Chronic Fatigue Syndrome: A Special Issue of applied Neuropsychology

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Chronic Fatigue Syndrome: A Special Issue of applied Neuropsychology

Applied Neuropsychology 2001, Vol. 8, No. 1, 1–3 Copyright 2001 by Lawrence Erlbaum Associates, Inc. INTRODUCTION Chr

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Applied Neuropsychology 2001, Vol. 8, No. 1, 1–3

Copyright 2001 by Lawrence Erlbaum Associates, Inc.

INTRODUCTION

Chronic Fatigue Syndrome and Neuropsychology: An Introduction and Historical Perspective

E

CHRONIC FATIGUE SYNDROME AND NEUROPSYCHOLOGY D LUCA

John DeLuca Department of Physical Medicine and Rehabilitation and Department of Neurosciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA, and Neuropsychology and Neuroscience Laboratory, Kessler Medical Rehabilitation Research and Education Corporation, West Orange, New Jersey, USA 1950s and 1960s, there was little interest in neurasthenia. In fact, the term was dropped from the Diagnostic and Statistical Manual of Mental Disorders (3rd ed.; American Psychiatric Association, 1980), although it is still maintained in the International Classification of Diseases (ICD–9 and ICD–10). With the decreased use of the term neurasthenia, physicians often avoided nosological entities in patients whose complaint was primarily fatigue, referring more to descriptive labels such as “tired, weak” or “fatigue and nervousness.” Chronic fatigue became invisible, with no name, no known etiology, and no research (Ware, 1992). However, there were outbreaks of epidemics throughout the world, which, in hindsight, often closely resembled CFS and neurasthenia. Two early influential epidemics took place in Los Angeles County in 1934 and in the Royal Free Hospital located in London in 1955. Contemporaneous concerns were often associated with possible links to polio. Sporadic cases of such outbreaks continued, as did the various terms used to describe these incidences, such as myalgic encephalomyelitis, Iceland disease, postviral fatigue syndrome, chronic Epstein–Barr virus, and so on. The publication of three influential articles (Jones et al., 1985; Straus et al., 1985; Tobi et al., 1982), as well as an increase in sporadic and epidemic cases throughout the United States, led to increased public and media attention, including testimony before a U.S. Senate subcommittee. Physicians and clinics across the country were inundated with requests to evaluate chronic fatigue. This activity culminated in an article published by the U.S. Centers for Disease Control in 1988 defin-

Complaints of cognitive problems are a very significant aspect of chronic fatigue syndrome (CFS), with such complaints occurring in up to 85% to 95% of CFS patients (Grafman, 1994; Komaroff & Buchwald, 1991). As such, the clinical neuropsychologist plays a key role in the assessment and treatment of persons with CFS. The purpose of this special issue on CFS is to present new research on CFS across a broad spectrum of scientific and clinical inquiry, including psychopathology, cognitive and cerebral functioning, genetic and immunological contributions, and disability and outcome. Despite the recent interest in the study of CFS, some have argued that CFS was first recognized in the midto late 19th century as neurasthenia (for a detailed history of fatigue, see Wesseley, Hotopf, & Sharpe, 1998). Neurasthenia was first recognized as a neurological illness resulting in extreme fatigability due to nervous exhaustion. However, this view changed by the turn of the century, perhaps partly due to the rise of the psychoanalytic school, and neurasthenia became known as a psychiatric condition. Fatigue was then viewed as a symptom of anxiety, depression, and somatoform disorders. In the years to follow, the term neurasthenia was used less and less, and treatment for patients shifted from the neurologist to the psychiatrist. By the

Requests for reprints should be sent to John DeLuca, Director of Neuroscience Research, Kessler Medical Rehabilitation and Education Corporation, 1199 Pleasant Valley Way, West Orange, NJ 07052, USA. E-mail: [email protected]

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DELUCA

ing CFS (Holmes et al., 1988). This definition was later modified (Schluederberg et al., 1992), followed by a revised definition for CFS in 1994 by a joint U.S. Centers for Disease Control and National Institutes of Health task force (Fukuda et al., 1994). Today, we are left with the remnants of the organic versus psychiatric debate in ascribing an etiology to CFS. Although finding the underlying cause of the illness should be a major research focus, applying one label versus the other to individual patients may not be as constructive. I know of few neurological illnesses that do not have a significant psychological component. Ascribing symptoms as organic versus psychiatric may not be the most productive way to help the individual patient who is ailing and seeking help. Several of the articles in this special issue present new data that address the broad concern of psychiatric versus neurological influences on cognition in CFS. This special issue was conceptualized as an attempt to bring together a broad array of issues that confront the neuropsychologist when evaluating and treating persons with CFS. The first article by Ross, Fantie, Straus, and Grafman examines divided attention in CFS. This work is an important extension of the most consistent finding in the literature of impaired information-processing efficiency in persons with CFS. Ross et al. found a selective deficit in divided attention in individuals with CFS relative to controls. The results were not associated with CFS symptom severity and could not be attributed to depression or anxiety because the CFS group scored below the cutoff for clinical significance. The second article, by Daly, Komaroff, Bloomingdale, Wilson, and Albert, examines neuropsychological functioning in persons with CFS, multiple sclerosis, and persons diagnosed with major depressive disorder. These authors found that all three clinical groups showed impaired neuropsychological performance relative to controls. However, when test scores were adjusted statistically for level of depression, patients with CFS and other groups continued to show impaired cognitive performance relative to controls. The authors suggest that the cognitive deficits in CFS cannot be attributed solely to the presence of depression. The article by Lange et al. presents the first study to examine quantitative measures of cerebral ventricular volumes in CFS individuals. Their findings show evidence for subtle structural changes in the brains of their participants with CFS. If replicated, such subtle cerebral changes may someday be directly linked to the subtle but consistent findings of compromised information-processing efficiency in persons with CFS. 2

