'Physical signs' to aid the diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)?

I have to say that I wasn't completely au fait with the Perrin technique mentioned in the article by Lucy Hives and colleagues [1] or the exploration of whether "the five physical signs of the Perrin technique can assist in the screening of patients with CFS/ME, which could then subsequently lead to quicker treatment" but I was interested.

Interested because CFS/ME remains a condition diagnosed on the basis of observable symptoms. As a result, it is still subject to quite a few 'debates' on what the best fitting criteria might be (see here). Anything that might potentially help that diagnostic position is therefore welcomed. Indeed, anything that might provide something approaching an objective diagnosis could potentially open up a whole new world of treatment and intervention...

Accepting that talk of 'Perrin's point' "lymphatic drainage" and "the principle that toxins within fluid in the brain or spine column do not drain away as they should" are probably not everyone's cup of 'science' tea, the authors set about testing the Perrin technique for potentially diagnosing CFS/ME. Also whether "newly trained allied health professional (AHP) with no prior experience of CFS/ME" had the same diagnostic accuracy as more expert AHP. I'm not actually sure what specific disciplines those AHPs were actually following, but looking at the text - "One had 10 years of experience of using the Perrin technique and working with patients with CFS/ME (experienced AHP)" - and the affiliations of the authorship list (see here) - it looks to me like something between physiotherapy and osteopathy as a rough guess.

Approaching 100 participants were recruited for study - "52 patients with CFS/ME and 42 non-CFS/ME controls" - all adults and for those diagnosed with CFS/ME, all with "a prior formal diagnosis of CFS/ME at a National Health Service (NHS) hospital specialised clinic" and displaying various core features of CFS/ME (i.e. persistent fatigue and "the fatigue should feel worse after physical activity"). I note that they also required "a clear starting point to the fatigue." Assessments - "standard clinical neurological and rheumatological" - were also carried out and CFS/ME diagnosis was pitted (blind) against the Perrin technique. Indeed: "A priori, the Perrin technique required all five symptoms to be present for a patient to be diagnosed as CFS/ME." Not to copy too much text from the Hives paper, the five symptoms were: "(1) postural/mechanical disturbances of the thoracic spine... ; (2) breast varicosities... ; (3) tender Perrin’s point... ; (4) tender coeliac plexus... ; and (5) dampened cranial flow."

How did the Perrin technique do? Well, not bad at all: "Results show that, on average, the experienced AHP was most accurate (86%) at correctly diagnosing participants. This was followed by the newly trained who correctly diagnosed 77% and the physician who correctly diagnosed 69% of participants." I reiterate that the clinical team were "blinded to the groupings" (whether or not they were seeing a patient with CFS/ME or not).

Hives et al also provide some data on the specificity and sensitivity of the Perrin technique in relation to CFS/ME diagnosis, as well as some initial chatter about whether all the five symptoms together represent the most efficient grouping. They concluded that: "accuracy for both AHPs, overall, is highest when using only tests of tender coeliac plexus and postural/mechanical disturbance of the thoracic spine" potentially suggesting that "not all of the five physical signs may be necessary."

Whilst pretty interesting results, there is a need for further independent replication before anyone gets too excited about a possible objective test for CFS/ME. The authors similarly note that this was a straight 'yes you're diagnosed with ME/CFS' vs 'no diagnosis of CFS/ME' but also in future need to take into account other conditions potentially overlapping with CFS/ME such as fibromyalgia (FM) and whether the diagnostic waters are still so clear with such comparisons in mind. As I've mentioned in other posts (see here), the tendency in some quarters to conflate CFS/ME with 'chronic fatigue' also perhaps needs some further investigation too.

Still, there are reasons to be optimistic about the Hives findings. How, even alongside more traditional ways and means of diagnosing CFS/ME, the Perrin technique (in whatever form) *might* serve as a useful accompaniment to aiding the diagnostic process and perhaps even further distancing CFS/ME from the whole biopsychosocial model of disease (see here)...

