VIROLOGY

Levine, S., Eastman, H and  Ablashi, DV. Prevalence of IgM and IgG antibody to HHV-6 and HHV-8 and results of plasma PCR to HHV-6 and HHV-7 in a group of CFS patients and healthy donors. Journal of Chronic Fatigue Syndrome, 2001, 9, 1/2, 31-40.

Human herpes virus-6 (HHV-6) is a beta herpes virus that was first described in 1986 and which occurs in the form of at least two variants, A and B. Healthy donors in the general population are carriers for mainly the B variant, in whom 90% harbor the DNA of this type in their peripheral blood mononuclear cells (PBMNC). A higher prevalence of this virus has been detected by testing of plasma and PBMNCs by IFA, ELISA and by the nested PCR technique, in addition to direct culture for HHV-6, in patients with multiple sclerosis (MS) and HIV. Variant A has been isolated in up to 70% of patients with CFS.

We determined IgG and IgM antibody titers to HHV-6, IgG to HHV-8, and performed PCR testing for HHV-6 using the plasma of 46 patients with CFS (CDC criteria '94) and 7 healthy donors (HD). We also performed PCR testing for HHV-7 on 15 CFS patients and on 4 HD(s).

We found a higher prevalence of IgM antibody in CFS patients (50%) compared to HD (28.5%). The prevalence of IgG antibody to HHV-8 was zero among both CFS patients and HD. Three out of 46 (6.5%) of CFS patients demonstrated a positive plasma by PCR to HHV-6 compared to 0% HD(s). None of the patients had clinically significant neurological symptoms. Finally, four out of fifteen (26.7%) CFS patients and 0% HD(s) demonstrated a positive plasma PCR to HHV-7.

The higher prevalence of IgM antibody to HHV-6 indicates viral activation or persistent infection. The low number of positive PCR tests is due to the relatively low amount of infectious cell-free virus being released but it must be remembered that this came from a single sample. Additional samples obtained over time may produce different results (cf. Ablashi et al 2000).

HHV-6 is probably not responsible on its own for the pathogenesis of this illness but as in HIV-infected patients, may hasten the disease process.

The study of plasma and perhaps other tissue samples, such as cerebrospinal fluid and gastric mucosa from patients with CFS in better defined subgroups, as well as defined populations of HDs using a variety of methodological techniques will increase our knowledge about the role of HHV-6 in this complex disorder.

Levine, S. Prevalence in the cerebrospinal fluid of the following infectious agents in a cohort of 12 CFS subjects: human herpes virus-6 and 8; chlamydia species; mycoplasma species; EBV; CMV; and Coxsackievirus. Journal of Chronic Fatigue Syndrome, 2001, 9, 1/2, 41-51.

Over the last decade a wide variety of infectious agents have been associated with the CFS as potential etiologies for this disorder. Many of these agents are neurotrophic and have been linked previously to other diseases involving the central nervous system (CNS). Human herpes virus-6 (HHV-6), especially the B variant, has been found in autopsy specimens of patients who suffered from MS. Because patients with CFS manifest a wide range of symptoms involving the CNS as shown by abnormalities on brain MRIs, SPECT scans of the brain and results of tilt table testing we sought to determine the prevalence of HHV-6, HHV-8, Epstein-Barr Virus (EBV), cytomegalovirus (CMV), mycoplasma species, chlamydia species, and Coxsackie virus in the spinal fluid of a group of 12 patients with CFS (CDC criteria '94).

We found evidence of HHV-6, HHV-8, chlamydia species, CMV and Coxsackie virus in 6/12 samples. Plasma tests were negative. It was surprising to obtain such a relatively high yield of infectious agents in cell free specimens of spinal fluid that had not been centrifuged. Future research in spinal fluid analysis, in addition to testing tissue samples by polymerase chain reaction (PCR) and other direct viral isolation techniques will be important in characterizing subpopulations of CFS patients, especially those with involvement of the CNS.

The low rate of isolation of HHV-6 may be related to the lack of gross neurological findings in the patients at the time of testing.

[Ed. note: A number of patients had high Karnofsky scores suggesting levels of impairment inconsistent with the CDC criteria relating to severity.]

IMMUNOLOGY

Repka-Ramirez., MS, Naranch., K, Park., YJ, Velarde., A, Clauw.,D and Baraniuk JN. IgE levels are the same in chronic fatigue syndrome (CFS) and control subjects when stratified by allergy skin test results and rhinitis types. Annals of Allergy, Asthma and Immunology,  2001, 87, 218-221.

Allergies have been suggested as one cause of CFS. The aim of this study was to compare serum immunoglobulin (Ig)E in CFS and control subjects to determine whether IgE levels were elevated in CFS. This would be suggestive of increased atopy in CFS.

IgE was measured by quantitative ELISA (sandwich) immunoassay in 95 CFS and 109 non-CFS control subjects.

IgE was not significantly different between control and CFS groups. This indicates that atopy was probably not more prevalent in CFS.

Englebienne, P., Herst, CV., De Smet, K., D'Haese, A and De Meirleir, K. Interactions between RNase L Ankyrin-like domain and ABC transporters as a possible origin for pain, ion transport, CNS and immune disorders of chronic fatigue immune dysfunction syndrome. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 83-102.

Low molecular weight (LMW) ribonuclease L (RNase L) forms have been identified in peripheral blood mononuclear cells (PBMC) of patients with chronic fatigue immune dysfunction syndrome (CFIDS). Data from our laboratory indicate that these LMW RNase L proteins are produced by proteolytic cleavage of the native monomeric enzyme and we have identified calpain as one of the possible proteases involved. We show here that both calpain and PBMC extracts from CFIDS patients cleave the protein in fragments of identical sizes containing ankyrin-like repeat sequences. Moreover, the activity of RNase L is modulated by its interaction with a specific inhibitor (RLI), a member of the ATP binding cassette (ABC) superfamily. RLI interacts with the ankyrin domain of RNase L, which results in a blockade of the 2',5'-oligoadenylate (2-5A)-binding site of the enzyme. We show that RLI contains a small ankyrin-interacting peptide cluster through which it interacts with the first two Beta-hairpin coils of the RNase L ankyrin domain. A similarity search performed at the NCBI using RLI aminoacid sequence as the entry allowed us to identify several other ABC transporter proteins sharing significant identities with RLI, including the ankyrin-interacting peptide.

