Capita Selecta 1996

VIROLOGY

Zorzenon, M., Colle, R., Rukh, G., Barsanti, LA., Botta, GA and Ceccherini-Nelli, L. Active HHV-6 infection in chronic fatigue syndrome patients from Italy: new data. Journal of Chronic Fatigue Syndrome, 1996, 2, 1, 3-12.

Primary Human Herpesvirus-6 (HHV-6) infection has been related to different clinical pictures and, notably, to chronic fatigue syndrome (CFS). The researchers studied 52 patients fulfilling the CDC criteria ('88) for CFS and a control group of 51 matched healthy blood donors.

HHV-6 was recovered by culture and confirmed by immunofluorescence assay (IFA) and by PCR in 30/52 patients (57.7%) and in 6/51 (11.7%) of blood donors.

After a six months interval, blood samples (PBMC) from 8 patients again scored positive for both cytopathic effect and PCR, suggesting a chronically active and productive HHV-6 infection.

IMMUNOLOGY

Patarca, R., Klimas, N., Sandler, D., Garcia, MN and Fletcher, MA. Interindividual immune status variation patterns in patients with chronic fatigue syndrome: association with gender and the tumor necrosis factor system. Journal of Chronic Fatigue Syndrome, 1996, 2, 1, 13-39.

This article begins by noting that changes in soluble immune mediator levels in association with CFS usually occur within normal ranges and are apparent mainly as changes in the skewness of population distributions. The latter finding undermines the usefulness of cytokine levels as clinical tools at the individual level as has been seen in sepsis syndrome where a similar overlap occurs. Nonetheless, changes in cytokine levels at the population level can contribute to an understanding of the disease process. For example, the researchers reported previously that significant proportions of CFS patients showed elevated serum levels of either soluble tumor necrosis factor-receptor I (sTNF-RI, sCD120a) or TNF-a as compared to controls. The latter results could reflect different disease processes or extremes of a common disease process.

Using sera collected over a five-year period, the researchers studied an extended cohort of 108 patients with CFS (CDC criteria '94) and their results are consistent with a common graded disease process. When they assessed the effect of gender on the distributions of serum levels of immune mediators, levels of sTNF-RI, sTNF-RII (sCD120b), sIL-6R (sCD126), and sICAM-1 were found to be consistently higher among males than females and among CFS patients as compared to controls, regardless of gender. Moreover, differences in soluble immune mediator levels between CFS and control individuals were more clearly defined when restricting the analysis to the female gender. In their view, these observations are consistent with endocrine influences on immunological changes.

Sheng, WS., Hu, SX., Lamkin, A., Peterson, PK and Chao, CC. Susceptibility to immunologically mediated fatigue in C57BL/6 versus Balb/c mice. Clinical Immunology and Immunopathology, 1996, 81, 2, 161-167.

Four experiments were conducted to assess the role of pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF)-a in the pathogenesis of fatigue.

Two strains of mice were compared. In one experiment, the mice were injected with Corynebacterium parvum antigen (2 mg/mouse). Activity levels were then compared with those in the ten days prior to the injection. The results showed that activity levels were reduced after the injection and that this effect was most noticeable in the C57BL/6 strain.

In a further experiment, antibodies to murine TNF-a or IL-1b were given in order to neutralise circulating levels of these cytokines evoked after C. parvum antigen challenge. No significant effects on running activity were noted, indicating that fatigue after C. parvum antigen injection was not mediated by raised peripheral levels of cytokines.

Additional experiments showed increased TNF-a and IL-1b mRNA expression in the brains on day 6 post injection in the C57BL/6 strain. These findings "are consistent with the notion that cytokine-mediated fatigue could be due to cytokine production within the CNS".

PHYSIOLOGY AND BIOCHEMISTRY

De Lorenzo, F., Hargreaves, J and Kakkar, VV. Lung function test findings in patients with chronic fatigue syndrome (CFS). Australian and New Zealand Journal of Medicine, 1996, 26, 4, 563-564.

Lung function was assessed in 33 patients with CFS (CDC criteria '88) and 23 healthy controls using a microplus spirometer. After maximal inspiration at rest, subjects blew as hard as possible into a mouthpiece. Parameters measured included forced expired volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow.

Compared to the controls, patients with CFS showed a significant reduction in all lung function parameters (p<.01). The researchers state that further studies are required to clarify the pathogenetic relationship of lung function with the neuropsychological abnormalities seen in patients with CFS.

McGregor, NR., Dunstan, RH., Zerbes, M., Butt, HL., Roberts, TK and Klineberg, IJ. Preliminary determination of a molecular basis to chronic fatigue syndrome. Biochemical and Molecular Medicine, 1996, 57: 73-80.

The researchers studied 20 CFS patients (Oxford and CDC criteria '88) and 45 non-CFS subjects. Participants completed questionnaires (including the SCL-90-R), were clinically examined, and had first morning urine specimens collected, which were screened by gas chromatography-mass spectrometry for changes in metabolite excretion.

