association of PEM with worse overall function." Need I say anymore?

And then back to orthostatic intolerance (i.e. the "development of symptoms when standing upright which are relieved when reclining"). Researchers considered this present in participants if "(a) self-reported lightheadedness occurred at least several times per week, (b) there was a history of recurrent syncope in the presence of a structurally normal heart, considered consistent with NMH [neurally mediated hypotension]... or (c) previous upright tilt testing or a passive standing testing (performed in patients not being treated with medications for orthostatic intolerance) had confirmed the presence of NMH or POTS [postural tachycardia syndrome]." And present it was in 96% of participants. So much so that authors decided that with orthostatic intolerance being one of the core diagnostic criteria for the IOM diagnostic criteria for ME/CFS, 85% of their participants hit the diagnostic thresholds based on that scheme. Important stuff.

This takes us neatly back to the quote titling this post: "PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS." And perhaps a change is coming to research and clinical practice in this area. Having said that, change is going to be quite difficult for some groups it seems [2] as words like: "Parental representations could contribute to fatigue maintenance" still appear in the peer-reviewed science literature with CFS/ME in mind...

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[1] Roma M. et al. Impaired Health-Related Quality of Life in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Impact of Core Symptoms. Front. Pediatr. 2019. Feb 15.

[2] Loades ME. et al. Perfectionism and beliefs about emotions in adolescents with chronic fatigue syndrome and their parents: a preliminary investigation in a case control study nested within a cohort. Psychol Health. 2019 Mar 1:1-17.

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"Due to the definitions of ME and CFS, “ME/CFS” does not exist..."

Today, May 12th, is ME/CFS and Fibromyalgia International Awareness Day, a day to designed to "bring awareness to ME/CFS patients, families, caregivers, and researchers." Keep that terminology in mind...

The quote heading the title of this post - "Due to the definitions of ME and CFS, “ME/CFS” does not exist..." - comes from the viewpoint paper published by Frank Twisk [1]. The report covers an important topic in the realms of chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) also known as systemic exertion intolerance disease (SEID) in terms of whether it is appropriate to use such terms of defining the illness in a mixed or interchangeable fashion. Indeed, whether the connections between all those 'also known as' words I just used are actually accurately reflective of current diagnostic descriptions...

It's no secret that science and clinical practice is still coming to grips with some of the fundamentals of CFS, ME and SEID (see here and see here for examples) in terms of what to call it, how to define it and how to test for some of the fundamental diagnostic characteristics (see here). It's also still dealing with things like the definition of recovery (see here), which might seem like common sense (a complete and sustained remission of symptoms) but hasn't been particularly straightforward in this area for quite a few reasons.

Twisk takes the reader through some of the history of the terminology used and, how, whilst there is overlap in the way that ME, CFS and SEID are defined (chronic and long-lasting weakness or fatigue is a commonality), there are also some important differences. Take for example the authors description of the Ramsay criteria for ME and specifically onset: "Illness commonly initiated by respiratory and/or gastrointestinal infection, but an insidious or more dramatic onset following neurological, cardiac, or endocrine disability occurs." This contrasts with the onset criteria for CFS and SEID which basically says little about how symptoms start or come about.

Twisk concludes that: "ME is a neuromuscular disease" and should typically not to be viewed as 'equivalent' to CFS. CFS, he argues, tends to rely heavily on a single mandatory 'chronic fatigue' symptom, something that might intersect with ME but does not go far enough to evoke a full diagnosis of ME. As for SEID, well, trumpeted as being the solution to all the diagnostic confusion, SEID has it's own issues according to Twisk. Not least that it can't serve both masters (ME and CFS) in diagnostic terms. Also important: "SEID case criteria are also applicable to subsets of people with other diseases, for example, Multiple Sclerosis (MS) and lupus; and psychological conditions, for example, major depression." There is the propensity for diagnostic confusion.

