VIROLOGY
Martin, WJ. Detection of RNA sequences in cultures of a stealth virus isolated from the cerebrospinal fluid of a health care worker with chronic fatigue syndrome. Pathobiology, 1997, 65: 57-60.
A cytopathic stealth virus was cultured from the cerebrospinal fluid (CSF) of a nurse with CFS. Reverse transcriptase - polymerase chain reaction (RT-PCR) performed on the patient's culture yielded positive results with primer sets based on sequences of a previously isolated African green monkey simian cytomegalovirus (SCMV)-derived stealth virus. The same primer sets did not yield PCR products when tested directly on DNA extracted from the cultures.
Blood tests had also revealed raised antibody titres to cytomegalovirus, as a result of which the patient was treated with ganciclovir (IV). The drug lessened some of the reported symptoms, including headaches and cognitive dysfunction. The CSF was collected three weeks following treatment.
"The findings lend support to the possibility of replicative RNA forms of certain stealth viruses and have important implications concerning the choice of therapy in this type of patient".
Martin, WJ and Anderson, D. Stealth virus epidemic in the Mohave Valley. Pathobiology, 1997, 65, 51-56.
Stealth viral cultures were performed on the blood of 40 patients who had become ill during the spring and summer of 1996 within the Mohave Valley region of the United States. They were involved in an outbreak affecting several hundred individuals in all. The symptoms began with a flu-like gastrointestinal illness but following the acute phase, a significant number also reported episodes of neurological dysfunction. The manifestations were of varying duration and changed over time. Prominent among the symptoms were numbness, paraesthesia, gait disturbance, memory loss, sleep disturbance, attention deficit and personality changes. Except for the most severely affected, the onset, protracted course and neurological symptoms were similar to those encountered in patients with CFS and Gulf War Syndrome. A number of patients developed additional non-neurological conditions, including liver disease, hypothyroidism or arthritis. Two developed tumours, one of which proved fatal. Furthermore, several dogs belonging to an affected couple became sick with neurological signs.
The cultures "have been uniformly positive, yielding unequivocal transmissible cytopathic effect (CPE) in both human-and monkey-derived cell lines... Viral cultures and epidemiological data support human-to-human, and probably human-to-dog transmission of the Mohave stealth virus infection".
IMMUNOLOGY
Bennett, AL., Chao, CC., Hu, S., Buchwald, D., Fagioli, LR., Schur, PH., Peterson, PK and Komaroff, AL. Elevation of bioactive transforming growth factor-b in serum from patients with chronic fatigue syndrome. Journal of Clinical Immunology, 1997, 17, 2, 160-166.
The level of bioactive transforming growth factor-b (TGF-b) was measured in serum from 93 patients with CFS (CDC criteria '88 plus post-exertional malaise), 80 healthy controls, 46 patients with major depression, 50 patients with systemic lupus erythematosis and 57 patients with multiple sclerosis.
The patients with CFS were found to have significantly elevated levels of bioactive TGF-b compared with the other groups. This supports previous findings documented in smaller number of patients with CFS.
Buckwald, D., Wener, MH., Pearlman, T and Kith, P. Markers of inflammation and immune activation in chronic fatigue and chronic fatigue syndrome. Journal of Rheumatology, 1997, 24, 2, 372-276.
Five serum markers of inflammation and immune activation were measured in 98 patients with CFS (CDC criteria '88 and '94) and 55 patients with chronic fatigue (CF) who did not meet all the criteria for CFS. Patients were also subdivided according to the onset (viral/nonviral) or the presence of fever at the time of examination. Their results were compared with those of unpaid volunteer blood donors and healthy laboratory personnel.
The patients with CFS and CF had significantly higher mean concentrations of C-reactive protein, ß2-microglobulin and neopterin compared to the controls (p<.01). The presence of several markers was highly correlated.
There were no significant differences between the CFS and CF groups and none between the subgroups, with the exception that IL-6 was raised in patients with a temperature. Moreover, the patients without a viral onset were more likely to have elevated neopterin levels (p>.05) than those with this history.
"Our findings that levels of several markers were significantly correlated points to a subset of patients with immune activation. Whether this phenomenon reflects an intercurrent, transient, common condition, such as an upper respiratory infection, or is the result of an ongoing illness associated process is unknown. Overall, serum markers of inflammation and immune activation are of limited diagnostic usefulness in the evaluation of patients with CFS and CF."
Cannon, JG., Angel, JB., Abad, LW., Vannier, E., Mileno, MD., Fagioli, L., Wolff, SM and Komaroff, AL. Interleukin-1b, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome. Journal of Clinical Immunology, 1997, 17, 3, 253-261.
CFS is a condition that affects women in disproportionate numbers, and that is often exacerbated in the pre-menstrual period and following physical exertion. The signs and symptoms are similar to those experienced by patients infused with cytokines such as interleukin-1. The present study was carried out to test the hypotheses that
(1) cellular secretion of interleukin-1b (IL-1b), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-1 receptor type II (IL-1sRII) is abnormal in female CFS patients compared to age- and activity-matched healthy controls;
(2) that these abnormalities may be evident only at certain times in the menstrual cycle; and
(3) that physical exertion (stepping up and down on a platform for 15 min) may accentuate differences between these groups.
The patients were women with acute onset, post-infection CFS (CDC '88 criteria) who had been ill for less than three years and who regularly experienced post-exertional malaise. Eight were tested during the follicular phase and 8 during the luteal phase. Of the controls, 7 were tested during the follicular phase and 8 during the luteal phase.