The Claypoole et al. article utilizes an innovative and critically important variable to our understanding of cognitive processes in CFS: genetic analysis. They examined cognitive processing after exhaustive exercise in monozygotic twins discordant for CFS (i.e., only one twin has CFS). Although cognitive performance decreased after exercise, this decrement was found in both the twins with and without CFS. This article outlines the importance of examining genetic variables in the interpretation of CFS data. Tiersky et al. examine the critical role of neuropsychological and psychiatric factors on long-term measures of functional disability and employment status in CFS. These authors found some evidence of improvement in neuropsychological and mood measures over time, although participants remained severely ill with CFS and were largely unemployed. Psychiatric status at Time 1 was associated with greater improvement at Time 2 with regard to long-term outcome. This is important not only in providing the long-term course of the illness, but also in relating how psychiatric symptoms interact with this course in the everyday lives of persons with CFS. Finally, the article by Patarca-Montero, Antoni, Fletcher, and Klimas presents an exhaustive review of the literature relating cytokine and immunological factors on psychological and neuropsychological functioning. Unfortunately, there is a paucity of studies that actually relate these physiological parameters with psychological factors in persons with CFS. Although highly technical, this article provides the interested reader with the breadth and depth necessary to pursue important research questions in psychoneuroimmunology as it relates specifically to CFS. The article clearly outlines the need for future research in this area that is likely to be fruitful.

References American Psychiatric Association. (1980). Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: Author. Fukuda, K., Straus, S. E., Hickie, I., Sharpe, M. C., Dobbins, J. G., Komaroff, A. L., & the International Chronic Fatigue Syndrome Study Group. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121, 953–959. Grafman, J. (1994). Neuropsychological features of chronic fatigue syndrome. In E. Straus (Ed.), Chronic fatigue syndrome (pp. 263–284). New York: Marcel Dekker. Holmes, G. P., Kaplan, J. E., Gantz, N. M., Komaroff, A. L., Schonberger, L. B., Straus, S. E., Jones, J. F., DuBois, R. E., Cunningham-Rundles, C., Pahwa, S., Tosato, G., Zegans, L. S., Purtilo, D. T., Brown, N., Schooley, R. T., & Brus, I. (1988).

CHRONIC FATIGUE SYNDROME AND NEUROPSYCHOLOGY Chronic fatigue syndrome: A working case definition. Annals of Internal Medicine, 108, 387–389. Jones, J., Ray, G., Minnich, L., Hicks, M., Kibler, R., & Lucas, D. (1985). Evidence for active Epstein–Barr virus infection in patients with persistent, unexplained illnesses; elevated anti-early antigen antibodies. Annals of Internal Medicine, 102, 1–7. Komaroff, A. L., & Buchwald, D. (1991). Symptoms and signs in chronic fatigue syndrome. Reviews of Infectious Diseases, 13, S8–S11. Schluederberg, A., Straus, S. E., Peterson, P., Blumenthal, S., Komaroff, A. L., Spring, S. B., Landay, A., & Buchwald, D. (1992). NIH conference: Chronic fatigue syndrome research. Definition and medical outcome assessment. Annals of Internal Medicine, 117, 325–331.

Straus, S., Tosato, G., Armstrong, G., Lawley, T., Preble, D. T., Henle, W., Davey, R., Pearson, G., Epstein, J., Brus, R., & Blaese, R. M. (1985). Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Annals of Internal Medicine, 102, 7–16. Tobi, M., Morag, A., Ravid, Z., Chowers, I., Feldman-Weiss, V., Michaeli, Y., Ben-Chetrit, E., Shalit, M., & Knobler, H. (1982). Prolonged illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet, i, 61–64. Ware, N. (1992). Suffering and the social construction of illness: The deligitimisation of illness experience in chronic fatigue syndrome. Medical Anthropology, 6, 347–361. Wessely, S., Hotopf, M., & Sharpe, M. (1998). Chronic fatigue and its syndromes. Oxford, England: Oxford University Press.

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Applied Neuropsychology 2001, Vol. 8, No. 1, 4–11

ARTICLES

Divided Attention Deficits in Patients With Chronic Fatigue Syndrome

DIVIDED ATTENTION DEFICITS IN PATIENTS WITH ROSS,CHRONIC FANTIE, STRAUS, FATIGUE&SYNDROME GRAFMAN

Sharon Ross and Bryan Fantie Department of Psychology, American University, Washington, DC, USA