I do think that Twisk is on to something with his observations. I know quite a few people who don't like the confusion caused by combination terminology like 'ME/CFS'; often seeing it as conflating two (or even more!) quite different conditions. Add in yet another potentially important variable to such an argument - the addition of chronic disabling fatigue (CDF) as "a proxy for clinically diagnosed CFS/ME" as some authors have (see here) - and things get even more muddled. I daresay a lot of this confusion might also intersect with discussions/debates/arguments as to how far something like the biopsychosical (BPS) model should or rather shouldn't be applied to such fatigue related conditions (see here)...

You want to do something for ME/CFS and Fibromyalgia International Awareness Day? Well, first thing you could do is watch 'Unrest', then follow the #millionsmissing hashtag and then push for more research, biological research...

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[1] Twisk FNM. Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, and Systemic Exertion Intolerance Disease: Three Distinct Clinical Entities. Challenges. 2018; 9(1): 19.

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The effects of acute exercise on ME/CFS/SEID meta-analysed

Accepting that the science recipe that is a meta-analysis is only as good as the research ingredients that go into it, I was interested to see the results published by Bryan Loy and colleagues [1] who concluded that: "preliminary evidence indicates that acute exercise increases fatigue in people with ME/CFS/SEID more than in control groups, but effects were heterogeneous between studies."

ME - myalgic encephalomyelitis - and CFS - chronic fatigue syndrome - are conditions that I'm interested to talk about on this blog; specifically how after seemingly years and years in the research-clinical wilderness, science is starting to put some real effort into determining cause(s) and importantly, what might be done about ameliorating this quality of life-crushing condition. SEID - systemic exertion intolerance disease - by the way, is a rather newer description of symptoms (just in case you were not already confused enough).

Loy et al set about combing the peer-reviewed research literature for studies pertinent to their examination of the "population effect of a single bout of exercise on fatigue symptoms in people with ME/CFS/SEID." Interestingly, Google Scholar and not PubMed was there search engine of choice, where 7 studies "examining 159 people with ME/CFS/SEID met inclusion criteria" went on to be included for study. After some statistical analysis, authors concluded that: "Fatigue increases were larger for people with ME/CFS/SEID when fatigue was measured four or more hours after exercise ended rather than during or immediately after exercise ceased." They also suggested that more precise research is required in terms of the effects of exercise on this population.

If, like me, you assume that quite a lot of people who have been included under the headings of ME/CFS/SEID are actually suffering (yes, suffering) with an organic illness/illnesses [2] potentially affecting the way energy is created, stored or used in the body, such results are probably not unexpected. Words like 'mitochrondrial issues' are not totally unfamiliar to at least some parts of the ME/CFS/SEID continuum (see here and see here) and given the link between mitochondria and energy, may well provide at least one answer why post-exertional fatigue/malaise is present for some. The idea of immune system involvement in ME/CFS/SEID cannot also be left out of the equation (see here) although the precise relationship to fatigue is slightly less clear-cut.

I'd agree with the authors that more needs to be done on the hows and whys of post-exertional fatigue following acute exercise in this patient group including why other reviews [3] have reported contrary findings when it comes to exercise therapy lasting "from 12 to 26 weeks." And before you mention, yes, I'm well aware of the various goings-on with regards to a certain trial for CFS where exercise of the graded variety was used...

Of course acute exercise vs. chronic exercise (if I can call it that) are not one and the same thing so one has to be slightly cautious of making any direct comparisons. I would however like to see a little more research on the biological processes linked to fatigue post-exercise in this group; as per the suggestion by Rutherford and colleagues [4] that: "Bioenergetic muscle dysfunction is evident in CFS/ME" and what implications this might have. That also a few other favourite topics of mine (gut bacteria and bacterial translocation) might also be something to look at (see here) in the area of exercise effects and ME/CFS is worthwhile mentioning too...

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[1] Loy BD. et al. Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis. Med Sci Sports Exerc. 2016 May 17.

