Research News

Are patients with chronic fatigue syndrome just 'tired' or also 'sleepy'?

Intro from the MEAO: There has been a great deal of research trying to determine if people with M.E. have sleep disturbances, which either cause or contribute to the chronic fatigue symptoms. The results of a study that were published online by the Journal of Sleep Research on 7 Oct 2008 were described well by Lourdes Salvador of MCS America

Monday, December 8th, 2008:
Scientists Say Chronic Fatigue Syndrome Is Not Sleepiness
by Lourdes Salvador

Anyone with chronic fatigue syndrome (CFS) can attest to the frustration of trying to explain to well meaning people how a good night of sleep has no value for relieving their fatigue. Sleep and their fatigue are just not related, they say. Taking a day off won't help. Now scientists agree.

Scientists at the University Hospital Brugmann Sleep Laboratory in Belgium now have data that supports a clinical distinction between fatigue and sleepiness in a study which examined CFS patients with primary fatigue. The patients did not also suffer primary sleep or psychiatric disorders.

While, unrefreshing sleep is reported in CFS, lack of sleep is not behind the fatigue and sleepiness is not reported during the day.

Sleepiness is defined as being ready or inclined to sleep or drowsy.

Fatigue, on the other hand, is defined as diminution of the irritability or functioning of organs, tissues, or cells after exertion or stimulation. So, one could be fatigued without actually being sleepy. This is the case in CFS and exactly what CFS patients have been saying all along.

A good night of sleep does not reduce fatigue. The fatigue has another source. People who suffer from CFS have unrelenting fatigue severe enough to limit most basic daily living tasks of bathing, cleaning, and dressing can be exhausting.

Several possible causes of CFS include:

  • Infectious Agents
  • Immunology
  • Hypothalamic-Pituitary Adrenal (HPA) Axis
  • NeurallyMediated Hypotension

According to the Centers for Disease Control and Prevention (CDC), chronic fatigue syndrome (CFS) "is a serious illness and poses a dilemma for patients, their families, and health care providers."

The CDC says "a variety of studies by CDC and others have shown that between 1 and 4 million Americans suffer from Chronic Fatigue Syndrome (CFS). They are seriously impaired, at least a quarter are unemployed or on disability because of CFS."

A serious illness, CFS poses a dilemma for patients, their families, and health care providers.

A panel of CFS research experts from around the world drafted a definition of CFS in 1994. It was designed for research and diagnosing. They settled on two criteria which must be met to diagnose CFS:

Severe chronic fatigue of six months or longer duration with other known medical conditions excluded by clinical diagnosis; and

2. Concurrently have four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours.

Sleepiness or lack of sleep is not part of chronic fatigue syndrome. CFS fatigue is not reduced by sleep. No wonder this group is so disabled.

Reference:
Neu D, Hoffmann G, Moutrier R, Verbanck P, Linkowski P, LE Bon O. Are patients with chronic fatigue syndrome just 'tired' or also 'sleepy'? J Sleep Res. 2008 Oct 7. [Epub ahead of print]

Copyrighted 2008 Lourdes Salvador MCS America - To read the article on the Environmental Illness Resource Website, click here



Intro from the MEAO: The following two articles try to pinpoint why people with M.E. have what is known as "post-exertion fatigue". One of the hallmarks of M.E. is a delayed exhaustion, combined with muscle and body pain, that often occurs 24-48 hours after activity. The first article was written by in 2003 and still provides one of the best descriptions of this condition. The second article, written in 2008, provides some evidence on possible causes.

ME/CFS Post-Exertional Malaise / Fatigue and Exercise

Marjorie van de Sande B.Ed, Grad. Dip. Ed.
Director of Education

Quest #60, June/July, 2003

Post-exertional malaise and/or fatigue of inappropriate severity can temporarily immobilize the patient and worsen her/his symptoms following normal physical or mental activity. It takes the patient an inordinate amount of time to recover – 24 hours or more.(1,2,3,) De Becker et al (4) assessed 2073 consecutive patients with major complaints of prolonged fatigue. Of the 1578 patients that met the Fukuda criteria,(2) 97.3% had post-exertional malaise with a severity of 2.7 out of three. Of the 951 who met the Holmes criteria,(3) 98.8% had post-exertional malaise with a severity of 2.8 out of 3. Post-exertional malaise and/or fatigue are necessary criteria in the Clinical Case Definition for ME/CFS.(1)

Even though post-exertional malaise is a hallmark feature of ME/CFS, exercise programs are often prescribed with little thought to the effect they may have on patients. The panel of experts for the ME/CFS clinical consensus document(1) stressed that a thorough evaluation of patients and their total illness burden, optimizing medical management, and a careful evaluation of pain generators and risk factors must be done before even considering an exercise program. As much care must be taken in prescribing appropriate exercise for ME/CFS patients as in prescribing pharmaceuticals.(5)

ME/CFS patients do not respond to exercise in a manner that is expected of healthy people. The following chart summarizes some of the abnormal reactions to exercise which ME/CFS patients often experience.