Isolated peripheral blood mononuclear cells from healthy women, but not CFS patients, exhibited significant menstrual cycle-related differences in IL-1b secretion that were related to oestradiol and progesterone levels (p<0.01). IL-1Ra secretion for CFS patients was twofold higher than controls during the follicular phase (p=0.023), but luteal-phase levels were similar between groups. In both phases of the menstrual cycle, IL-1sRII release was significantly higher for CFS patients compared to controls (p=0.0002). The only changes that might be attributable to exertion occurred in the control subjects during the follicular phase, who exhibited an increase in IL-1b secretion 48 hours after the stress (p=0.020).
"These results suggest that an abnormality exists in IL-1b secretion in CFS patients that may be related to altered sensitivity to estradiol and progesterone. Furthermore, the increased release of IL-1Ra and IL-1sRII by cells from CFS patients is consistent with the hypothesis that CFS is associated with chronic, low-level activation of the immune system". However, the findings do not support the view that the clinical manifestations of CFS are due to increased IL-1 bioactivity since the levels of IL-1b in the control group during the luteal phase exceeded those of the women with CFS.
Mawle, AC., Nisenbaum, R., Dobbins, JG., Gary, HE., Stewart, JA., Reyes, M., Steele, L., Schmid, DS and Reeves, WC. Immune responses associated with chronic fatigue syndrome: a case control study. Journal of Infectious Diseases, 1997, 175, 1, 136-141.
Twenty-six patients with CFS (CDC '88) were compared with 50 age, gender and race-matched controls on measures of immune function. Patients were subgrouped according to disease onset (sudden or gradual), wellness at time of testing (well or sick) and duration of illness (long or short).
No group differences were found in terms of delayed type hypersensitivity responses to allergens or proliferative response to antigens and mitogens. There were no differences in white blood cell numbers; immune complex, complement or serum immunoglobulin levels and NK cell function. Marginal differences were detected in cytokine responses and in cell surface markers in the total CFS population. However, when the patients were subgrouped according to the type of disease onset or by how well they were feeling on the day of testing, more pronounced differences were seen.
For instance, the sudden group had significantly more CD8 cells expressing CD11b (seen in acute infections). They also had higher levels of IL-2 than controls, as did people who were sick. The gradual group had lower levels of IL-1a and IL-1b than controls, and a lower percentage of CD56 (NK) cells expressing CD2. Sicker patients had lower levels of IL-1a than controls and fewer CD8 cells expressing CD25. Well patients had more bright CD8 cells. Those who had been ill for longer than 63 months showed an increased percentage of CD19 (B) cells expressing CD5 (responsible for autoantibody production).
The researchers note the lack of differences when taking the sample as a whole. They suggest that patients with a sudden onset of CFS had cytokine and a cell surface markers profile reminiscent of acute infection.
Von Mikecz, A. Konstantinov, K., Buchwald, DS., Gerace, L and Tan, EM. High frequency of autoantibodies to insoluble cellular antigens in patients with chronic fatigue syndrome. Arthritis and Rheumatism, 1997, 40, 2, 295-305.
The aim of this study was to elucidate the humoral immune re-sponse in 60 patients with CFS (CDC criteria '88, '94), by identification and characterisation of autoantibodies. The results were compared with those of 30 controls and 41 healthy blood donors.
Initial immunofluorescence histochem-istry studies of sera using human HEp-2 cell substrate were followed by antibody class subtyping and co--localisation studies with reference antibodies. Associa-tion of CFS autoantigens with insoluble cellular compo-nents was determined by in situ extraction of soluble components and subsequent immunofluorescence histo-chemistry studies on the extracted cell substrate.
Of the 60 CFS patients, 41 (68%) were posi-tive for antinuclear antibodies. Localisation of nuclear staining was found at the nuclear envelope (52%), in reticulated speckles (25%), in nucleoli (13%), and in dense fine speckles (5%). Twenty-eight CFS sera (47%) also had antibodies to cytoplasmic antigens. The major cytoplasmic staining pattern was of the intermediate filament type (35%). The observed nuclear envelope pattern of staining co-localised with lamina-associated polypeptide 2 (an integral nuclear membrane protein), the reticulated speckle pattern co-localized with non-small nuclear RNP splicing factor SC-35, and the intermediate filament pattern co-localized with vimen-tin. The intermediate filament antigen was shown to be vimentin in immunoblotting experiments using recom-binant human vimentin, and one of the nuclear envelope antigens was shown previously to be lamin B1. Fifty of the CFS patients (83%) had antibodies to one or another of these antigens, all of which are relatively insoluble cellular antigens, whereas a control group of patients without chronic fatigue had a significantly lower frequency of such antibodies (17%).
"The high frequency of autoantibodies to insoluble cellular antigens in CFS represents a unique feature which might help to distinguish CFS from other rheumatic autoimmune diseases."
PHYSIOLOGY, NEUROPHYSIOLOGY AND NEUROENDOCRINOLOGY
Hoskin, L., Clifton-Bligh, P., Fulcher, G, Hansen, R and Gates, F. Bone mineral density in premenopausal nulliparous women with chronic fatigue syndrome compared with age, weight matched controls. Journal of Bone and Mineral Research, 1997, 12, Suppl. S. 228. Meeting Abstract.