Multivariate analysis of the urinary metabolite profiles differed significantly in the CFS patients compared to the non-CFS subjects (p<0.004). The CFS patients had increases in aminohydroxy-N-methylpyrrolidine (p<0.00003, referred to as chronic fatigue symptom urinary marker 1, or CFSUM1), tyrosine (p<0.02), b-alanine (p<0.02), aconitic acid (p<0.05), and succinic acid (p<0.05) and reductions in an unidentified urinary metabolite, CFSUM2 (p<0.0007), alanine (p<0.005), and glutamic acid (p<0.02).

CFSUM1, b-alanine, and CFSUM2 were found by discriminant function analysis to be the first, second and third most important metabolites, respectively, for discriminating between CFS and non-CFS subjects. The abundance's of CFSUM1 and b-alanine were positively correlated with symptom incidence (p<0.01 and p<0.001 respectively), symptom severity, core CFS symptoms and SCL-90-R somatisation (p<0.00001), suggesting a molecular basis for CFS.

Pizzigallo, E., Di Girolamo, A., Montanari, G., Dragani, L., Vecchiet, J and Calella, G. Alterations in muscles of CFS patients at morphological, biochemical and molecular level. Journal of Chronic Fatigue Syndrome, 1996, 2, 2/3, 76-77.

The peripheral origin of symptoms related to CFS has been hypothesised and is still under investigation to determine if symptoms can be related to muscular damage. These researchers looked for specific alterations in the muscles of CFS patients followed in their clinic and enrolled according to the CDC criteria ('88 and '94).

Fourteen CFS patients, mean illness duration 49.9 months, post viral onset in 10 cases, underwent muscular biopsy of the vastus lateralis according to Edwards et al., using a UCH needle. The researchers analysed the specimens by electron (EM) and light (LM) microscopy. Moreover, the researchers performed histochemical and quantitative analysis of enzymatic activities and studies of mitochondrial DNA (mtDNA) deletions.

All specimens showed: hypotrophy, especially of the type 11 (a and b) fibres; fibres fragmentation, red ragged fibres and fusion events with nuclei centralisation; and fatty and fibrous degeneration. EM observations confirmed these alterations, showed degenerative changes in the I band, and allowed the researchers to detect the poli/pleiomorphism and cristae thickening of the mitochondria. The alterations of the fibres always began from an I band of a sarcomere. The histochemical and quantitative determination of the enzymatic activities showed important reduction, in particular of the cytochrome-oxidase and citrate-synthetase. Finally, the "common deletion" of 4977 base pairs of the mtDNA was increased as high as 3,000 times the normal values in 3 patients.

The researchers state that their results agree with those of others (Behan et al., 1991; Gow et al., 1994). The alterations are compatible with a myopathy of probable mitochondrial origin. This could explain the drop in the functional capability of the muscle as a reduction in potency but, above all, as a reduction in resistance.

"In conclusion, even if CFS seems to be attributable to mitochondrial and/or muscular alterations, a damage in the central nervous system cannot be excluded."

Plioplys, AV and Plioplys S. Serum levels of carnitine in chronic fatigue syndrome: clinical correlates. Neuropsychobiology, 1995, 32: 132-138.

Carnitine is essential for mitochondrial energy production. Disturbance in mitochondrial function may contribute to or cause the fatigue seen in CFS patients. One previous investigation has reported decreased acylcarnitine levels in 38 CFS patients.

The researchers investigated 35 CFS patients (27 females and 8 males, CDC criteria '88); their results indicate that CFS patients have statistically significantly lower serum total carnitine, free carnitine and acylcarnitine levels, not only lower acylcarnitine levels as previously reported. The researchers also found a statistically significant correlation between serum levels of total and free carnitine and clinical symptomatology. Higher serum carnitine levels correlated with better functional capacity.

"These findings may be indicative of mitochondrial dysfunction, which may contribute to or cause symptoms of fatigue in CFS patients."

PSYCHOLOGY, NEUROPSYCHOLOGY AND PSYCHIATRY

Chalder, T., Power, MJ and Wessely, S. Chronic fatigue in the community: 'a question of attribution'. Psychological Medicine, 1996, 26, 4, 791-800.

Thirty eight patients who attributed their chronic fatigue to 'ME' were compared to 38 patients who attributed their fatigue to social variables and 40 who attributed their fatigue to psychological factors. All three groups were followed up eighteen months later.

Measures at Time 1 (initial screening) included a fatigue questionnaire (Chalder et al 1993) and the General Health Questionnaire (GHQ)-12. At Time 2 (follow-up), measures included the above plus the Hospital Anxiety and Depression Scale (HAD), the Physical Symptom Checklist, the adapted Attributional Style Questionnaire (ASQ) and the Social Adjustment Scale.

At Time 1, there were a number of differences between the groups. For instance, the ME patients were more physically and mentally fatigued than the others (p<.05) and they had significantly lower GHQ scores than the psychological group.

At Time 2, it was found that the ME group had been ill longer (p<.05) but now there was no difference in the total fatigue scores. The psychological group had more psychiatric morbidity than the other two; they were more depressed and anxious and were more likely to have a past history of psychiatric disorder. The ME group had the lowest scores for anxiety and depression on the HAD and there were comparatively few patients with a past psychiatric history as indicated by the GP's notes. They also had the lowest GHQ scores and the lowest proportion of GHQ 'cases' (28% compared with 70% in the psychological group and 53% in the social group).