Stephen F. Straus Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

Jordan Grafman Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA Chronic fatigue syndrome (CFS) patients and controls were compared on a variety of mood state, personality, and neuropsychological measures, including memory, word finding, and attentional tasks that required participants to focus, sustain, or divide their attention, or to perform a combination of these functions. CFS patients demonstrated a selective deficit on 3 measures of divided attention. Their performance on the other neuropsychological tests of intelligence, fluency, and memory was no different than that of normal controls despite their reports of generally diminished cognitive capacity. There was an inverse relation between CFS patient fatigue severity and performance on 1 of the divided attention measures. Given these findings, it is probable that CFS patients will report more cognitive difficulties in real-life situations that cause them to divide their effort or rapidly reallocate cognitive resources between 2 response channels (vision and audition). Key words: attention, divided attention, memory, chronic fatigue syndrome the U.S. Centers for Disease Control (CDC). To meet the CFS case definition, a patient is required to have unexplained persistent or recurring fatigue of new or definite onset that is not due to ongoing exertion, is not relieved by rest, and results in a substantial reduction in previous levels of activity. Four or more of the following symptoms also need to be present for 6 months or longer: impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, multijoint pain, new headaches, unrefreshing sleep, or postexertion malaise. A physician must rule out other disorders that may cause fatigue

Although the disorder currently called chronic fatigue syndrome (CFS) appears to have existed for centuries (Demitrack, 1996; Straus, 1991), systematic research into its nature and treatment has only begun in the last several years. There is no biological assay or diagnostic test for the diagnosis of CFS. Rather, it is diagnosed by a set of clinical criteria developed by Requests for reprints should be sent to Jordan Grafman, Cognitive Neuroscience Section, NINDS, NIH, Building 10; Room 5C205, 10 Center Drive, MSC 1440, Bethesda, MD 20892–1440, USA. E-mail: [email protected]

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DIVIDED ATTENTION DEFICITS IN PATIENTS WITH CHRONIC FATIGUE SYNDROME

before making a clinical diagnosis of CFS (Fukuda et al., 1994). Of the symptoms that are associated with CFS, decreased mental functioning or neuropsychological problems are among the most troubling to patients (Fukuda et al., 1994; Holmes et al., 1988; Sharpe et al., 1991). The type of neuropsychological dysfunction reported by CFS patients varies. Many, but not all, formal neuropsychological studies report that CFS patients have impaired memory for designs (DeLuca, Johnson, Beldowicz, & Natelson, 1995; Grafman et al., 1993; Riccio, Thompson, Wilson, Morgan, & Lant, 1992), story memory (DeLuca et al., 1995; Grafman et al., 1993; Riccio et al., 1992; Smith, 1991), semantic processing (Riccio et al., 1992; Smith, 1991), and digit span (DeLuca et al., 1995; DeLuca, Johnson, & Natelson, 1993; Grafman et al., 1993; Smith, 1991). One CFS study reported absent or delayed event-related potentials (Prasher, Smith, & Findley, 1990), whereas another did not (Scheffers, Johnson, Grafman, Dale, & Straus, 1992). Various SPECT studies (e.g., Costa, Brostoff, Douli, & Ell, 1992; Schwartz et al., 1994) have cited some evidence of hypoperfusion in CFS patients, but no particular areas of the brain have been consistently identified as showing the most involvement. Almost all neuropsychological studies report that CFS patients performed more poorly than did the matched controls on at least one test. One reason that CFS patients may have difficulty on memory tests is because they are unable to use strategic encoding to remember information (Johnson, DeLuca, Diamond, & Natelson, 1998). Recent evidence has indicated that CFS patients are impaired when having to control their attention or process speeded information (Abbey & Garfinkel, 1991; Holmes et al., 1988; Lloyd, Wakefield, Boughton, & Dwyer, 1988). It is possible that this latter impairment could diminish the patient’s ability to encode information efficiently for later recall. In this study, we tested the hypothesis that CFS patients should have particular trouble focusing, sustaining, or dividing their attention. In addition, we compared the cognitive abilities of CFS patients on a variety of other mood state, personality, and neuropsychological measures with those of healthy controls, focusing on cognitive areas in which CFS patients frequently claim impairment, including memory (Hickie, Lloyd, Wakefield, & Parker, 1990; Holmes et al., 1988; Lloyd et al., 1988) and word finding (Abbey & Garfinkel, 1990; Hickie et al., 1990).

Method Participants Nineteen normal controls (15 women and 4 men) and 17 CFS patients (13 women and 4 men) agreed to participate in this study and signed institutional review board-approved informed consent documents. All CFS patients met the CDC’s diagnostic criteria (Fukuda et al., 1994; Holmes et al., 1988) for CFS and were medication-free at the time of the study. Mean length of illness for the patients was 3 (±1) years. All of the CFS patients had been participants in one or more other prospective studies on the nature or management of their disorder during which they underwent extensive clinical and laboratory evaluations to exclude other medical conditions. They did not, however, receive neuropsychological testing prior to this study. The screening for this study excluded patients who had a history of any neurological illness, head injury resulting in loss of consciousness, learning disability, or excessive alcohol or recreational drug use, or for whom English was not their first language. Control patients also had to be in good health and not using any medications.