----------

[1] Hives L. et al. Can physical assessment techniques aid diagnosis in people with chronic fatigue syndrome/myalgic encephalomyelitis? A diagnostic accuracy study. BMJ Open. 2017; 7: e017521.

----------

"a gradual decline in recorded diagnoses of CFS/ME since 2001"?

The quote forming the title of today's post comes from the paper by Simon Collin and colleagues [1] (open-access available here) who, based on analysis of the UK "Clinical Practice Research Datalink (CPRD), formerly known as the General Practice Research Database (GPRD)" set out to look at the "Incidence of CFS/ME [chronic fatigue syndrome/ myalgic encephalomyelitis], FM [fibromyalgia], post-viral fatigue syndrome (PVFS), and asthenia/debility." I say incidence but that last sentence should really read as  'recorded incidence'.

Searching the research database between January 2001 and December 2013, researchers looked at the [recorded] incidence (that's incidence not prevalence) of the various fatigue-related conditions/labels recorded by participating GP (general practice) surgeries.

Recorded diagnoses of CFS/ME showed a soft but noticeable decline over the period of study: "Annual incidence of CFS/ME decreased from 17.5 [per 100,000 people] in 2001 to 12.6 in 2013." A similar decline was also noted in respect of PVFS and asthenia/debility. When however it came to FM, there was an overall increase in cases between 2001 and 2013 (albeit characterised by peaks and troughs in recorded diagnoses across specific years).

Some other important data were also reported on. So: "All diagnoses showed strong evidence of variation by age and sex" and estimated socio-economic status (SES). Further: "Incidence rates of CFS/ME were 2.4-fold higher among women... with peak incidence in the 40–49 years age group." Women were also more likely to be over-represented in relation to a diagnosis of FM too.

This is potentially important data. It suggests that at least among participating GP practices in the CPRD, recorded diagnoses of CFS/ME seem to be going down. The caveats however mentioned by the researchers do need to be highlighted, not least that they "examined recorded data rather than actual incidence, i.e. we are describing incidence rates of GPs’ recording of diagnostic codes" and "diagnoses were not independently validated." In other words, this is data based on "GPs enter[ing] medical diagnoses and symptoms as Read codes." I might also add in another quote from the authors too: "In 2005, 48% of GPs in one English region did not feel confident about making a diagnosis of CFS/ME, and 28% did not recognise CFS/ME as a legitimate illness." A bit of an issue by all accounts if one would like to get accurate data on incidence or prevalence.

I also have a to raise a point in relation to this latest data and how it compares with other data produced by the same research group (see here). Keeping in mind that incidence is not the same as prevalence, I bring back to your attention the findings reported by Collin and colleagues [2] on another occasion suggesting that nearly 2% of 16-year olds in the ALSPAC cohort were affected by CFS. More work needs to be done when it comes to official monitoring of the numbers of cases of CFS/ME (and FM) outside of just reliance on GP practice recordings in order to get a true picture of numbers of cases. Of course, there is another possible explanation for the fall in recorded diagnoses: GPs are increasingly understanding that some of the symptoms included under the banner of CFS/ME overlap with various other conditions/labels too...

----------

[1] Collin SM. et al. Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001-2013: a Clinical Practice Research Datalink study. J R Soc Med. 2017 Jan 1:141076817702530.

[2] Collin SM. et al. Chronic Fatigue Syndrome at Age 16 Years. Pediatrics. 2016 Feb;137(2):e20153434.

----------

Collin SM, Bakken IJ, Nazareth I, Crawley E, & White PD (2017). Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001-2013: a Clinical Practice Research Datalink study. Journal of the Royal Society of Medicine PMID: 28358988

Gender differences in chronic fatigue syndrome

The title of this post matches the title of the paper published by Monica Faro and colleagues [1] (open-access here) and some potentially important data on "whether there are gender-related differences in CFS [Chronic Fatigue Syndrome], and to define a clinical phenotype in men."