Taken together, these results show that upon pathological cleavage of RNase L, fragments containing the ankyrin domain are released, which could be capable of interacting with selected members of the human ABC superfamily, preventing their interaction with the normal cognate ankyrin protein and hence impairing their proper cellular function. This interaction constitutes a common physiological mechanism explaining numerous and currently unexplained symptoms experienced by patients with CFIDS, which are otherwise totally unrelated.

Gow, JW., Simpson, K., Behan, PO., Chaudhuri, A., McKay, IC and Behan WM. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Journal of Infectious Diseases, 2001, 33, 12, 2080-2081 E-CID: www.journals.uchicago.edu/CID/journal/rapid.html

Short report. It has been suggested that activation of interferon-induced antiviral pathways, 2-5A synthetase RNase L and RNA-regulated protein kinase (PKR) could be used as a biochemical marker for the diagnosis of CFS. In this study, RNase L, RNAse L inhibitor, 2,5A synthetase as well as PKR were compared in the PBMC of 22 patients with CFS (CDC criteria '94), 10 patients with acute gastroenteritis admitted to an Infectious Diseases Unit, and 21 healthy volunteers.

Pathway activation in the group of patients with the acute infections differed significantly from that of the other 2 groups, in whom there was no evidence of upregulation. Therefore, assay of RNase L or PKR antiviral pathway activation is unlikely to provide the basis for a diagnostic test for CFS.

Because these pathways are known to be activated during routine infection, patients with known infection are a very important control group. The pathways "can remain up-regulated to a degree for months after normal endemic infection, and residual nonspecific increases may account for the results reported elsewhere".

[Ed. note: The earlier reports involved strictly defined CFS whereas this study selected people using broader criteria. While the data support the view that RNase L is not a useful marker for the illness as a whole, it may still be of clinical significance in more strictly-defined, post-infectious CFS.]

Roelens, S., Herst, V., D'Haese, A., De Smet, K, Frémont, M., de Meirleir, K and Englebienne, P.  G-Actin cleavage parallels 2-5A-dependent RNase L cleavage in peripheral blood mononuclear cells - relevance to a possible serum-based screening test for dysregulations in the 2-5A pathway. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 63-82.

A dysregulation in the 2',5'-oligoadenylate (2-5A)-dependent RNase L antiviral pathway has been detected in PBMC of CFS patients, which is characterized by an unregulated RNase L activity and the presence of a low molecular weight (LMW) 2-5A-binding protein (37-kDa 2-5A-BP). This study was undertaken to test the possibility that the 37-kDa 2-5A-BP of CFS is produced by proteolytic cleavage of the 80-kDa monomeric enzyme.

The results indicate that the LMW form present in CFS PBMC does indeed arise by proteolytic cleavage of the 80-kDa monomeric enzyme. Moreover, G-actin, a cellular substrate of calpain is also cleaved in PBMC and the presence of actin fragments correlates with the presence of RNase L fragments. G-actin plays a critical role in antigen presentation and T-cell signalling and increased G-actin cleavage in blood of CFS patients might partly explain the immunological disorders. 

Since G-actin is cleared by serum transport, we further screened serum samples for the presence of LMW forms. A single LMW actin fragment could be detected in serum, the presence of which correlated significantly with the presence of both G-actin and RNase L fragments in PBMC. This latter observation offers the opportunity to screen large populations of patients for dysregulations in the RNase L pathway by a serum-based assay.

Calpain is involved in the generation of the 37-kDa 2-5A-BP but it's not the only protease involved in the process. It is particularly active during apoptosis. These data further support the involvement of an increased rate of immune cell apoptosis in the onset and maintenance of CFS.

Visser, J., Graffelman, W., Blauw, B., Haspels, I., Lentjes, E., de Kloet, ER and Nagelkerken, L. LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. Journal of Neuroimmunology, 2001, 119, 2, 343-349.

Interleukin-10 (IL-10) down-regulates IL-12 and interferon-ã production as well as lymphocyte proliferation. Lymphocytes from CFS patients show an increased dexamethasone sensitivity. This may explain reduced Th1 activity.

There was no evidence of viral IL-10 in the patients with CFS (CDC criteria '94). However, when blood samples were stimulated with LPS to induce IL-10 release, there was a significant increase in IL-10 and a trend towards a decrease in IL-12 as compared with the healthy controls. (Patient numbers varied per test but maximum was 49.)

In patients and controls, IL-12 secretion was equally sensitive to suppression by dexamethasone, whereas IL-10 secretion appeared more sensitive in CFS patients. In controls, IL-10 and IL-12 secretion were inversely correlated with free serum cortisol (r=-0.49, p<0.02 and r=-0.43, p<0.05, respectively). In CFS, such an inverse correlation was found for IL-12 (r=-0.61, p<0.02) but not for IL-10 (r=-0.34, ns).

These data show that IL-10 and IL-12 are differently affected by glucocorticoids and that IL-10 is subject to an altered HPA-axis in CFS.

PHYSIOLOGY, NEUROPHYSIOLOGY AND NEUROENDOCRINOLOGY

Brewer, JH and Berg, D. Hypercoaguable state associated with active Human Herpesvirus-6 (HHV-6) viremia in patients with chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2001, 8,  3/4, 111-116.

Thirty patients with CFS (CDC criteria '94) who had at least one prior positive blood culture for active HHV-6 by rapid culture method were studied. A hypercoaguable panel was obtained to assess activation of coagulation. Two or more positive tests were determined to represent activation of coagulation. Hereditary thrombosis risk panels were also performed which included eight different genetic tests to assess hereditary abnormalities.

Twenty-four of thirty (80%) patients had a hypercoaguable state. Twenty-five of thirty (83%) of patients had a hereditary abnormality.

CFS patients with active HHV-6 infection (viremia) have activation of coagulation and are hypercoaguable. Hereditary thrombosis risk factors are very prevalent in these patients. These hereditary abnormalities increase the hypercoaguable tendencies. The hypercoaguable state associated with active HHV-6 infection may be a significant contributing factor to the symptoms seen in CFS patients.

Inbar, O., Dlin, R., Rotstein, A and Whipp, BJ. Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Medicine and Science in Sports and Exercise 2001, 33, 9, 1463-1470.

The purpose of this investigation was to characterize the physiological response profiles of patients with CFS, to an incremental exercise test, performed to the limit of tolerance.