Instruments Mood State and Physical Symptoms The participants’ levels of depression and anxiety were measured with the Hospital Anxiety and Depression Scale (HADS; Zigmond & Snaith, 1983). The Fatigue Severity Scale (FSS; Krupp, LaRocca, Muir-Nash, & Steinberg, 1989) assessed self-reported degree of disability stemming from fatigue. A symptom rating scale (SRS) was used to provide a measure of severity of illness. Designed for this study, the scale consisted of 15 symptoms that are commonly associated with CFS and included space for participants to write in additional symptoms. There were two versions of this scale. One was designed to assess the number and severity of symptoms that participants usually experienced. The other version of the scale assessed the number and severity of symptoms that participants were experiencing on the day of the study. Neuropsychological Measures Attention tests. Two versions of the Continuous Performance Test (CPT; Rosvold, Mirsky, Sarason,

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ROSS, FANTIE, STRAUS, & GRAFMAN

Bransome, & Beck, 1956), a test of sustained attention and vigilance, were administered to participants. In Version 1 of the CPT, participants watched a computer screen, on which letters appeared one at a time. In the first part of Version 1 of the CPT, participants had to press a hand-held button each time they detected the letter X. In the second part of Version 1, participants responded only when the X immediately followed the letter A. Participants’ reaction times, correct responses, and errors of commission and omission were recorded. In Version 2 of the CPT, participants had to perform a dichotic listening task while performing the CPT. The dichotic listening task required participants to listen to six or eight different words or numbers, half of which were simultaneously presented to each ear. Immediately after each group of numbers or words was presented, participants were asked to report what they had heard. Performing the CPT in conjunction with the dichotic listening task demands that cognitive resources be allocated between the two tasks, and we anticipated that it would be the most difficult task in our battery for controls and CFS patients to perform. In Version 2 of the CPT, scores were calculated as in Version 1; the dichotic listening scores comprised the total number of words or numbers correctly recalled for the right and left ears. The CPT with dichotic listening was performed using both the X and AX parts (see previous discussion). General intellectual functioning. The Shipley Institute of Living Scale (Zachary, 1986) was used to assess the participants’ general level of intellectual functioning. Memory tests. The Wechsler Memory Scale–Revised (Wechsler, 1987) is a standardized, comprehensive memory test that we used to evaluate various areas of memory, including attention and concentration, visual memory, verbal memory, and delayed recall. Hebb’s Recurring Digits test (Lezak, 1995) was used to examine longer term storage of memory for digits by presenting lists of digits that are one digit longer than the participant’s digit span (supraspan), with the digit list on every third trial being the same. The two scores on this test indicate the digit span (a measure of attention) and the number of times an individual performed the repeated supraspan list correctly (a measure of memory). Corsi blocks and supraspan learning tests were used to assess both immediate recall and longer term storage of visual-spatial sequences (Lezak, 1995). The supraspan learning task is similar to the Hebbs Recurring Digits test except that it uses nine blocks fastened in random order to a board on which the examiner 6

taps a prearranged sequence that the participant attempts to reproduce. The Recurring Figures Test (Kimura, 1963) was used to evaluate visual-spatial recognition. The participant viewed 20 different drawn figures, in succession, on a computer screen, and then viewed 100 figures, including 8 of the original 20, each repeated 7 times. For each figure, participants had to decide whether they had previously seen it or not. The final score equals the number of correct identifications minus the number of false positive responses (to correct for guessing). The Rey Auditory–Verbal Learning Test (RAVLT) was used to evaluate immediate and long-term verbal memory and the effects of proactive and retroactive interference (Ichise et al., 1992). Participants listened to a list of 15 words (List A) and then immediately attempted to recall them. Five trials were given in this fashion. On the sixth trial, participants listened to a new list of 15 words (List B) and then attempted to recall this new list. After a 30-min delay, participants were asked to recall the original list (List A). The scores generated from the RAVLT included the sum of the number of words recalled on Trials 1 through 5, the number of words recalled on the delay trial of List A, the number of words recalled on Trial 6 (the presentation of List B), and a primacy and recency score made up of the number of words that were recalled from the first and last three words of the initial presentation of Lists A and B.

Tests of Verbal Fluency In the Newcombe test of verbal fluency (Lezak, 1995), participants were given 1 min each to generate as many names of objects, animals, and birds and colors (in the third condition, they have to alternate between each of the two categories) as they can. The three scores on this test indicate the total number of correctly generated words given for each category. In the Thurstone word fluency test (Lezak, 1995), participants had 5 min to write, without repetitions, as many words as possible that start with the letter S. The participants then had 4 min to produce four-letter words that begin with C. The two scores on this test indicate the total number of correct words for each letter.

Procedure All participants completed their testing during a single session. The HADS, FSS, SRS, and Shipley Institute of Living Scale were always administered at the begin-

DIVIDED ATTENTION DEFICITS IN PATIENTS WITH CHRONIC FATIGUE SYNDROME

ning of the session. The remaining tests were in four blocks requiring roughly equal amounts of time to complete; four different orders of these blocks were used to counterbalance the order of presentation of the tests. In the analyses of the neuropsychological battery, data from three left-handed controls were removed from the data on dichotic listening. Also, data were discarded from the supraspan totals of the Hebb’s Digits and Corsi blocks if the individual performed accurately on the first presentation of the repeating supraspan item, as this indicates that the individual’s span had been underestimated. This was the case on the Corsi blocks for 2 patients and 4 controls, and on the Hebb’s Digits for 3 patients and 1 control.

Statistical Analyses T tests were used to compare the patients’ and controls’ demographic information and data from the symptom scales and cognitive tasks. The t tests were two-tailed, with p values calculated using an assumption of unequal variance, and, unless otherwise noted, the tests were independent sample t tests. Two-tailed sign tests and correlations were also utilized. A significance level of p < .05 was set for all comparisons.

Results As Table 1 shows, controls and patients did not differ significantly from each other on age, years of education, or estimated IQ. No test-order effect (by block) was detected using a one-factor analysis of variance.

