Symptom occurrence in persons with chronic fatigue syndrome

Transcription

1 Biological Psychology 59 (2002) Symptom occurrence in persons with chronic fatigue syndrome L.A. Jason *, S.R. Torres-Harding, A.W. Carrico, R.R. Taylor DePaul Uni ersity, Center for Community Research, 990 West Fullerton Road, Chicago, IL 60614, USA Received 19 April 2001; accepted 3 July 2001 Abstract This investigation compared differences in the occurrence of symptoms in participants with CFS, melancholic depression, and no fatigue (controls). The following Fukuda et al. [Ann. Intern. Med. 121 (1994) 953] criteria symptoms differentiated the CFS group from controls, but did not differentiate the melancholic depression group from controls: headaches, lymph node pain, sore throat, joint pain, and muscle pain. In addition, participants with CFS uniquely differed from controls in the occurrence of muscle weakness at multiple sites as well as in the occurrence of various cardiopulmonary, neurological, and other symptoms not currently included in the current case definition. Implications of these findings are discussed Elsevier Science B.V. All rights reserved. Keywords: CFS; Symptoms; Diagnostic criteria 1. Introduction Chronic fatigue syndrome (CFS) remains a poorly understood and controversial disease, because the exact causal agents are unknown, physical signs and symptoms are variant, and diagnostic laboratory tests have poor sensitivity and specificity (Holmes, 1991; Jason et al., 1995). In the absence of laboratory tests or other objective indicators, case identification of CFS relies upon the clinical assessment of a constellation of symptoms that have been present for 6 or more months since the onset of the fatiguing illness (Fukuda et al., 1994). Since its emergence as a new * Corresponding author. Tel.: ; fax: address: Ljason@depaul.edu (L.A. Jason) /02/$ - see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S (01)00120-X

2 16 L.A. Jason et al. / Biological Psychology 59 (2002) disease category in the 1980s, four definitions of CFS have been proposed, but none have been empirically derived (Jason et al., 1997). The current US case definition of CFS (Fukuda et al., 1994) requires that the following criteria be met for diagnosis: (a) 6 or more months of persistent or relapsing chronic fatigue of a new or definite onset that is neither the result of ongoing exertion nor alleviated by rest, which results in substantial reductions in previous levels of occupational, educational, social, or personal activities; and (b) the concurrent occurrence of at least four of eight symptoms (postexertional malaise, unrefreshing sleep, memory and concentration difficulties, new headaches, sore throat, lymph node pain, muscle pain, and joint pain) that persist or reoccur during 6 or more months of the illness and do not predate the fatigue. Researchers have sought to validate the criteria for CFS established by the CDC using factor analytic methods. Nisenbaum et al. (1998) found that three correlated factors (fatigue-mood-cognition symptoms, flu-type symptoms, and visual impairment symptoms) explained a set of additional correlations between fatigue lasting for 6 or more months and 14 inter-related symptoms. No factor explained observed correlations among fatigue lasting for 1 5 months and other symptoms, indicating that only fatigue lasting 6 or more months (with selected symptoms) overlaps with published criteria to define CFS. In another study, Friedberg et al. (2000) examined symptoms of patients with CFS who had an illness duration of 10 or more years and found three factors: cognitive problems, flu-like symptoms, and neurologic symptoms. Other research has focused on classifying persons with CFS based on symptom profiles. Using latent class analysis, Hadzi-Pavlovic et al. (2000) determined that patients with CFS could be grouped into three classes: those with multiple severe symptoms, those with lower rates of cognitive symptoms and higher rates of pain; and those with a less severe form of multiple symptoms. Participants with a less severe form of multiple symptoms tended to be younger and with shorter illness duration. Jason and Taylor (2002) performed a cluster analysis of persons in a community-based sample of persons with chronic fatigue (fatigue lasting 6 or more months) to define a typology of chronic fatigue symptomatology. Among the participants with CFS, findings suggested that a majority of individuals with moderate to severe symptoms could be classified into two important subgroups: one distinguished by severe postexertional malaise with fatigue that was partially alleviated by rest; and one distinguished by severe overall symptomatology, severe postexertional malaise, and fatigue that was not alleviated by rest. Researchers have also examined the occurrence of specific symptoms reported by persons with chronic fatigue and CFS (Hartz et al., 1998; Komaroff et al., 1996). Komaroff et al. (1996) examined the occurrence of minor symptoms (Holmes et al., 1988), as well as respiratory, gastrointestinal, neurologic, rheumatologic, cardiac, and miscellaneous objective and subjective symptoms that were not included in the 1988 case definition. The occurrence of these symptoms were compared among persons with severe, disabling fatigue lasting for 6 or more