Higher GHQ score at Time 1 and an attribution of ME or psychological factors were found to be strongest predictors of fatigue at Time 2. However, all the risk factors explained only 38% of the variance in fatigue.

No group differences were found in the tendency to make internal, global, stable or controllable attributions across the five situations on the ASQ. However, when looking at the relationship between attributional style and other variables, uncontrollability and globality correlated with depression (and fatigue) in the ME group. Stability and uncontrollability correlated with depression in the social group.

There were also differences in coping styles with the ME group being more likely to reduce their activity than the others.

Finally, many patients attributed their fatigue to a number of causes, not just infection. The ME patients cited reasons such as workstress and emotional upset, although 13% referred to continuing infection and 25% cited a previous infection.

The authors note that the ME group were less psychologically distressed than the other two groups, although they reported greater fatigue and disability. The rate of psychiatric disorder was lower than that found in CF studies among hospital attenders or in primary care. It was also noted that while making an external attribution seemed to protect patients from psychological distress, it did not protect them from disability. "This challenges the idea that psychiatric disturbance explains the symptom of fatigue in this setting".

Farmer, A., Chubb, H., Jones, I., Hillier, J., Smith, A and Borysiewicz, L. Screening for psychiatric morbidity in subjects presenting with chronic fatigue syndrome. British Journal of Psychiatry, 1996, 168, 3, 354-358.

Ninety-five patients with CFS (CDC criteria '94) were assessed using the General Health Questionnaire (GHQ-60) and Schedules for the Clinical Assessment of Neuropsychiatry (SCAN). Their scores were compared with those of 48 healthy controls. Fifty-five patients were reassessed one week later with the Beck Depression Inventory.

The results indicated that the GHQ and BDI performed poorly as screeners of psychiatric morbidity when compared with various SCAN derived ratings, although the findings from the controls were comparable with other studies. The researchers conclude that "neither the GHQ nor BDI alone can be recommended as screeners for psychiatric morbidity in CFS subjects".

Johnson, SK., DeLuca, J and Natelson, BH. Personality dimensions in the chronic fatigue syndrome: a comparison with multiple sclerosis and depression. Journal of Psychiatric Research, 1996, 30, 1, 9-20.

This study assessed the relative rates of personality disturbances in 35 patients with CFS (CDC criteria '88 and '92), 35 sedentary but healthy controls, 20 people with multiple sclerosis (MS) and 24 patients with depression. Measures used included the Personality Diagnostic Questionnaire-Revised, the Neo Neuroticism scale and a computerised psychiatric interview (DIS).

In the CFS group, 45% had a concurrent Axis 1 psychiatric diagnosis (12 patients were suffering from major depression) and 37% had at least one personality disorder. The CFS and MS groups had scores on the personality measures which were intermediate between the depressed patients and the controls. The individuals with both CFS and concurrent major depression (34% of the group) were found to account for most of the personality pathology in the CFS sample. Interestingly, the prevalence of obsessive-compulsive disorder in the CFS group was similar to that in the MS patients.

According to the researchers, these findings suggest that CFS can-not be explained as a form of depression with predominantly somatic symptoms as the CFS group more closely resembled the MS group than the depressed group in terms of personality disturbance and trait neuroticism. They suggest that future research should delineate individuals with CFS with and without concurrent depression when investigating aetiology and treatments.

Johnson, SK., DeLuca, J and Natelson, BH. Assessing somatisation disorder in the chronic fatigue syndrome. Psychosomatic Medicine, 1996, 58, 50-57.

This study was conducted to examine the rates of somatisation disorder (SD) in patients with CFS (CDC criteria '88) relative to other fatiguing illnesses.

The samples comprised 42 people with CFS, 18 people with mild MS, 21 patients with major depression or dysthymia and 32 healthy, sedentary controls. They were assessed using the Diagnostic Interview Schedule (DIS) and again using a questionnaire listing all the symptoms from the somatisation disorder section of the DIS-III-R. All subjects were also given a medical examination, and their medical history was assessed.

The prevalence of SD was determined using four different criteria:

• Where all the 48 symptoms on the DIS were coded as psychiatric. Cut-off points were 6 SD symptoms (for women) and 4 for men (set 1a: according to Escobar), and 13 (set 1b: according to DSM-III-R).
• In set 2, the CFS criteria listed by the CDC were coded as 'organic' and therefore excluded from the assessment of SD. Cut-off points as above.
• In set 3, the CDC symptoms were again coded as 'organic' as were all symptoms which occurred since the onset of CFS (or MD and MS) and which the patient considered to be due to CFS.
• Set 4 used the strict DSM-III-R criteria specifying onset prior to age 30, as well as the presence of 13 or more symptoms. CFS symptoms were again coded as physical.