Fifteen patients who fulfilled the case definition for CFS and 15 healthy, sedentary, age- and sex-matched controls, performed an incremental progressive all-out treadmill test (cardiopulmonary exercise test).

As a group, the CFS patients demonstrated significantly lower cardiovascular as well as ventilatory values at peak exercise, compared with the control group. At similar relative submaximal exercise levels (% peak VO₂), the CFS patients portrayed response patterns (trending phenomenon) characterized, in most parameters, by similar intercepts, but either lower (VCO₂, HR, O_2pulse, V_E, V_T, PETCO₂) or higher (B_f, V_E/VCO₂) trending kinetics in the CFS compared with the control group. It was found that the primary exercise-related physiological difference between the CFS and the control group was their significantly lower heart rate at any equal relative and at maximal work level. Assuming maximal effort by all (indicated by RER, PETCO₂, and subjective exhaustion), these results could indicate either cardiac or peripheral insufficiency embedded in the pathology of CFS patients.

We conclude that indexes from cardiopulmonary exercise testing may be used as objective discriminatory indicators for evaluation of patients complaining of CFS.

LaManca., JJ, Peckerman., A, Sisto., SA, DeLuca., J, Cook., S and Natelson BH. Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise. Psychosomatic Medicine, 2001, 63, 5, 756-764.

The aim of this study was to compare the cardiovascular responses of patients with CFS to healthy control subjects when performing stressful cognitive tasks before and after strenuous exercise.

Beat-by-beat blood pressure and electrocardiogram were recorded on 19 women with CFS (CDC criteria '88 plus additional criteria) and 20 healthy nonexercising (i.e. sedentary) women while they performed cognitive tests before, immediately after, and 24 hours after incremental exercise to exhaustion.

Diminished heart rate (p<.01) and systolic (p<.01) and diastolic (p<.01) blood pressure responses to stressful cognitive testing were seen in patients with CFS compared with the controls. This diminished stress response was noted consistently in the patients across three separate cognitive testing sessions. Also, significant negative correlations between self-ratings of CFS symptom severity and cardiovascular responses were seen (r =-0.62, p<.01).

Women with CFS have a diminished cardiovascular response to cognitive stress; however, exercise did not magnify this effect. Also, the data showed that the patients with the lowest cardiovascular reactivity had the highest ratings of CFS symptom severity, which suggests that the individual response of the patient with CFS to stress plays a role in the common complaint of symptoms worsening after stress.

Zaman., R, Puri., BK, Main., J, Nowicky., AV and Davey NJ. Corticospinal inhibition appears normal in patients with chronic fatigue syndrome. Experimental Physiology, 2001, 86 (Pt 5): 547-550.

Thresholds and latencies of motor evoked potentials (MEPs) in response to transcranial magnetic stimulation (TMS) are normal in CFS but intracortical inhibition has not been investigated.

Eleven patients with CFS were compared with 11 control subjects. Each patient completed a questionnaire using visual analogue indices of pain, fatigue, anxiety and depression. Subjects released a button to initiate simple (SRTs) and choice reaction time (CRTs) tasks; for each task, movement times were measured between release of the initiation button and depression of a second button 15 cm away. Subjects held a 10 % maximum voluntary contraction in the thenar muscles of their dominant hand while TMS was applied to the motor cortex; the duration and extent of inhibition of surface electromyographic (EMG) activity were assessed at stimulus strengths above and below the threshold for MEPs.

Patients had significantly (p<0.05) higher mean indices of fatigue than of pain, anxiety or depression. Mean SRTs (but not CRTs) were longer in patients than in controls. Movement times were longer in patients for both SRTs and CRTs. TMS thresholds, expressed as a percentage of the maximum stimulator output, were not significantly different in both groups for both MEPs and inhibition of voluntary contraction. The duration and extent of inhibition did not differ significantly between groups at any stimulus strength. The pattern of change in duration and extent of inhibition with increasing stimulus intensity was no different in the two groups.

The duration and extent of corticospinal inhibition in patients with CFS did not differ from controls, adding further evidence to the notion that the feeling of fatigue and the slowness of movement seen in CFS is not manifest in corticospinal output pathways.

BIOCHEMISTRY

Schacterle, RS., Conti, F., Magrini, L., Komaroff, AL and Valesini, G. Increased eosinophil protein X levels in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2001, 9, 1/2, 21-30.

Studies of CFS have found chronic activation of the immune system, including one reporting elevated levels of eosinophil cationic protein (ECP), considered a marker of eosinophil activation. The aim of this study was to measure serum levels of eosinophil protein X (EPX), a cationic protein which like ECP is also released after antigen exposure (allergic or non-allergic) and causes tissue inflammation and damage. It has not previously been measured in this illness. Measurements are reported on serum samples from 29 patients with CFS (CDC criteria '94, 41% with allergic symptoms) and 30 healthy controls of similar age and gender. The authors also had data from the Medical Outcomes survey (SF-36).

The median serum eosinophil protein X level in patients was higher than controls: 37.9 vs. 25.3 ug/L (p=0.037). Forty-eight percent of patients versus 23% of controls had levels above the normal range. There was no significant correlation with duration of illness or reported health (SF-36). The marked increase in serum levels of eosinophil protein X in CFS patients could reflect eosinophil activation (and chronic immune activation) in this illness.

PSYCHOLOGY, NEUROPSYCHOLOGY AND PSYCHIATRY

Axe, EK and Satz, P. Depressive comorbidity in the fatiguing illnesses. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 23-29.

The present study examined whether subjects with fatiguing illnesses and comorbid major depressive disorder (MDD) have more symptoms than those without MDD.

The data was based on the CFS Surveillance System of the Centers for Disease Control and Prevention (CDC). Each of the 565 subjects enrolled in the study had a fatiguing illness and some had CFS. Subjects were evaluated for the duration and severity of the 11 symptoms and 3 physical signs listed in the CDC criteria '88. They completed the Diagnostic Interview Schedule which provided a diagnosis of several psychiatric disorders including MDD.

Group 1 comprised 130 patients with CFS, Group 2 included 99 people with less severe symptoms, some of whom had CFS. Groups 3 and 4 had other conditions thought to have caused the fatigue or prodromal psychiatric disorders.

The mean number of symptoms was similar in the patients with and without MDD. Three symptoms were found to be associated with MDD: neurobiological (cognitive complaints), sleep disturbance, and headache. Thus "comorbid MDD in the fatiguing illnesses is not associated with a higher mean number of symptoms."