Response to ExerciseHealthy PeopleME/CFS Patients
Sense of well-beingInvigorating Anti-depressant effectFeel malaise, fatigue and worsening of symptoms
Resting heart rateNormalElevated
Heart rate at maximum workloadElevatedReduced heart rate
Maximum oxygen uptakeElevatedApproximately ½ of sedentary controls
Age-predicted target heart rateCan achieve itCan NOT achieve it
Heart functioningIncreasedSub-optimal level
Cerebral blood flow IncreasedDecreased
Cerebral oxygenIncreasedDecreased
Body temperatureIncreasedDecreased
RespirationIncreasedBreathing irregularities: shortness of breath, and irregular breathing
Cognitive processingNormal, or more alertImpaired
Recovery periodShortAt least 24 hours but can last days or even weeks
Oxygen delivery to the musclesIncreasedImpaired
Gait kinematicsNormalGait abnormalities

1. ME/CFS patients have lost the anti-depressant effect of exercise, and it can make them feel worse. Healthy people or those who are depressed receive an increased supply of blood and oxygen to the brain during exercise and they feel better afterwards. ME/CFS patients receive less blood and oxygen to the brain making them feel worse after exercise.(6,7,)

2. While ME/CFS patients have elevated resting heart rates on average, they have a significantly reduced heart rate at maximum workload and an inability to reach the age-predicted target heart rates.(8,9,) The maximum oxygen uptake and maximum workload attained by ME/CFS patients was only approximately half that of sedentary controls.(8) As this could be due to the heart functioning at a sub-optimal level and/or autonomic disturbances, patients should NOT be pushed towards age-predicted target heart rates,(9) as this is potentially DANGEROUS!

3. ME/CFS patients have hypoprofusion in specific areas of the brain.(10) SPECT scans indicate that exercise causes a further marked decrease in cerebral region blood flow, and a worsening of symptoms. Goldstein(11) used a SPECT scan to test pre-exercise and post-exercise hypoprofusion of the brains of CFS patients. There was resting hypoperfusion in the anterior temporal lobes (more often in the right) and hypoperfusion in the prefrontal cortex. SPECT scans done both the same day after exercise and the following day showed there is usually a much greater degree of hypoperfusion after exercise.(11) This effect is the opposite of normal.

4. Body temperature normally increases with exercise. In ME/CFS patients, body temperature usually decreases in response to exercise,(7) which is the opposite of normal.

5. ME/CFS patients usually experience breathing irregularities during or immediately after exercise. Shortness of breath and irregular breathing are most common.(7) Automatic repiration is regulated by the limbic system.

6. Cognitive processing becomes more impaired in response to challenging physical exertion.(12)

7. Recovery period is prolonged. It takes at least 24 hours but can take several days or weeks or even longer to recover.(4) A long recovery period after exercise is included in the criteria for ME/CFS.(1,2,3,)

8. Orthostatic intolerance, low circulating blood volume and blood pooling in the legs often play a role in post-exertional malaise and fatigue.(13)

9. Significantly impaired oxygen delivery and consumption levels during exercise have been reported.(8)

10. Gait abnormalities have been found in ME/CFS patients when compared to sedentary controls. These abnormalities may be due to balance problems, muscle weakness, or central nervous system dysfunction.(14)

Research studies on graded exercise for ME/CFS vary greatly in their inclusion and exclusion criteria and many subjects do not meet the criteria for ME/CFS. In the study by Fulcher and White,(15) which compared aerobic exercise to flexibility therapy, patients who had considerable sleep disturbance were excluded. This is puzzling, as sleep disturbance is a necessary criterion in the clinical definition.(1) In the De Becker et al study,(4) 94.8 of the 951 patients meeting the Holmes criteria(3) had sleep disturbance of 2.5 out of 3 average severity, and 91.9% of the 1578 patients meeting the Fukuda criteria,(2) reported sleep disturbance of an average of 2.4 out of 3 severity. This raises the question as to whether the results of the Fulcher and White study even apply to ME/CFS patients. Most graded exercise studies reviewed by Whiting et al,(16) used the Oxford criteria which are much less restrictive. Patients who meet this less restrictive definition may include patients who respond to exercise more positively and have a much better prognosis than those who meet the more restrictive criteria for myalgic encephalomyelitis / chronic fatigue syndrome. In a systematic review of prognosis of numerous studies, Joyce et al(17) concluded that the less stringent the criteria, the better the prognosis. Therefore, it is of the utmost importance that patients meet all the criteria for ME/CFS or the validity of the study is in question.