The results indicated prevalence rates varying from 0% to 98%. The lowest estimates were found using criteria sets 3 and 4. (No patient with CFS had SD using set 3 and only one fulfilled the criteria in set 4). The highest prevalence was obtained using set 1, and this also revealed a greater number of cases among the CFS group compared to the others. When CDC symptoms were excluded from the diagnosis of SD (cut-off point 13), the CFS group differed significantly from the healthy controls, but not from the people with MS and depression. Indeed, comparing sets 1b and 2b indicated that coding CFS symptoms as due to physical illness reduced the estimates of SD from 55% to 12%.

Both the CFS and depression groups endorsed a greater percentage of DIS symptoms than either the MS or healthy groups. However, CFS patients with anxiety or depression did not report significantly more symptoms than patients with no DIS diagnosis. These results "strongly suggest that psychiatric factors alone are not a sufficient explanation for the broad array of somatic symptoms reported in CFS".

The authors note the discrepancy in estimates depending on whether CFS symptoms are regarded as psychiatric or organic. "If CFS is considered an organic disease, then CFS patients cannot have SD". They also mention that the comparative absence of SD symptoms prior to the onset of CFS (cf set 3) is inconsistent with a diagnosis of SD.

As regards other diagnoses, 31% CFS patients fulfilled criteria for major depression and 7% met those for generalised anxiety disorder. Eleven per cent of MS patients were diagnosed as depressed.

"The present study illustrates that the terminology used to interpret symptoms (i.e. psychiatric or physical) will determine which category CFS falls into. The diagnosis of SD is of limited use in populations in which the aetiology of the illness has not been established".

Johnson, SK., DeLuca, J., Diamond, BJ and Natelson, BH. Selective impairment of auditory processing in chronic fatigue syndrome: a comparison with multiple sclerosis and healthy controls. Perceptual and Motor Skills, 1996, 83, 51-62.

To examine the possibility of a modality-specific impairment in information processing, this study assessed 20 subjects with CFS (CDC criteria '88 and '92), 20 patients with multiple sclerosis (MS) and 20 sedentary, healthy controls. One half of the subjects in each group were administered the Paced Auditory Serial Addition Test and the other half were administered the Paced Visual Serial Addition Test. Other measures included the Beck Depression Inventory (BDI).

The group with CFS was differentially impaired on the auditory relative to the visual processing task whereas the MS group was equally impaired on both versions of the task.

Two people with CFS and 4 patients with MS were found to have scores on the BDI indicating moderate to severe depression. There was no significant association between depression scores and performance on the Addition Tests.

According to the authors, the data suggest that individuals with CFS have a selective impairment in processing auditory material.

McKenzie, M, Dechene, L., Friedberg, F and Fontanetta, R. Coping reports of patients with long-term chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 1995, 1, 3/4, 59-67.

A study of 265 patients who had been ill for at least 10 years found that many had developed effective coping strategies. There was no association between type of strategy and illness progression. Moreover, scores on the Illness Management Questionnaire (Ray et al) failed to distinguish those who were worsening from those who were not. According to the researchers, the findings suggest that coping strategies may lessen the emotional distress of patients but that coping does not influence the course of the illness.

EPIDEMIOLOGY

Buchwald, D., Manson, SM., Pearlman, T., Umali, J and Kith, P. Race and ethnicity in patients with chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 1996, 2, 1, 53-66.

In this study, 690 consecutive patients presenting with chronic fatigue were assessed using questionnaires (MOS Short-Form, Ways of Coping Checklist, the Perceived Social Support Inventory, Multidimensional Health Locus of Control scale, an attribution scale and the General Health Questionnaire-28). They were also asked about present and current medical problems, given a psychiatric interview (DIS-III-A), and a physical examination. The majority of those investigated were Caucasian (n=651), the rest, referred to as 'the minority', included Asian, Indians and Hispanics (n=39). Of the former, 50 fulfilled modified CDC criteria ('88) for CFS, among the latter, 59% did so.

The minority patients perceived less social support from family (p<.05) and friends (p<.01) but aside from these, no other significant race/ethnicity-related differences were identified. However, minority patients also tended to have poorer social function and lower rates of lifetime major depression.

The researchers conclude that demographic, clinical and psycho-social factors do not distinguish Caucasian from minority patients with chronic fatigue. Help-seeking behaviours, access to care, and the significance attributed to the central complaints should be examined as potentially competing explanations for these findings.

Buchwald, D., Umali, J., Pearlman, T., Kith, P., Ashley, R and Wener, M. Postinfectious chronic fatigue: a distinct syndrome? Clinical Infectious Diseases, 1996, 23, 2, 385-387.

This study assessed 717 patients with unexplained fatigue who attended a University clinic. Those who reported a post-infectious onset were compared with those who did not.

The patients with a post-infectious onset differed significantly from the others in terms of more frequent symptoms such as fever, body pain, chills, sore throat and lymphadenopathy. They also had poorer functional status and poorer role functioning, and they were more likely to attribute their illness to a physical cause. There were no differences in psychiatric diagnoses nor on laboratory investigations. Thirty-three per cent did not meet the major criteria for CFS.

Buchwald D., Pearlman, T., Umali, J., Schmaling, K and Katon, W. Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals. American Journal of Medicine, 1996, 101, 364-370.