[2] Edwards JC. et al. The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem. Fatigue. 2016 Apr 2;4(2):63-69.

[3] Larun L. et al. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2015 Feb 10;2:CD003200.

[4] Rutherford G. et al. Understanding Muscle Dysfunction in Chronic Fatigue Syndrome. J Aging Res. 2016;2016:2497348.

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Loy BD, O'Connor PJ, & Dishman RK (2016). Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis. Medicine and science in sports and exercise PMID: 27187093

On defining chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME)

Most people who know a little bit about chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) will probably understand the potential importance of the findings reported by Leonard Jason and colleagues [1] (open-access available here). Suggesting that there may be "four groupings of patients" when it comes to how we "name and define the illnesses", this research group who surveyed over 500 people "in the United States, Great Britain, and Norway" report on one of the biggest challenges facing ME/CFS... how do we accurately define it?

The problem of defining CFS/ME stems from the fact that there are currently several clinical presentations where CFS/ME might figure (or at least where patients fulfil ME/CFS criteria) and several different ways of clinically defining the condition(s) (see here and see here). That list of definitions may indeed also be growing (see here). With all that confusion about clinical overlap and what criteria are defining what patient group, it's little wonder that research is just starting to come to grips with some of the potential underlying biology of [some] CFS/ME (see here) after so many years in the scientific wilderness. Indeed, as with many conditions resting in that 'unexplained symptoms' category, not knowing can sometimes be fertile ground for various [unfounded] theorising...

Jason et al (whose research has graced this blog before) set about categorising their participant group based on various case definitions and symptom presentations. They reported four groupings; by far the largest group of their participants (n=346) fell into a categorisation that "involves more specific criteria" defining CFS/ME including use of the relative new term SEID (Systemic Exertion Intolerance Disease). Further: "efforts have specified domains of substantial reductions of activity, post-exertional malaise, neurocognitive impairment, and sleep dysfunction" and "Patients with these characteristics were more functionally impaired than those meeting just chronic fatigue criteria." The term used by authors for this group was Neuroendocrineimmune Dysfunction Syndrome (NDS) following on from previous work [2]. Smaller numbers of people included on their study did meet criteria for chronic fatigue (greater than 6 months) with (n=47) or without (n=62) explanation "by medical or psychiatric conditions." Jason and colleagues also defined a smaller group who met the Ramsay ME criteria and who were described as an "even more impaired group." I wonder if this might include the 'housebound' group described in other research?

The authors accept that there are 'limitations' to their research including issues around how they chose their sample(s) and some of the tools used relying on self-report; further work is indicated. But as a start trying to disentangle both the heterogeneity and issues with clinical classification when it comes to CFS/ME, their paper represents a good attempt to further focus minds on the spectrum of various overlapping fatigue conditions present and how we go about teasing apart phenotypes with a focus on core symptoms [2]. Minus the psychiatry focus, perhaps it is time to also looking at applying something like the principles of RDoC to the issue of ME/CFS?

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[1] Jason LA. et al. Case definitions integrating empiric and consensus perspectives. Fatigue. 2016;4(1):1-23.

[2] Jason LA. et al. Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains. J Neurol Neurobiol. 2015 Sep;1(4).

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Jason LA, McManimen S, Sunnquist M, Brown A, Furst J, Newton JL, & Strand EB (2016). Case definitions integrating empiric and consensus perspectives. Fatigue : biomedicine, health & behavior, 4 (1), 1-23 PMID: 27088059

On the question of suicide risk and chronic fatigue syndrome

The paper by Emmert Roberts and colleagues [1] (open-access) forms the basis of today's post and the finding that: "There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality... or cancer-specific mortality in patients with chronic fatigue syndrome when compared with the general population in England and Wales." This is good news indeed bearing in mind how much a diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) can affect so many aspects of a person's life (see here).