In a British study,(5,18,) 1214 of 2338 ME/CFS patients had tried graded exercise. Of these 416 found it to be helpful, 197 reported no change and 610 (50%) indicated that it mad their condition worse. This was the highest negative rating of any of the parmacological, non pharmacolgical and laternate approaches of management covered in the questionnaire and may explain the hich drop out rates noted in some of these programs.

It is essential that the treating physician and all other personnel involved with treatment progreams are very knowledgeable about the more discriminating creteria for ME/CFS, the biological reality of the illness with its severe and fluctuations of symptoms and activities boundaried and the overload phenomena. As the treating physician knows the patient best and s/he is responsible for the patient's ongoing care, s/he should oversee any exercise / rehabilitative programs. Exercise must be individualized to accommodate the patient's total illness burden, and fluctuation in severity and triggers of exacerbation. The patient must have autonomy over the pacing of any exercise program and be able to incorporate rest perilds as required. Great care must be taken in order that patients do not exceed their activity boundaries which fluctuate, as this can cause post-exertional relapse. The consensus document, "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols"(1) has an excellent sectio non the goals and guidelines for individualizing ME/CFS exercise programs.

Bruce Carruthers, MD,CM, FRCP(C), kindly reviewed this article for medical accuracy. Dr. Carruthers was the lead author of the ME/CFS Consensus Document and co-editor of the FMS Consensus Document.



References

1. Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. J CFS 2002;11(1):7 – 116
2. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A, and the International Chronic Fatigue Syndrome Study Group. Chronic Fatigue Syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953-959.
3. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann of Intern Med 1988;108:387-389.
4. De Becker P, McGregor N, De Meirleir K. A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med 2001;250:234-240.
5. Sheperd C. Pacing and exercise in chronic fatigue syndrome. Physiother 2001 Aug;87(8):395-396.
6. Goldstein JA. Chronic Fatigue Syndrome: The Limbic Hypothesis. Haworth Medical Press, Binghampton, NY 1993;pg 42-43.
7. Goldstein J. CFS and FMS: Dysregulation of the limbic system. Fibromyalgia Network Oct 1993:pp 10-11.
8. De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med 2000, Nov 27;160(21):3270-3277.
9. Inbar O, Dlin R, Rotstein A, et al. Phyiological responses to incremental exercise in patients with chronic fatigue syndrome. Med Sci Sports Exerc 2001 Sept;33(9):1463-1470.
10. Ischise M, Salit I, Abbey S, et al. Assessment of regional cerebral perfusion by Tc-HMPAO Spect in Chronic Fatigue Syndrome. Nuclear Med Commun 1992;13:7657-772.
11. Goldstein JA. Chronic Fatigue Syndrome: The Limbic Hypothesis. Haworth Medical Press, Binghampton, NY 1993;pg 116.
12. La Manca JJ, Sisto SA, DeLuca J, Johnson SK, Lange G, Pareja J, Cook S, Natelson BH. Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. Am J Med 1998 Sept 28;105(3A):59S-65S.
13. Streeten DH. Role of impaired lower-limb venous innervation in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci 2001 Mar;321:163-167.
14. Boda WL, Natelson BH, Sisto SA, Tapp WN. Gait abnormalities in chronic fatigue syndrome. J Neurol Sci 1995 Aug;131(2):156-161.
15. Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ June 7, 1997;314:1647-1662.
16. Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Pamirez G. Interventions for the treatment and management of chronic fatigue syndrome. A systematic review. JAMA 2001, Sept 11;354(9182):936-939.
17. Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndromes: a systematic review. QJ Med 1997;90:223-233.
18. Sheperd C. Re: "Chronic fatigue syndrome – trials and tribulations". Letter to the editor of JAMA 2001 Sept.



Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome

Abstract

Summary: This study examined the effects of maximal incremental exercise on cerebral oxygenation in chronic fatigue syndrome (CFS) subjects. Furthermore, we tested the hypothesis that CFS subjects have a reduced oxygen delivery to the brain during exercise. Six female CFS and eight control (CON) subjects (similar in height, weight, body mass index and physical activity level) performed an incremental cycle ergometer test to exhaustion, while changes in cerebral oxy-haemoglobin (HbO2), deoxy-haemoglobin (HHb), total blood volume (tHb = HbO2 + HHb) and O2 saturation [tissue oxygenation index (TOI), %)] was monitored in the left prefrontal lobe using a near-infrared spectrophotometer. Heart rate (HR) and rating of perceived exertion (RPE) were recorded at each workload throughout the test. Predicted VO2peak in CFS (1331 ± 377 ml) subjects was significantly (P ≤  0·05) lower than the CON group (1990 ± 332 ml), and CFS subjects achieved volitional exhaustion significantly faster (CFS: 351 ± 224 s; CON: 715 ± 176 s) at a lower power output (CFS: 100 ± 39 W; CON: 163 ± 34 W). CFS subjects also exhibited a significantly lower maximum HR (CFS: 154 ± 13 bpm; CON: 186 ± 11 bpm) and consistently reported a higher RPE at the same absolute workload when compared with CON subjects. Prefrontal cortex HbO2, HHb and tHb were significantly lower at maximal exercise in CFS versus CON, as was TOI during exercise and recovery. The CFS subjects exhibited significant exercise intolerance and reduced prefrontal oxygenation and tHb response when compared with CON subjects. These data suggest that the altered cerebral oxygenation and blood volume may contribute to the reduced exercise load in CFS, and supports the contention that CFS, in part, is mediated centrally.

Clinical Physiology and Functional Imaging, Volume 28, Number 6, November 2008 , pp. 364-372(9)

Clicking on the link below will take you to the Abstract on the National Institutes for Health website, with other similar articles listed as recommended reading: http://www.ncbi.nlm.nih.gov/pubmed/18671793



Neuropsychological Performance in Persons With Chronic Fatigue Syndrome: Results From a Population-Based Study

Intro from the MEAO: People with M.E. often self-report certain neurological symptoms such as slow reaction times, memory problems, difficulty concentrating or making decisions (brain fog). Some studies also objectively founds some of these deficits. However, many studies have reported that they believed these symptoms were psychosomatic or due to a previous psychiatric history or medication use. The study below indicates these symptoms do not seem related to psychiatric disease or medications.

Matthias Majer, PhD, Leonie A. M. Welberg, PhD, Lucile Capuron, PhD, Andrew H. Miller, MD, Giuseppe Pagnoni, PhD and William C. Reeves, MD, MSc

From the Department of Psychiatry and Behavioral Sciences (M.M., L.A.M.W., L.C., A.H.M., G.P.), Emory University School of Medicine, Atlanta, Georgia; 2Chronic Viral Diseases Branch (W.C.R.), Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

Objective: To examine the neuropsychological function characterized in subjects with chronic fatigue syndrome (CFS) at the same time controlling for relevant confounding factors. CFS is associated with symptoms of neuropsychological dysfunction. Objective measures of neuropsychological performance have yielded inconsistent results possibly due to sample selection bias, diagnostic heterogeneity, comorbid psychiatric disorders, and medication usage.

Method: CFS subjects (n = 58) and well controls (n = 104) from a population-based sample were evaluated, using standardized symptom severity criteria. Subjects who had major psychiatric disorders or took medications known to influence cognition were excluded. Neuropsychological function was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Results: Compared with controls, CFS subjects exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task. CFS subjects also exhibited alterations in working memory as manifested by a less efficient search strategy on the spatial working memory task, fewer % correct responses on the spatial recognition task, and prolonged latency to a correct response on the pattern recognition task. A significantly higher percentage of CFS subjects versus controls exhibited evidence of neuropsychological impairment (defined by performance 1 standard deviation below the CANTAB normative mean) in tasks of motor speed and spatial working memory. Impairment in CFS subjects versus control subjects ranged from 20% versus 4.8% in five-choice movement time (p = .002) to 27.8% versus 10.6% in search strategy on the spatial working memory task (p = .006).

Conclusions: These results confirm and quantify alterations in motor speed and working memory in CFS subjects independent of comorbid psychiatric disease and medication usage.

Link to article URL



Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome

Intro from the MEAO: People living with M.E. who have symptoms on standing, including fatigue, dizziness, changes in heart rate, and a perceived shortness of breath or panic, may have a condition known as POTS. This condition can exist with other health conditions but all people with M.E. who have these symptoms should speak with a specialist about testing for POTS. When the condition is found, there are guidelines that can be followed to minimize the condition.