3 L.A. Jason et al. / Biological Psychology 59 (2002) months, persons with multiple sclerosis, persons with major depression, and healthy controls. Komaroff et al. (1996) concluded that rheumatologic and gastrointestinal symptoms were found more frequently in patients meeting the major criteria. Based upon these findings, researchers recommended adding anorexia and nausea as well as eliminating the symptoms of muscle weakness, arthralgias, and sleep disturbance to strengthen the case definition. Finally, Hartz et al. (1998) examined the association between the number and severity of symptoms of CFS in persons with idiopathic chronic fatigue and determined that persons with fatigue could be classified by the degree to which they match the case definition of CFS (Fukuda et al., 1994). In addition, Hartz et al. (1998) suggested including symptoms such as frequent fever and chills, muscle weakness, and sensitivity to alcohol in the current US case definition. The occurrence of neurally mediated hypotension (NMH) has also been investigated in persons with CFS. NMH is defined as a 30 mmhg drop in systolic (or a 15 mmhg drop in diastolic) blood pressure in response to an orthostatic challenge such as standing upright (Rowe and Calkins, 1998). This precipitous drop in blood pressure is thought to be due to low blood volume (Streeten and Bell, 1998) or excessive venous pooling in the extremities (Stewart et al., 1999; Stewart and Weldon, 2000). Symptoms of NMH include but are not limited to: lightheadedness, dizziness when standing, nausea, fatigue, tremors, breathing or swallowing difficulties, headaches, visual disturbances, and pallor (Streeten et al., 2000). While the frequency of NMH in persons with CFS has not been consistently reported across investigations, cardiopulmonary and neurological abnormalities are heterogeneous and common (Wilke et al., 1998). The findings reviewed herein suggest that other symptoms in addition to the eight symptoms listed as part of the definitional criteria may be important and occur frequently in persons with CFS. The present investigation examined the occurrence of symptoms in the Fukuda et al. (1994) case definition of CFS to determine whether these symptoms uniquely differentiated those with CFS from controls. In addition, other fatigue/weakness related, sleep related, neuropsychiatric, infectious, rheumatological, cardiopulmonary, gastrointestinal, neurological, and reproductive symptoms not specified in the current US case definition were examined. The occurrence of these additional symptoms was examined to determine whether other symptoms occur with greater frequency in persons with CFS when compared to controls, as well as what symptoms occurred with greater frequency in the melancholic depression group compared to controls. 2. Methods 2.1. Procedure The data are derived from a larger community-based study of the prevalence of chronic fatigue syndrome (for more details of this study see Jason et al., 1999). This larger study was carried out in three stages. Stage 1 involved admin-

