User:Tekaphor/CFS research

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Disclaimer:

This page is a temporary/dynamic cache collection of research references for issues relating to the ME/CFS (chronic fatigue syndrome) article, particularly weak spots and controversial arguments. It is not intended to be a complete collection, nor promote a particular point of view, nor give equal weight to each reference. It may be inappropriate to simply copy and paste any content from here into the article without first looking into the related references and checking Wikipedia guidelines. Keep in mind that the research usually reflects the CDC 1994 criteria, and it doesn't help that CFS is arguably heterogeneous, which may explain the common discrepancies in research. Please do not edit this page. Feel free to post on the talk page. Previous links to here from other pages may have become outdated or irrelevant.

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Contents 1 STRESS AND INFECTION IN CFS 2 SELECTED RESEARCH COMPILED LATE 2007 2.1 Depression and other psychiatric comorbidities in CFS 2.1.1 General 2.1.2 Prevalence 2.1.3 Premorbidity 2.2 Onset and possible risk factors 2.2.1 Majority report flu-like onset 2.2.2 More likely to occur in winter 2.2.3 Other risk factors 2.2.4 Sudden vs gradual 2.2.5 ICF vs CFS 2.3 Assorted findings 3 SUMMARY OF RESEARCH COMPILED EARLY 2007 3.1 Post-exertion symptom exacerbation 3.2 Physical fitness 3.3 Neurological abnormalities 3.3.1 Neurocognitive dysfunction 3.3.2 Neurostructural abnormalities 3.3.3 Neurochemical abnormalities 3.3.4 Other neurological findings 3.4 Psychological and psychiatric studies 3.5 Assorted findings 3.5.1 Possible risk factors 3.5.2 Other findings 3.5.3 Other treatments 3.5.4 Proposed etiologies 3.6 References

[edit] STRESS AND INFECTION IN CFS

The strong findings in the PMID 9201648 study were unusual and haven't been replicated by other studies. The abstract states "CFS started with an apparently infectious illness in 96 (72%) but a definite infection was only found in seven of these 96 (7%)."; it also says they used serology tests to identify infection, but without accessing the full text I can only speculate on the relevancy and accuracy of such testing in an illness which is diagnosed a minimum of 6 months and typically years after the supposed short-term active infection. It also doesn't say which CFS criteria they used, although this is a problem with many abstracts. It had a decent number of CFS patients but had about 1/4 of the number of controls. Furthermore, these findings weren't mirrored by similar case-control studies (below), while other studies (below) have shown that infections were involved at onset and represent a major risk factor for many patients: ...

The other stress-related study which also currently accompanies the Onset section of the chronic fatigue syndrome article (PMID 10367610) ...

• found; "The prevalence ratio (CFS patients/control subjects) for negative events was around 1.0 for the periods 4 to 12 months preceding CFS but 1.9 during the quarter year preceding the onset. For infections, the prevalence ratio increased successively during the four quarters preceding CFS (from 1.4 to 2.3)." ...
• concluded; "According to the retrospective self-reports, there were differences between the groups in fatigue, pain, and feeling of fever during the months preceding the crisis. With regard to depressive and irritable feelings, no preillness differences were reported between the groups. There was a reported excess prevalence of both infections and negative life events during the quarter year preceding the onset of CFS or crisis." ...
• discusses in the full text [1]; "In the two study groups, the occurrence of psychosocial adverse stress differs with more negative life events occurring during the last quarter preceding the onset of CFS. However, the number of infections had increased among CFS patients during the months preceding this last quarter year. This observation may suggest that infections could have sensitized the patients; that is, when the final negative life events occur during the last quarter year preceding CFS onset, vulnerability to CFS increases. In the present study, the CFS patients reported more fatigue and symptoms of infections during the year before CFS than subjects in the control group. However, we do not know whether this was due to repeated infections or other factors. With regard to psychological symptoms, no differences were observed between the groups. The cause of the predisposition, whether genetic or resulting from environmental influence of some kind, remains to be elucidated."

A more recent case-control study was published in 2003 (PMID 14580073); in the full text [2] ...

• states in the "Conventional analysis of life events" section; "For the 12 months prior to onset of the chronic fatigue syndrome, patients reported a total of 168 events of which 38 (23%) were severe. For the 12 months before hypothetical onset, controls reported 141 events of which 32 (23%) were severe. For the 3 months prior to onset patients reported 17 severe events compared to five reported by controls. Considering all events in the 3 months before onset, cases reported a total of 66 events while controls reported 37 events. Difficulties of all sorts were more common among the patients than the controls both in the year and 3 months before onset. All the CFS patients were clear that their fatigue symptoms had started before any psychiatric symptoms. There was no connection between current psychiatric state and provoking agents prior to onset in the CFS patients. Of the 21 patients with a current psychiatric disorder eight (32%) reported no provoking factors 3 months prior to onset of the chronic fatigue, compared with 25 out of 43 patients (58%) without current psychiatric disorder (x2=2.03, df=1, P<0.25)." ...
• states in the "Dilemmas" section; "The inter-rater reliability study for the measure of dilemmas yielded a kappa of 0.6 (moderate to good). In the 3 months prior to onset 19 of the 64 patients (30%) experienced a dilemma while none of the controls experienced a dilemma prior to the hypothetical onset (McNemar’s x2=43, df=1, P<0.001). In the patients 12 of the dilemmas were major difficulties, five marked difficulties, one a severe event and one was rated contextually as a non-major difficulty but the subject rated it as a major difficulty. The dilemmas involved partners or immediate family members in 14 instances and work in the remaining five."

Looking at the "Dubbo study" (abstract: PMID 16950834 ... full text: [3]) where specific infections were confirmed at onset (therefore focusing exclusively on post-infectious CFS): "Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors." If the general population prevalence of CFS is 0.4%, wouldn't that suggest those infections increased the likelihood of developing CFS by over 27 times after each incidence?; this doesn't take into account the chances someone has of catching these infections, but it certainly highlights infection as a massive risk factor regardless of the overall % of CFS cases which start with a "definite infection". Unfortunately in this study there was no specific measurements of stress prior to CFS, but upon reading the "Interview schedules and self report instruments" subsection of the full text it becomes apparent that they took care into recording a wide range of (pre-existing and concurrent) psychological and psychiatric factors which were deemed insignificant compared to the obvious observation that the severity of the acute infection was the most important factor.