A study of 34 premenopausal women with CFS (Oxford criteria), aged 16-38, were assessed using the Norland Bone Mineral Densitometer.
The patients had significantly lower fat free mass than 20 asymptomatic controls and significantly lower bone mineral density at the femoral neck, the wards triangle and the trochanter. However, there were no group differences at L2-L4, or in terms of total bone mineral density.
PATHOLOGY
Vojdani, A., Ghoneum, M., Choppa, PC., Magtoto, L and Lapp, CW. Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. Journal of Internal Medicine, 1997, 242, 6, 465-478.
Evidence of immune dysfunction is present in many patients with CFS. It has recently been shown that apoptosis (programmed cell death) might be mediated by the upregulation of growth inhibitory cytokines and thus be a mechanism for the elimination of cancer cells and virus-infected cells. In this study, the apoptotic cell population, interferon-alpha (IFN-a), and IFN-induced protein kinase RNA (PKR) gene transcripts in the peripheral blood lymphocytes (PBL) and plasma of patients with CFS were evaluated and compared with those of healthy controls.
PBL were obtained from a total of 29 CFS patients (CDC criteria '94) consisting of two groups: three males and six females from a North Carolina clinic and seven males and 13 females from Los Angeles County. All patients complained of fatigue; 80% complained of exhaustion fatigue, sleep disorder, arthralgia/myalgia and sore throat with a duration of symptoms between one and five years. 15 healthy controls seen for routine physical examination came from the Los Angeles area. After the clinical information had been analysed, it was found that the patients could be placed into a single group. None of the patients' symptoms were present in the controls.
65% and 73% of patients had IFN-a levels above lOpg/mL in plasma and cell [lymphocyte] lysate, respectively, compared with 25% and 8% of controls with similar respective levels. Additionally 44% and 33% of the patients had levels exceeding 100pg/mL, respectively, but none of the controls. The mean value for PKR mRNA in the CFS patients was significantly upregulated as compared with the controls and this was reflected in the raised PKR protein levels in the CFS group. Using flow cytometry with fluorescent staining, the apoptotic cell [lymphocyte] population was measured, revealing a significantly raised level in CFS patients compared with the controls. Analysis of the non-apoptotic cell population in CFS patients indicated an arrest of cells in the late S and G2/M boundaries with a concomitant increase in the cell population in the S and G2/M phases, demonstrating an abnormality of mitotic cell division. Treating the PBL with the PKR inhibitor 2-aminopurine reduced the apoptotic cell population in some of the CFS patients and also those cell populations arrested in the S and G/2M phases.
The authors suggest that the upregulation of PKR levels resulting in disregulated cell metabolism due to inhibition of protein synthesis might be the mechanism responsible for the fatigue observed in CFS patients.
[Ed. note: This study provides further evidence of immune dysfunction in some CFS patients.]
Watson, WS., McCreath, GT., Chaudhuri, A and Behan, PO. Possible cell membrane transport defect in chronic fatigue syndrome? Journal of Chronic Fatigue Syndrome, 1997, 3, 3, 1-13.
Cardiac thallium-201 single photon emission computerised tomography was carried out on 10 patients with CFS (not defined), aged 23-56, all of whom also had significant exertional dyspnoea. The scans were obtained after exercise and 7 days later, after rest.
Seven of the patients had defects in the thallium tracer distribution within the left ventricle; this was significantly greater than would be expected in the normal adult population. Similar abnormal scans have been observed in patients with syndrome X, a condition which has symptom overlap with CFS.
It is suggested that an abnormally high efflux of cellular potassium may be the cause of the abnormal scans in syndrome X, and it is proposed that this mechanism may also play a role in CFS.
PSYCHOLOGY, NEUROPSYCHOLOGY AND PSYCHIATRY
Anderson, JS and Ferrans, CE. The quality of life of persons with chronic fatigue syndrome. Journal of Nervous and Mental Disease, 1997, 185, 6, 359-367.
One hundred and ten patients with CFS (CDC criteria '88) were assessed using a CFS questionnaire and the Ferrans and Powers Quality of Life Index. A subset of 22 patients were then interviewed to obtain more detailed information.
The people with CFS had lower quality of life scores than all other chronically ill patients tested to date. Fifty per cent reported that cognitive dysfunction was the most disabling and disruptive symptom. Less than a half (45%) felt that they had no control over their illness while 55% had sought counselling to help them cope. Many noted the variability of the symptoms. Depression was common (82%) but generally related to the impact of the illness.
The researchers conclude that quality of life is particularly and uniquely disrupted in CFS.
Bazelmans, E., Bleijenberg, G., Vercoulen, JHMM., van der Meer, JWM and Folgering, H. The chronic fatigue syndrome and hyperventilation. Journal of Psychosomatic Research, 1997, 43, 4, 371-377.
This article reports three studies on patients with CFS (Oxford criteria). Study 1 involved 39 patients with CFS, 32 healthy controls and 17 people with hyperventilation but no CFS. Measures included physical activity levels (actometer), fatigue, the Beck Depression Inventory and a hyperventilation questionnaire. Using moderately strict criteria, 59% of the CFS patients scored above the cut-off point for hyperventilation compared with 3% of the healthy controls and 65% of the non-CFS hyperventilation group. Using even stricter criteria (cf. Saisch et al), only 19% of the CFS and none of the controls were diagnosed with hyperventilation.