In this study, 185 patients with CFS (modified '88 criteria) were compared with 246 people with chronic fatigue (CF), 111 individuals with acute infectious mononucleosis, 25 patients with major depression and 99 healthy controls. Measures included the Medical Outcomes Study Short Form (MOS), and a psychiatric interview (DIS-III-A).

The patients with CFS had significantly lower scores than the CF group on three of the eight MOS subscales (physical functioning, body pain and role functioning). "The CFS patients showed greater impairment across all functional domains than previously observed for any medical or psychiatric disorder". The disability was correlated with a number of symptoms, not just fatigue. Psychiatric disorders predicted scores indicating poor emotional function, mental health, physical function and general health. In contrast to the depressed patients, emotional function and mental health in people with CFS were relatively preserved.

Euba, R., Chalder, T., Deale, A and Wessely, S. A comparison of the characteristics of chronic fatigue syndrome in primary and tertiary care. British Journal of Psychiatry, 1996, 168, 121-126.

This study evaluated the characteristics of CFS in primary and tertiary care. Thirty three patients with CFS (Oxford and CDC criteria '94) recruited from general practices were compared with 79 cases attending a hospital unit specialising in CFS.

Measures included the Fatigue Questionnaire (Chalder et al 1993), the GHQ-12, the Somatic Symptom Check List and the Medical Outcomes Study Short-Form (20-item). Information regarding past psychiatric history and psychotropic drugs was obtained from the subjects themselves as well as their GP's clinical notes.

The GP attenders had significantly less fatigue, were less likely to belong to social class 1, had higher GHQ-12 scores, were more likely to be cases on the GHQ (79% versus 58.3% respectively), had worse mental health scores on the MOS Short Form, were more likely to have received a psychiatric diagnosis before the onset of the fatigue, had a more favourable health perception, were less likely to be impaired in terms of work, had fewer somatic symptoms, made fewer physical attributions (33% versus 56%), made more psychological or psychosocial attributions (59% versus 7%) and were less likely to use terms such as 'M.E.' or 'PVFS'. The GP group also contained fewer people who had reduced or stopped drinking alcohol, and there were fewer individuals who had joined a self-help group (10.3% versus 33%). The results further indicated that patients who were members of a self-help group had significantly lower GHQ scores than non-members (p<.05) and that non-members were more likely to have received a previous psychiatric diagnosis.

There were no differences between the GP attenders and the hospital samples in relation to gender or age. Finally, it was noted that nearly half of those referred to the hospital clinic did not fulfil the operational criteria for CFS.

The researchers conclude that the high rates of psychiatric morbidity and female excess which has been reported elsewhere are not due to selection bias. "On the other hand higher social class and physical illness attributions may be the result of selection bias and not intrinsic to CFS".

Gibbons, R., Macintyre, A and Richards, C. Features of chronicity in ME/CFS: a case series in the UK. Journal of Chronic Fatigue Syndrome, 1996, 2, 2/3, 111-112.

The objectives of the research were to identify the group of patients in the UK who have been rendered so chronically disabled by myalgic encephalomyelitis/CFS that they cannot leave home unassisted and to assess aspects of their physical and cognitive levels of disability at the onset of the illness and at present.

Participants were sought through patient organisations and individual physicians; data, in the form of detailed case histories, were collected by means of self-report questionnaires. All patients fulfilled the CDC criteria and had received a diagnosis of myalgic encephalomyelitis (ME)/post-viral syndrome (PVS) or CFS from a general practitioner or a hospital consultant. The following further criteria were also applied: (i) chronicity (duration of illness of not less than two years); (ii) a specified level of disability (inability to leave home without assistance).

Patients identified: 147 to date (and steadily accumulating). Duration of illness: > 5 years: 81 %; > 10 years: 38 %; death: 2 (the first after a 15 year illness, the second after 7 years).

These preliminary results suggest that in a percentage of cases of ME/CFS, chronicity of a scale not previously documented is a significant feature of the disease. They also suggest that certain physical and cognitive disabilities increase with increasing chronicity.

Hilgers, A and Frank, J. Chronic fatigue syndrome: evaluation of a 30-criteria-score and correlation with immune activation. Journal of Chronic Fatigue Syndrome, 1996, 2, 4, 35-47.

The aim of this study was to evaluate the development of a score for the severity of CFS, the correlation of CFS with parameters of immune activation and the association with pathogens.

Five hundred and five patients with suspected CFS and no other definitive diagnosis were checked by a 45-criteria-score, basic laboratory programmes and immunological profiles. In most of the patients further tests concerning complement system, immune activation markers, hormones and serology of herpesviruses, Chlamydia and Borrelia could be evaluated.

Of the patients, 385 fulfilling the '94 CDC criteria showed significant differences to 53 healthy controls in 40 of the 45 symptoms assessed (p<0.001, twitches and food allergies p<0.05). Thirteen symptoms corresponding to CDC criteria were all significant (p<0.001), but 17 further significant criteria were added to improve precision: respiratory infections, palpitations, dizziness, dyspepsia, dryness of mouth/eyes, allergies, nausea, paraesthesia, loss of hair, skin alterations, dyscoordination, chest pain, personality changes, eczema, general infections, twitches and urogenital infections. This resulted in a 30-criteria score.