The incidence of infection is obviously an issue that warrants further research and review. In the 2002 Australian guidelines [4] (full text), the authors mention a higher rate of CFS after specific infections rather than infection in general, although they don't recommend using serology for diagnosis. According to a recent post on the CFS article talk page (by Bricker), this relevance of specific infection is also mentioned in the "Prospective cohort studies" section of the full text of PMID 15036250 (which I don't have full access to): "One of the major risk factors that has been studied is that of severe viral illness [2]. For example, about six months after an episode of Epstein-Barr virus infection, ~22% of sufferers will have chronic fatigue and 9% more strictly defined CFS [15], in contrast to common and minor viral infections, where the rates of CFS are not higher than normal [16]." So again, infection is clearly a massive risk factor. If you look at the Onset section of the CFS article, it states with references that the majority of cases start suddenly with a self-reported "flu-like illness" which is more likely to occur in winter. Of course, it could be reasonably argued that stress plays a role in lowering defence against infection or even that the effects of stress could mimic an infection, but keep in mind what the researchers in one of the above studies said about the rising rate of other infections preceding the rise in the rate of adverse stress prior to the onset of CFS (questioning the assumption that psychosocial stress is always the initial "stressor").

Not everyone experiences a flu-like illness prior to CFS, and not everyone experiences psychological stress prior to CFS, so if in general it is difficult to retrospectively tell whether infectious-onsets are an actual trigger or just another symptom due to stress, perhaps something similar could also be said for the "stressful state" that supposedly existed prior to the onset of CFS; is it a trigger or symptom? If for whatever reason the person became sensitized to stress prior to the "crisis" which supposedly triggered CFS, it may have even had a role in the crisis itself and caused the effects to snowball (e.g. "feeling stressed" contributing to a marriage breakdown or work problems or emotional issues or whatever). I'm willing to gamble that people who develop CFS aren't "virgins to stress" who somehow managed to reach 30 years of age without ever experiencing serious stress before in their lives and then suddenly fall ill as a result of their first bout of serious stress or infectious illness. This is probably where "allostatic load" becomes relevant if chronic stress really is a key factor. With the retrospective weaknesses and diagnostic controversy aside, stress seems to play some role and I'm not arguing against any association between stress and CFS, but I'm critical of exaggerations and overgeneralisations (especially when the exact nature and extent of that role is currently unknown). The lack of association of stress or infection with HPA axis biochemistry in CFS onset has already been discussed on the CFS talk page. The possible role of infections shouldn't be oversimplified as only a "HPA stressor", we don't know much yet about the role of infection either; although I tend to agree with the model that while stress may be a catalyst, infection plays a more serious and direct triggering role for many people's CFS. Stress itself shouldn't be oversimplified as just a "HPA stressor" either and doesn't necessarily include all forms of exertion; while there is major overlap, different stressors and activities still involve some different biological mechanisms and have some different effects on the body, some of which may be related to the abnormalities already found in some patients.

If 0.4% of the general population have CFS, and severe psychological stress supposedly doubles or triples the risk, wouldn't that suggest about 1% then develop CFS following such stress? Compare this to the 10% of those who endure specific infections and then develop CFS; so while said stress can increase the risk of developing CFS by a few times in the short term and perhaps several times in the long term, infection can increase the risk by about 25 times! So regardless of the overall prevalence of stress and/or infection in CFS cases, the risk factor from some infections is much higher than that of severe psychological stress. The majority of people who undergo psychological stress or relevant infection never develop CFS, but the risk seems far more pronounced in infection than it is in psychological stress, and it would be interesting to determine if those infected who didn't develop CFS straight away are still more likely to develop CFS later in life. However, most people experience many infections during their life, it is rather odd than a single one triggers CFS while the others usually don't play much of an obvious role either before or after onset.

While the 3 month sensitive period of severe stress prior to some cases of CFS onset is noteworthy, it seems that stress increases the risk of developing many well known illnesses and diseases by up to several fold as well as exacerbating them once acquired (references coming in January 2008), the same two reasons CFS is often downplayed as being psychiatric or even psychological. Perhaps many of these could therefore be viewed as "psychosomatic diseases" by some people because stress apparently played a biological role in their onset, as these researchers (PMID 17385469) have done, classifying arterial hypertension, ischemic heart disease, duodenal ulcer, bronchial asthma, diabetes mellitus type 1 and 2; all as psychosomatic diseases, and supposedly finding a "stress factor" in the onset in more than 90% of cases. CFS-like symptoms are apparently so common that a wide range of other illnesses and diseases have to be excluded before diagnosis; all this suggests that illnesses sharing similar symptoms or supposedly occurring after stressful events is an unreliable predictor of association between them or the natures of the individual illnesses. It could just as easily be pointed out that exercise intolerance is usually only found in organic disease, how's that for an "association"? In the earlier days CFS was proposed to be a form of depression, but that turned out to be a dead-end. Some studies suggest that depression and anxiety disorders are risk factors for CFS too, but again this is not exclusive to CFS and applies to a wide range of illnesses. Considering what stress can do to one's health, it isn't unreasonable to speculate with the current research that even an apparently stress-triggered CFS involves a deeper more serious chronic mechanism than a "psychological maladaptation". Furthermore, the findings of stress doubling the risk of CFS within 3 months and child trauma as a several fold risk factor for CFS in adults are in a similar league of stress being a short term and long term risk factor for a wide range of illness and disease. However, the issue of stress and infection in CFS is about prevalence rather than the nature of CFS, the latter being outside the current scope of this post. The point here was just that the existence of stress prior to onset by itself doesn't tell us much; as long as the science is sound, the findings don't necessarily contradict those who prefer an organic explanation of CFS and shouldn't be abused by those who prefer a psychiatric explanation. Essentially, the issue shouldn't be oversimplified to fit one's own opinion or even experience.