The news about the diagnosis of CFS/ME not increasing 'all-cause mortality' is however tempered by the finding that author's results did show "a substantial increase in mortality from suicide"; something that has been picked up by some quarters of the media (see here). I might also direct readers to an accompanying commentary attached to the Roberts paper (see here).

The Roberts paper is open-access but a few points are worth highlighting.

Based on a participant group of over 2000 people diagnosed with CFS identified "using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register", authors set about calculating mortality rates over a 7-year observation period (2007-2013). As per previous 'issues' on how a diagnosis of CFS is arrived at (see here) we are told that "the most inclusive criteria, and thus included all patients with a clinical diagnosis of chronic fatigue syndrome" were used.

Mortality details were cross-referenced with the participant group data initially "from the “Service User Death Report” of “the Spine”, maintained by NHS Care Records Service." Some further checking on the basis of the death certificate details and cross-referencing with ICD-10 codes "for cause of death" provided further details. Various other variables were also analysed including ethnicity, socio-economic status (SES) and the: "Presence of a lifetime diagnosis of depression was defined as having had a recorded depressive episode (ICD-10 code: F32.x) or recurrent depressive disorder (F33.x)."

Results: after some examination of the data authors "identified 2147 cases of chronic fatigue syndrome in CRIS with 17 deaths." Just over 1500 women were included for study and 11 of them had died (11/1533). Of 614 men included for study, 6 had died (6/614). Most deaths (n=8) were "from malignant neoplasm" but 5 deaths were recorded as suicide. Further: "When stratified by lifetime diagnosis of depression, 216 patients had a recorded lifetime diagnosis of F32.x or F33.x. Four (26%) of 17 patients who died had a lifetime diagnosis of depression, for two of whom the cause of death was suicide." The authors conclude that theirs is "the first study to show a specific increased risk of suicide in a population of patients with chronic fatigue syndrome compared with the general population." But also: "if there had been two fewer deaths by suicide, this risk would not be significantly increased."

Without belittling the tragedy that is suicide and the devastating impact it can have on a person's family and friends (as well as themselves), I do think it is worth reiterating a few cold, objective points. First, yes the suicide rate was heightened in this group over this period in comparison to population figures, but the overall number of cases was still low. Second, without making too many sweeping generalisations about depression, two of those five cases of suicide had a history of depression. Given the quite widely accepted greater vulnerability to suicide (attempted or actual) following a diagnosis of depression (see here), one could argue that a diagnosis of CFS/ME is potentially only coincidental to any such association. Other research has asked similar questions [2]. That is also if you assume that depression as a condition should not be included under the banner of ME/CFS [3]? Indeed reiterating that statement about 'if there were two fewer deaths by suicide, this risk would not be significantly increased' one *could* argue that the suicide rate in relation to CFS/ME is actually not increased with the depression findings taken into account. Finally, I'd also suggest that given the extent of the debilitating symptoms often associated with CFS/ME and the 'cruel' way that some/many people with CFS/ME have been treated down the years, the suicide rate reported by Roberts is perhaps lower than I think many people would have expected. Although not directly comparable with the Roberts data, suicide has been discussed on other occasions in the peer-reviewed domain with CFS/ME in mind [4].

Continuing: "This study highlights the importance of adequate assessment of mood and other psychiatric symptoms in patients with chronic fatigue syndrome, because lifetime diagnosis of depression is an independent risk factor for increased risk of completed suicide in this population. Although completed suicide was a rare event, the findings strengthen the case for robust psychiatric assessment by mental health professionals when managing individuals with chronic fatigue syndrome." I don't think anyone would quibble with the idea that a comprehensive assessment be provided to patients with ME/CFS given what is known about how psychology can be affected by the presentation of the condition (see here) and also that depression is not something to be taken lightly. I am however cautious of the idea that a 'robust psychiatric assessment' is the only thing offered to patients - "when managing" -  particularly when there is a wealth of peer-reviewed evidence on the more 'biological side' of the condition too (see here) with potentially important implications for treatment for example. I am, for example, going to be talking about the case report from Galán and colleagues [5] soon on how the "initial symptoms of mitochondrial disease in adults can easily be mistaken with CFS." Indeed, going back to that paper by Zdunke and colleagues [6] on how "there may be important differences in illness characteristics across individuals with CFS in the US and the UK, and this has implications for the comparability of research findings across these two countries" one might appreciate how much further the UK experience of CFS/ME needs to go in order to put biology and genetics on a research/clinical practice par with the influence of psychology and psychiatry in relation to the label.