Creswell, C and Chalder, T. Defensive coping styles in chronic fatigue syndrome. Journal of Psychosomatic Research, 2001, 51, 4, 607-610.

The cognitive-behavioural model of CFS proposes that rigidly held beliefs act to defend individuals against low self-esteem. This study is the first to investigate the prevalence of a potential mechanism, the Defensive High Anxious coping style, among individuals with CFS.

The study comprised 68 participants (24 CFS- Oxford criteria; 24 healthy volunteers; 20 chronic illness volunteers). Participants completed the Bendig short form of the Taylor Manifest Anxiety Scale (B-MAS) and the Marlowe-Crowne Social Desirability Scale (MC) in order to ascertain the distribution of participants in each group within the four coping styles defined by Weinberger et al.

A greater number of participants in the CFS group (46%) were classified as Defensive High Anxious compared to the two comparison groups (p=.012).

This study provides support for the existence of defensive coping mechanisms as described by the cognitive-behavioural model of CFS. This particular coping style may impinge directly on physical well-being.

[Ed. Note: there is no information about the severity of disability and other confounders. There is no evidence of low self-esteem in this population, and high levels of anxiety are associated with high cortisol levels. In people with CFS, cortisol levels tend to be normal or low].

Darbishire, L., Ridsdale, L., Ogden, J and Seed, P. Chronic fatigue syndrome (CFS) vs prolonged fatigue (PF): a comparison of psychological characteristics.  Proceedings of the British Psychological Society, 2001, 9, 2, 175-176.

The aim of this study was to explore the differences in psychological characteristics between patients with prolonged fatigue (PF) and those with CFS. Patients entered the study if they had consulted a doctor within three months or more of fatigue which was not explained by a medical condition. They completed a questionnaire and a fitness test. Of the 123 patients recruited, 29% met the criteria for CFS.

There was no difference between the groups in terms of duration, illness attributions, and perception of control. However, the CFS group had higher fatigue, depression and anxiety, perception of consequences and functional impairment. They also consulted their GP more often and were more likely to be unemployed. They were less physically fit and perceived that their fatigue would last longer. The researchers conclude that the fatigued population is not homogeneous. 

Dendy, C., Cooper, M and Sharpe, M. Interpretation of symptoms in chronic fatigue syndrome. Behaviour Research and Therapy, 2001, 39, 11, 1369-1380.

It has been suggested (a) that patients with CFS tend to interpret their symptoms as indicating physical illness and (b) they tend not to interpret these symptoms in terms of negative emotion. In order to test these hypotheses we developed a self-report questionnaire to assess the interpretation of symptoms in patients with CFS. It was administered to 19 patients with CFS (Oxford and CDC '94 criteria), 28 patients with depression, 19 patients with MS, and 28 normal controls.

The CFS patients had a lower mean depression (HAD) score than the MS patients (5.4 versus 6.2) as well as a lower anxiety score (4.5 versus 7.9).

Patients with CFS were more likely than either depressed patients or normal controls to interpret symptoms  (characteristic of CFS) in terms of physical illness, but did not differ in this from the MS patients. When compared with all three other groups (including the MS patients), the patients with CFS were least likely to interpret symptoms in terms of negative emotional states. Conversely, they tended to use normalising explanations to the same degree as the healthy controls. According to the authors, the findings support their hypotheses.

Fuentes, K., Hunter, MA., Strauss, E and Hultsch, DF. Intra-individual variability in cognitive performance in persons with CFS. Clinical Neuropsychology, 2001, 15, 2, 210-227.

Studies of cognitive performance among persons with CFS have yielded inconsistent results. We sought to contribute to findings in this area by examining intraindividual variability as well as level of performance in cognitive functioning.

A battery of cognitive measures was administered to 14 CFS patients and 16 healthy individuals on 10 weekly occasions.

Comparing the two groups in terms of level of performance revealed that the CFS patients were slower but not less accurate than healthy persons. The CFS group showed greater intraindividual variability than the healthy group, although the results varied by task and time frame.

Intraindividual variability was found to be stable across time and correlated across tasks at each testing occasion. Intraindividual variability also uniquely differentiated the groups.

The present findings support the proposition that intraindividual variability is a meaningful indicator of cognitive functioning in CFS patients.

Gray, D., Parker-Cohen, NY., White, T., Clark, ST., Seiner, SH., Achilles, J and McMahon, WM.  A comparison of individual and family psychology of adolescents with chronic fatigue syndrome, rheumatoid arthritis, and mood disorders. Journal of Developmental and Behavioral Pediatrics, 2001, 22, 4, 234-242.

Adult studies indicate high rates of psychosocial dysfunction and psychiatric comorbidity in people with CFS. The authors compared three groups of pediatric patients: CFS (n=15); juvenile rheumatoid arthritis (n=15), and mood disorders (n=15), using various psychological measures.

CFS subjects had dramatic elevation of the Somatic Complaints subscale whereas the mood disorders group had higher externalizing scores on the Child Behavior Checklist. The CFS subjects missed significantly more school compared with the two control groups. After the onset of CFS, 13 of 15 of the CFS patients required significant educational accommodation. Only 4 of the 15 CFS patients had an Axis I psychiatric diagnosis, as determined by the Computerized Diagnostic Interview for Children. Despite a low rate of psychiatric diagnosis in the CFS sample, these data attest to their psychosocial and school dysfunction.

Jason LA and Taylor RR. Measuring attributions about chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 31-40

Review of three studies showing that attributions for CFS appear to change based upon the diagnostic label given for the syndrome and the type of treatment recommended. In comparison to the CFS label, the Myalgic Encephalopathy label prompts attributions that this syndrome is a serious condition associated with a physiologically-based etiology, a poor prognosis, and decreased potential for organ donation. Results also suggest that, compared with cognitive coping skills treatment, reference to treatment with Ampligen appears to be associated with perceptions of CFS as an accurate diagnosis and a severely disabling condition.

Johnson, SK., Lange, G., Tiersky, L., DeLuca, J and Natelson, BH. Health-related personality variables in chronic fatigue syndrome and multiple sclerosis. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 41-52.

This study investigated personality variables in 22 patients with CFS (CDC criteria '88), 16 people with MS and 16 healthy, sedentary subjects as controls.