Table 2. Measures of Psychological and Physical Symptoms, Means, and Standard Deviations

HADS–Anxiety HADS–Depression FSS SRS–Usual Sum SRS–Usual Number SRS–Today Sum SRS–Today Number

Patients

Controls

M

SD

M

SD

p

3.0 5.1 55.1 58.1 13.6 34.4 9.0

3.4 2.6 5.4 14.3 2.0 16.9 3.1

6.4 2.0 26.2 18.5 10.5 4.2 2.3

3.0 1.9 8.3 8.3 3.2 4.9 2.2

.001 .001 .001 .001 .001 .001 .001

Note: HADS = Hospital Anxiety and Depression Scale; FSS = Fatigue Severity Scale; SRS = Symptom Rating Scale.

scoring higher on anxiety than the patients, and the patients scoring higher on depression than the controls. However, the means obtained for both groups on the HADS fell below the cutoff for clinical significance. Thus, although there were discernable differences between the two groups, neither group appeared to be clinically anxious or depressed. Table 2 also presents the means for the FSS and SRS. The four means for the SRS represent the two versions of the scale (for ratings of commonly experienced symptoms vs. symptoms experienced on the day of testing) and include the scores for both the number of symptoms endorsed and the sum of the ratings of the severity of symptoms. As expected, the patients scored significantly higher than the controls on the FSS and on all four scores of the SRS. Dependent sample t tests on the SRS scores show that both the controls and the patients rated their number of symptoms and level of symptoms to be significantly lower on the day of testing as compared to their usual levels (p < .001 for all four analyses).

Mood State and Personality Table 2 shows that the controls and patients had significantly different scores on both the anxiety and depression components of the HADS, with the controls Table 1. Participant Characteristics, Means, and Standard Deviations Patientsa

Age Years of Education Estimated IQ a

n = 17. bn = 19.

Controlsb

M

SD

M

SD

35.9 16.1 108.6

6.3 2.4 8.3

35.4 16.0 109.3

6.9 2.3 6.1

Neuropsychological Test Results The performance of the CFS and control groups differed significantly on three measures of divided attention in which the normal control participants outperformed the CFS patients: Version 2 of the CPT—the number correct on the X task (t = –2.2, p = .04) and the number of words reported from the left ear in both dichotic listening tasks (t = –2.1, p < .05) given with Version 2 (X and AX parts) of the CPT. There were no other significant between-group differences on the neuropsychological measures. To evaluate the possibility that the CFS patients would have an overrepresentation of the lowest scores 7

ROSS, FANTIE, STRAUS, & GRAFMAN

on the neuropsychological measures (despite no overall between-group differences), two-tailed sign tests were performed on the scores from each of the 36 measures. None of the comparisons were significant.

Correlations To determine whether the degree of cognitive impairment CFS patients reported was associated with their impaired divided-attention performance, post hoc analyses were conducted with Spearman’s Rho using just CFS patient data. CFS patients demonstrated a significant inverse correlation between FSS scores and CPT, Version 2, number correct (p < .001). None of the other correlations, including those between memory and divided-attention variables, were significant.

Discussion The main finding of this study was that CFS patients demonstrated a selective deficit on three measures of divided attention. Their performance on neuropsychological tests of intelligence, fluency, memory, and focused or sustained attention was no different than that of normal controls despite their reports of generally diminished cognitive capacity. As expected, the CFS patients scored significantly higher than the controls on all of the measures of physical symptoms. There was no relation, however, between CFS symptom severity scores and their neuropsychological performance. There were also between-group differences on both components of the HADS, with the controls scoring higher on the anxiety component and the patients scoring higher for depression. However, the means of both groups were below the cutoff for clinical significance and do not likely reflect clinical depression or anxiety. The CFS patients showed poor performance only on the measures of divided attention: the number correct on the X task in the divided-attention presentation of the CPT, and the number of words reported from the left ear on the dichotic listening tests. Examination of the data from the right-handed participants on the two dichotic listening tasks reveals distinctly different patterns for the patients compared to the controls. The controls, as a group, did not exhibit a distinct advantage for either ear. However, on both dichotic listening tasks (given in conjunction with Parts A and B of Version 2 of the CPT), 14 of the CFS patients dis8

played a right-ear superiority, with only 2 showing a left-ear superiority. Although it is common to find a slight right-ear advantage for right-handed normal individuals in verbal dichotic listening tasks (Kolb & Whishaw, 1990), this has been found in studies that have used dichotic listening as the only task performed at that time. In the dual task condition (requiring both visual and auditory processing), it is possible that attentional resources would be redistributed between the processing of visual and auditory stimuli (thereby reducing the amount of attention that could be paid to auditory stimuli) leading to a diminished or absent ear advantage effect. One speculative explanation for the continued right-ear advantage in CFS patients during the divided-attention task is that they are experiencing some form of right temporal lobe dysfunction that would diminish their ability to report stimuli being presented to the left ear. Some SPECT research has found hypoperfusion in the temporal lobes of CFS patients, with Costa et al. (1992) specifically identifying the right temporal lobe as one of the areas most affected in their study. Another possibility for the disparity in performance between the two ears in the CFS group is that the patients are choosing to disproportionately allocate their mental resources to the dichotic listening task even though the divided-attention paradigm required them to allocate their resources in a more distributed fashion. This may have represented a strategy to maximize the use of potentially insufficient resources and, as the right ear has a slight, natural superiority in dichotic listening tasks, may explain the particular allocation of attention seen in this study. The generally adequate neuropsychological performance of the CFS patients reinforces the view that cognitive impairments in CFS are not due to a pronounced general effect of central fatigue. It is possible, though, that the patients’ perceived fatigue is causing a more subtle impairment or reduction of mental efficiency that is only manifesting itself in more demanding situations. This may explain the significant correlation between the patients’ scores on the divided-attention presentation of the CPT X task and their FSS scores. However, as the FSS did not correlate with the patients’ scores from the left ear of the dichotic listening tasks, it is difficult to state with certainty that it is the fatigue alone that is responsible for the patients’ performance deficits in this study. The results of this study are in disagreement with Ichise et al.’s (1992) finding that CFS patients show extreme hypoperfusion in various areas of the brain. If there were extreme hypoperfusion, then a variety of