In study 2, 27 patients with CFS were compared with 32 healthy controls. On the basis of respiratory measures such as Petco2, breathing frequency and irregularity of breathing, significantly more CFS patients showed signs of hyperventilation than did healthy controls. However, CFS patients only differed on the Petco2 and recognition of complaints, not the other respiratory parameters.
In study 3, 16 CFS patients with hyperventilation were compared with 11 CFS patients without hyperventilation on a number of measures including activity levels, fatigue, depression, psychopathology, and number of complaints. No significant differences were found.
According to the researchers, hyperventilation is probably an epiphenomenon in CFS and does not play a substantial role in causing or perpetuating the condition.
Clements, A., Sharpe, M., Simkin, S., Borrill, J and Hawton, K. Chronic fatigue syndrome: a qualitative investigation of patients' beliefs about the illness. Journal of Psychosomatic Research, 1997, 42, 6, 615-624.
Sixty-six patients with CFS (Oxford and CDC criteria '94) were interviewed to determine their beliefs about what caused the illness, where those beliefs originated, if they felt control over their illness and how they tried to control their illness.
Ninety-seven per cent attributed their illness to physical and disease factors, of which 45% believed these to be the sole factors. Of the respondents who mentioned an infection, 24% specified flu, 11% cited glandular fever, but 44% referred to a non-specific viral infection. Nearly a half (47%) mentioned social stressors and 15% described activity and lifestyle (e.g. little rest).
Seventy-six per cent felt that they had some control over their symptoms but few believed they had control over the course of the illness. Their beliefs about causation were largely the result of their own experiences and non-professional literature (e.g. from patient groups). Patients reported that reducing activity resulted in a short-term reduction of symptoms.
Cooper, L. Myalgic encephalomyelitis and the medical encounter. Sociology of Health and Illness, 1997, 19, 2, 186-207.
This paper set out to explore the consequences of uncertainty and controversy for those who suffer from ME. The subjects were ten patients recruited through a self-help group and information was obtained using unstructured interviews. Further data was obtained from a postal survey of doctors as well as interviews with doctors and researchers.
Some patients did not respond to their initial symptoms by resting, and not everyone attributed their illness solely to a virus.
Many patients reported difficulties in finding an acceptable diagnosis. They were generally denied full and decisive entry into the sick role and they found their social identity devalued and stigmatized. One was told that "ME does not exist...it's all in your head". Interactions with doctors after such experiences became conflictual and emotional. Finding the label of ME reduced uncertainty but where the diagnosis was obtained elsewhere, their own doctors became angry and abusive. The latter undermined the patients' trust in their physicians and their authority, and led many towards complementary medicine. One doctor, however, was greatly appreciated by several respondents, not because he offered a quick fix but because he "accepted his patients as fellow human beings whose suffering needed to be understood and accepted".
The majority reported that others misunderstood the nature of their illness. For instance, patients used the word fatigue to refer to exhaustion but this meaning was not shared by their doctors. Similarly, depression was seen as a part of the illness by the patients but as the main cause by doctors.
Being accepted as genuinely ill and 'good' or 'normal' patients was important. This meant that sufferers tried to avoid provoking their doctors, for instance, by referring to knowledge procured from other sources.
There were some differences in terms of gender. For example, two of the three male patients reported that their GP accepted their condition. In contrast, the women were viewed as malingerers, school phobics or bored housewives.
Cooper suggests that self-help groups represent a perceived threat to physicians as holders of authoritative knowledge and that this might explain the doctors' hostility towards them. "Nonetheless, as a profession which holds the rights to possession of scientific medical knowledge, and as gatekeepers to social and community support, they are not seriously challenged".
Finally, Cooper notes that of 125 GPs who replied to her survey, 57 accepted ME and 81 accepted CFS as a valid medical condition, whilst 35% expressed supportive or sympathetic feelings towards such patients.
DeLuca, J., Johnson, SK, Ellis, SP and Natelson, BH. Cognitive functioning is impaired in patients with chronic fatigue syndrome devoid of psychiatric disease. Journal of Neurology, Neurosurgery and Psychiatry, 1997, 62, 151-155.
Thirty-six patients with CFS (CDC criteria '88 and '92, duration >4 years, moderate symptoms at time of intake) were studied using a battery of neuropsychological tests. None of the CFS patients had a psychiatric illness in the five years prior to the onset of symptoms. The CFS group was subdivided according to the presence or absence of current or earlier psychiatric history (CFS-nopsych, N=21). Their results were compared with those of 31 healthy controls who did not exercise regularly.
Assessments included a psychiatric interview (DIS), the paced auditory serial addition tests (PASAT), the Rey-Osterreith complex figure test, the California verbal learning test and the BDI.
The overall performance of the CFS patients was significantly below that of the controls. On some tests, the patients with no psychiatric disorders scored below those of the controls and the CFS group with psychiatric disorders. According to the researchers: "impaired cognition in chronic fatigue syndrome cannot be explained solely by the presence of a psychiatric condition".
Jason, LA., Richman, JA., Friedberg, F., Wagner, L., Taylor, R and Jordan, KM. Politics, science, and the emergence of a new disease. The case of chronic fatigue syndrome. American Psychologist, 1997, 52, 9, 973-983.
This article examines the controversy surrounding the relationship between CFS and neurasthenia by exploring how the establishment of diagnostic criteria and the design of early epidemiological studies led to inaccurate and biased characterisations of CFS.