Suggested leading statement for the CFS article:

• The onset of most cases of CFS seems to be accompanied by a "flu-like illness" which is more likely to occur in winter, while a significant proportion of cases begin within several months of severe adverse stress. However, the accurate prevalence and exact roles of stress and infection prior to CFS are still currently unknown.

[edit] SELECTED RESEARCH COMPILED LATE 2007

A selection of research compiled during later half of 2007, mostly in response to the discussion about depression in CFS and also the relevance of a sudden flu-like onset vs a gradual onset.

[edit] Depression and other psychiatric comorbidities in CFS

SUMMARY: A range of studies suggest that about 25% to 60% of people with CFS experience depressive-like symptoms, with this rate depending significantly on the methodology used. The lower end of the range is similar to that found in other chronic diseases and the higher end of the range depends substantially on comorbidities with other illnesses such as FM and MCS. The depressive-like symptoms in CFS are usually different than those found in primary depression and often lack key clinical features (such as indifference and suicidal thoughts). Some people with major depression experience chronic pain, but the pain symptoms experienced in CFS don't seem to be associated with depression. Anxiety-like symptoms can also be present in CFS, although the prevalence is lower despite being a stronger risk factor than depression for developing CFS. At least half of patients do not qualify for any current Axis I psychiatric diagnosis.

[edit] General

• This is an extraction from page 269 of the full text of PMID 15243847, which I found to be a rather interesting summary of what's going on with depression in CFS: Depression: Among the sensory symptoms of depression, e.g. feeling numb, empty, fatigue may be one of the complaints. If fatigue predominates and is of long duration, CFS may become the diagnosis. CFS-patients rarely express worthlessness, guilt, self-depreciation and suicidal ideation. Concentration difficulties, memory impairment, sleep disturbance, and mood swings occur in CFS patients as well as in depressed individuals. CFS patients usually show intensification of symptoms to activity and exercise, whereas depressed patients may react with elevation of mood [13]. Depressed patients show a loss of interest while CFS-subjects state to feel motivated. Consequently studies of CFS-patients present a high correlation with depression. About 30 to 70% of CFS-patients show the features of major depression [14–16], but it is not easy to decide in an individual patient if he suffers from CFS and shows features of depression, or vice versa. The premorbid rate of psychiatric disorder including depression in CFS-patients is increased [17].

• Another two paragraphs I found interesting (when taken as a whole) comes from the introduction and discussion sections of the full text of PMID 12671155: ... [Introduction] Because there is a well-established relationship between anxiety, depression, and fatigue,[17] it is reasonable to consider psychological factors as contributing to either the cause or maintenance of adolescent CFS. In addition, it is important to note that of adolescents who meet CFS criteria, more than one-third may have concurrent psychiatric diagnoses (predominantly depression and anxiety disorders).[3],[4],[18] Several adolescent studies have found CFS patients have more internalizing symptoms,[16],[19–21] somatic complaints,[20] or functional disability[22] than comparison groups of adolescents with arthritis, cancer, or cystic fibrosis. Adolescents with CFS who do not have concurrent psychiatric diagnoses often endorse symptoms such as decreased energy, difficulty with concentration and memory, and sleep problems, but they do not often endorse depressed or anxious mood, self-deprecating thoughts, anhedonia, or suicidal ideation.[3] Thus, psychological factors seem to be of major importance in at least one third of adolescents with CFS, but their etiologic role remains primarily undetermined. ... [Discussion] Regarding anxiety and depression, it is important to note that the mean scores reported in this study were not in the clinical range. Therefore, significant findings between groups indicate relative differences in symptomatology and not necessarily the presence of specific anxiety or depressive disorders. Nevertheless, similar to several other studies,[16],[19–21] adolescents in this study who met CDC criteria for CFS showed increased internalizing symptoms. Whether the anxiety and depression scores reflect primary or secondary conditions in adolescents with chronic fatigue cannot be determined by these data. It is plausible that the presence of a disabling chronic condition could result in internalizing thoughts and emotions. Likewise, the association between primary anxiety and depressive disorders and fatigue is well established.[17] ...

• [PMID 16473456] - "Depression and anxiety, while frequently present, were not more prevalent in any particular subtype, and did not increase with the severity of specific symptom reports."

• Bryan Hyde in "the complexities of diagnosis", states that ME/CFS is accompanied by "an acute onset of CNS changes of memory impairment, mood changes, sleep disorders, irritability, and reactive depression".

[edit] Prevalence

• [PMID 15159267] (full text) - systematic review: Seventeen studies reported the incidence of current psychiatric diagnoses in 1830 patients with CFS (40%). The lifetime incidence of psychiatric diagnoses was even higher in the 12 studies with this information: 65% of 930 patients with CFS. The most common psychiatric diagnosis was depression, which was reported in 45% of 1718 patients with CFS.
• [PMID 12651994] - "Patients with additional illness were more likely to have major depression and a higher risk of psychiatric morbidity compared with patients in the CFS only group (p <.01). Rates of lifetime depression increased from 27.4% in the CFS only group to 52.3% in the CFS/FM group, 45.2% in the CFS/MCS group, and 69.2% in the CFS/FM/MCS group."
• [PMID 16198192] - "Thirty-one percent of the patients were depressed according to the SCID-P." (Structured Clinical Interview for DSM-III-R) (The study also suggested different depression subscales and cutoff points either overestimated or underestimated the rates of depression.)
• [PMID 16324367] - "The symptoms with a factor score > or = 2.0 in SCL-90 included ... depression (57/91, 63%) ... " ... "The CFS patients in China have an obvious impairment of remembrance and show different psychological abnormalities that are different from those of the patients with primary psychological diseases."
• [PMID 2386862] - "The prevalence of psychiatric disorder in 48 patients with chronic fatigue syndrome (CFS) was determined. Twenty-two had had a major depressive (non-endogenous) episode during the course of their illness, while seven had a current major (non-endogenous) depression." ... "The pattern of psychiatric symptoms in the CFS patients was significantly different to that of 48 patients with non-endogenous depression, but was comparable with that observed in other medical disorders."
• [PMID 8829720] - "Fifty percent of CFS subjects also had depressive or anxiety disorders, some categories of which remit spontaneously over time."
• [PMID 8678174] - "Most subjects with chronic fatigue syndrome also had current psychiatric disorder when assessed by interview (75%) or questionnaire (78%)."
• [PMID 12668371] - (from this table in the full text) ... CFS comorbidity: depression ~ 67%, generalized anxiety disorder ~ 34%, either ~ 81% ...
• [PMID 8491100] - " ... CFS patients had a similarly high prevalence of current psychiatric disorders (78%) ..."
• [PMID 8677287] - "61% of CFS did not qualify for any current Axis I psychiatric diagnosis".
• [PMID 10596251] - "At assessment, psychiatric disorders (mainly anxiety and depressive disorders) were present in half the subjects with a history of CFS, a rate significantly higher than in healthy controls." ... "Anxiety disorders were significantly more common in recovered subjects than in those with active CFS illness status."
• [PMID 9314795] (full text freely available) - The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. | Wessely S, Chalder T, Hirsch S, Wallace P, Wright D. | Am J Public Health. 1997 Sep;87(9):1449-55
• [PMID 9301342] Politics, science, and the emergence of a new disease. The case of chronic fatigue syndrome. | Jason LA, Richman JA, Friedberg F, Wagner L, Taylor R, Jordan KM | Am Psychol. 1997 Sep;52(9):973-83. | discusses the issues with measuring psychiatric comorbidity - full text available from http://www.cfs-news.org/jason.htm