DIVIDED ATTENTION DEFICITS IN PATIENTS WITH CHRONIC FATIGUE SYNDROME

cognitive processes should be impaired in a heterogeneous fashion. As the CFS patients participating in this study did not account for a disproportionate number of the lowest scores on the neuropsychological measures, we can reject that hypothesis. Further, the pattern of results does not conform to one that subcortical dysfunction would be likely to produce, in that the patients did not show slower reaction times, impaired recall, or simple sustained attention deficits. The results of this study are concordant with Simon, Cowden, Seastrunk, Weiner, and Hickey’s (1991) finding of temporal asymmetry in blood flow, as the CFS patients in our study showed significantly greater differences than did the controls between their left and right ears on both of the dichotic listening tasks. This finding seems unlikely to be due to chance factors, because our finding of significantly lower scores on both presentations to the left ear on the dichotic listening tasks provides a measure of replication. However, the patients did not show a significant disparity between the span or supraspan scores on the Corsi blocks and the Hebb’s Digits compared with the controls, and such a disparity might also be predicted by such a hypothesis. The CFS patients’ impairment on the divided-attention task in this study is consistent with the findings of DeLuca et al. (1995; DeLuca et al., 1993) in which CFS patients performed poorly on the Paced Auditory Serial Addition Test, a very demanding and sensitive test requiring complex information processing. There has been an argument in the literature (Johnson, DeLuca, Fiedler, & Natelson, 1994) that despite patients’ consistent complaints of memory impairment, memory functioning is intact in CFS. DeLuca and colleagues (1995; DeLuca et al., 1993) suggested that an impairment in the efficiency of information processing, which is particularly apparent during tasks requiring simultaneous cognitive activities, may be providing the basis for the more general cognitive complaints of CFS patients. These authors posited that such an impairment in complex information processing can lead to a functional memory impairment and the patients’ perception of impaired memory. The results of our study provide partial support for the hypothesis advanced. It is possible that the poorer CFS patient performance seen in the CPT dichotic listening conditions represents a specific impairment in efficiently allocating cognitive resources to sequential or simultaneous components of complex tasks. Deficits in cognitive efficiency or resource allocation may be subtle (at least in highly educated participants) and are more likely to be evoked by demanding tasks.

Divided-attention tasks are particularly sensitive to any condition that impairs attention or general mental efficiency, and thus many conditions cause impaired performance on such tasks. Lezak (1995) noted that impairment in divided attention is seen in Alzheimer’s disease, Korsakoff’s disease, normal aging, and in conditions of diffuse brain damage (e.g., the results of toxin exposure or hypoxia). Lezak reported that patients with diffuse impairments frequently complain of an inability to concentrate or perform complex mental operations and of feelings of confusion and generally reduced performance on cognitive tasks; these complaints are reminiscent of those given by CFS patients (Abbey & Garfinkel, 1990; Holmes et al., 1988). Further, Lezak noted that such patients may still perform well on standard cognitive tests. Other researchers have reported that divided attention is impaired in Huntington’s disease (Sprengelmeyer, Lange, & Homberg, 1995), in individuals who have experienced experimentally induced disrupted sleep (Roehrs, Meriotti, Petrucelli, Stepanski, & Roth, 1994), and following mild traumatic brain injury (Alexander, 1995). Thus, our results pointing to an impairment in divided attention in CFS are not specific as they are observed in multiple neurological conditions and when non-neurological participants report decreased mental effort, feel fatigue or tiredness, are sleep deprived, or are depressed. Few of the previous studies of cognitive functioning in CFS have assessed the severity of the current symptom levels in their patients. In our study, both the CFS patients and the controls rated themselves on the SRS as having significantly fewer symptoms and lower levels of severity of symptoms on the day of testing as compared to their usual functioning. Thus, it is likely that rather than giving ratings that reflected their usual level of functioning, participants instead were indicating whether they ever experienced the symptoms listed. This would account for the controls’ responses that indicate that they are usually experiencing an average of 10.5 symptoms, quite a large number of symptoms for “healthy” controls. The SRS scores, nevertheless, were unrelated to neuropsychological performance. As noted previously, increasing severity of CFS patient fatigue ratings was negatively associated with one performance measure in a divided-attention condition. In everyday life, people often perform multiple tasks simultaneously, such as conversing while driving or attempting to write down dictated information (Koechlin, Basso, Pietrini, Panzer, & Grafman, 1999). Given our findings, it is likely that CFS patients will report more cognitive difficulties in real-life situations that cause 9

ROSS, FANTIE, STRAUS, & GRAFMAN

them to divide their effort or rapidly reallocate cognitive resources between two response channels (vision and audition) over a short period of time. We hypothesize that this impairment causes CFS patients (particularly those with lower education levels and greater reports of fatigue) to perform poorly on a wide range of neuropsychological tests.