The authors note the differences between the narrow and broader criteria, showing how the latter may have produced more heterogeneous groups and inadvertently selected subgroups with high levels of psychiatric morbidity. As a result, this may have increased the prevalence rates in epidemiological surveys. Instruments used to assess psychiatric comorbidity may not give an accurate picture either. For instance, one study found that the DIS identified 50% of a CFS group as having a current psychiatric diagnosis whereas the SCID identified only 22%. In the authors' opinion, patients suffering solely from psychiatric disorders should not be included within the CFS rubric.
The article lists several differences between CFS and depression (the latter has more anhedonia and worthlessness; the former has a higher incidence of severe fatigue, post-exertional malaise, intolerance to alcohol, nausea, flu-like symptoms and acute onset). They suggest that the depression which accompanies a long illness might be better conceptualised as demoralisation rather than as a discrete psychiatric illness.
The use of particular measures may have resulted from practitioner bias, relating to the link with neurasthenia. These biases have been filtered to the media, which have portrayed CFS in simplistic and stereotypical ways.
With regard to treatment, the authors note the difficulties in interpreting the research into CBT, given the possible differences in samples, severity of symptoms, inclusion of patients with psychiatric morbidity etc. They agree with Friedberg and Krupp that CBT is appropriate if activity is avoided due to depressed mood and an unrealistic fear of symptom flare-ups. Otherwise, it might be more prudent to evaluate each CFS patient individually and to develop a tailor-made rehabilitation programme in the light of the symptomatology and actual activity levels.
The authors acknowledge the problem of different types of illnesses within the CFS construct, the need to differentiate the different dimensions relating to fatigue (post-exertional symptoms, allergy fatigue etc) and the importance of cut-off points for various symptoms. It is also important to clarify exactly what 'new or definite onset' means and, given that many patients have only minimal symptoms when engaging in fewer activities, further guidelines are needed in respect of the criterium requiring that symptoms are not substantially alleviated by rest.
Lindal E., Bergmann S., Thorlacius S and Stefansson, JG. Anxiety disorders: A result of long-term chronic fatigue - the psychiatric characteristics of the sufferers of Iceland disease. Acta Neurologica Scandinavica, 1997, 96, 3, 158-162.
The aim of this study was to clarify the lifetime likelihood of developing psychiatric disorder following Akureyri disease*.
The researchers investigated 55 well documented cases of Akureyri disease who were still experiencing symptoms. All participants were interviewed using the DIS and diagnosed according to DSM-III. The results were compared to those of 421 members of the general population who had also been interviewed using the DIS. A further comparison was made with 10 patients suffering from systemic lupus erythematosus (SLE).
Of the 55 subjects included in this analysis, 53 were women. The mean age of the participants was 67.7 years. The following lifetime disorders were found more commonly among the patients compared with the controls: agoraphobia with panic attacks 12.7% (p<0.0001); agoraphobia without panic attacks 21.8% (p<0.0001); social phobia 14.5% (p<0.001); simple phobia 18.1% (p<0.05); schizophrenia 3.6% (p<0.01); and alcohol dependence 5.4% (p<0.05). The rate of recurrent major depression was also higher than in the controls (5.4 vs 4.2) but the difference did not reach significance.
The one year prevalence rates showed significantly more phobic disorders (p=.0001), schizophrenia (p=.01) and alcohol abuse (p=.05). The only significant difference between the patients with CFS and SLE was in the prevalence of lifetime generalised anxiety (p=0.01).
The researchers conclude that prolonged chronic fatigue most commonly results in anxiety disorders, particularly those relating to social conspicuousness. This is also found in people with SLE. "Following the infection, the more serious psychiatric disorders do not seem to play a major role in the long run".
[* Some regard this illness as a form of ME (cf. Ramsay 1988)].
Ray, C., Jefferies, S and Weir, WRC. Coping and other predictors of outcome in chronic fatigue syndrome: A 1-year follow-up. Journal of Psychosomatic Research, 1997, 43, 4, 405-415.
In this prospective study, 137 patients with CFS were followed-up at a 1-year interval to determine factors relating to outcomes. All patients fulfilled the Oxford criteria with the additional requirement of exercise-induced fatigue precipitated by relatively trivial exertion. After investigating alternative explanations for their symptoms, the therapeutic approach was to recommend a regime of rest balanced with modest exercise, together with a meditation technique to help reduce psychological stress. Patients with apparent depressive illness were given low-dose antidepressants. The mean duration of illness was 40.26 months.
Time 1 measures included the Profile of Fatigue-Related Symptoms (PFRS), a measure of functional impairment, the Hospital Anxiety and Depression Scale, the Illness Management Questionnaire (IMQ), the Behavioural Disengagement subscale of the COPE (representing giving-up or withdrawing efforts from dealing with the illness), the Multidimensional Health Locus of Control Scales (Form C) and a measure of illness attributions. Status at Time 2 was assessed using the fatigue scale of the PFRS and the functional impairment scale. There was also an overall assessment of change based on questions about symptoms and coping.
At follow-up, 63.2% of the patients reported a positive overall change and 13.2% recorded a negative change. This was consistent with a question asking about the trajectory of the illness, where 64.4% reported improvement and 14.8% reported a worsening.
After controlling for earlier status it was found that illness duration, cognitive difficulty and somatic symptoms predicted both fatigue and functional impairment at Time 2. There was also a relationship between information seeking and fatigue; the more severely ill patients being more likely to seek information. Cognitive difficulty was a better predictor of fatigue at follow-up than prior fatigue. Behavioural disengagement and a low internal locus of control were predictors of impairment. There was no influence of anxiety, depression or illness attributions.