[edit] Premorbidity

• [PMID 2386862] - "The pre-morbid prevalence of major depression (12.5%) and of total psychiatric disorder (24.5%) was no higher than general community estimates. The pattern of psychiatric symptoms in the CFS patients was significantly different to that of 48 patients with non-endogenous depression, but was comparable with that observed in other medical disorders. Patients with CFS were not excessively hypochondriacal. We conclude that psychological disturbance is likely to be a consequence of, rather than an antecedent risk factor to the syndrome."
• [PMID 8644768] - (CFS patients had) " ... pre-morbid history of depression (15% of cases, 11% of controls) ... "

VS ...

• [PMID 17976252] "Increased levels of psychiatric illness, in particular depression and anxiety, were present prior to the occurrence of fatigue symptoms. There was a dose-response relationship between the severity of psychiatric symptoms and the likelihood of later CFS/ME. Personality factors were not associated with a self-reported diagnosis of CFS/ME ... This temporal, dose-response relationship suggests that psychiatric disorders, or shared risk factors for psychiatric disorders, are likely to have an aetiological role in some cases of CFS/ME."
• [PMID 8678174] - "Both the prevalence and incidence of chronic fatigue syndrome were associated with measures of previous psychiatric disorder."
• [PMID 16738080] - "Anxiety and depression were the strongest predictors of CF/CFS ..."

Also see the "Other risk factors" subsection below.

[edit] Onset and possible risk factors

[edit] Majority report flu-like onset

• [PMID 12839515] - "A majority of CFS patients (80%) had an acute infectious onset ..."
• [PMID 10583715] - "A majority of patients describe an infectious onset but the link between infections and CFS remains uncertain."
• [PMID 17561687] - "Epidemiological studies reveal that a flu-like sickness precedes the onset in the majority of cases. The major hypothesis of the pathogenesis of CFS is that infectious agents such as viruses, may trigger and lead to chronic activation of the immune system with abnormal regulation of cytokine production."

[edit] More likely to occur in winter

• [PMID 11379670] - "It was determined that the distribution of the month of illness onset for the CFS and ICF groups was nonrandom, with greater numbers of participants than expected reporting an onset of CFS and ICF during January."
• [PMID 10672437] - "Date of illness onset was distinctly nonrandom. It peaked from November through January and was at its lowest from April through May. These data support the hypothesis that an infectious illness can trigger the onset of CFS."

[edit] Other risk factors

• "Various potential risk factors for the development of ME/CFS have been assessed but definitive evidence that appears meaningful for clinicians is lacking." - 'Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies.' Hempel S, et al. [PMID 17892624]
• "Maternal psychological disorder, psychological problems in childhood, birth weight, birth order, atopy, obesity, school absence, academic ability, and parental illness were not associated with risk of CFS/ME." - 'Childhood predictors of self reported chronic fatigue syndrome/myalgic encephalomyelitis in adults: national birth cohort study.' Viner R, Hotopf M. [PMID 15469945]
• "The key risk factor for post-infective fatigue syndrome is the severity of the acute illness and not age, sex, or psychological factors." - abstract [PMID 16950834] - full text [5]
• "CFS patients were more likely than healthy controls to have exercised regularly before illness onset (67% vs 40%) [PMID 8644768]

Also see the "Premorbidity" subsection above.

[edit] Sudden vs gradual

• [PMID 12839515] - "A majority of CFS patients (80%) had an acute infectious onset ... "
• [PMID 12442562] - " ... suggest that the (two groups) differed in their pathogenesis until the onset of CFS ... "
• [PMID 15642984] - " ... levels of interleukin-8 (IL-8) were higher in patients with sudden, influenza-like onset than in patients with gradual onset or in controls ... "
• [PMID 17605583] - " ...sudden onset (compared with gradual) was associated with reduced speed of information processing ... "
• [PMID 8985207] - "Marginal differences were detected in cytokine responses and in cell surface markers in the total CFS population. However, when the patients were subgrouped by type of disease onset (gradual or sudden) or by how well they were feeling on the day of testing, more pronounced differences were seen."
• [PMID 9037629] - " ... (when subgrouped by onset), differences in immunologic markers were detected ... "
• [PMID 9201650] - "concurrent psychiatric disease was significantly greater in the CFS-gradual group" ... "impairment in memory was more severe in the CFS-sudden group"
• [PMID 9201643] - " ... those with an acute onset have a better prognosis than those with gradual onset ... "