Abstract

Background: It has been suggested that postural orthostatic tachycardia syndrome (POTS) be considered in the differential diagnosis of those with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Currently, measurement of haemodynamic response to standing is not recommended in the UK NICE CFS/ME guidelines.

Objectives: To determine prevalence of POTS in patients with CFS/ME.

Design: Observational cohort study.

Methods: Fifty-nine patients with CFS/ME (Fukuda criteria) and 52 age- and sex-matched controls underwent formal autonomic assessment in the cardiovascular laboratory with continuous heart rate and beat-to-beat blood pressure measurement (Task Force, CNSystems, Graz Austria). Haemodynamic responses to standing over 2 min were measured. POTS was defined as symptoms of orthostatic intolerance associated with an increase in heart rate from the supine to upright position of >30 beats per minute or to a heart rate of >120 beats per minute on standing.

Results: Maximum heart rate on standing was significantly higher in the CFS/ME group compared with controls (106 ± 20 vs. 98 ± 13; P = 0.02). Of the CFS/ME group, 27% (16/59) had POTS compared with 9% (5) in the control population (P = 0.006). This difference was predominantly related to the increased proportion of those in the CFS/ME group whose heart rate increased to >120 beats per minute on standing (P = 0.0002). Increasing fatigue was associated with increase in heart rate (P = 0.04; r2 = 0.1).

Conclusions: POTS is a frequent finding in patients with CFS/ME. We suggest that clinical evaluation of patients with CFS/ME should include response to standing. Studies are needed to determine the optimum intervention strategy to manage POTS in those with CFS/ME.


Chronic Fatigue Syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function

Intro from the MEAO: This complex article indicates that people with severe M.E. have lower blood volume and suggests that the cardiac problems seen in many people with M.E. are likely due to this lower volume and not due to any problems in the cardiac muscle fibre and its ability to pump or contract

Barry E. Hurwitz, Virginia T Coryell, Meela Parker, Pedro Martin, Arthur LaPerriere, Nancy G Klimas, George N Sfakianakis and Martin S Bilsker
Clinical Science (2009) Immediate Publication, doi:10.1042/CS20090055
University of Miami, Miami, FL 33136, U.S.A.. bhurwitz@miami.edu
Received 3 February 2009/21 May 2009; Accepted 26 May 2009
Published as Immediate Publication 26 May 2009

This study examined whether deficits in cardiac output and blood volume in a Chronic Fatigue Syndrome (CFS) cohort were present and linked to illness severity and sedentary lifestyle. Follow-up analyses assessed whether differences between CFS and control groups in cardiac output levels were corrected by controlling for cardiac contractility and total blood volume (TBV). The 146 participants were subdivided into two CFS groups based on symptom severity data, severe (n=30) vs. non-severe (n=26), and two healthy non-CFS control groups based on physical activity, sedentary (n=58) vs. non-sedentary (n=32). Controls were matched to CFS participants using age, sex, ethnicity and body mass. Echocardiographic measures indicated that the severe CFS participants displayed 10.2% lower cardiac volume (i.e., stroke index and end diastolic volume) and 25.1% lower contractility (velocity of circumferential shortening corrected by heart rate) than the control groups. Dual tag blood volume assessments indicated that CFS groups had lower TBV, plasma volume (PV) and red blood cell volume (RBCV) than control groups. Of the CFS subjects with a TBV deficit (i.e., ≥8% below ideal levels), the mean ±SD percent deficit in TBV, PV and RBCV were 15.4±4.0, 13.2±5.0, and 19.1±6.3, respectively. Lower CFS cardiac volume levels were substantially corrected by controlling for prevailing TBV deficits, but were not affected by controlling for cardiac contractility. Analyses indicated that the TBV deficit explained 91-94% of the group differences in cardiac volume indices. Group differences in cardiac structure were offsetting and hence no differences emerged for LV mass index. Therefore, the findings indicate that lower cardiac volume levels, displayed primarily by persons with severe-CFS, were not linked to diminished cardiac contractility levels, but were likely a consequence of a comorbid hypovolemic condition. Further study is needed to address the extent to which the CFS cardiac and blood volume alterations have physiological and clinical significance.



Dear Readers: In the next few articles you can read about research looking into possible infections causes to M.E. for some people. While no one infection has been shown to cause M.E. in everyone, researchers do believe that people with M.E. should be tested for infections such as Lyme Disease, Mycoplasma, Epstein Barr Virus, Human Herpes Virus and more. It's important to follow this research as many people with M.E. report becoming ill quite suddenly after experiencing "flu-like viruses" or other obvious infectious outbreaks.