The CFS and MS groups scored higher for alexithymia, characterized as difficulty in describing and differentiating emotions and marked externalization. CFS and MS groups reported a more depressive attributional style than healthy participants, reflecting beliefs that causes for good events are not diffused into other areas of life while causes for bad events will always be present. The CFS group was significantly lower on doctors/others locus of control indicating lack of trust in medical professionals.

Results indicate that CFS and MS are similar to each other while different from the healthy group on certain personality variables that likely reflect the demoralizing effects of coping with a chronic, disabling illness marked by uncertainty.

Stainton Rogers, W.  Explaining illness as a discursive strategy. Health Psychology Update, 2001, 10, 4, 29-32.

Article implying that people with CFS are motivated by a desire to avoid blame.

Taylor, RR and Jason, LA. Sexual abuse, physical abuse, chronic fatigue, and chronic fatigue syndrome: A community-based study. Journal of Nervous and Mental Disease, 2001, 189, 10, 709-715.

Using a randomly selected community-based sample, this investigation examined whether histories of childhood sexual, physical, and death threat abuse predicted adulthood outcomes of specific medical and psychiatric conditions involving chronic fatigue. This study also tested prior suggestions that most individuals with CFS report a past history of interpersonal abuse. Multinomial logistic regression was used to examine the relationship between abuse history and chronic fatigue group outcomes while controlling for the effects of sociodemographics.

Compared with healthy controls, childhood sexual abuse was significantly more likely to be associated with outcomes of idiopathic chronic fatigue, chronic fatigue explained by a psychiatric condition, and chronic fatigue explained by a medical condition. None of the abuse history types were significant predictors of CFS. A closer examination of individuals revealed that significantly fewer individuals with CFS reported abuse as compared with those who did not.

Van Houdenhove, B., Neerinckx, E., Onghena, P., Lysens, R and Vertommen H. Premorbid "overactive" lifestyle in chronic fatigue syndrome and fibromyalgia. An etiological factor or proof of good citizenship? Journal of  Psychosomatic Research, 2001, 51, 571-576.

In a former study, we have shown that patients suffering from CFS or chronic pain reported a high level of pre-morbid "action-proneness" as compared to control groups. The aim of the present study was to control for the patients' possible idealisation of their previous attitude towards action.

A validated Dutch self-report questionnaire measuring "action-proneness" (the HAB) was completed by 62 randomly selected tertiary care patients with CFS (not defined) and fibromyalgia (FM), as well as by their significant others (SOs).

HAB scores of the patients and those of the SOs were very similar and significantly higher than the norm values. Whether or not the SO showed sympathy for the patient's illness did not influence the results to a great extent. SOs with a negative attitude towards the illness even characterized the patients as more "action-prone."

These results provide further support for the hypothesis that a high level of "action-proneness" may play a predisposing, initiating and/or perpetuating role in CFS and FM. The patient's views were similar to the assessment by significant others, so they did not idealise their premorbid lifestyle. 

EPIDEMIOLOGY

De Becker, P., McGregor, N and De Meirleir, K. A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. Journal of Internal Medicine, 2001, 250, 3, 234-240.

This study was performed to assess the homogeneity of a large CFS population in relationship to the Fukuda or Holmes definitions and to establish the importance of a symptom severity scale.

A total of 2073 consecutive patients with major complaints of prolonged fatigue participated in this study. Multivariate analyses were performed to assess the symptom presentation and severity as well as the differences between the Fukuda and Holmes definitions.

Of the patients with chronic fatigue (CF), 1578 CFS patients fulfilled the Fukuda criteria and 951 (60.3% of the CFS group) fulfilled the Holmes criteria. The CFS patients fulfilling the Holmes criteria had an increased prevalence and severity of many symptoms. Patients fulfilling the Fukuda criteria were less severely affected. The Holmes definition was more strongly associated than the Fukuda definition with the symptoms that differentiated the CFS patients from the patients that did not comply with the CFS definitions.

The inclusion of 10 additional symptoms was found to improve the sensitivity/specificity and accuracy for selection of CFS patients. These included: cold extremities (also common in ME), new sensitivities to foods/drugs, paralysis, urinary frequency (ME), photophobia, fasciculations (ME), exertional dyspnoea, gastrointestinal disturbances and attention deficits (ME).

There were no differences in terms of psychological symptoms such as anxiety and depression.  Thus these findings do not support the theory that the Fukuda criteria select more patients with stress and other psychological problems.  However, they are less severely affected and have fewer of the listed somatic symptoms.

Nimnuan, C., Rabe-Hesketh., S, Wessely, S and Hotopf M. How many functional somatic syndromes? Journal of Psychosomatic Research, 2001, 51, 4, 549-557.

The purpose of this paper is to establish whether 13 different syndromes, including CFS, fibromyalgia and premenstrual syndrome are discrete entities.

Consecutive new patients in seven outpatient clinics at two general hospitals were recruited. Patients completed questionnaires measuring symptoms and demographic data. Case notes were reviewed to ascertain whether the presenting symptoms were medically explained 3 months after the initial visit. CFS was diagnosed according to the presence of physical and mental fatigue for six months (Oxford criteria?).

Complete data were available for 550 subjects. With 37 unexplained symptoms included in the model, 30% of the total variance could be explained by one factor using unrotated principal component analysis. When the 13 identified functional syndromes were included, it was evident that functional syndromes could not be assumed to be independent. A two-factor model was the best fit for the present data after rotation.

This study suggests that the existence of distinct functional somatic syndromes as defined clinically should be reconsidered.

[Ed. note: It is unclear how the diagnosis of CFS was confirmed. The list of symptoms reported in this paper does not include all the criteria required for strictly-defined CFS (e.g. CDC '92).]

Walsh, CM., Zainal, NZ., Middleton, SJ and Paykel, ES. A family history study of chronic fatigue syndrome. Psychiatric Genetics, 2001, 11, 3, 123-128.

The aims of the present study were: (i) to examine whether CFS is familial by comparing the rates of CFS in the first-degree relatives of CFS cases and medical control subjects; and (ii) to determine whether the high rate of comorbid depression in CFS is reflected in a greater familial loading for affective disorder.

Twenty-five CFS cases (CDC criteria '94) and 36 medical control subjects were assessed for fatigue symptoms and for lifetime psychiatric symptoms using the Schedule for Schizophrenia and Affective Disorders - Lifetime Version. Informant family history was obtained regarding first-degree relatives using the CDC criteria and the Family History Research Diagnostic Criteria. In addition, informant history was supplemented by sending a questionnaire to first-degree relatives.