Starting with the idea that the prevalence of CFS - a generic term covering a spectrum of conditions characterised by severe and debilitating fatigue among several other things - may have a gender skew towards females over males [2], Faro and colleagues set about looking at whether the presentation of CFS might also differ between males and females. I should perhaps back-up a little and highlight how the sex differences in CFS frequency might be somewhat clouded by the fact that quite a few diagnostic criteria systems are currently around for CFS (also called myalgic encephalomyelitis, ME) and that under-diagnosis of men cannot yet be discounted as contributing to any gender differences. Think autism and the perceived gender skew there as an example of potential under-diagnosis in action with another label in mind.

Based on the analysis of over 1300 patients formally diagnosed with CFS (using the Fukuda 1994 definition), 119 (9%) of the cohort were described as male. Following the administration of a clinical interview "conducted by 2 specialized internists in the diagnosis of the disease" among other things, researchers reported a few interesting details. First, men in general seemed to be diagnosed slightly earlier than women. It wasn't a stark difference measured in decades for example, but a difference of on average, 4-5 years. Further: "Widespread pain, muscle spasms, dizziness, sexual dysfunction, Raynaud's phenomenon, morning stiffness, migratory arthralgias, drug and metals allergy, and facial oedema were less frequent in men." Fibromyalgia as "defined by the criteria of the ACR" was also reported to be less frequent in men than women (29% vs 58% respectively). Also of interest was the suggestion that: "The most common triggering factor was an infection" where men were more likely than women to relate their symptoms to such a factor.

These are interesting findings that add an extra dimension to discussions about CFS with a view to a possible role for gender differences. Obviously one has to be a little guarded about making too many sweeping generalisations that for example, CFS is a 'different condition' for men and women because we don't really have a great deal of evidence to back up such a claim. Insofar as the possibility that men are diagnosed earlier than women, this could point to a number of things. Either this is reflective of an earlier onset of the illness in men or that women find it more difficult to get diagnosed with CFS. I'd be interested to see how this variable pans out as and when more research in this area is forthcoming.

Music: The Calling - Wherever You Will Go.

----------

[1] Faro M. et al. Gender differences in chronic fatigue syndrome. Reumatol Clin. 2015 Jul 16. pii: S1699-258X(15)00081-9.

[2] Líndal E. et al. The prevalence of chronic fatigue syndrome in Iceland - a national comparison by gender drawing on four different criteria. Nord J Psychiatry. 2002;56(4):273-7.

----------

Faro M, Sàez-Francás N, Castro-Marrero J, Aliste L, Fernández de Sevilla T, & Alegre J (2015). Gender differences in chronic fatigue syndrome. Reumatologia clinica PMID: 26190206

Metal sensitisation and chronic fatigue syndrome?

I have to admit that I pondered longer than usual over whether I should talk about the paper by Vera Stejskal [1] (open-access here) and the idea that: "Patients with CFS [chronic fatigue syndrome] and fibromyalgia are frequently sensitized to metals found in the environment or used in dentistry and surgery."

It was't that I doubted that metals - certain types present in the wrong place or wrong concentration - can affect physical and psychological health and wellbeing as per the example of lead (see here). I was even happy to accept some mention of ASIA (‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’) in the Stejskal paper given my previous exploration of this potentially tricky concept with chronic fatigue syndrome in mind (see here) and some more recent data [2]. The editor-in-chief of the publishing journal, I should add, knows a little more about this than I.

It's just that when I read the paper in its entirety and then googled the analytical weapon of choice - MELISA (Memory Lymphocyte ImmunoStimulation Assay) or rather the lymphocyte transformation test (LTT) - I couldn't help but be a little unsettled at some of the results displayed. When I also found that Dr Stejskal "is the inventor of the MELISA test and holder of trademarks" (see here) without however seemingly any mention of this as a potential conflict of interest on her paper, my brow furrowed a little more.