The following article was written for the HHV-6 in California and can also be found on their website as a pdf document:

http://www.hhv-6foundation.org/Baltimore-CFS-Lay.pdf

Summary of the Viruses in Chronic Fatigue Syndrome & Post-Viral Fatigue Conference

The Viruses in Chronic Fatigue Syndrome & Post-Viral Fatigue Conference was held in Baltimore, Maryland, on June 22-23, 2008. Investigators from around the world examined evidence for the possible role of several different viruses in initiating and perpetuating chronic fatigue syndrome (CFS).

Post-Infectious Fatigue Syndrome (PIFS)

For over 60 years, scientists have reported sporadic cases of a chronic fatiguing illness developing in the wake of a well-documented infection. Nevertheless, it is only in the last few years that scientists have systematically studied this PIFS. These studies have begun by identifying all cases of a well-documented type of infection in a large group of people. Then, the research team carefully follows the patients for a long time thereafter, evaluating symptoms, and performing physical examinations and laboratory testing.

In 2006, a landmark study of post-infectious fatigue syndrome that was conducted in Dubbo, Australia, was published. The team studied people with each of three different kinds of infections—Epstein-Barr virus infection, Ross River virus infection, and infection with a bacterium, Coxiella burnetii, the cause of a disease called Q fever. The study showed that about 10% of patients in each of the three groups developed a post-infectious fatigue syndrome that met the Centers for Disease Control and Prevention (CDC) criteria for CFS.

At the Conference, the team reported in detail on this study. The chronic illness was most likely to develop in those patients who were sickest at the time of the initial infection: demographic, psychological and microbiological factors did not predict who would develop PIFS. Although final results were not presented, the team reported that the activity of a handful of genes predicted who would become most severely ill with PIFS, and that genes were plausible candidates to explain the symptoms of PIFS. In particular, the team found variations in the genes for two immune system chemicals that affect inflammation (cytokines)—interferon-γ and interleukin-10.

Human Herpesvirus-6 (HHV-6) and HHV-7

For almost 20 years, studies have found evidence associating HHV-6 with chronic fatigue syndrome (CFS). Most human beings are permanently infected with HHV-6, although the virus usually remains "asleep" (inactive) inside certain cells and is not making copies of itself. However, sometimes the virus "reawakens" and begins to multiply—a condition called active infection.

Any human being with an inactive infection—which is to say, most human beings—will have detectable antibodies against the virus in their blood. People with active infections can be identified by tests of antibodies, virus antigens, and viral nucleic acids in the blood. Most researchers who have studied it report that patients with CFS more often have active infection with HHV-6 than either healthy people or people with other illnesses than can cause fatigue.

At the Barcelona Conference in 2006, a preliminary study reported that patients with CFS and evidence of active infection with HHV-6 and/or a related virus, Epstein-Barr virus, improved when treated with an antiviral drug, valganciclovir (Valcyte®). However, that study did not give some patients the antiviral drug and other patients a placebo (i.e., sugar pill), and so it could not prove that the treatment actually helped . At the Baltimore Conference, the same group from Stanford University reported on a randomized, placebo-controlled trial. The study had ended just before the conference began, and only a small amount of the data had been analyzed. The patients who received the valganciclovir seemed to improve more than the patients given placebo, but further analysis of the data is required to determine the results of the study.

A team from Latvia reported that latent (inactive) infection with HHV-7 was present more often in patients with CFS than in healthy control subjects. The team also found that active infection with HHV-6 was present in many more patients with CFS than in healthy control subjects.

Epstein-Barr Virus

In the mid-1980's, some cases of (what came to be called) CFS were associated with reactivated Epstein-Barr virus (EBV) infection.

At the Baltimore Conference, one team reported that a protein made by EBV during active infection stimulates the production of several cytokines. These cytokines can produce many of the symptoms of CFS. The team reported that the mechanism by which EBV induces the production of these cytokines is through triggering an immune system "master switch" called NF-κB.

Parvovirus

PIFS following infection with parvovirus B19 has been reported for more than a decade. A team from Japan followed over 200 patients immediately after they had been infected with the virus. PIFS was not associated with continued presence of viral DNA in the blood, but levels of complement—proteins involved in inflammation—were.

Another study found that people experiencing a lot of stress at the time they developed a new infection with parvovirus were more likely to go on to develop a PIFS that met criteria for CFS. In addition, as was found in the Dubbo study (above), patients whose immune system cells produced high levels of inflammatory cytokines at the time of initial infection were also more likely to go on to develop a PIFS.