And just in case you might not believe that CFS/ME can be a life-limiting condition, due respect should be paid to those who've paid the ultimate price as a result of their diagnosis.

For those who might need it, details of someone who will listen...

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[1] Roberts E. et al. Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register. Lancet. 2016. Feb 9.

[2] Fuller-Thomson E. & Nimigon J. Factors associated with depression among individuals with chronic fatigue syndrome: findings from a nationally representative survey. Fam Pract. 2008 Dec;25(6):414-22.

[3] Jason LA. et al. Unintended Consequences of not Specifying Exclusionary Illnesses for Systemic Exertion Intolerance Disease. Diagnostics (Basel). 2015 Jun 23;5(2):272-86.

[4] Jason LA. et al. Causes of death among patients with chronic fatigue syndrome. Health Care Women Int. 2006 Aug;27(7):615-26.

[5] Galán F. et al. Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue Syndrome. J Investig Med High Impact Case Rep. 2015 Sep 24;3(3):2324709615607908.

[6] Zdunek M. et al. A Cross Cultural Comparison of Disability and Symptomatology Associated with CFS. Int J Psychol Behav Sci. 2015;5(2):98-107.

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Roberts, E., Wessely, S., Chalder, T., Chang, C., & Hotopf, M. (2016). Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register The Lancet DOI: 10.1016/S0140-6736(15)01223-4

First there was CFS/ME, then SEID, now... NIOF

A quick-ish post for you today, to bring the paper by Michael Maes [1] to your attention and illustrate how when it comes to research at least, this year (2015) seems to be truly moving forward when it comes to the topic of chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME).

The latest Maes paper (one of many by this author on this topic) provides some further research discussion on how progress in getting to the root cause of CFS/ME and developing suitable interventions has to some degree been hindered by how the condition(s) have been described down the years. This all came to a head recently with the proclamation that a name change might be in order (SEID - see here) and confirmation that, yes, CFS/ME (or SEID if you will) is a real condition (see here). That last statement is probably not new news to the thousands of people who suffer (yes, they do suffer) with CFS/ME, having been derided for years with labels such as yuppie flu or even worse.

In this recent paper, Maes argues that based on the presentation of various symptoms combined with specific "neuro-immune, inflammatory, oxidative and nitrosative stress (neuro-IO&NS) biomarkers" there may be something to see in terms of "the presence of two well-separated clusters with highly significant differences in symptoms and biomarkers."

Termed NIOF (Neuro-Inflammatory and Oxidative Fatigue), Maes also reports: "An algorithm was constructed which defined NIOF as chronic fatigue and 4 or more of the following 6 symptoms: muscle tension, memory disturbances, sleep disorders, irritable bowel, headache or a flu-like malaise."

Suffice to say that quite a bit more research is required in this area before NIOF becomes part of SEID (or CFS/ME). Independent verification and replication is the way forward; so I'll be waiting to see if anyone takes up the research gauntlet. Personally, I do find it refreshing that research is turning towards the idea that there maybe various different conditions classified under the umbrella of CFS/ME or SEID. The concept of plurality is key to finding both possible reasons for causation [2] and effective interventions for the debilitating aspects of the condition based on the idea of heterogeneity, subgroups and symptoms. It all sounds awfully familiar...

Music: Spiller - Groovejet.