[edit] ICF vs CFS

• [PMID 12839515] - "A higher degree of psychiatric comorbidity was observed in CF than in CFS patients."
• [PMID 8678174] - "Only postexertion malaise, muscle weakness, and myalgia were significantly more likely to be observed in chronic fatigue syndrome than in chronic fatigue."
• [PMID 8931166] - "Twenty-three of the cases fulfilled criteria for chronic fatigue syndrome (CFS). Such cases were significantly more fatigued than those not fulfilling criteria, but had little excess psychiatric disorder." (compared with CF)
• [PMID 8491100] - "Compared with age- and gender-matched control subjects with chronic fatigue, CFS patients had a similarly high prevalence of current psychiatric disorders (78% versus 82%), but were significantly more likely to have somatization disorder (28% versus 5%) and to attribute their illness to a viral infection (70% versus 33%)."
• [PMID 12839515] - "No difference was found as to social situation, occupation and illness attributions for patients in the two categories. Patients with CFS reported in general a higher degree of 'sickness' with more self-reported somatic symptoms, more self-reported functional impairment and more absence from work. A higher degree of psychiatric comorbidity was observed in CF than in CFS patients. A majority of CFS patients (80%) had an acute infectious onset compared to 43% in the CF group. Presently used criteria might, according to findings presented here, define two different patient categories in a population characterized by severe, prolonged fatigue. Because CFS patients (compared to patients with CF) have more somatic symptoms, more often report an infectious, sudden onset and have less psychiatric comorbidity, and CF patients seem to have more of an emotional, burn-out-like component one could speculate about the existence of different pathogenetic backgrounds behind the two diagnoses." ...
• [PMID 12939888] - "A study comparing CFS with chronic fatigue found that: most people with chronic fatigue do not match CFS criteria; CFS patients experience more severe fatigue, reduced functioning, associated symptoms, and psychological distress; CFS patients are twice as likely to be depressed and twice as likely to be unemployed; and about half of the patients in either group (irrespective of CFS status) attribute their fatigue to psychological causes."
• [PMID 12668371] - (inferred from this table in the full text) ... rates of Depression and Generalized Anxiety in CFS higher than both neurasthenia and "substantial unexplained fatigue" ...
• The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. | Wessely S, Chalder T, Hirsch S, Wallace P, Wright D | Am J Public Health. 1997 Sep;87(9):1449-55 | PMID 9314795 | full text here.

[edit] Assorted findings

• [PMID 17606539] - "Abnormal thermoregulatory responses in adolescents with chronic fatigue syndrome: relation to clinical symptoms."
• [PMID 18057078] - "Seven genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): a detailed analysis of gene networks and clinical phenotypes."
• [PMID 17174731] - "Erythrocyte oxidative damage in chronic fatigue syndrome."
• [PMID 12069870] - "Illness legitimization is a source of dissatisfaction for CFS patients and it may aggravate psychiatric morbidity." ... "Those who believed that limiting their physical exertion was the path to recovery (55%) had lower depression and anxiety scores (P's<.01) than their counterparts." ^[1]
• [PMID 12131069] - "Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report."
• DOI 10.1300/J092v14n01_05 "In conclusion, the CFS group shows a lower work capacity in arm or leg exercise that would not be justified exclusively by their personal characteristics or deconditioning."
• DOI 10.1300/J092v14n01_06 "All in all, the personality structure does not appear to play a major role in the CFS."
• [PMID 17528680] "Metabolic And Neurocognitive Responses To An Exercise Challenge In Chronic Fatigue Syndrome (CFS): 2401: Board #80 June 1 3:30 PM - 5:00 PM." http://www.immunesupport.com/library/showarticle.cfm/ID/8103
• [PMID 17528679] "Post-exertional Symptomology In Chronic Fatigue Syndrome (CFS): 2402: Board #81 June 1 3:30 PM - 5:00 PM." http://www.immunesupport.com/library/showarticle.cfm/ID/8098
• [PMID 16356178] "There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF (insufficient symptoms or fatigue), who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm." ... "To some extent, the inconsistent and often conflicting results from studies of CFS reflect referral bias. Most published studies concerning CFS recruited patients from tertiary referral clinics. Patients receiving care for CFS are neither similar across clinics nor necessarily representative of the population of people who suffer from CFS." ... "In addition, the lack of consistent findings concerning the etiology, pathophysiology and risk factors for CFS reflects lack of standardized reproducible diagnostic criteria for CFS." ... "In contrast, most studies of CFS merely note that they used the 1994 case definition and they do not generally specify how disability, fatigue and symptom occurrence were elucidated. Thus, it is difficult to assess the validity of their diagnostic criteria and essentially impossible to compare results between studies critically."
• [PMID 16730652] - Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples. | The SIMCA model predicted 54 of 54 (100%) healthy donors and 42 of 45 (93.3%) CFS patients of Vis-NIR spectra from masked serum samples correctly.

[edit] SUMMARY OF RESEARCH COMPILED EARLY 2007

This is a condensed summary of accumulated research that I did during the first half of 2007, but includes a few recent additions. Although not intended to be such, it may read like a synthesis rather than a summary (and therefore could violate Wikipedia guidelines if used in the article, so take extra care if extracting the content). Also, each main section is "reference independent"; meaning that if references were used more than once in different main sections, they contain the full reference information (in case they end up on different pages). However, to avoid orphaning any references, the subsections should not be split up; for example, do not remove the "neurostructural abnormalities" subsection from the "neurological abnormalities" main section (without first filling in the missing reference information from truncated <ref> tags).

[edit] Post-exertion symptom exacerbation

Many CFS patients experience a worsening of symptoms after exercise or relapses of severe symptoms following even moderate levels of exertion.^[2][3][4] This worsening of symptoms after exertion differentiates CFS from several other fatigue-associated disorders.^[5] CFS patients consistently report a delay in recovery of muscle function after exercise, which was mentioned and objectively found in one study^[6]; with another study finding that exercise increased fatigue for 2 days in CFS patients but only for 2 hours in healthy controls.^[7] In another study, it was found that CFS patients could only maintain a gradual increase in exercise activity for about a week, after which their overall activity levels declined, with the researchers concluding that that CFS patients who experience post-exertion symptom exacerbation may not be able to maintain increased activity due to worsening symptoms (fatigue, pain, mood) and a possible "activity limit".^[8] Other researchers have stated that post-exertion muscle pain is an important reason for disability in CFS patients, and found that exercise lowered pain threshold in CFS while increased it in controls.^[9] Other studies have also found that after CFS patients exercise there is a reduction in overall activity^[10] and a circadian rhythm disturbance.^[11][12]