4 18 L.A. Jason et al. / Biological Psychology 59 (2002) istering an initial telephone screening questionnaire in order to identify the symptoms of chronic fatigue syndrome. Stage 2 involved administering a semistructured psychiatric interview. In stage 3, participants underwent a complete physical examination. Following the completion of the medical evaluation, four physicians and a psychiatrist were responsible for making a final diagnosis with two physicians independently rating each case using the current US case definition of CFS (Fukuda et al., 1994). Where disagreement occurred, a third physician rater was used Sample Procedures developed by Kish (1965) were used to select one adult from each household. Birth dates for each adult were gathered, and the person with the most recent birthday was selected for interview. A stratified random sample of several neighborhoods in Chicago was utilized (see Jason et al., 1999 for more details). In stage 1, 28,673 residential/working telephone numbers were contacted, and 18,675 adults completed the initial screening interview (65.1% completion rate). The stage 1 screen revealed that of the 18,765 participants who were interviewed, 780 (4.2%) had chronic fatigue. Of these, 408 had chronic fatigue and the concurrent occurrence of four or more symptoms. These participants were defined as CFS-like (the suffix like was used to clarify that individuals in this group only met the Fukuda et al. (1994) criteria by self-report, and did not necessarily qualify as having a final diagnosis of CFS rendered by a physician). One hundred and sixty-six of the 408 CFS-like participants agreed to complete a structured psychiatric interview and a comprehensive physical examination. There were no significant differences on sociodemographic (i.e. gender, ethnic identification, age, occupation, education, and marital status) or fatigue scores between these 166 screened positive (CFS-like) participants and the 242 screened positive (CFS-like) non-participants. The control group was composed of 199 individuals selected randomly from the remaining 18,260 screened negatives (seven cases were excluded due to missing data). Of these 199 individuals, 47 completed medical evaluations. There were no sociodemographic differences (i.e. gender, ethnic identification, age, occupation, education, and marital status) or fatigue scores between the 152 screened negative non-participants and 47 screened negative participants. Participants were then classified by independent physician consensus Participants The present investigation examined the occurrence of symptoms in three groups of participants. The first group consisted of 32 persons from the larger group of 166 persons with CFS-like symptoms who were diagnosed with CFS by the independent physician review panel (CFS group). The second group consisted of 19 individuals with melancholic depression, who were taken from a larger

5 L.A. Jason et al. / Biological Psychology 59 (2002) group of 33 CFS-like persons with a psychiatric explanation for their chronic fatigue illness (Melancholic Depression group). Melancholic Depression was diagnosed using the Structured Clinical Interview for the DSM-IV (SCID) (Spitzer et al., 1995), which is a valid and reliable semi-structured interview guide that approximates a traditional psychiatric interview. Melancholic Depression is defined by either the absence of pleasure in almost all activities or lack of reactivity to usually pleasurable stimuli. In addition, there would need to be three or more other symptoms, such as excessive guilt, significant weight loss, and marked psychomotor retardation or agitation. The control group consisted of 47 randomly selected individuals who screened negative for having a CFS-like illness (control group). Three participants who initially screened negative for a CFS-like illness were excluded from the control group following examination by the study physicians who determined that they had idiopathic chronic fatigue or chronic fatigue explained by a psychiatric condition Measures Medical questionnaire As part of a detailed medical questionnaire, participants were asked if they were experiencing or had experienced each of the eight Fukuda et al. (1994) symptoms of CFS in the past 6 months. Additional symptoms examined included other medical symptoms and neuropsychiatric symptoms that incorporated questions from a measure used by Komaroff et al. (1996). The definitional symptoms and the additional symptoms were then classified into the following categories: weakness/fatigue, disturbed sleep, neuropsychiatric, infectious, rheumatological, cardiopulmonary, neurological, and reproductive abnormalities. We examined the occurrence of Fukuda et al. (1994) symptoms in the past 6 months because it was most comparable to available data on the occurrence of other symptoms examined in the medical questionnaire. Also, examining the occurrence of Fukuda et al. (1994) defined symptoms in the past 6 months allows results of the present investigation to be compared to those of Komaroff et al. (1996) Statistical analyses First, the sociodemographic variables of gender, age, ethnicity, marital status, parental status, work status, and socioeconomic status were examined, using chi-squares across the three groups: CFS, melancholic depression, and controls. The occurrence of symptoms was compared between the CFS and control groups, and between the melancholic depression and control groups. Using binomial logistic regression, sociodemographic variables that were found to be significant between the groups were entered as predictors in the logistic regression model to control for the effects of these variables on the occurrence of symptoms. We first made the CFS group the referent group, and have compared it to the controls and the depression group. We next made the control group as a