References Abbey, S. E., & Garfinkel, P. E. (1990). Chronic fatigue syndrome and the psychiatrist. Canadian Journal of Psychiatry, 35, 625–633. Abbey, S. E., & Garfinkel, P. E. (1991). Chronic fatigue syndrome and depression: Cause, effect or covariate. Review of Infectious Diseases, 13(Suppl. 1), S8–11. Alexander, M. P. (1995). Mild traumatic brain injury: Pathophysiology, natural history, and clinical management. Neurology, 45, 1253–1260. Costa, D. C., Brostoff, J., Douli, V., & Ell, P. J. (1992). Brain stem hypoperfusion in patients with myalgic encephalomyelitis-chronic fatigue syndrome. European Journal of Nuclear Medicine, 19, 733. DeLuca, J., Johnson, S. K., Beldowicz, D., & Natelson, B. H. (1995). Neuropsychological impairments in chronic fatigue syndrome, multiple sclerosis, and depression. Journal of Neurology, Neurosurgery, and Psychiatry, 58, 38–43. DeLuca, J., Johnson, S. K., & Natelson, B. H. (1993). Information processing efficiency in chronic fatigue syndrome and multiple sclerosis. Archives of Neurology, 50, 301–304. Demitrack, M. A. (1996). The psychobiology of chronic fatigue: The central nervous system as a final common pathway. In M. A. Demitrack & S. E. Abbey (Eds.), Chronic fatigue syndrome: An integrative approach to evaluation and treatment (pp. 72–109). New York: Guilford. Fukuda, K., Straus, S. E., Hickie, I., Sharpe, M. C., Dobbins, J. G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121, 953–959. Grafman, J., Schwartz, V., Dale, J. K., Scheffers, M., Houser, C., & Straus, S. E. (1993). Analysis of neuropsychological functioning in patients with chronic fatigue syndrome. Journal of Neurology, Neurosurgery, and Psychiatry, 56, 684–689. Hickie, I., Lloyd, A., Wakefield, D., & Parker, G. (1990). The psychiatric status of patients with the chronic fatigue syndrome. British Journal of Psychiatry, 156, 534–540. Holmes, G. P., Kaplan, J. E., Gantz, N. M., Komaroff, A. L., Schonberger, L. B., Straus, S. E., Jones, J. F., Dubois, R. E., Cunningham-Rundles, C., Pahwa, S., Tosato, G., Zegans, L. S., Purtilo, D. T., Brown, N., Schooley, R. T., & Brus, I. (1988). Chronic fatigue syndrome: A working case definition. Annals of Internal Medicine, 108, 387–389. Ichise, M., Salit, I. E., Abbey, S. E., Chung, D.-G., Gray, B., Kirsh, J. C., & Freedman, M. (1992). Assessment of regional cerebral 99 m perfusion by Tc -HMPAO SPECT in chronic fatigue syndrome. Nuclear Medicine Communications, 13, 767–772. Johnson, S. K., Deluca, J., Diamond, B. J., & Natelson, B. H. (1998). Memory dysfunction in fatiguing illness: Examining interfer-

10

ence and distraction in working memory. Cognitive Neuropsychiatry, 3, 269–285. Johnson, S. K., DeLuca, J., Fiedler, N., & Natelson, B. H. (1994). Cognitive functioning of patients with chronic fatigue syndrome. Clinical Infectious Diseases, 18(Suppl. 1), S84–S85. Kimura, D. (1963). Right temporal lobe damage. Archives of Neurology, 8, 264–271. Koechlin, E., Basso, G., Pietrini, P., Panzer, S., & Grafman, J. (1999). The role of anterior prefrontal cortex in human cognition. Nature, 399, 148–151. Kolb, B., & Whishaw, I. Q. (1990). Fundamentals of human neuropsychology (3rd ed.). New York: Freeman. Krupp, L. B., LaRocca, N. G., Muir-Nash, J., & Steinberg, A. D. (1989). The Fatigue Severity Scale: Application to patients with multiple sclerosis and systemic lupus erythematosus. Archives of Neurology, 46, 1121–1123. Lezak, M. D. (1995). Neuropsychological assessment (3rd ed.). New York: Oxford University Press. Lloyd, A. R., Wakefield, D., Boughton, C., & Dwyer, J. (1988). What is myalgic encephalomyelitis? Lancet, 1, 1286–1287. Prasher, D., Smith, A., & Findley, L. (1990). Sensory and cognitive event-related potentials in myalgic encephalomyelitis. Journal of Neurology, Neurosurgery, and Psychiatry, 53, 247–253. Riccio, M., Thompson, C., Wilson, B., Morgan, D. J. R., & Lant, A. F. (1992). Neuropsychological and psychiatric abnormalities in myalgic encephalomyelitis: A preliminary report. British Journal of Clinical Psychology, 31, 111–120. Roehrs, T., Meriotti, L., Petrucelli, N., Stepanski, E., & Roth, T. (1994). Experimental sleep fragmentation. Sleep, 17, 438–443. Rosvold, H. E., Mirsky, A. F., Sarason, I., Bransome, E. D., Jr., & Beck, L. H. (1956). A continuous performance test of brain damage. Journal of Consulting Psychology, 20, 343–350. Scheffers, M. K., Johnson, R., Jr., Grafman, J., Dale, J. K., & Straus, S. E. (1992). Attention and short-term memory in chronic fatigue syndrome patients: An event-related potential analysis. Neurology, 42, 1667–1675. Schwartz, R. B., Komaroff, A. L., Garada, B. M., Gleit, M., Doolittle, T. H., Bates, D. W., Vasile, R. G., & Holman, B. L. (1994). SPECT imaging of the brain: Comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. American Journal of Roentgenology, 162, 943–951. Sharpe, M. C., Archard, L. C., Banatvala, J. E., Borysiewicz, L. K., Clare, A. W., David, A., Edwards, R. H. T., Hawton, K. E. H., Lambert, H. P., Lane, R. J. M., McDonald, E. M., Mowbray, J. F., Pearson, D. J., Peto, T. E. A., Preedy, V. R., Smith, A. P., Smith, D. G., Taylor, D. J., Tyrrell, D. A. J., Wessely, S., & White, P. D. (1991). A report—chronic fatigue syndrome: Guidelines for doing research. Journal of the Royal Society of Medicine, 84, 118–121. Simon, T. R., Cowden, E., Seastrunk, J. W., Weiner, E., & Hickey, D. C. (1991). Chronic fatigue syndrome: Flow and functional abnormalities seen with SPECT. Radiology, 181(Suppl.), 173. Smith, A. (1991). Cognitive changes in myalgic encephalomyelitis. In R. Jenkins & J. Mowbray (Eds.), Post-viral fatigue syndrome (pp. 179–194). Chichester, England: Wiley. Sprengelmeyer, R., Lange, H., & Homberg, V. (1995). The pattern of attentional deficits in Huntington’s disease. Brain, 118, 145–152.