There were significantly higher rates of CFS in the relatives of CFS cases compared with the relatives of control subjects (7% vs 0.5%). The rate of depression in the CFS cases was similar to previous studies but did not appear to reflect a greater familial loading for depression when compared with control subjects. However, these analyses were complicated by higher than expected rates of depression in the control group. These findings suggest that familial factors are important in the aetiology of CFS.

Wilson, A., Hickie,. I, Hadzi‑Pavlovic, D., Wakefield, D., Parker, G., Straus, SE., Dale, J., McCluskey, D., Hinds, G., Brickman, A., Goldenberg, D., Demitrack, M., Blakely, T., Wessely, S., Sharpe, M and Lloyd A. What is chronic fatigue syndrome? Heterogeneity within an international multicentre study. Australian and New Zealand Journal of Psychiatry, 2001, 35, 4, 520-527.

We sought to compare the characteristics of patients presenting with chronic fatigue and related syndromes in eight international centres and to subclassify these subjects based on symptom profiles. The validity of the subclasses was then tested against clinical data.

Subjects with a clinical diagnosis of CFS completed a 119-item self-report questionnaire to provide clinical symptom data and other information such as illness course and functional impairment. Subclasses were generated using a principal components-like analysis followed by latent profile analysis (LPA).

A total of 744 subjects returned complete data sets (mean age 40.8 years, mean length of illness 7.9 years, female to male ratio 3:1). Overall, the subjects had a high rate of reporting typical CFS symptoms (fatigue, neuropsychological dysfunction, sleep disturbance). Using LPA, two subclasses were generated. Class one (68% sample) was characterized by: younger age, lower female to male ratio; shorter episode duration; less premorbid, current and familial psychiatric morbidity; and less functional disability. Class two subjects (32%) had features more consistent with a somatoform illness. There was substantial variation in subclass prevalences between the study centres (Class two range 6-48%).

Criteria-based approaches to the diagnosis of CFS and related syndromes do not select a homogeneous patient group. While substratification of patients is essential for further aetiological and treatment research, the basis for allocating such subcategories remains controversial.

THERAPEUTICS 

Akagi, H., Klimas, I and Bass, C. Cognitive behavioral therapy for chronic fatigue syndrome in a general hospital - feasible and effective. General Hospital Psychiatry, 2001, 23, 254-260.

This article describes the outcome of 94 patients with CFS (Oxford criteria or neurasthenia) seen in a general hospital, for a median of 6 sessions of CBT. The follow up was a mean 20 months after completion (range 3-66 months). Assessment was by questionnaire, plus contact with GP.

Of the original 94 patients, 14 (15%) did not return after the initial assessment, leaving 80, of whom 27.5% dropped out (having a median of 3 sessions only). The therapists rated 55% of those who completed the treatment (n=58) as moderately improved or recovered. Only 23% of the drop-outs were rated as such.

Follow-up: The response rate (questionnaires) was 61% (n=56, this includes drop-outs). Few of the patients had changed their ideas about aetiology, attributing the illness to viruses or infection, but 65% mentioned occupational stress. 88% had changed occupation, mostly as a result of the illness. Patients rated themselves as follows: 18% were back to normal (over half of those who completed treatment), 51% stated they were very much or moderately recovered since the end of treatment; 10% felt worse and 22% said they were unchanged.

There was no change in the number taking antidepressants. 81% still had fatigue, 75% were functionally impaired and 63% had an emotional disorder (HAD). There were fewer consultations with the GP in the year after treatment.

CBT appears to be an acceptable form of treatment for most patients, though a proportion do not benefit and remain very ill. "CBT may be more effective in promoting coping with than relieving the symptoms of the condition".

Snell, CR., Stevens, SR and VanNess, JM. Chronic fatigue syndrome, Ampligen, and quality of life: A phenomenological perspective. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 117-121.

This article reports the experiences of two women previously diagnosed with CFS and their families. Both women were participants in a clinical trial of the antiviral and immunomodulatory drug, Ampligen.

The results revealed a number of significant quality of life improvements for the women and their families, for which they perceived the drug therapy responsible.

MEETING ABSTRACTS

Axe, EK and Satz, P. Neuropsychological correlates in chronic fatigue syndrome. Journal of Women's Health & Gender‑Based Medicine, 2001, 10, 4, 402.

Chia, JK., Jou, NS., Najera, L., Chia, L., Khachatryan, A and Liebling, MR. The presence of enteroviral RNA (EV RNA) in peripheral blood mononuclear cells (PBMC) of patients with the chronic fatigue syndrome (CFS) associated with high levels of neutralizing antibodies to enteroviruses. Clinical Infectious Diseases, 2001, 33, 7, 1157.

Gordon, R., Michalewski, H and Starr, A. Cortical motor abnormalities in chronic fatigue syndrome: premovement event-related potentials. Applied Psychophysiology and Biofeedback, 2001, 26, 3, 230.

Harrison, HH., Berg, LH and Berg, DE. Low-level activation of coagulation in chronic fatigue syndrome and fibromyalgia. American Journal of Clinical Pathology, 2001, 116, 4, 597.

Kisely, S. Assessing the internet as a source of information on chronic fatigue syndrome: a survey of 225 sites. Australian and New Zealand Journal of Psychiatry, 2001, 35, 4, A15.

Levine, P et al. Nevada chronic fatigue syndrome consensus conference. Journal of Chronic Fatigue Syndrome, 2001, 9, 1/2, 53-62.

REVIEWS

Jason, LA., Taylor, RR., Kennedy, CL., Torres Harding, S., Song, S., Johnson, D and Chimata, R. Subtypes of chronic fatigue syndrome: a review of findings. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 1-21.

Review of the literature and in particular, studies by the authors. Distinctions between subtype groups based on socio-demographics, illness onset and duration, stressful precipitating events, symptom frequency, and comorbidity characteristics are made with respect to outcome measures of fatigue and symptom severity, functional ability, and psychiatric comorbidity.

Whiting, P., Bagnall, A‑M., Sowden, AJ., Cornell, JE., Mulrow, CD and Ramirez, G. Interventions for the treatment and management of chronic fatigue syndrome. A systematic review. JAMA, 2001, 286, 1360-1368.

Review of clinically tested treatments.

Nineteen specialist databases were searched from inception to either January or July 2000 for published or unpublished studies in any language. The search was updated through October 2000 using PubMed. Other sources included scanning citations, Internet searching, contacting experts, and online requests for articles.