6 20 L.A. Jason et al. / Biological Psychology 59 (2002) referent group to compare it with the depressed group. Due to the numerous comparisons made, the overall statistical significance was set at P 1 for all analyses in order to minimize the likelihood of type I error. 3. Results 3.1. Sociodemographic ariables Analyses indicated that there were significantly more men in the control group than in the Melancholic Depression group [ 2 (2,95)=11.297, P 1]. Furthermore, participants with CFS were significantly more likely to have children than controls [ 2 (2,95)=9.431, P 5]. Thus, gender and parental status were entered as predictors in the subsequent binomial logistic regression analyses of symptom occurrence Symptoms Table 1 presents symptoms of Fatigue/Weakness, Disturbed Sleep, Neuropsychiatric, Infectious, and Rheumatological symptoms, and these are the symptom categories in which are located the current Fukuda et al. (1994) CFS symptom criteria. Table 2 lists other categories (Cardiopulmonary, Gastrointestinal, Neurological, and Reproductive) that consist of symptoms that are not found within the Fukuda et al. (1994) criteria Fatigue/weakness Participants with CFS differed significantly from controls in the occurrence of generalized muscle weakness, and more specific weakness in their legs, arms, neck, and back. Weak legs was the most frequently reported form of weakness for the CFS group. Also, participants with CFS and those with melancholic depression both reported significantly more postexertional malaise than controls Disturbed sleep The occurrence of unrefreshing sleep was reported with significantly greater frequency in both the CFS and melancholic depression groups compared to controls. Those in the CFS group had significantly more insomnia than the controls Neuropsychiatric Participants with CFS reported the occurrence of new headaches with significantly greater frequency than controls. Both the CFS and melancholic depression groups reported the occurrence of memory and concentration difficulties, depression, and irritability with significantly greater frequency than controls.

7 L.A. Jason et al. / Biological Psychology 59 (2002) Table 1 Occurrence of symptoms in Fukuda Symptom Categories CFS Melancholic No Depression Fatigue (N=32) (N=19) (N=44) % % % Significance Fatigue/weakness General muscle weakness 75.0 a ** Postexertional malaise 68.8 a 47.4 b 13.6 ** Legs weak 62.5 a ** Arms weak 53.1 a ** Neck weak 40.6 a ** Shoulders weak Back weak 40.6 a ** Head weak Abdomen weak Buttocks weak 3.1 Other weak muscles Disturbed sleep Unrefreshing sleep 90.6 a 84.2 b 25.0 ** Insomnia 59.4 a ** Early morning awakening Trouble staying asleep Hypersomnia Neuropsychiatric Memory and concentration 87.5 a 63.2 b 20.5 ** New headaches 75.0 a ** Depression 56.3 a 73.7 b 13.6 ** Irritability 5 a 42.1 b 11.4 ** Disturbances in eyesight Infectious Sore throat 62.5 a ** Lymph pain 40.6 a ** Fever/chills Oral herpes Shingles Oral thrush Genital herpes Rheumatological 15.8 Muscle pain 84.4 a ** Joint pain 56.3 a ** Morning stiffness 56.3 a ** Stiff after sitting Hay fever 46.9 a ** Puffy face Dry mouth b 11.4 ** Night sweats Sinus infection Earaches Dry eyes Eye pain Jaw pain Italics indicate symptoms that are part of the current CFS case definition (Fukuda et al., 1994). a Statistically significant difference between CFS and No Fatigue groups. b Statistically significant difference between Melancholic Depression and No Fatigue groups. ** Using binomial logistic regression analyses, difference is statistically significant at the P 1 level.