The belief that one's actions can influence outcomes modified the relationship between accommodation to the illness (i.e. coping by planning one's life to avoid overexertion and stress) and both fatigue and impairment; adverse outcomes were associated only in the context of lower levels of perceived control. In other words, the group of patients who did not expect that their actions could lead to real benefit may have used this strategy to withdraw or avoid activities to prevent short-term exacerbations only. In contrast, patients with an internal locus (i.e. who believed that they could influence outcomes), may have moderated their activities in order to recover; this strategy therefore has a goal-directed function which could hence lead to a more balanced and consistent approach.
The researchers suggest that interventions that discourage the avoidance of activity and/or enhance perceived control may benefit the course of the illness.
EPIDEMIOLOGY
Lawrie, SM., Manders, DN., Geddes, JR and Pelosi, AJ. A population-based incidence study of chronic fatigue. Psychological Medicine, 1997, 27, 343-353.
Six hundred and ninety five adult men and women were surveyed one year following a previous assessment. The postal questionnaires included a fatigue scale (David et al 1990), the GHQ-12 and questions about fatigue and the reasons for fatigue. People who described physical or psychiatric disorders which could explain their fatigue scores were excluded as were cases previously identified as having chronic fatigue. The medical records of all those with high fatigue scores were examined. They were also interviewed (CIS-R), and assessed using the Beck Depression Inventory, the Social Stresses and Supports Instrument, the Hamilton Rating Scale for Depression, the fatigue questionnaire and GHQ-12. Some patients were interviewed over the phone and some who were identified during the initial survey were also interviewed. Their results were compared with those of 13 people with possible psychiatric conditions (based on the response to the GHQ-12) and 15 normal controls.
There was a 78% response rate to the survey. Of 41 new cases of chronic fatigue, 23 were unexplained. Of the 19 cases of possible CFS (including patients from the initial survey), 53% had a current psychiatric diagnosis and 35% had a past history of psychiatric morbidity. Two fulfilled the Oxford criteria for CFS (giving a prevalence rate of 740/100000), but one was found to have a psychiatric diagnosis at interview. Two cases of CFS diagnosed previously had been ill longer and were described in their medical records as cases of 'ME'. Both of these also fulfilled criteria for psychiatric disorders at interview.
Fatigue at the initial survey was found to be a risk factor for chronic fatigue (corrected for confounding) but the presence of emotional distress or physical attributions were not. After correcting the CIS-R scores for fatigue and excluding cases of neurasthenia, the relatively high levels of psychiatric morbidity were reduced to those found in normal controls. "CFS should not, therefore, be seen simply as a manifestation of psychiatric disorder, such as depression, as this ignores the difference between presenting complaints of fatigue as opposed to low mood, and also disregards some differences in the quality of affective disorder in CFS and classically depressed subjects". Symptom severity and the presence of psychiatric disorder increased the likelihood of a medical consultation.
These findings on a general population sample suggest that different factors are predominantly responsible for syndromes of chronic fatigue at different stages. "Studies that examine the similarities and differences between chronic fatigue syndromes and psychiatric disorder should consider both the stage of the illness and the research setting".
Levine, PH., Snow, PG., Ranum, BA., Paul, C and Holmes, MJ. Epidemic neuromyasthenia and chronic fatigue syndrome in West Otago, New Zealand: a 10-year follow-up. Archives of Internal Medicine, 1997, 157, 7, 750-754.
Twenty-three patients out of 28 who had become ill during an outbreak resembling epidemic neuromyasthenia in Otago, New Zealand in 1984, were contacted. The report covers information from 21 patients who had completed satisfactory interviews.
Eight were retrospectively diagnosed as having CFS, two more were classed as possible cases. The others were classified as having had prolonged or idiopathic fatigue (they did not have the required number of symptoms listed in the CDC criteria '94).
A return to premorbid activity was seen in 16 (76%) of patients although some noted having to modify their lifestyle to prevent relapses.
Although the numbers of men and women interviewed was similar (13 men, 10 women), there were more females among the cases of CFS. This may reflect the likelihood that women are more prone to develop CFS than men due to "a more active humoral immune response".
The favourable outcome in these epidemic-associated CFS contrasts with the data from sporadic cases. The researchers suggest several reasons for this: there may be more than one aetiological trigger and pathogenesis that result in CFS; the epidemic meant early recognition among the physicians that a non-psychiatric disorder appeared to be involved and the epidemic form of the illness may have been caused by infection whereas in other cases, genetic predisposition may play a role. Finally, the current criteria for CFS depend on the duration and severity of symptoms which introduces unavoidable bias when it is not possible to identify people with transient (i.e. less chronic) symptoms.
THERAPEUTICS
King, CP., Jason, LA., Frankenberry, L., Jordan, K and Tryon, W. Think inside the envelope. The CFIDS Chronicle, 1997, 10, 4, 10-14.
This article discusses an alternative treatment programme to graded exercise. By promoting the use of moderation and energy conservation, and more specifically, by monitoring the levels of perceived and expended energy, and keeping the two relatively close, patients remain as active as possible. A case history shows that this approach decreased fatigue and increased levels of perceived energy.
"Our data strongly suggest that patients with CFS need to continuously monitor and assess their current levels of expended energy, perceived energy and fatigue".