A correlation between the 30-criteria score and immunological parameters could be evaluated in 472 of the 505 patients. Significant positive correlation was found in numbers of CD8+ T-lymphocytes, HLA-DR+ T-lymphocytes, gamma globulins, IgM, IgG, and for the number of types of autoantibodies (mainly ANA, ACA, antithyroid and antiparietal cell antibodies). Significant negative correlation was found in albumin-globulin-ratio, eosinophils and IgE. Most of these parameters also correlated with one another.

In subgroups, the frequency of positivity in serological tests for HHV-6 (49.9%), EBV (35.4%), HSV (29.2%), CMV (12.5%) and Chlamydia (35,0%) was striking. Borrelia Western blots showed 3 or more specific IgG-bands in 54 of 131 patients (41.2%). In some cases, infection with EBV, HHV-6 and CMV, respectively, was confirmed by DNA-PCR-test and antigen detection.

"In increasingly larger groups of patients with CFS and related constellations we often see clinical signs and longer anamnesis of other symptoms besides the classical criteria of CFS, especially a high prevalence of local and general susceptibility to infections and hints to prolonged inflammation processes. Together with other results, the data confirm the hypothesis that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens, possibly triggered by common infections or other environmental factors, can lead to a chronic neuro-immune activation state and auto-immune disorders. Hypersensitivity symptoms of the patients might not be mediated by classical allergies alone but also result from a type-IV-hypersensitivity."

Hotopf, M., Noah, N and Wessely, S. Chronic fatigue and minor psychiatric morbidity after viral meningitis: a controlled study. Journal of Neurology, Neurosurgery and Psychiatry, 1996, 60, 504-509.

This study compared 83 patients who had been diagnosed with viral meningitis* with 76 people who had suffered from non-enteroviral, non-CNS infections. Measures at follow-up (6-24 months after the infection) included the Beck Depression Inventory, the GHQ-12, and questionnaires assessing fatigue, somatic symptoms and functional impairment. CFS was diagnosed using the Oxford and CDC '94 criteria.

There was no significant difference between the groups in terms of the number of patients developing CFS. Moreover, fatigue was not related to duration of hospital stay or gender.

There were more cases who fulfilled the Oxford criteria than the CDC criteria (among meningitis group 14% versus 10%). CFS was more common in the groups (12.6%) compared to primary care attenders assessed elsewhere. Predictors were time off work and history of psychiatric illness.

The researchers conclude that:

• the prevalence of CFS is higher than expected for the range of infections examined,
• that enteroviral infection is unlikely to be a specific risk factor for its development and
• that onset of CFS after infection is predicted by prolonged convalescence and a history of psychiatric morbidity.

This is "most often now caused by enteroviruses".

Komaroff, AL., Fagioli, LR., Geiger, AM., Doolittle, TH., Lee, J., Kornish, J., Gleit, MA and Guerriero, RT. An examination of the working case definition of chronic fatigue syndrome. American Journal of Medicine, 1996, 100, 1, 56-64.

Predefined clinical and laboratory data were collected prospectively from 369 patients with debilitating fatigue, of whom 281 (76%) met the major criteria of the original CDC definition ('88) for CFS. The same clinical data were also obtained from 311 healthy controls plus patients with relapsing-remitting MS (N=25) and major depression (MD, N=19).

Patients completed questionnaires to assess the prevalence of symptoms, current and past psychiatric and organic illnesses, and the onset and course of their present condition. In addition, 293 individuals were assessed using the Diagnostic Interval Schedule (DIS) and 309 completed the MOS Short-Form. The physical examination was repeated every 4 to 12 months in 310 patients.

The mean duration of the illness among the fatigue group was 7.2 years. Of the sample as a whole, 52% described themselves as intermittently bedridden or house bound. Among the comparison groups, 80% of the patients with MS reported severe, debilitating fatigue, as did 28% of those with MD.

The results indicated that all the minor criteria from the original CDC definition distinguished the patients with chronic fatigue from the healthy control subjects, and many also distinguished these patients from the comparison groups with MS and MD, particularly myalgias, post-exertional malaise, headaches, and infectious-type symptoms such as chronic fever, chills, sore throat and swollen glands under the arm or in the neck. In addition, two other symptoms not currently part of the case definition discriminated the chronic fatigue patients from the controls and comparison groups: anorexia and nausea. The physical examination criteria only infrequently contributed to the diagnosis. Of the 281 patients who met the major criteria, 255 (91%) also met the minor criteria.

Symptoms which were less useful in distinguishing between CFS and other disorders were muscle weakness, arthralgias and sleep disturbance. Indeed, the researchers note that the presence of early morning awakening "might be considered evidence against CFS, as it was reported more often in depression than in the other patient groups".

The finding that patients with chronic fatigue reported a number of control symptoms infrequently indicates that they do not "exhibit a tendency to overreport all bodily experiences".

The researchers recommend that anorexia and nausea be added to the case definition and that muscle weakness, arthralgias and sleep disorders be removed.

Komaroff, AL., Fagioli, LR., Doolittle, TH., Gandek, B., Gleit, MA., Guerriero, RT., Kornish, J., Ware, NC., Ware, JE and Bates, DW. Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. American Journal of Medicine, 1996, 101, 3, 281-290.