Putting those issues to one side and hopefully avoiding any terse replies from proponents of MELISA, I am actually quite interested in the findings reported as they were in a peer-reviewed journal. A paper by Kern and colleagues [3] potentially intersecting with the Stejskal results bolstered my decision to blog about this issue and the potential to offer something important for at least some people falling onto the ME/CFS spectrum, subject to further inquiry. Oh, and by the way, when I say ME/CFS I mean SEID...

The Stejskal paper is open-access but that's never stopped me before...

• Based on a very, very small participant number - three subjects with CFS and two with fibromyalgia - where metal exposure was "as a trigger for their ill health", MELISA testing was undertaken to measure "delayed-type hypersensitivity to metals (metal allergy)".
• The assay involves culturing lymphocytes (white blood cells) with selected metals at various concentrations and then measuring lymphocyte proliferation and using something called the Stimulation Index (SI) to describe "reactivity to metals". Just in case you might be querying the method, it has been validated by others as per the paper from Valentine-Thon and colleagues [4].
• Results are presented in a case-by-case format. Control participant data (n=9) based on MELISA testing is also provided: "In the majority of controls, MELISA was negative, indicating non-responsiveness to metals at the lymphocyte level." The same could not however be said for the symptomatic participants who presented with a range of results suggestive of issues with metal allergy. Interestingly, data is presented at both initial testing and "follow-up" after removal of various metal sources and is also complemented in some cases by more traditional patch testing results.
• The author concludes: "In this study, reduction of inflammation-causing metals resulted in an alleviation of symptoms and long-term health improvement. The decrease of metal-specific lymphocyte responses in vitro after removal of sensitizing metals supports the clinical relevance of these findings."

As per other discussions on this blog, CFS/ME is a condition which has seen it's fair share of discussion and debate down the years (see here). A few weeks back, part of those discussions 'kicked off' again focused on the paper by Chalder and colleagues [5] and headlines about 'fear of exercise'. I might also draw your attention to a pretty good critique on that Chalder paper too (see here) alongside what the Cochrane Library recently said about exercise 'therapy' and CFS [6]. In this context, the Stejskal paper talking about metals potentially perpetuating symptoms and even the notion that something else - "As a child she had received at least eight thimerosal and aluminium-containing vaccines" - *might* be implicated in cases, is never going to be particularly well-received in some quarters.

I'm not falling hook, line and sinker for the Stejskal results by the way, based as they were, on case reports and with very little discussion of objective measures of symptom profiles for example, outside of sentences like: "Rapid health improvement followed and she became symptom free." I am however interested in research which talks about clinical improvement in cases of ME/CFS recognising how destructive an illness this can be and the stigma which still pervades some discussions of the condition. The Stejskal paper perhaps offers a template for the consideration of further, more controlled study is this area, expanding on our current understanding of metal allergy [7] outside of just a generalised reaction to jewellery and possibly contributing further to some of the biology potentially involved in at least some CFS/ME [8].

Music then... One by Johnny Cash. Oh and happy birthday Questioning Answers (4 today and therefore ready for reception!)

----------

[1] Stejskal V. Metals as a common trigger of inflammation resulting in non-specific symptoms: diagnosis and treatment. Isr Med Assoc J. 2014 Dec;16(12):753-8.

[2] Somers EC. et al. Mercury Exposure and Antinuclear Antibodies among Females of Reproductive Age in the United States: NHANES. Environ Health Perspect. 2015. Feb 10.

[3] Kern JK. et al. Evidence supporting a link between dental amalgams and chronic illness, fatigue, depression, anxiety, and suicide. Neuro Endocrinol Lett. 2014 Dec 24;35(7):537-552.

[4] Valentine-Thon E. et al. LTT-MELISA is clinically relevant for detecting and monitoring metal sensitivity. Neuro Endocrinol Lett. 2006 Dec;27 Suppl 1:17-24.

[5] Chalder T. et al. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. The Lancet Psychiatry. 2015. Jan 13.