Lerner, AM., Zervos, M., Dworkin, HJ., Chang, CH., Fitzgerald, JT., Goldstein, J., Lawrie-Hoppen, C., Franklin, B., Krotkin, SM., Brodsky, M., Walsh, D and O'Neill, W. New cardiomyopathy: pilot study of intravenous gangiclovir in a subset of the chronic fatigue syndrome. Infectious Diseases in Clinical Practice, 1997, 6, 2, 110-117.
This study involved a subset of 18 patients with CFS (CDC criteria), reporting overwhelming fatigue for less than 2 years, and with oscillating repeti-tively abnormal aberrant T-waves at 24-hour electrocardiogram (ECG) recordings (Holter monitors). Baseline 12-lead ECG, 2-D echocardiogram, rest/stress myocar-dial perfusion (thallium 201 or TC-99 sestamibi) and rest/stress multiple-gaited acquisition studies, as well as coronary angiography excluded coronary artery disease. Patients in this CFS subset had significant Ig (with or without positive IgM) human cytomegalovirus (HCMV) enzyme-linked immunoassay antibody titers. They had little or no evidence of concurrent Epstein-Barr virus (EBV) multiplication, corroborated by negative viral capsid antigen IgM antibody titer and an EBV total early antigen antibody titer of <40.
All patients were given intravenous ganciclovir (5 mg/kg ql2h for 30 days). They were instructed to avoid exercise and alcohol. Temazepam and/or fluoxetine were prescribed for insomnia or severe reactive depression as needed. Before this treatment, none of 18 patients could work or manage a household (assessed using the Energy Index).
After the treatment was completed, the patients were asked to renew normal activities in gradual increments as tolerated. At the follow-up (24 weeks after ganciclovir), 13 patients (72%) had returned to their premorbid healthy states (p<.05). The patients who did not respond tended to have lower levels of HCMV IgG prior to treatment. There were no adverse effects from ganci-clovir in these non-immunosuppressed patients.
The type of abnormalities documented in the cardiac study "are not seen in normal persons leading a sedentary life". The immunological tests suggest that these patients had a "non-lytic, nonpermissive, persistent HCMV infection".
TREATMENTS
See, DM and Tilles, DM. Alpha interferon treatment of patients with chronic fatigue syndrome. Immunological Investigations, 1996, 25, 1-2, 153-164.
Twenty-six patients with CFS (CDC '88) completed a trial of alpha 2a interferon and placebo in a double-blind crossover study. Outcome was evaluated by natural killer (NK) cell function, lymphocyte proliferation to mitogens and soluble antigens, CD4/CD8 counts and a 10-item Quality of Life (QOL) survey. Patients were subdivided into four groups according to baseline NK function and lymphocyte proliferation.
Three patients had normal results when compared to 20 healthy controls; seven had diminished NK cell function and seven had abnormal values on both parameters while nine had abnormalities on the lymphocyte tests. Four patients dropped out of the trial.
According to the researchers, alpha interferon therapy only helped the patients with decreased NK function.
MISCELLANEOUS
Freeman, R and Komaroff, AL. Does the chronic fatigue syndrome involve the autonomic nervous system? American Journal of Medicine, 1997, 102, 4, 357-364.
The aim of this study was to investigate the role of the autonomic nervous system in the symptoms of 20 patients with CFS (CDC criteria '88), selected if they had one out of three criteria indicating autonomic nervous system dysfunction. They completed questionnaires pertaining to autonomic and CFS symptoms and their level of physical activity. Interviews (DIS) were used to determine the presence of premorbid and co-existing psychiatric disorders. The findings were compared with those of 20 healthy age and gender-matched controls.
The CFS subjects had a significant increase in baseline (p<0.01) and maximum heart rate (HR) on standing and tilting (both p<0.0001). Tests of parasympathetic nervous system function (the expiratory inspiratory [E:I] ratio, p<0.005; maximum minus minimum HR difference [Max-Min], p<0.05), were significantly less in the CFS group as were measures of sympathetic nervous system function (systolic blood pressure decrease with tilting, p<0.01; diastolic blood pressure decrease with tilting, p<0.05; and the systolic blood pressure decrease during phase II of a Valsalva manoeuvre, p<0.05). Twenty-five percent of CFS subjects had a positive tilt table test (at 60 degrees, without isoproterenol infusion, n=16).
The past history of depression or the presence of co-existing psychiatric disorders did not predict the autonomic test results. However, the physical activity index was a significant predictor of some autonomic test results (including resting HR, explaining 45% of the variance; sitting HR; standing HR and heart rate on tilt). Physical activity was not related to other measures (e.g. Max-Min, E:I ratio; systolic and diastolic blood pressure on tilt). Thus deconditioning alone did not fully explain the autonomic nervous system abnormalities documented above.
Among the patients, 89% reported that an infectious illness had preceded the onset of fatigue. In 46%, the autonomic symptoms occurred within 4 weeks of the infection, "a temporal pattern that is consistent with a postviral, idiopathic autonomic neuropathy".
The researchers conclude that patients with CFS show alterations in sympathetic and para-sympathetic nervous system function. The results, which provide the physiological basis for the orthostatic intolerance and other symptoms of autonomic function in this patient group, may be explained by cardiovascular deconditioning, a postviral idiopathic autonomic neuropathy, or both. However, "some symptoms of CFS, such as sore throats, myalgias, lymphadenopathy cannot be explained by autonomic dysfunction or orthostatic intolerance."