Controlled trials (randomized or nonrandomized) that evaluated interventions in patients diagnosed as having CFS according to any criteria were included. Study inclusion was assessed independently by 2 reviewers. Of 350 studies initially identified, 44 met inclusion criteria, including 36 randomized controlled trials and 8 controlled trials.

Data extraction was conducted by 1 reviewer and checked by a second. Validity assessment was carried out by 2 reviewers with disagreements resolved by consensus. A qualitative synthesis was carried out and studies were grouped according to type of intervention and outcomes assessed.

A total of 2801 participants were included in the 44 trials combined. Studies were grouped into 6 different categories. In the behavioral category, graded exercise therapy and cognitive behavioral therapy showed positive results and also scored highly on the validity assessment. In the immunological category, both immunoglobulin and hydrocortisone showed some limited effects but, overall, the evidence was inconclusive. There was insufficient evidence about effectiveness in the other 4 categories (pharmacological, supplements, complementary/alternative, and other interventions).

Overall, the interventions demonstrated mixed results in terms of effectiveness. All conclusions about effectiveness should be considered together with the methodological inadequacies of the studies. Interventions which have shown promising results include cognitive behavioral therapy and graded exercise therapy. Further research into these and other treatments is required using standardized outcome measures.

See also editorial by Wessely (ibid, p. 1378-1379).

[Ed. Note: This analysis contains factual errors, some of which were pointed out to the British authors before publication. The validity criteria used did not include validity of definitions or outcome measures, the inclusion of symptoms other than fatigue and emotional distress, the success of randomisation etc. Data in relation to one trial was lost and some of the information was misinterpreted, thus the validity score for that trial (Goudsmit 1996) is inaccurate. Wessely was a chief advisor to the York review.]

MISCELLANEOUS

De Becker, P., Roeykens, J., Reynders, M., McGregor, N and De Meirleir, K. Exercise capacity in chronic fatigue syndrome. (Correction). Archives of Internal Medicine, 2001, 161, 16, 2051-2052.

Corrected data relating to figures 1-4 in original text (ibid, 200, 160, 3270).

Cleare, AJ. Regulatory disturbance of energy. In Everyday Biological Stress Mechanisms. Theorell, T (ed.). Advances in Psychosomatic Medicine. Basel: Karger. 2001, 22, 17-34.

Review focusing on the cognitive-behavioural model of CFS. Author notes that enforced inactivity does not have a significant effect on the HPA axis, at least in the medium term. 

Coetzer, P., Lockyer, I., Schorn, D and Boshoff, L. Assessing impairment and disability for syndromes presenting with chronic fatigue. Journal of Insurance Medicine, 2001, 33, 2, 170-182.

Many disability claims are based on the subjective symptom of fatigue, which can be caused by a wide spectrum of diagnoses including fibromyalgia, CFS and cardiopulmonary diseases. Chronic pain is very often a compounding problem. It is vital for every insurer to have fair and objective criteria to distinguish between invalid claims and those with merit. This review article proposes objective tools and parameters to achieve this goal.

Cordingley, L., Wearden, A., Appleby, L and Fisher L. The Family Response Questionnaire. A new scale to assess the responses of family members to people with chronic fatigue syndrome. Journal of Psychosomatic Research, 2001, 51, 2, 417-424.

Family responses to patients with CFS may influence the course of the disorder and family members themselves are likely to be adversely affected. However, the beliefs and responses of relatives of CFS patients have been under-researched. The aim of this study was to produce an easy-to-administer questionnaire to assess the responses of family members to people with CFS.

Seventy-eight people, all close relatives of (physician-diagnosed) CFS sufferers, completed the first version of the Family Response Questionnaire (FRQ). Examination of the correlation matrix and a cluster analysis of the items support four scales rather than the original five. The four scales were labelled: sympathetic-empathic, active engagement, rejecting-hostile, and concern with self. Measures of test-retest and internal reliability were high. Participants found the items both comprehensible and relevant to their experiences of living with people with CFS. The new version of the FRQ will be useful in further examination of the responses of CFS on individuals and their families. 

Coutts, R., Weatherby, R and Davie A. The use of a symptom "self-report" inventory to evaluate the acceptability and efficacy of a walking program for patients suffering with chronic fatigue syndrome. Journal of Psychosomatic Research, 2001, 51, 2, 425-429.

The purpose of this research was to evaluate the effectiveness of the modality of walking as a management strategy for patients suffering with CFS.

Six males and fourteen females with medically diagnosed CFS (CDC criteria '94), completed a 12-week walking program. Prior to starting the program subjects underwent an incremental walking exercise test to predetermine their walking intensity. The SCL-90-R symptom "self-report" questionnaire was administered prior to, and at the completion of, the walking program.

At the completion of the 12 weeks of walking, changes in four of the nine SCL-90-R dimensions were significant (somatisation, paranoid ideation, phobic anxiety, and psychoticism). Also significant were the changes in the combination indices, the Global Indices of Distress (GID) and the Positive Symptom Total (PST).

This group of CFS subjects, by way of "self-report", indicated the possibility of an exercise-induced decrease in psychological stress. The walking intervention may have evoked positive changes in their well-being and, furthermore, provided no evidence of any exacerbation in their symptoms.

Hardt, J., Buchwald, D., Wilks, D., Sharpe, M., Nix, WA and Egle, UT. Health-related quality of life in patients with chronic fatigue syndrome.  An international study. Journal of Psychosomatic Research 2001, 51, 2, 431-434.

Our objectives were to determine if patients from different countries have similar profiles of impairments.

Health-related quality of life (HRQoL) was assessed in 740 CFS patients in the US, 82 in the UK, and 65 in Germany using the eight subscales of the Short-Form General Health Survey (SF-36). To examine the internal structure, factor analyses were performed.

Overall, there was a remarkable similarity in HRQoL among all CFS patients, regardless of location. Patients scored two to three standard deviations below normal on six subscales and one standard deviation below normal on the other two subscales. HRQoL is poor in CFS patients from three countries.

Hyland, ME.  Extended network learning error: A new way of conceptualising chronic fatigue syndrome. Psychology and Health, 2001, 16, 3, 273-287.

This paper suggests an interactional way of conceptualising CFS using developments in complexity theory (networks, parallel processing or connectionism). It proposes a psychoneuroimmunoendocrinological model.