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

[7] Thyssen JP. & Menné T. Metal allergy--a review on exposures, penetration, genetics, prevalence, and clinical implications. Chem Res Toxicol. 2010 Feb 15;23(2):309-18.

[8] Morris G. & Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014 Mar;12(2):168-85.

----------

Stejskal V (2014). Metals as a common trigger of inflammation resulting in non-specific symptoms: diagnosis and treatment. The Israel Medical Association journal : IMAJ, 16 (12), 753-8 PMID: 25630203

Chronic fatigue syndrome by ASIA?

Unicorns, I love them. Unicorns, I love them. 

ASIA, in the context of this post, does not refer to the continent but rather the suggestion of an: ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ and some potentially contentious findings reported by Nancy Agmon-Levin and colleagues [1].

Describing a small cohort of participants diagnosed with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM), the authors put forward the idea that "some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome", more specifically following hepatitis B vaccination (HBVv). They report on a latency period (the interval between exposure and clinical appearance of symptoms) ranging "from days to a year" with a mean temporal period of around 38 days. They also report specific manifestations of symptoms (neurological, fatigue, muscoskeletal and gastrointestinal) and importantly that: "Autoantibodies were detected in 71 % of patients tested". Autoantibodies by the way, refers to antibodies against self tissue as per what has been noted in various autoimmune conditions/diseases. The authors conclude: "ASIA criteria were fulfilled in all patients eluding the plausible link between ASIA and CFS/FM."

OK. There are a few words of caution that one needs to exercise with this kind of work before anyone gets too enthusiastic. This was an information-gathering study, so authors were specifically describing their cohort of participants "following HBVv immunization". There were no control groups, so one also needs to be aware of that.

A quick trawl of the other research literature on the topic of ASIA reveals however that this is not the first time that this concept has cropped up in the peer-reviewed science sector. Shoenfeld &Agmon-Levin [2] (the same authors on the current paper) first advanced the concept of ASIA or [Yehuda] Shoenfeld's syndrome a few years back. Based on the examination of four conditions: "siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena" they concluded that some commonalities were present and ASIA was born. An editorial accompanying their paper [3] kinda said it all: "It is an intriguing issue and one that is likely to be provocative and lead to further biologic and molecular investigations". I might also direct you to other discussions titled: What is ASIA?

Since then, a number of articles have appeared discussing ASIA / Shoenfeld's syndrome. Bassi and colleagues [4] reported findings involving a mouse model of lupus - "a lupus-prone murine model" - injected with complete Freund's adjuvant (CFA) (an immunostimulant). They reported that: "the injection of CFA in NZB/NZWF1 mice accelerated autoimmune manifestations resembling 'ASIA' syndrome in humans." A more thorough review of the animal model findings can be found in the article by Cruz-Tapias and colleagues [5].

The types of adjuvant noted as being potentially connected to ASIA have also been discussed, as per the article by Vera-Lastra and colleagues [6]. Squalene, aluminum hydroxide and silicone are mentioned. Squalene with regards to Gulf-War syndrome was something which particularly stuck out to me given my previous interest in this collection of symptoms present for some post Operation Desert Storm (see here). Although the source of some speculation, papers such as the one from Pamela Asa and colleagues [7] noting that squalene antibodies were linked to the "majority of symptomatic GWS patients" is an interesting finding. For balance, I will also refer you to the paper by Lippi and colleagues [8] standing up for squalene.

The paper from Perricone and colleagues [9] (open-access) brings us back to the involvement of ASIA in the 'mosaic of autoimmunity' and how genetics and environment might merge. The discussions move into various areas including that of anti-phospholipid syndrome (Hughes syndrome) as well as other well-known autoimmune areas (e.g. coeliac disease). Connective tissues disorders also discussed in the Perricone paper also bring in one reason why hepatitis B vaccine was also considered in the starting paper in question, as per the report by Perricone and Shoenfeld [10] and their discussions on hepatitis B vaccine and 'undifferentiated connective tissue disease' as being: "Another brick in the wall of the.. ASIA". Further research has added to such sentiments [11].