8 22 L.A. Jason et al. / Biological Psychology 59 (2002) Table 2 Occurrence of symptoms in Non-Fukuda Symptom Categories CFS Melancholic No depression fatigue (N=32) (N=19) (N=44) % % % Significance Cardiopulmonary Shortness of breath 65.6 a 26.3 c 22.7 ** Chest pains 40.6 a ** Rapid heartbeat Cough 28.1 a ** Heartbeat in ears Raynaud phenomenon Gastrointestinal Bloating Lower abdominal pain Upper abdominal pain Anorexia Nausea Diarrhea Black bowel movement Blood in bowel movement Neurological Dizzy after standing 46.9 a ** Skin sensations 46.9 a ** General dizziness 43.8 a ** Alcohol intolerance 43.8 a ** Dizzy moving head 37.5 a ** Unsteady upright Ringing in ears Tingling sensations Paralysis 3.1 Temporary blindness Reproducti e Decreased sexual interest a 15.8 c 6.8 ** Impairment of sexual functioning 5 a 36.8 b 2.3 ** Nocturia Irregular periods d Incontinence Menopause d Vaginal discharge d Excessive menstrual bleeding d Recurrent urinary infections Recurrent vaginal infections d Dysuria 6.3 Nipple discharge d Positive pap smear d 4.8 Blood in urine a Statistically significant difference between CFS and No Fatigue groups. b Statistically significant difference between Melancholic Depression and No Fatigue groups. c Statistically significant difference between the CFS and Melancholic depression groups. d Women only. ** Using binomial logistic regression analyses, difference is statistically significant at the P 1 level.

9 L.A. Jason et al. / Biological Psychology 59 (2002) Infectious The occurrence of sore throats and lymph node pain was significantly greater in the CFS group when compared to controls. There were no significant differences between the melancholic depression and control groups in the occurrence of other infectious symptoms Rheumatological The CFS group reported muscle pain, joint pain, morning stiffness, and hay fever with significantly greater frequency than controls. Participants with melancholic depression only reported the occurrence of dry mouth with significantly greater frequency than controls Cardiopulmonary The CFS group reported the occurrence of chest pain and cough with significantly greater frequency than controls. The CFS group and melancholic depression group significantly differed on shortness of breath Gastrointestinal Neither the CFS nor the melancholic depression groups reported gastrointestinal symptoms with significantly greater frequency than controls Neurological The CFS group reported dizziness after standing, skin sensations, general dizziness, alcohol intolerance and dizzy moving head with significantly greater frequency than controls Reproducti e Participants with CFS reported the occurrence of decreased sexual interest with significantly greater frequency than controls and those with melancholic depression. The occurrence of impairment of sexual functioning was reported with significantly greater frequency in both the CFS and melancholic depression groups when compared to controls. 4. Discussion Results of this investigation lend support to the importance of the CFS diagnostic criteria (Fukuda et al., 1994). Participants with CFS more frequently experienced the Fukuda et al. (1994) CFS symptoms when compared to other symptoms in their respective categories, with the exception of postexertional malaise. These findings were anticipated, given the selection criteria of four of eight symptoms to receive a diagnosis of CFS. In addition, the CFS group in comparison to controls reported significantly higher frequencies of all eight