The functional status of 223 patients with CFS (CDC criteria '94) was compared with that of a general population controls group (n=2474) and disease comparison groups with hypertension (n=2089), congestive heart failure (n=216), type II diabetes mellitus (n=163), acute myocardial infarction (n=107), multiple sclerosis (n=25) and depression (n=502).

Measures included the MOS, interviews relating to medical history and symptoms and a psychiatric assessment (DIS).

Patients with CFS had far lower mean scores than the general population controls on all eight MOS scales, showing their greater impairment. They also scored significantly lower than patients from the disease comparison groups other than the individuals with depression. When compared with the depressed group, CFS patients scored significantly lower on all the scales except for those relating to mental health and role functioning due to emotional problems. The two MOS scales reflecting mental health did not correlate with any CFS symptoms except for depression and irritability. Certain key symptoms of CFS, including post-exertional malaise, fevers and muscle weakness correlated with the functional impairment scores but depression did not. Thus "most of the symptoms of CFS are unlikely to represent expression of an underlying primary depressive disorder".

The patients with CFS who were or had been depressed reported slightly more impairment on most scales compared to the patients with CFS who were not and had never been depressed. There was significant greater impairment on the scales measuring mental health and role functioning in relation to emotional problems in the CFS-depressed groups.

The researchers conclude that their CFS patients reported significantly greater impairment compared to disease comparison groups, and that the pattern and degree of impairment was different from that seen in people with major depression.

Reyes, M., Dobbins, JG., Mawle, AC., Steele, L., Gary, HE., Malani, H., Schmid, S., Fukuda, K., Stewart, J., Nisenbaum, R and Reeves, WC. Risk factors for chronic fatigue syndrome: a case-control study. Journal of Chronic Fatigue Syndrome, 1996, 2, 4, 17-33.

The aim of this case-control study was to examine various risk factors previously reported to be associated with CFS.

Twenty-five CFS patients identified from the Centers for Disease Control and Prevention, Atlanta CFS study site ('88 CDC criteria), were matched by race, sex, and age to two randomly selected healthy controls (n=47). Cases were further subgrouped by type of illness: onset - sudden, occurring within a few days or gradual, occurring over a longer time period. Median duration of illness was 5.8 years.

All subjects were interviewed. The main outcome measures assessed a broad panel of risk factors previously associated with CFS e.g., dental procedures, diet, exposure to chemicals, travel and stress prior to illness.

CFS patients were significantly more likely than controls to report a history of stress, persistent nasal symptoms, ear infections and ingestion of B-complex vitamins during the year prior to the case's onset of illness. In addition, women patients were significantly more likely to have had a hysterectomy. Compared to those with an acute onset, the patients (n = 17) who experienced a gradual onset were significantly more likely to report stressful events in the year prior to onset, certain dental procedures, sinusitis, exposures to herbicides, pesticides, or insecticides, and a history of hysterectomy. The links with stress etc. were not observed in the acute cases. The researchers could not confirm previously reported associations of CFS with a history of asthma or eczema; exposure to sick animals; exposure to solvents, paint, or other chemicals; ingestion of raw-milk; or travel, occupation, or recreational activity.

"While no risk factors were identified that effectively distinguish CFS cases from controls, the data do suggest that gradual and sudden onset CFS constitute distinct subclasses of the syndrome. The association between 'others' and case status was seen only amongst patients with a gradual onset. Future studies should subgroup patients based on type of illness onset and further evaluate risk factors of interest, focusing on the role of stress, exposure to herbicides, pesticides, insecticides, and dental and medical histories".

TREATMENT

Natelson, BH., Cheu, J., Pareja, J., Ellis, SP., Policastro, T and Findley, TW. Randomised, double-blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome. Psychopharmacology, 1996, 124, 226-230.

Patients with CFS (CDC criteria '88 and '94) were randomised to receive either phenelzine (15 mg) or placebo. The treatment group were initially given a placebo for two weeks, then the drug was given on alternate days with the placebo for another two weeks before a third period of two weeks when the patients received the drug only. In the placebo group, tablets were given for six weeks. Six patients given the drug dropped out of the trial. Data was available for nine patients in each group.

Measures included the Fatigue Severity Scale, the Illness Severity Scale, the Profile of Mood States and the Centers for Epidemiologic Study Depression Scale. A psychiatric interview (Q-DIS) was administered to exclude all patients with a history of psychiatric disorders in the previous five years and anyone with current depression.

Although the treatment groups showed improvements on a number of measures, the extent of that improvement was limited. The effect on depression was greater in the placebo group, and there were only limited changes in functional status in the treated patients. No placebo effect was observed.

According to the researchers, the significant pattern of improvement in patients taking phenelzine supports the view of reduced sympathetic drive in CFS. In their opinion, the action of the drug was probably not due to its antidepressant effects. The lack of placebo effect seems to indicate that this illness is not due to "patients' being overly suggestible".

Vercoulen, JHMM., Swanink, CMA., Zitman, FG., Vreden, SGS., Hoofs, MPE., Fennis, JFM., Galama, JMD., van der Meer, JWM and Bleijenberg, G. Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet, 1996, 347, 858-861.