As things stand with the body of research detailing ASIA, I don't think that this is a concept we can readily discard as being potentially real and relevant to at least some clinical presentation potentially including CFS/FM. I know to talk adverse effects from vaccination, or their adjuvants, can stir up some heated discussions in some quarters (see here) but even in contentious areas covering something like autism or autistic presentation, science might still have a role to play [12]. I say this reiterating the important value of vaccination as per this CDC infographic.

This is also the second time that I've talked about vaccination and autoimmunity as potentially being linked on this blog as per another contentious paper in another contentious area (see here). It strikes me that there is quite a bit more to do in looking at any possible connection, particularly when one considers that ASIA has been similarly discussed (albeit in case studies) with other biologics in mind [13].

Music: The Ragtime Gals and a certain celebrity..

----------

[1] Agmon-Levin N. et al. Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA). Immunol Res. 2014 Nov 27.

[2] Shoenfeld Y. & Agmon-Levin N. 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011 Feb;36(1):4-8.

[3] Meroni PL. Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome? J Autoimmun. 2011 Feb;36(1):1-3.

[4] Bassi N. et al. Induction of the 'ASIA' syndrome in NZB/NZWF1 mice after injection of complete Freund's adjuvant (CFA). Lupus. 2012 Feb;21(2):203-9.

[5] Cruz-Tapias P. et al. Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)--animal models as a proof of concept. Curr Med Chem. 2013;20(32):4030-6.

[6] Vera-Lastra O. et al. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld's syndrome): clinical and immunological spectrum. Expert Rev Clin Immunol. 2013 Apr;9(4):361-73.

[7] Asa PB. et al. Antibodies to squalene in Gulf War syndrome. Exp Mol Pathol. 2000 Feb;68(1):55-64.

[8] Lippi G. et al. Vaccination, squalene and anti-squalene antibodies: facts or fiction? Eur J Intern Med. 2010 Apr;21(2):70-3.

[9] Perricone C. et al. Novel pebbles in the mosaic of autoimmunity. BMC Med. 2013 Apr 4;11:101.

[10] Perricone C. & Shoenfeld Y. Hepatitis B Vaccination and Undifferentiated Connective Tissue Disease: Another Brick in the Wall of the Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA). JCR: Journal of Clinical Rheumatology. 2013; 19: 231-233.

[11] Zafrir Y. et al. Autoimmunity following hepatitis B vaccine as part of the spectrum of 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants' (ASIA): analysis of 93 cases. Lupus. 2012 Feb;21(2):146-52.

[12] Singh VK. Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism. Ann Clin Psychiatry. 2009 Jul-Sep;21(3):148-61.

[13] Barros SM. & Carvalho JF. Shoenfeld's syndrome after pandemic influenza A/H1N1 vaccination. Acta Reumatol Port. 2011 Jan-Mar;36(1):65-8.

----------

Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A, Amital H, & Shoenfeld Y (2014). Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA). Immunologic research PMID: 25427994

Pain and adolescent Chronic Fatigue Syndrome

"We found a higher prevalence of severe pain among adolescents with CFS [Chronic Fatigue Syndrome] and lowered pain thresholds compared with HCs [healthy controls]".

That was the headline generated by the study from Anette Winger and colleagues [1] (open-access) looking to describe several parameters tied into experience of pain in the context of CFS. Further: "The total sum of bodily symptoms represented a heavy burden with great functional consequences".

Your hokey pokey dragon is out helpin' Santa Claus pull his sled!

The Winger paper is open-access, and pretty self-explanatory in terms of the hows and whys of the study (including strengths and limitations) so no need for me to further complicate things. As part of the NorCAPITAL project (The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial) (ClinicalTrial.gov entry here) which has already reported on the use of clonidine for CFS [2], the latest publication is an important add-on.