10 24 L.A. Jason et al. / Biological Psychology 59 (2002) Fukuda et al. (1994) definitional symptoms. Furthermore, the occurrence of postexertional malaise, cognitive and memory difficulties and unrefreshing sleep did not uniquely discriminate between the CFS and control groups, as individuals in the melancholic depression group also experienced these symptoms with significantly greater frequency than controls. Interpreting these findings, it is important to note that the present investigation examined only the occurrence of symptoms. The CFS group may also uniquely differ from controls in symptom duration and severity. For example, Jason et al. (2000) found that examining symptoms utilizing severity criteria has proven useful in uniquely differentiating CFS from fatigue explained by a psychiatric disorder (Jason et al., 2000). Also, the frequency of the occurrence of the Fukuda et al. (1994) defined symptoms in the melancholic depression group may have been elevated due to the screening process. Only chronically fatigued participants initially reporting four or more symptoms specified in the current US case definition of CFS were classified as CFS-like and subsequently received a medical examination. Cardiopulmonary and neurological abnormalities have been investigated as they relate to neurally mediated hypotension (NMH) in persons with CFS (Rowe and Calkins, 1998; Streeten et al., 2000; Wilke et al., 1998). NMH occurs when the central nervous system misinterprets the body s needs when it is in an upright position, then sends a message to the heart to slow down and lower the blood pressure, responses that are directly opposite to the responses the body s needs. Several cardiopulmonary and neurological symptoms in the present investigation occurred with higher frequency and uniquely differentiated the CFS group from controls. Shortness of breath, chest pain, dizziness after standing, skin sensations, general dizziness, dizzy moving the head, and alcohol intolerance uniquely differentiate those with CFS from controls. It is possible that examining these cardiopulmonary and neurological abnormalities not currently assessed by the current case definition (Fukuda et al., 1994) could provide greater diagnostic reliability. The CFS and melancholic depression group only significantly differed for two symptoms: decreased sexual interest and shortness of breath. Decreased sexual interest might very well be a result of low levels of cortisol. A deficit of cortisol has been found in patients with CFS, and is linked to lethargy and fatigue, and this deficit might be contributing to an overactive immune system (Scott and Dinan, 1999). Shortness of breath as well as other neurological symptoms might reflect a finding that has been confirmed by other investigators, who have not found neurally mediated hypotension to play a major role in CFS (Poole et al., 2000). Komaroff et al. (1996) have suggested that eliminating the symptoms of muscle weakness, arthralgias, and sleep disturbance would provide greater sensitivity and specificity in CFS diagnosis. In contrast, the present investigation found that muscle weakness and arthralgias were reported in over half of participants with CFS and uniquely differentiated this group from controls. Regarding sleep dis-

11 L.A. Jason et al. / Biological Psychology 59 (2002) turbance, results of the present investigation did not support the ability of any symptoms in this category to uniquely discriminate between CFS and control groups. Komaroff et al. (1996) also suggested adding anorexia and nausea as minor symptoms in the CFS case definition. However, in the present study, both occurred with relatively low frequency and neither uniquely differentiated those with CFS from controls. Hartz et al. (1998) also investigated the occurrence of symptoms in persons with fatigue, and recommended the inclusion of fever and chills, muscle weakness, and sensitivity to alcohol as CFS case definition symptoms. Results of the current investigation also indicated that muscle weakness and sensitivity to alcohol uniquely differentiated the CFS group from controls, but neither the CFS nor the melancholic depression groups significantly differed from controls in the occurrence of fever and chills. Furthermore, it appeared that muscle weakness in the CFS group occurred at multiple sites, with weak legs being the most frequently reported form of weakness. These findings concur with those of Hartz et al. (1998), and therefore provide further support for the inclusion of muscle weakness in the case definition of CFS. Differences between the present investigation and previous work could be a result of the sampling methods employed. Other research has relied on predominantly clinic-based samples that may report greater occurrence and severity of symptoms, especially those of a viral or infectious nature (Wessely, 1998). Persons with CFS found in clinic-based samples may represent a more severely ill population. Current findings should be interpreted within the context of limitations on statistical power imposed by a small sample size. Small sample sizes might have precluded the detection of significant differences between groups, and this may be especially true for all comparisons with the depressed group because they have the smallest sample size and because they appear to be mid-way on most measures between the CFS group and controls. Because some differences between groups may have not been detected, more research with larger samples is necessary to replicate these results. In summary, results from this investigation in a community-based sample support the use of the symptoms included in the current CFS case definition (Fukuda, et al., 1994). Furthermore, this investigation found that weakness and various neurological, cardiopulmonary, neuropsychiatric, and rheumatological symptoms uniquely differentiated persons with CFS from the control group. In contrast, relatively few of these symptoms significantly differentiated the group of individuals with melancholic depression from the control group. Acknowledgements Financial support for this study was provided by NIAID grant number AI Requests for reprints should be sent to Leonard Jason, Ph.D., Center for Community Research, DePaul University, 990 W. Fullerton Ave. Chicago, IL

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