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[1] Maes M. A new case definition of Neuro-Inflammatory and Oxidative Fatigue (NIOF), a neuroprogressive disorder, formerly known as chronic fatigue syndrome or Myalgic Encephalomyelitis: results of multivariate pattern recognition methods and external validation by neuro-immune biomarkers. Neuro Endocrinol Lett. 2015 Sep 12;36(4):320-329.

[2] Magnus P. et al. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. Vaccine. 2015 Oct 13. pii: S0264-410X(15)01433-4.

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Maes M (2015). A new case definition of Neuro-Inflammatory and Oxidative Fatigue (NIOF), a neuroprogressive disorder, formerly known as chronic fatigue syndrome or Myalgic Encephalomyelitis: results of multivariate pattern recognition methods and external validation by Neuro endocrinology letters, 36 (4), 320-329 PMID: 26454487

Psychological morbidity of coeliac disease

"Anxiety, depression and fatigue are common complaints in patients with untreated celiac disease and contribute to lower quality of life."

That was one of the conclusions reached in the paper by Fabiana Zingone and colleagues [1] (open-access available here) following their review of the research literature "on psychological morbidity of celiac disease." Celiac (coeliac) disease (CD), by the way, is the autoimmune condition classically treated via the use of a gluten-free diet (GFD). Readers might wish to peruse my training post on the condition for some further background information about some of the known 'hows and whys' (see here) as well as other posts on what we don't know about CD (see here) (hint: quite a bit).

The Zingone paper is open-access so it doesn't require any grand discussions from me at this point. "Our search of the available literature suggests that CD has a considerable psychological impact" is another way the authors discuss their findings and I for one, would not argue with such sentiments on potential extraintestinal manifestations of the condition. Importantly, they make a distinction between whether such 'psychological impact' may directly derive from having the disease itself or other reasons potentially relating "to the patient’s subjective perception of the disorder and of the GFD used to treat it."

I was also taken by some of the 'clinical implications' listed by the authors when it comes to the 'considerable psychological impact' including that: (1) "GFD improves quality of life (QoL) in symptomatic patients, but not always in asymptomatic patients", (2) "Anxiety and depression may affect dietary adherence and QoL" and (3) "Fatigue is sometimes the unique symptom at CD presentation."

Point (1) taps into the idea of a better cost-benefit profile from the use of a GFD when people actually see such a diet improving their health and wellbeing. As per other rumblings on this blog, I might also suggest that this effect extends into some of the asymptomatic group too (see here). Point (2) raises an important issue that potential psychological effects associated with CD might have important implications for things like sticking to the diet. I wonder if that also includes those slightly outside of the classical presentation of CD too? Point (3) on fatigue as a possible 'unique' symptom of CD takes me back to a distant post titled 'gluten relations' and the idea that screening for CD or even the broader non-coeliac gluten sensitivity (NCGS) might be indicated in a few 'fatigue-linked' conditions including cases of chronic fatigue syndrome / myalgic encephalomyelitis (CFS / ME) (sorry, SEID). By saying that I'm not making any value judgements about SEID simply being CD or vice-versa, merely that within the spectrum of fatigue-manifesting conditions, one might find one or two surprising results [2] as you might in other conditions too [3].

Yet after all that, mass screening for CD is still not indicated? [4]

Music: Muse - Plug In Baby.

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[1] Zingone F. et al. Psychological morbidity of celiac disease: A review of the literature. United European Gastroenterol J. 2015 Apr;3(2):136-45.

[2] Isasi C. et al. Fibromyalgia and chronic fatigue syndrome caused by non-celiac gluten sensitivity. Reumatol Clin. 2015 Jan-Feb;11(1):56-7.

[3] Gadoth A. et al. Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015. April 13.

[4] Ludvigsson JF. et al. Screening for celiac disease in the general population and in high-risk groups. United European Gastroenterol J. 2015 Apr;3(2):106-20.