Lipschitz, EL. Chronic fatigue syndrome and posttraumatic stress  disorder. JAMA, 2001, 286, 8, 916. With reply by Natelson, BH, ibid, 916-917.

Letter noting similarities between PTSD and CFS and asking whether CFS is another of the protean manifestations of PTSD (cf Natelson, ibid, 285, 2557).

Natelson replies that their assessment of patients included a psychiatric diagnostic interview which would have identified cases of PTSD.  New research (in press) found few cases of the latter in nonveteran populations with CFS.

Lin, KM., Lin, M and Zheng, YP. Neurasthenia and chronic fatigue syndrome: Lessons from cross-cultural study. Cultural Psychiatry: Euro-International Perspectives. 2001, 169, 68-80. Basel: Karger.

Murdoch, JC. Chronic fatigue syndrome. British Journal of General Practice, 2001, 51, 470, 758. Letter.

Response to Hamilton et al (ibid 2001, 51, 553).

"The study of Hamilton et al... claims that a higher consultation rate in people with chronic fatigue syndrome (CFS) before they develop the diagnosis supports the hypothesis that behavioural factors have a role in its aetiology. A similar case-control study of mothers and fathers of Down's syndrome children showed that both mothers and fathers had significantly more recorded illnesses before the birth of the child and that the mothers had significantly more psychosis, neurosis or self-poisoning.

The problem with such findings is deciding what they mean. No-one would suggest that Down's syndrome is caused by 'behavioural factors,' so why should anyone believe that of CFS? There is no more evidence that increased frequency of attendance before diagnosis points to behavioural factors in CFS than that it points to non-dysjunction in the germ cells of mothers of Down's syndrome children."

Stein, E. Chronic fatigue syndrome: overcoming the attitudinal impasse. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 53-61.

A discussion paper analyzing the reasons behind the conflict between patients and practitioners.

Studies show that 46% to 90% of GPs accept CFS as a discrete clinical entity and 30-82% are willing to make the diagnosis in qualifying patients. According to the author, CFS is a heterogeneous, multifactorial host response disorder that is inadequately described by the biomedical model. Despite substantial evidence of multisystemic physical abnormality in CFS, the lack of pathognomic tests and the female gender predominance cause some physicians to continue to treat CFS as a psychosocial disorder. This leads to conflict between patients and physicians. CFS challenges physicians to think beyond current disease models, to tolerate diagnostic and therapeutic uncertainty, and to work collaboratively with patients rather than taking the role of expert.

Stevens, DL.  Chronic fatigue. Western Journal of Medicine, 2001, 175, 315-319.

[Ed. note: This article is extremely biased towards the psychiatric aspects of the illness.]

Tarello, W.  Chronic fatigue syndrome (CFS) associated with Staphylococcus spp. bacteremia, responsive to potassium arsenite 0.5% in a veterinary surgeon and his co-working wife, handling with CFS animal cases. Comparative Immunology, Microbiology and Infectious Diseases, 2001, 24, 4, 233-246.

A veterinary surgeon (the author) and his co-working wife, both diagnosed with CFS and meeting the CDC working case definition, were submitted to rapid blood cultures and fresh blood smears investigations to evaluate the possibility of bacteremia. Blood cultures proved Staph-positive and micrococci-like organisms in the blood were repeatedly observed in the 3-year period preceding the arsenical therapy, during which several medicaments, including antibiotics, proved unsuccessful. Following treatment with a low dosage arsenical drug (potassium arsenite 0.5%, im., 1 ml/12 h, for 10 days) both patients experienced complete remission. At the post-treatment control made 1 month later, micrococci had disappeared from the blood, and the CD4/CD8 ratio was rising.

VanNess, JM., Snell, CR., Fredrickson, DM., Strayer, DR and Stevens, SR. Assessment of functional impairment by cardiopulmonary exercise testing in patients with chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2001, 8, 3/4, 103-109.

Functional impairment in a population of patients with CFS was determined by exercise testing. The criteria established by Weber and Janicki were employed because impairment levels are based on maximal oxygen consumption. Oxygen consumption was obtained by cardiopulmonary exercise testing and was used to classify subjects according to the severity of impairment. All patients underwent at least two maximal graded exercise tests in which expired air was collected for assessment of V0₂max. Data are included for eighty-seven CFS patients, the highest VO₂ was used for determining impairment. Although all patients met the 1988 and 1994 CDC criteria for CFS, only 35 (40%) would be classified as having greater than "Mild" functional impairment.

The highest VO₂ of any of the patients in this study was 29.5 ml/kg/min, very close to what normative data predicts to be the average maximal value for the entire group. Without a sedentary control group it is unclear if the low V0₂ in this population is due to the pathology of CFS or results from the inactivity that accompanies the disease. However, use of maximal V0₂ during exercise can clearly discriminate between levels of functional impairment and may be efficacious for diagnosis of CFS. Additionally, in cases where cardiopulmonary analysis is unavailable, exercise duration on a standardized test may also be employed.

RESEARCH ON OTHER DISORDERS

Giovannoni, G., Thompson, AJ., Miller, DH and Thompson, EJ. Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology, 2001, 57, 4, 676-681.

This study tested the hypothesis that fatigue in MS is related to inflammatory disease activity as measured by systemic markers of inflammation.

Fatigue, as assessed by the Chalder Fatigue Questionnaire Scale (FQS) and Krupp's Fatigue Severity Scale (KFSS), was correlated with several inflammatory markers in 38 patients with MS. The markers included daily urinary neopterin excretion, a marker of interferon-gamma-activated macrophage activity, serum C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) levels. Urinary neopterin excretion was measured daily for 2 weeks.

No correlation was found between urinary neopterin excretion, CRP, or sICAM-1 and the fatigue scores. However, patients with a raised serum CRP level had higher KFSS but not FQS scores than patients with normal CRP levels. The patients with benign MS were as fatigued as patients with nonbenign disease.

The pathogenesis of fatigue in MS ... does not appear to be directly related to systemic markers of inflammatory disease activity. Nor is it related to disability. The two fatigue scales did not correlate with each other, which begs the question what they are actually measuring. Patients with primary-progressive MS were less fatigued than patients with relapsing-remitting disease.

Sources used include ISI Personal Alert, Co-Cure and Medline. With thanks to Dr. Marc Fluks and Mrs. Sandra Howes.

Copyright EM. Goudsmit 2001. ©
Psychologist/Archivist, London.
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