A study found a diminished cardiovascular response to cognitive stress, although exercise did not magnify this effect, with the lowest cardiovascular reactivities correlating with the highest ratings of CFS symptom severity; which the researchers concluded suggests that the individual response of CFS patients to stress plays a role in the common complaint of symptoms worsening after stress^[13] Some studies have found that exercise further impairs cognitive function in CFS patients^[14][15], although another study found that exercise did not improve or worsen cognitive function in CFS patients.^[16] A study found that while exercise worsened symptoms in CFS patients, it also increased allergen challenge response only in the CFS group, regardless of allergy status.^[2] It has also been found that while levels of some hormones may be abnormal in CFS patients several minutes after exertion when compared with healthy controls, there were no difference the next day and therefore was unlikely to be a cause of the prolonged fatigue that occurs in CFS patients after exertion.^[17] In several other studies the worsening of symptoms after exercise has been associated with oxidative stress, abnormal 2-5A synthetase/RNase L enzyme (antiviral) activity and abnormal gene expression (see the main article).

More encouragingly, one study did not find a "major" exacerbation in symptoms after a maximal treadmill exercise test^[18] and another found that no abnormal response to exercise occurred when the exercise was intermittent and light-intensity for up to 30 minutes.^[19] These studies suggest that light exercise may be tolerable for some CFS patients, although it should be noted that if symptoms are severe at baseline, even a minor exacerbation can cause them to become intolerable or as previously stated be at the cost of overall activity. However, graded exercise therapy has been used as a treatment for CFS and has been found to be at least partially effective in some patients, although there is a lack of research into its effects on severely affected patients, with some patient group surverys reporting it to be unhelpful or even dangerous (see the main article). The Canadian 2003 definition/criteria of CFS requires post-exertional malaise to be a necessarily present symptom for diagnosis, however most others do not, including the CDC-1994/Fukuda version), which is used in most research studies.^[20]

[edit] Physical fitness

A study published in 1996 found that CFS patients were more likely than healthy controls to have exercised regularly before illness onset (67% vs 40%).^[21] CFS patients consistently report a delay in recovery of muscle function after exercise, which has been confirmed by at least one study.^[22] However, studies into physical fitness have been inconsistent; with some studies finding normal sedentary fitness^[23][24][18] and others finding reduced fitness^[25][26][27], although cardiopulmonary exercise tests may differentiate a subset of CFS patients and correlate with impairment.^[28] Similarly inconsistent, one study found that physical deconditioning may help to maintain physical disability in CFS^[29]; while another found it did not seem to be a perpetuating factor, with almost half of the CFS patients actually having better fitness than their healthy controls.^[30] A different study found that only a moderate association between exercise capacity and activity limitations/participation restrictions exists in CFS patients and is not strong enough to be a predictor.^[31]

Studies have found abnormalities in the cardiovascular response to orthostatic stress^[32][33] in CFS patients as well as left ventricular dysfunction (the half of the heart that pumps blood into the body)^[34][35]; however studies into blood flow and oxygen delivery have been somewhat inconsistent, with at least one finding no deficit^[36], another finding a deficit^[37], and another also finding a deficit but not one that seemed responsible for CFS symptoms.^[38] Muscle abnormalities may exist in a minority of CFS patients^[39] and may correspond with increased muscle pain sensitivity^[40], however these studies and several others have not consistently identified an obvious muscle dysfunction in CFS.^{[41][42][43][44][4]} Researchers involved in some of these studies concluded that their findings are suggestive of central factors in CFS patients; and other studies have shown that central activation is diminished^[45] and that there is an inability to fully activate muscle during intense sustained exercise.^[41] It was also found that CFS patients reached exhaustion much more rapidly and also had relatively reduced intracellular concentrations of ATP.^[43] At least one other study further supports the suggestion of a central basis for the fatigue.^[46]

While several studies have found a raised perceived effort in CFS patients^{[47][48][15][26][42]}, at least one study did not^[49]; with researchers of another related study concluding that raised perceived effort was only found when their data was expressed in terms of absolute exercise intensity with such a difference not being observed when the perceived effort is relative to a common maximum, and they also found that pre-exercise fatigue ratings were not a significant predictor of perceived exertion during exercise.^[50] Another study found that only CFS patients with comorbid Fibromyalgia perceive exercise as more effortful and painful than controls.^[24] Researchers of a recent study concluded their findings demonstrated objectively that CFS subjects experienced a greater sense of effort in the elbow flexors while performing a fatiguing task.^[51] Studies into kinesiophobia ("fear of movement") in CFS have found that while it seems to be associated with activity limitations/participation restrictions but not with exercise capacity^[52], in CFS patients who also experience widespread muscle or joint pain there seems to be a lack of correlation between kinesiophobia and exercise capacity, activity limitations, or participation restrictions.^[53]

Clearer evidence for the abnormal response to exercise and post-exertion malaise experienced by some CFS patients has been gained from studies into oxidative stress, abnormal 2-5A synthetase/RNase L enzyme (antiviral) activity and abnormal gene expression (see the main article).

[edit] Neurological abnormalities

According to a review into the phenomenology and pathophysiology of CFS (published in 2006), recent advances continue to demonstrate involvement of the central nervous system.^[54]