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Zingone F, Swift GL, Card TR, Sanders DS, Ludvigsson JF, & Bai JC (2015). Psychological morbidity of celiac disease: A review of the literature. United European gastroenterology journal, 3 (2), 136-45 PMID: 25922673

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

ME/CFS is real: confirmation if it is needed...

"Scientists discover robust evidence that chronic fatigue syndrome is a biological illness" went the title of the press release for the study by Mady Hornig and colleagues [1] (open-access) detailing an immune 'signature' and also possible staging of the illness.

I couldn't help but wince at some of the media headlines reporting on this study as 'proof' that chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) is a real illness. As I've indicated before on this blog (see here) anyone who has trawled through the collected peer-reviewed research in this area would be hard pressed to arrive at any other conclusion than that CFS/ME is very real and severely impacts on a person's quality of life. I say that accepting that the various definitions and descriptions of the conditions (note the plural) have not always been kind to CFS/ME research and to a large extent, perhaps held back science from making the breakthroughs we've potentially seen with the Hornig results. Hopefully SEID [systemic exertion intolerance disease] might help this process along a little...

Back to the paper:

• The authorship of the latest research paper includes the great and the good of CFS/ME (and autism) research. Mady Hornig and Ian 'virus hunter' Lipkin have talked quite a bit in recent times about their research commitment to CFS/ME following the whole XMRV de-discovery issue a few years back (see here). José Montoya has similarly impressed with the idea that certain anti-virals *might* be indicated for some cases of CFS/ME (see here).
• Cytokines - those chemical messengers of the immune system - were the target molecules predominating in the Hornig paper taking into account "diagnosis and other clinical variables". Said immune molecules (over 50 of them) were analysed in nearly 300 participants diagnosed with CFS/ME compared against nearly 350 asymptomatic controls. Authors drew on participants derived from two large US studies of CFS/ME, and those all-important case definitions relied on meeting either or both of the "1994 CDC Fukuda criteria... and the 2003 Canadian consensus criteria for ME/CFS." Participants were also categorised according to how long they had reported experiencing symptoms.
• Results: "No substantive differences were found between cases and controls when short- and long-duration cases were combined and compared with healthy control subjects." You could see how that sentence could be taken by certain people/groups. But... "Analyses that considered duration of illness revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as a dissociation of characteristic intercytokine regulatory networks." Those describing a shorter duration of illness, as a group, presented with elevated levels of several proinflammatory cytokines than controls or longer illness duration participants. As per the press release: "The association was unusually strong with a cytokine called interferon gamma that has been linked to the fatigue that follows many viral infections, including Epstein-Barr virus (the cause of infectious mononucleosis)." When they say 'unusually strong association', they talk about an odds ratio (OR) of 104.77 (95% CI, 6.975 to 1574.021; P = 0.001) (noting the very wide confidence intervals too).
• Various other analyses were also applied to the data. "The CART (Classification and Regression Tree) decision tree machine learning method was applied to plasma cytokine and clinical covariate data to find predictors that distinguished ME/CFS cases of short illness duration (≤3 years) from those with a long illness duration (>3 years)." In that respect, the age of participants seemed to play something of a role in the results obtained. But, the authors also acknowledge that this data was "not then validated on an independent test set."
• Discussions surround the possible reasons for the results obtained, particularly how symptom duration seemed to play an important role in the authors' findings. I do like the idea that "an “exhaustion” of the cytokine-producing cells" might account for why there seems to be a 'burst' of immune system involvement in the early stages of the disease followed by a kind of cytokine burn-out. "The study supports the idea that ME/CFS may reflect an infectious "hit-and-run" event" is one way of looking at it.