There are a few details included in the results which do however merit some additional highlighting. So:

• "In the present study, almost three-quarters of the adolescents with CFS suffered from weekly pain, and pain on a daily basis was a problem for half of the patients". This was "highly significant" when compared with reports from controls, particularly where two-thirds of CFS participants reported weekly headaches. 
• Muscle and joint pain were also recorded by adolescents with CFS alongside almost half reporting abdominal pain. Indeed, joint pain showed the most disparity between the groups with reports of such pain tipping 70% in the CFS group compared with only 10% of controls reporting this more frequently than once a month.
• When looking at result examining the pressure pain threshold (PPT) - "the minimum intensity of a stimulus that is perceived as painful" - and examining scores based on completion of the Brief Pain Inventory (BPI), authors concluded that: "At all measure points, PPTs were significantly lower (all p<0.001) among patients with CFS than HCs".
• "In our study, the adolescents reported that pain interfered with school, general activity and mood; however, we cannot conclude from this study that pain has a causal effect, because it could be the other way around". 

What's more to say about this research? Well, the very important message that the presentation of CFS might go well beyond just 'chronic fatigue' is paramount. This is not new news to science and practice as per the various reviews on the topic of pain exemplified by Nijs and colleagues [3]. I dare say that some public perceptions of CFS/ME would also change if more people understood that pain is a seemingly important manifestation of the condition. Oh and that CFS and pain sensation might not just be all in the mind...

I'm also inclined to introduce the condition fibromyalgia (FM) into proceedings, given the many and varied reports talking about key symptoms overlapping [4]. I'm not altogether sure of the hows and whys of FM and CFS connecting, but certainly the primary FM symptom of widespread pain and extreme sensitivity strikes me as being potentially important. With no medical advice given or intended and perhaps somewhat counter-intuitive to analgesia, the increasing body of work looking at the use of something like low-dose naltrexone (see here for some of my interest in this area) for pain in FM [5] may also very well be something in need of a little more study with pain in CFS in mind, alongside other possible pain relief options.

So then, The White Stripes with Ball and Biscuit.

----------

[1] Winger A. et al. Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study. BMJ Open. 2014; 4(10): e005920.

[2] Fagermoen E. et al. Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial. BMC Research Notes 2012, 5:418

[3] Nijs J. et al. Pain in patients with chronic fatigue syndrome: time for specific pain treatment? Pain Physician. 2012 Sep-Oct;15(5):E677-86.

[4] Aaron LA. et al. Overlapping Conditions Among Patients With Chronic Fatigue Syndrome, Fibromyalgia, and Temporomandibular Disorder. Arch Intern Med. 2000;160(2):221-227.

[5] Younger J. et al. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38.

----------

Winger, A., Kvarstein, G., Wyller, V., Sulheim, D., Fagermoen, E., Smastuen, M., & Helseth, S. (2014). Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study BMJ Open, 4 (10) DOI: 10.1136/bmjopen-2014-005920

Mitochondrial dysfunction and ME/CFS

I continue my interest in research examining chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) in this post looking at what might turn out to be quite an important paper by Booth and colleagues* (full-text) on a potential role for mitochondrial dysfunction.


Where to start....

Mitochondria (plural) are not to be confused with the midi-chlorians of a Galaxy far, far away. A few associated words: organelles, eukaryotic cell, the power plant of cells, cellular respiration (this link carries a really easy to understand description of this process). In short, mitochondria provide energy to the cell in the form of ATP. Cells like most thing need energy to function properly; where insufficient energy is produced... well, cells don't work as well as they should and the results can be serious and wide-ranging.

I've kinda eluded to mitochondrial function, or rather dysfunction, in posts like this one on lactate levels in autism although I dare say that as some point I will come back to the topic in more detail. Indeed elevations in lactate levels do seem to indicate some potential issue with mitochondrial dysfunction as per studies like this one from Magner and colleagues**.