[edit] Neurocognitive dysfunction

Studies and reviews suggest that significant cognitive dysfunction occurs in CFS patients^[55]: with the most significant and consistently prominent cognitive impairment being the reduction of information processing speed and efficiency (although general intellectual abilities and higher order cognitive skills remain intact)^[56][57]; as well as impaired working memory, long term memory and poor learning of information.^[58][59] Associative learning is also impaired^[60]; and like in multiple sclerosis, CFS patients have difficulty in tasks that require the simultaneous processing of complex cognitive information.^[61] It has been found that greater cognitive fatigability occurs in CFS patients who report greater mental fatigue^[62]; as well as cognitive abnormalities that indicated attentional deficits in some patients and slower speed of information processing in others.^[63] Cortical motor potential alterations have also been found.^[64] Studies have also shown that cognitive impairment in CFS patients cannot be fully explained by psychiatric factors.^[65][66] Neuroimaging studies have provided objective evidence for the subjective experience of cognitive difficulties, such as: an association between subjective feelings of mental fatigue and brain responses during fatiguing cognition^[67]; increased neural recruitment during cognitive tasks^[59]; affected verbal working memory with altered brain function when performing certain tasks (especially as they got more demanding)^[68]; normal accuracy but with greater exertion of the brain when processing challenging auditory information^[69]; significantly slower times in a motor imagery task and a control visual imagery task (with stronger responses in visually related structures during the motor imagery task) as well as a lack of error response in the brain that occurred in healthy controls^[70]; and reduction of the responsiveness to stimuli which didn't happen in healthy controls and correlated with the subjective sensation of fatigue in CFS (but may not be directly related to the fatigue-inducing task).^[71]

[edit] Neurostructural abnormalities

In an early study, brain abnormalities had been found in some CFS patients using both single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), with SPECT abnormalities being more common and seemingly correlative with clinical status.^[72] Some preliminary evidence suggested the involvement of cerebral white matter^[57], but other studies found no MRI pattern of white matter abnormalities that is specific to CFS^[73][74] Different studies suggest that occurring brain changes may be quite subtle^[75], or that MRI brain abnormalities may also indicate the presence of other medical illnesses with similar symptoms to CFS.^[76] A review published in 2001 found that no specific pattern of cerebral abnormalities had yet been identified to uniquely characterize CFS patients^[58], although CFS patients with MRI brain abnormalities may report being more physically impaired than those patients without brain abnormalities^[77], and another review published in 2006 found that neuroimaging studies demonstrate cerebral abnormalities.^[59] Frontal lobe pathology may explain the more severe cognitive impairment in a subset of CFS patients^[78] and a study revealed that when compared with sedentary controls, CFS patients have significant reductions of gray matter volume in the brain, with this decline being associated with a reduction of physical activity.^[79] A similar study found reduced gray-matter volume in the bilateral prefrontal cortex, with the volume reduction in the right prefrontal cortex matching the severity of the reported fatigue.^[80]

[edit] Neurochemical abnormalities

• Researchers reported enhanced skin vasodilatation in response to cumulative doses of transdermally applied acetylcholine, and upon further investigation found no differences in peak blood flow (between controls and CFS patients) but a prolonged recovery to baseline, which they proposed was suggestive of disturbance to cholinergic pathways and possibly related to some of the unusual vascular symptoms in CFS patients (such as hypotension and orthostatic intolerance).^[81]
• According to some researchers, most diseases are accompanied by a blunted response to acetylcholine but the opposite seems to occur in CFS, and such sensitivity is normally associated with physical training.^[82]
• Alteration of the serotonergic system (significant reduction of serotonin transporters in the rostral anterior cingulate) has been found to play a key role in CFS pathophysiology.^[83] Another study found abnormal levels of serotonin and dopamine precursors, as well as branched-chain and large neutral amino acids, in CFS patients during exhaustion and recovery (with the dopamine precursor also being lower at rest).^[84]

[edit] Other neurological findings

• Two preliminary studies found abnormalities in the cerebrospinal fluid of CFS patients.^[85][86]
• A study found that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue.^[87]
• Researchers of a small study into cerebral blood flow in children concluded that the various clinical symptoms in CFS patients may be closely related to an abnormal brain function, as they found abnormal blood flow as well as an abnormal choline/creatine ratio.^[88]
• Researchers involved in a review suggest that CFS may involve abnormal brain barrier permeability.^[89]

[edit] Psychological and psychiatric studies

A study assessing the "subjective quality of life" of CFS patients found that it is particularly low^[90] and another found that "acceptance" (of the chronic nature of CFS) has a positive effect on fatigue and psychological aspects of well-being^[91] Researchers have stated that psychological adaptation to CFS is similar to adaptive coping in other chronic illnesses, "subjective perceptions of health status can predict functional status", and found that CFS patients exhibited a mixture of neurotic and healthy defenses, with a low proportion of defenses associated with personality disorders.^[92] It has been found that CFS patients endure a heavy psychosocial burden and are likely to be preoccupied and distressed by daily hassles that have a severe impact on their self-image, as well as their personal, social and professional functioning.^[93] Other findings have been that CFS patients are not excessively hypochondriacal and the rate of comorbid psychiatric disorders in CFS patients were comparable to that observed in other medical disorders, with premorbid prevalence of major depression and of total psychiatric disorder being no higher than general community estimates.^[94] A study found that CFS patients are more likely than either depressed patients or normal controls to interpret symptoms that are characteristic of CFS in terms of physical illness, but the same occurred in the multiple sclerosis patients, and CFS patients were least likely to interpret symptoms in terms of negative emotional states.^[95] Similar studies found that CFS patients tend to attribute their symptoms to external causes whereas the depressed controls experience inward attribution^[96], however a external attribution style does not necessarily protect the CFS patients with a low self-esteem from depression.^[97] A study found that CFS patients were more symptomatically anxious at all times than controls but this did not increase with exercise or afterwards, with the researchers concluding that CFS patients without a comorbid psychiatric disorder do not have an "exercise phobia".^[98] Somatic attributions, neuroticism, and depression can all contribute to illness worry in chronic illness, but these factors do not seem to account for the higher levels of illness worry in CFS as opposed to MS, which may be due to other cognitive and social processes.^[99] It has been proposed that CFS is a belief system fueled by somatic attribution and secondary gains^[100], but it has been found that even when cognitive behavioral therapy is effective in some CFS patients it was associated with a change in avoidance behavior rather than causal somatic attributions.^[101] There may be higher scores on general hypochondriasis in some CFS patients^[102] but researchers have pointed out that scores on the illness behaviour questionnaire cannot be taken as evidence for abnormal illness behaviour because the same profile occurs in multiple sclerosis.^[103] "Escape-avoiding behavior" in CFS patients is associated with fatigue severity, pain, and disability^[104]; and while some view CFS as a behavioral disorder, other researchers have proposed that the behavioral changes observed in CFS patients (such as catastrophizing, avoidance, and somatization) are caused by "sensitization" of the central nervous system by nitric oxide toxicity.^[105] A recent (2007) review of studies on personality and CFS found results ranging from no evidence to strong correlations, possibly due to the various study methods as the researchers stated, with them concluding that although personality seems to play a role it is difficult to draw general conclusions on the association.^[106] Studies suggest that while personality and/or psychiatric factors do not explain the effects of CFS on physical functioning and disability^[107][108], they are increased in some CFS patients (in adults as previously implied, but also in adolescents^[109][110]) and may be associated with a poor outcome.^[111][110] High levels of comorbid emotional disorders has been found in children with CFS; but when compared to children with primary emotional disorders the CFS children experienced more fatigue and other somatic symptoms, with the parents of the CFS children also reporting more biological illness precipitants plus more premorbid recurrent medical problems and infections.^[112]