Enteroviruses

Enteroviruses include three families of human viruses: Coxsackievirus, echovirus and poliovirus. These viruses can infect the cells of the brain and spinal cord, respiratory tract, muscle and gut cells, and have been suspected as a possible cause of CFS for many decades.

A research team reported finding enterovirus RNA (viral genetic material) and high levels of antibodies against enteroviruses more often in patients with CFS than in healthy control subjects. Stomach biopsies were performed in some patients with CFS who had abdominal symptoms: enterovirus antigens were found much more often in their stomach tissue than in stomach tissue from patients who had biopsies for reasons other than CFS (like possible stomach ulcers). In patients with enterovirus antigens in the stomach, enterovirus RNA was also found.

Borna disease virus

Borna disease virus has long been recognized to infect animals that are in close contact with humans—horses, cattle, dogs and cats. It causes infection of the brain, particularly the limbic system, which is involved in emotion, behavior, and long-term memory. A team from Germany reported the latest research from its laboratory indicating that the virus also can infect humans, and may cause various mood disorders.

The team reported that it had isolated Borna disease virus from the blood of a U.S. patient with CFS. In the test tube, they found that the virus was killed by an antiviral drug called amantadine. They then found that a German patient with CFS and evidence of Borna disease virus infection improved clinically with amantadine treatment.

A team from Japan reported finding evidence of Borna disease virus in about 10% of patients with CFS.

Endogenous retroviruses

Nested among each of our genes are sequences of DNA that may make viruses called endogenous retroviruses. These DNA segments have been inherited from our parents, and entered the human genome millions of years ago. Most of them are thought to be unable to actually make retroviruses.

One research team reported that a particular endogenous retrovirus called human endogenous retrovirus-K18 (HERV-K18) can be induced to make viruses when a cell is infected with Epstein-Barr virus or stimulated by a chemical called interferon-α (which is both a natural chemical and a drug used to treat various diseases). Three different variants of HERV-K18 exist. The team reported that one variant, K18.3, is found more often in patients with CFS.

The possibility that HERV-K18 might trigger CFS in some people is plausible: HERV-K18 makes a protein called a "superantigen" that triggers a strong immune response and dysregulates the immune system. Such a response could theoretically trigger the symptoms of CFS. This research is preliminary, but intriguing.

Immunological and genetic studies

Gene polymorphisms. Contemporary biology allows scientists to do something that was impossible only 30 years ago: to easily identify gene variations. Some genes exist in several subtly different forms, called polymorphisms. The polymorphisms were caused by a mutation, typically one that occurred in a distant ancestor and was passed on to future generations. Tiny mutations in a gene can change the function of the protein made by the gene, and that can lead to disease.

A team using genetic data collected by the CDC reported that several polymorphisms in genes that are part of the brain hormone system ("neuroendocrine system") are found much more often in people with CFS. It is well known that the brain hormone system "talks" to the immune system, through various chemical signals. The team showed that the communication between these two systems was quite different in patients with CFS than in healthy control subjects.

Gene expression studies. Contemporary biology also allows scientists to do something else that was impossible only 20 years ago: to identify every gene in a cell, and determine if it is turned on or off. Genes that are turned on are said to be "expressed": they are making the protein that they were built to make. For example, scientists can take a group of cells—like white blood cells in patients with a particular disease, or diseased tissue (such as a particular type of cancer)—and see which of the roughly 22,000 human genes are being expressed, and which are not: a "gene expression fingerprint".

A research team from England reported that 88 genes (out of the approximately 22,000 human genes) were uniquely expressed in the white blood cells of patients with CFS: 85 genes were turned on, and 3 were turned off. The 88 genes typically involved biological functions that are central to the immune response to infection—which is consistent with the idea that CFS can be triggered and/or perpetuated by certain infections.

Immunological abnormalities and symptoms. One presentation summarized the immunological measurements that distinguish patients with CFS from healthy controls, including: increased numbers of activated T cells (a type of white blood cell); impaired function of T cells and natural killer cells (NK cells), another type of white blood cell; TH2 cytokine shift (a change in the type of cytokines produced); increased levels and production of inflammatory cytokines; reduced amounts of a molecule called soluble CD26; and increased amounts of a molecule called NPY.

But did these measurable abnormalities have any connection to the symptoms that patients with CFS were experiencing? Data were presented indicating that diminished T cell and NK cell function correlate with cognitive impairment and reduced level of function.