I digress. Booth et al have previously reported on mitochondrial dysfunction in cases of CFS/ME in this paper*** (full-text); the current study being a sort of extension and elaboration effort. I might add that they are by no means the first to suggest that there may be some mitochondrial 'involvement' in cases of CFS/ME (see here and here). Low carnitine levels? Now where have I heard that before?

Their latest paper is full-text and contains quite a bit of data but a short summary is perhaps in order:

• The ATP profile features quite strongly in the paper. This is described as containing among other things, ATP concentration in blood neutrophils (in the presence of excess magnesium, deficiencies of which have been linked to CFS) and is a part of a so-called mitochondrial energy score (MES). In their previous paper (***) the authors reported an impressive correlation between MES and CFS Ability as described using the Bell Ability Scale, a rough and ready measure of the level of disability as a consequence of the condition (see here). 
• It looks like there were a few elements to this paper including a reanalysis of the cohort reported in their previous paper - cohort 1 (minus 10 participants who were outside of the age range of controls, again taken from their original publication) and analysis of a new participant group - cohort 2 - made up of 138 participants aged between 18-65, mean age 41 years.
• Similar to the last paper, the MES showed a pretty good correlation with CFS Ability (correlation coefficient = 0.80). I have to admit that quite a lot of the rest of the results are beyond the limits of my biochemistry as various measures of ATP inhibition, functionality of the translocator proteins (e.g. ANT) and efficiency of oxidative phosphorylation are tested ( I think!). The end result is that the mitochondrial dysfunction noted by the authors in this patient group seems to (a) frequent, very frequent and (b) particularly involves issues with the translocator protein (TL) regulating the passage of ATP and ADP across mitochondrial membranes (see here - no endorsement intended). Other preliminary studies of oxidative phosphorylation capacity in CFS for example, suggested that this is probably not the main reason for mitochondrial dysfunction**** (full-text).
• The authors conclude: "Taken together, these measurements show that ME/CFS is a serious illness which may affect every cell in the body".

And relax. 

I should point out that my interpretation of the Booth results should not be taken as Gospel or anything like that. I do however believe that these results are important for CFS/ME and potentially represent at least one part of the puzzle that is this debilitating set of conditions. Independent replication of the Booth results is the next step.

I was drawn to the fact that other conditions presenting with a fatigue component such as fibromyalgia have also been suggested to be linked to issues with mitochondria as per this case study by Abdullah and colleagues***** (full-text). The 'solution' to their reported case was supplementation with various compounds including coenzyme Q10, creatine and carnitine among other things. Whilst I am not in a position to endorse anything like such a treatment protocol (please do speak to your healthcare provider first), I note that supplements like coenzyme Q10 have cropped up more than once in relation to CFS/ME as per articles like this one****** from a familiar name to this area of study, Michael Maes and colleagues.

ME/CFS are a heterogeneous set of conditions which, similar to the description of autism, probably include quite a few different paths to the development of symptoms. Whilst the area of mitochondrial dysfunction is an attractive potential marker showing involvement in cases - at least some cases - the question of whether this is a 'core' aspect of the conditions still remains to be seen alongside its connection with other pathways of interest. 


To finish, Kate Bush sings Wuthering Heights. A lesson in the art of dance and music (and its absolutely fantastic).

----------

* Booth NE. et al. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). International Journal of Clinical & Experimental Medicine. 2012; 5: 208-220.


** Magner M. et al. Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures. European Journal of Paediatric Neurology. 2011; 15: 101-108.

*** Myhill S. et al. Chronic fatigue syndrome and mitochondrial dysfunction. International Journal of Clinical & Experimental Medicine. 2009; 2: 1-16.

**** Vermeulen RC. et al. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. Journal of Translational Medicine. 2010; 8: 93.

***** Abdullah M. et al. Mitochondrial myopathy presenting as fibromyalgia: a case report. Journal of Medical Case Reports. 2012; 6: 55.

****** Maes M. et al. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinology Letters. 2009; 30: 470-476.