What's more to say about this work? Well, we might be seeing 'immune markers' mentioned a little more in CFS/ME research circles in the near future on top of what has been previously reported (see here). Whether specific cytokine profiles might be considered 'diagnostic' for CFS/ME needs quite a bit more replication before anyone gets too ahead of themselves. That being said, as and when such a profile is detected, one might reasonably assume that there could be ways and means to intervene. Another quote: "There are already human monoclonal antibodies on the market that can dampen levels of a cytokine called interleukin-17A that is among those the study shows were elevated in early-stage patients." I say this without making any judgement calls nor providing anything that looks, sounds or smells like clinical/medical advice. I might also advance the idea that other factors might also link into something like IL-17A (see here).

I'm also minded to say that the excitement over immune issues being associated with CFS/ME shouldn't also push other areas back into the shadows as per the very interesting findings being reported on things like mitochondrial function (see here), the gut microbiota (see here) and potential intervention options (see here) to name but a few.

Still, only a few months into 2015 and CFS/ME (or SEID if you wish) is really making some research headlines...

[Update: 2 March 2015: The full IoM report is available here].

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[1] 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.

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Mady Hornig, José G. Montoya, Nancy G. Klimas, Susan Levine, Donna Felsenstein, Lucinda Bateman, Daniel L. Peterson, C. Gunnar Gottschalk, Andrew F. Schultz, Xiaoyu Che, Meredith L. Eddy, Anthony L. Komaroff, & W. Ian Lipkin (2015). Distinct plasma immune signatures in ME/CFS are present early in the course of illness Science Advances, 1 (1) : http://dx.doi.org/10.1126/sciadv.1400121

New name: Systemic Exertion Intolerance Disease?

The name is: Systemic Exertion Intolerance Disease (SEID) (which as one of my very observant Facebook friends pointed out is DIES backwards).

A very quick post to direct you to the public release of the findings from the US Institute of Medicine (IoM) looking at the name and current criteria used to diagnose Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) (see here). The proposed diagnostic criteria for CFS/ME, sorry SEID can be viewed here.

Some of the background to these findings can be seen here and some of the media about the new IoM recommendations can be seen here and here.

Many with either personal or professional experience of CFS/ME will know all about the issue of diagnosis and CFS/ME, and outside of the struggle to recognise that this is a very real condition which can severely impact on a person's life, how confusing the diagnostic criteria can be. This has also had various implications on both research and practice [1].

The IoM was charged with looking at the existing ways and means that CFS/ME was defined and "recommend clinical diagnostic criteria for the disorder to address the needs of health providers, patients, and their caregivers" (see here). To that end, their guidance now reflects these efforts although at the current time I'm having some difficulty in locating how they tackled the idea of "distinguish[ing] between disease subgroups" which I think should have represented quite a big leap forward in these days of plural labels and heterogeneity in symptoms and comorbidity (see here). At this point I might refer you to a paper I wrote that touched upon this a few years back [2]. I am however happy to see that pediatric ME/CFS or SEID has been mentioned in their various guidance in light of the growing realisation that the condition can manifest in children and young people too (see here).

Obviously it's going to take time for these findings to find their way from guidance to practice and beyond so I don't think massive changes will be immediately forthcoming. One would hope that alongside the growing interest in the biology/genetics of CFS/ME (acknowledging how the condition can also impact on psychology too) that moves towards the development and testing of biological therapeutics in particular, might be accelerated (see here).

To close: Breaking Bad and Say My Name... 'sorta Greg'.

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[1] Morris G. & Maes M. Case definitions and diagnostic criteria for Myalgic Encephalomyelitis and Chronic fatigue Syndrome: from clinical-consensus to evidence-based case definitions. Neuro Endocrinol Lett. 2013;34(3):185-99.

[2] Whiteley P. et al. Correlates of Overlapping Fatigue Syndromes. Journal of Nutritional and Environmental Medicine. 2004; 14: 247-259.

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Morris G, & Maes M (2013). Case definitions and diagnostic criteria for Myalgic Encephalomyelitis and Chronic fatigue Syndrome: from clinical-consensus to evidence-based case definitions. Neuro endocrinology letters, 34 (3), 185-99 PMID: 23685416