Summary

CFS was named and defined only 20 years ago, although a similar illness had been described in the medical literature for hundreds of years. The possibility that CFS is often triggered by infectious agents has been widely discussed and debated. Few scientists have argued that a single novel infectious agent is responsible for CFS, in the way that HIV is the central and necessary cause of AIDS. Indeed, most illnesses caused by infectious agents can be caused by multiple different types of infectious agents. For example, bronchitis, gastroenteritis, hepatitis, urinary infections, and the common cold are each caused by multiple infectious agents.

This conference presented evidence that a handful of infectious agents are plausible triggers of CFS. The evidence was both direct—associations between an infectious agent and CFS—and indirect—evidence of an immune response in CFS that suggests the body may be attempting to battle an infectious agent.

Altogether, both proponents and opponents of the theory that CFS can be triggered by infectious agents had much food for thought.



Chronic Fatigue Syndrome Patients Subsequently Diagnosed with Lyme Disease Borrelia burgdorferi: Evidence for Mycoplasma Species Coinfections

Abstract

Objective: We examined the blood of 48 North American chronic fatigue syndrome (CFS) patients subsequently diagnosed with Lyme disease (Borrelia burgdorferi infection) and compared these with 50 North American CFS patients without evidence of Borrelia burgdorferi infections for presence of Mycoplasma species coinfections using forensic polymerase chain reaction.

Results: We found that 68.75% of CFS/Lyme patients show evidence of mycoplasma coinfections (odds ratio [OR] = 41.8; confidence limits [CL] = 11.3–155; and p < .001) compared with controls, whereas 50% of CFS patients without a diagnosis of Lyme disease show Mycoplasma coinfections (OR = 19.0; CL = 5.3–69; and p < .001) compared with controls. Because CFS patients without a diagnosis of Lyme disease have a high prevalence of one of four Mycoplasma species and a majority show evidence of multiple infections, we examined CFS/Lyme patients' blood for various Mycoplasma species. We found that CFS patients with Lyme disease mostly had single species Mycoplasma infections (OR = 31.7; CL = 8.6–116; and p < .001) with a preponderance of Mycoplasma fermentans infections (50% of patients; OR = 59.0; CL = 7.6–460; and p < .001), whereas the most commonly found Mycoplasma species in CFS patients without Lyme disease was Mycoplasma pneumoniae(34% of patients; OR = 14.94; CL = 3.3–69; and p < .001).

Conclusions: The results indicate that a subset of CFS patients show evidence of infection with Borrelia burgdorferi, and a large fraction of these patients were also infected with Mycoplasma fermentans and to a lesser degree with other Mycoplasma species.

Journal Title: Journal of Chronic Fatigue Syndrome:
Multidisciplinary Innovations in Research, Theory, and Clinical Practice
Volume: 14 Issue: 4
ISSN: 1057-3321 Pub Date: 6/16/2008

Link to article URL



Chronic Fatigue Syndrome and Mitochondrial Dysfunction

Intro from the MEAO: This recent article joins many other articles in looking at the role of the mitochondria in producing chemicals needed for healthy functioning, such as ATP (adenosine triphosphate).

Abstract

This study aims to improve the health of patients suffering from chronic fatigue syndrome (CFS) by interventions based on the biochemistry of the illness, specifically the function of mitochondria in producing ATP (adenosine triphosphate), the energy currency for all body functions, and recycling ADP (adenosine diphosphate) to replenish the ATP supply as needed. Patients attending a private medical practice specializing in CFS were diagnosed using the Centers for Disease Control criteria. In consultation with each patient, an integer on the Bell Ability Scale was assigned, and a blood sample was taken for the "ATP profile" test, designed for CFS and other fatigue conditions. Each test produced 5 numerical factors which describe the availability of ATP in neutrophils, the fraction complexed with magnesium, the efficiency of oxidative phosphorylation, and the transfer efficiencies of ADP into the mitochondria and ATP into the cytosol where the energy is used. With the consent of each of 71 patients and 53 normal, healthy controls the 5 factors have been collated and compared with the Bell Ability Scale. The individual numerical factors show that patients have different combinations of biochemical lesions. When the factors are combined, a remarkable correlation is observed between the degree of mitochondrial dysfunction and the severity of illness (P<0.001). Only 1 of the 71 patients overlaps the normal region. The "ATP profile" test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms as a result of energy wastage by stress and psychological factors from those who have insufficient energy due to cellular respiration dysfunction. The individual factors indicate which remedial actions, in the form of dietary supplements, drugs and detoxification, are most likely to be of benefit, and what further tests should be carried out.

The full article can be found at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2680051