CFS can be distinguished from depression and anxiety^[113], but some CFS patients have comorbid depression and/or anxiety.^[114] A review found that CFS is related to, but not fully dependent on, depression and anxiety; with the severity of "somatization" seemingly related to higher levels of depression and anxiety.^[115] A study published in 1996 suggested that people with CFS who also have a concurrent depressive disorder account for most of personality pathology in the CFS sample.^[116] A systematic review found that chronic pain in CFS does not seem associated with depression.^[117] A study found that those with comorbid multiple chemical sensitivity and/or fibromyalgia were more likely to have major depression and were at higher risk of psychiatric morbidity.^[118] People meeting either the CDC 1994 or Canadian criteria have been compared with people who had a chronically fatiguing illness explained by a psychiatric condition; and it was found that both CFS groups had variables that differentiated them from the psychiatric comparison group, with the Canadian criteria group having over twice the number of differential variables than the CDC 1994 group.^[119] Compared with people who experience chronic fatigue for psychiatric reasons, people with CFS experience significant differences occurring primarily with neurologic, neuropsychiatric, fatigue/weakness, and rheumatological symptoms.^[120] Studies comparing CFS patients to multiple sclerosis patients (MS) have found that CFS patients have more depressive symptoms but less cognitive impairment and although the poor performance of logical memory in CFS appeared to be related to depression^[121], cognitive deficits found in CFS cannot be attributed solely to the presence of depressive symptomatology.^[122] It has been found that CFS patients have less depression and fewer incidence of personality disorder than people with major depression, with CFS patients and multiple sclerosis patients not differing in regard to the rate of personality disorders, but CFS patients did have more frequent current depression than MS patients (particularly following onset of their illness).^[123] It has also been found that both CFS and MS groups exhibited a significantly lower percentage of self-reproach symptoms than depressed patients, whereas the depressed patient group showed a lower percentage of somatic symptoms than both the CFS and MS groups.^[124]

[edit] Assorted findings

[edit] Possible risk factors

• According to researchers of a study, a subset of healthy individuals who have hypoactive function of the biological stress response systems unknowingly exercise regularly to augment the function of these systems and thus suppress symptoms and may be at risk of developing chronic multisymptom illnesses like CFS when a stressor leads to lifestyle changes that disrupt regular exercise.^[125]
• A review published in 2006 found that Gulf War deployment increased the likelihood of developing CFS and other "chronic multi-symptom illnesses" by several fold.^[126]

[edit] Other findings

• "Chronic fatigue" is a typical symptom of neurological disease and is most disabling in CFS; plus enhanced perception of effort and limited endurance of sustained physical and mental activities are the main characteristics of central fatigue.^[127]
• A study comparing CFS with chronic fatigue found that: most people with chronic fatigue do not match CFS criteria; CFS patients experience more severe fatigue, reduced functioning, associated symptoms, and psychological distress; CFS patients are twice as likely to be depressed and twice as likely to be unemployed; and about half of the patients in either group (irrespective of CFS status) attribute their fatigue to psychological causes.^[128]
• The gait of CFS patients is affected, although not changed by exercise.^[129]
• Researchers have found that lower serum zinc levels in some CFS patients is related to immune dysfunction and oxidative stress.^[130]
• It typically takes years of symptomatic distress before many patients seek clinical help.^[131]
• CFS patients may experience lower levels of functional status and greater fatigue compared with MS patients.^[132]
• A study found that participants with CFS uniquely differed from controls in the occurrence of muscle weakness at multiple sites as well as in the occurrence of various cardiopulmonary, neurological, and other symptoms not currently included in the current case definition.^[133]
• From the talk page: "Preliminary studies have suggested that the risk of developing CFS may be influenced by polymorphisms in genes affecting the nervous,^[134] endocrine,^{[135][136][137]} immune,^[138][139] and/or cardiovascular systems.^[140]"

[edit] Other treatments

• A few studies have shown that oral nicotinamide adenine dinucleotide (NADH) may be helpful in treating some CFS patients, although larger trials are still needed.^[141][142]
• Several studies have found that the essential fatty acids found in fish oil and evening primrose oil may be helpful in treating CFS.^{[143][144][145][146]}

[edit] Proposed etiologies

• It has been proposed that: Recent studies indicate that CFS can be understood as a special condition based on abnormality of the psycho-neuro-endocrino-immunological system, with the distinguishing feature of CFS seeming to be the secondary brain dysfunction caused by several cytokines and/or autoantibodies. In this paper, we summarize these abnormalities found in CFS and show the neuro-molecular mechanism leading to chronic fatigue.^[147]
• CFS may be a neurophysiological disorder focusing on the amygdala.^[148]
• Biopsychosocial models have been proposed.^[149][150]
• It has been proposed that abnormal ion channel function underlies the symptoms of CFS, and that increased resting energy expenditure occurs in CFS patients.^[151]
• A review published in 2007 stated that "Present knowledge suggests that certain genetic polymorphisms and personality traits might be regarded as predisposing factors, some infections and severe psychosocial stress constitute precipitating factors, whereas disturbances of immunity, skeletal muscle, cognitive abilities, endocrine control and cardiovascular homeostasis are possible perpetuating factors."^[20]
• It has been proposed that "all documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition."^[152]

[edit] References

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