Hock, AD. Fatigue and 25-hydroxyvitamin D levels. Journal of Chronic Fatigue Syndrome, 1997, 3, 3, 117-127.
This article describes 504 fatigued patients, of whom all but eleven had low levels of 25-hydroxyvitamin D. They were treated using appropriate doses of cholecalciferol.
There was an excellent response in those with a mild deficiency, but a more variable outcome for patients with extremely low levels and/or chronic ill health.
The author suggests that measurements of vitamin D should be included in the screening of patients with fatigue.
Jason, LA., Tryon, WW., Frankenberry, E and King, C. Chronic fatigue syndrome: relationships of self-ratings and actigraphy. Psychological Reports, 1997, 81, 1223-1226
Case study of one person with CFS (CDC criteria '94) who was assessed for six days using a waist actigraph to measure activity, plus hourly subjective measures (from 6.00 am to 9.00 pm) for fatigue, physical and mental exertion, positive and negative affect plus perceived and expended energy.
Correlations between the hourly measures included significant relationships between actigraphy on the one hand and expended energy, physical exertion, mental exertion and negative affect but not with fatigue, perceived energy or positive affect.
This study suggests that activity and fatigue may not be as closely related as was previously thought.
Lapp, C. Exercise limits in chronic fatigue syndrome. American Journal of Medicine, 1997, 103, 83-84.
In this letter, Lapp responds to Sisto et al (ibid., 1996, 100, 634) whose research suggested that CFS patients could withstand a maximal treadmill exercise test without a major exacerbation in either fatigue or other symptoms. Lapp reports a trial involving 31 consecutive new patients who were asked to record their symptoms on a simple integer scale starting three weeks before until 12 days after maximal exercise testing. They used an electronically braked bicycle ergometer on which the work of peddling increased steadily with time. This allowed patients to reach their maximum oxygen consumption within 8 to 10 minutes of exercise.
The results showed that 74% of patients experienced worsening fatigue and that 26% stayed the same. None improved. The average relapse lasted 8.82 days although 22% were still in relapse when the study ended at 12 days. There were similar changes with exercise in lymph pain, depression, abdominal pain, sleep quality, joint and muscle pain and sore throat. These findings suggest that pushed to maximal exertion, patients may relapse.
Packer, TL., Foster, DM and Brouwer, B. Fatigue and activity patterns of people with chronic fatigue syndrome. The Occupational Therapy Journal of Research, 1997, 17, 3, 186-199.
This study assessed 17 people with CFS (no definition) and 11 healthy controls. Measures included the Fatigue Severity Scale, the Human Activity Profile and the Activity Record.
The patients spend more time resting during the daytime than the controls (16.18% versus 2.28%), and they reported significantly more fatigue and poorer health.
The researchers suggest that energy conservation and work simplification may help patients with CFS.
Plioplys, AV., Plioplys, S and Davis, JS. Meeting the frustrations of chronic fatigue syndrome. Hospital Practice, 1997, 32, 6, 147-166.
Discussion of the diagnosis and treatment of CFS. The authors note that they have not been able to replicate the Johns Hopkins' study (on neurally mediated hypotension), nor did they find amantadine useful. A subset of patients responded to L-carnitine (1 gm tds).
Regland, B., Andersson, M., Abrahamsson, L., Bagby, J., Dyrehag, LE and Gottfries, CG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scandinavian Journal of Rheumatology, 1997, 26, 301-307.
A group of outpatients who were diagnosed with fibromyalgia and CFS (CDC criteria '88) were compared to 18 healthy controls and 73 people requiring minor surgery. Blood (n=24) and cerebrospinal fluid (CSF, n=12) samples were examined.
The patients had significantly higher levels of homocysteine in the CSF than the controls. Moreover, the levels correlated with fatiguability. Also noteworthy were the low levels of vitamin B12 in the CSF which correlated with fatiguability, tension, memory problems and aches and pains.
According to the researchers, vitamin B12 deficiency may be contributing to the increased homocysteine levels found in the patients.
Vedhara, K., Llewelyn, MB., Fox, JD., Jones, M., Jones, R., Clements, GB., Wang, ECY., Smith, AP and Borysiewicz, LK. Consequences of live poliovirus administration in chronic fatigue syndrome. Journal of Neuroimmunology, 1997, 75, 183-195.
Fourteen patients with CFS (Oxford criteria) were randomly allocated to receive either live oral polio virus vaccination or a placebo. Measures assessed symptoms, anxiety, depression, self-esteem, locus of control and life events. There was also an immunological assessment. The results were compared with those of 9 controls who all received the vaccine.
The vaccination did not affect symptoms or mood. However, there were differences between the vaccinated patients and controls in terms of altered immune reactivity and virus clearance, as evidenced by increased poliovirus isolation, lower T-cell subsets on certain days and a trend for reduced gamma-interferon in the vaccinated patient group.
CONFERENCE REPORT
Journal of Psychiatric Research, 1997, 31, 1.
Selected presentations from the proceedings of the American Association for Chronic Fatigue Syndrome Research and Clinical Conference, Fort Lauderdale, Florida, USA, 7-9 October 1994.
This issue contains 15 articles on a number of topics relating to chronic fatigue and CFS. They include:
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This Capita Selecta was compiled by Dr. E.M. Goudsmit and Dr. A. Macintyre. Copyright EM. Goudsmit
1998. ©
Be sure to see the many
other valuable articles
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