The subjects in this trial were 44 depressed CFS patients (Oxford criteria, fatigue lasting more than a year with a diagnosis of major depressive disorder and BDI score of >16 corrected for fatigue and loss of energy) plus 52 CFS patients who were not depressed (corrected BDI score <10). The two groups were matched in terms of age, gender, employment and marital status. Measures included questionnaires (e.g. BDI, Sickness Impact Profile, attributions), a self-observation list (fatigue, sleep, activity) plus tests assessing cognitive function. A motion-sensing device (Actometer) was used on the first and last day of treatment.

Patients were randomly assigned to receive fluoxetine capsules (20mg) or placebo for 8 weeks. Compliance and side-effects were assessed after 1 week, 2 weeks and 6 weeks of treatment.

The statistical analysis revealed that there were no significant differences between the two groups in terms of change on any measure.

Fifteen per cent of patients on the drug withdrew due to side-effects (e.g. tremor) and were not included in the analysis above. No patient reported complete recovery although there was a trend for a drug effect on self-reported change at post-treatment (patients taking the fluoxetine were more likely to report a deterioration).

The researchers conclude that "fluoxetine in a 20mg daily does not have a beneficial effect on any characteristic of CFS. The lack of effect of fluoxetine on depressive symptoms in CFS suggests that processes underlying the presentation of depressive symptoms in CFS may differ from those in patients with major depressive disorder".

MISCELLANEOUS

Behan, PO. Chronic fatigue syndrome as a delayed reaction to chronic low-dose organophosphate exposure. Journal of Nutritional and Environmental Medicine, 1996, 6, 341-350.

Ten patients who had been exposed to organophosphate insecticides, of whom 9 later developed symptoms following an infection, were investigated using three tests. None had a past history of psychiatric illness. The results were compared with those of 10 healthy controls.

The tests assessed the effect of buspirone (60 mg) on prolactin plus the response to pyridostigmine (120 mg) and dexamethasone (4 mg) on the level of growth hormone.

Significant increases in levels of prolactin were found in the patients following buspirone compared to the controls. There was also a slight increase in levels of growth hormone following pyridostigmine while there was a depressed response to dexamethasone compared to the controls.

Behan notes that the clinical features of these patients appear to be identical to those documented in people with CFS. Other research suggests that exposure to organophosphates makes people more prone to viral infections. According to Behan, the findings in this study suggest "that both entities share a common pathogenesis".

Grant, JE., Veldee, MS and Buchwald, D. Analysis of dietary intake and selected nutrient concentrations in patients with chronic fatigue syndrome. Journal of the American Dietetic Association, 1996, 96, 4, 383-385.

The patients in this trial were 28 women with CFS (modified CDC criteria '88) and 10 healthy controls. They completed 4-day food records which were analyzed for intake of vitamins and certain minerals. Blood was taken for further nutrient analysis.

The nutrient intake as revealed by the food records did not differ between the groups. The dietary quality was also similar. However, the patients with CFS had higher a-tocopherol concentrations (p<.001) and tended to have higher levels of ascorbic acid, acylcarnitine and free carnitine and lower RBC magnesium and zinc concentrations. However, while 36% of the patients and 20% of the controls had nutrient deficiencies, all mean results were within normal ranges.

Marcel, B., Komaroff, AL., Fagioli, LR., Kornish, RJ and Albert, MS. Cognitive deficits in patients with chronic fatigue syndrome. Biological Psychiatry, 1996, 40, 535-541.

Twenty-nine patients with CFS (CDC '88) and 25 healthy controls were administered a neuropsychological battery of tests assessing memory, attention, set shifting, conceptualization, spatial abili-ty, hand-eye co-ordination and overall IQ. Psychiatric symptoms were assessed using the Hopkins Symptom Check List (SCL-90). All patients were severely ill and two-thirds were taking antidepressants. Twenty-three had an abnormal Romberg test or abnormal tandem gait on neurological examination.

The primary significant differences between patients and controls were found on tests of learning and memory, both verbal and non-verbal. However, the impairments were specific rather than global. For instance, there were problems with immediate recall but not delayed recall. These differences remained when the degree of psychiatric symptomatology was covaried. Patients on psychoactive medication did not differ in their performance on these tasks though they did affect the results on some of the other tests.

"These results suggest that at least a subset of CFS patients may experience significant impairments in learning and memory". "Executive function abilities are compromised in CFS". They add that the inconsistencies between studies may reflect the heterogeneous precipitating factors and possibly "different clinical subgroups" within CFS.

Steinberg, P., Pheley, A and Peterson, PK. Influence of immediate hypersensitivity skin reactions on delayed reactions in patients with chronic fatigue syndrome. Journal of Allergy and Clinical Immunology, 1996, 98, 6, 1126-1128.

Delayed type hypersensitivity skin reactions to five antigens were assessed in 30 patients with CFS (CDC criteria '88).

All patients had one positive delayed reaction to at least one antigen. There was a mean of 2.3 positive skin responses per patient. A small percentage also had an immediate reaction but there was no association between these and delayed hypersensitivity reactions.