DIVIDED ATTENTION DEFICITS IN PATIENTS WITH CHRONIC FATIGUE SYNDROME Straus, S. E. (1991). History of chronic fatigue syndrome. Reviews of Infectious Diseases, 13(Suppl. 1), S2–S7. Wechsler, D. (1987). Wechsler Memory Scale–Revised manual. San Antonio, TX: Psychological Corporation. Zachary, R. A. (1986). Shipley Institute of Living Scale (revised manual). Los Angeles: Western Psychological Services.

Zigmond, A. S., & Snaith, R. P. (1983). The Hospital and Anxiety Scale. Acta Psychiatrica Scandinavica, 67, 361–370.

Original submission September 3, 1999 Accepted May 17, 2000

11

Applied Neuropsychology 2001, Vol. 8, No. 1, 12–22

Copyright 2001 by Lawrence Erlbaum Associates, Inc.

Neuropsychological Function in Patients With Chronic Fatigue Syndrome, Multiple Sclerosis, and Depression

NEUROPSYCHOLOGICAL FUNCTION WITH CFS, MS, AND DALY DEPRESSION ET AL.

Ella Daly Department of Psychiatry, Massachusetts General Hospital, Charleston, Massachusetts, USA

Anthony L. Komaroff Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Kerry Bloomingdale Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Scott Wilson Department of Psychiatry, Massachusetts General Hospital, Charleston, Massachusetts, USA

Marilyn S. Albert Departments of Psychiatry and Neurology, Massachusetts General Hospital, Charleston, Massachusetts, USA Patients with chronic fatigue syndrome (CFS), multiple sclerosis (MS), and major depression were compared with controls and with each other on a neuropsychological battery that included standard neuropsychological tests and a computerized set of tasks that spanned the same areas of ability. A total of 101 participants were examined, including 29 participants with CFS, 24 with MS, 23 with major depressive disorder, and 25 healthy controls. There were significant differences among the groups in 3 out of 5 cognitive domains: memory, language, and spatial ability. Assessment of psychiatric symptoms indicated that all 3 patient groups had a higher prevalence of depression than the controls. A total measure of psychiatric symptomatology also differentiated the patients from the controls. After covarying the cognitive test scores by a measure of depression, the patient groups continued to differ from controls primarily in the area of memory. The findings support the view that the cognitive deficits found in CFS cannot be attributed solely to the presence of depressive symptomatology in the patients. Key words: chronic fatigue syndrome, neuropsychological tests, computerized tests

multiple

sclerosis,

major

depression,

Support for this work was provided in part by Grants R01–A127314 and U01–A132246 from the National Institute of Allergy and Infectious Diseases and by a gift from the De Young Foundation. Requests for reprints should be sent to Marilyn S. Albert, Massachusetts General Hospital, Psychiatry/Gerontology (149-9124), 149 13th Street, Charlestown, MA 02129, USA. E-mail: [email protected]

12

NEUROPSYCHOLOGICAL FUNCTION WITH CFS, MS, AND DEPRESSION

The majority of studies indicate that patients with chronic fatigue syndrome (CFS) have subtle cognitive deficits (Bastien, 1992; DeLuca, Johnson, Beldwicz, & Natelson, 1995; DeLuca, Johnson, & Natelson, 1993; McDonald, Cope, & David, 1993; Marcel, Komaroff, Fagioli, Kornish, & Albert, 1996; Marshall, Forstot, Caillies, Peterson, & Schenck, 1997; Millon, Salvato, & Blaney, 1989; Riccio, Thompson, Wilson, Morgan, & Lant, 1992; Sandman, Barron, Nackoul, Goldstein, & Fidler, 1993; Smith, 1991; Smith, Behan, Bell, Millar, & Bakheit, 1993), although some investigators report minimal or no impairment (Altay et al., 1990; Johnson, DeLuca, & Fiedler, 1994; Kane, Gantz, & DiPino, 1997; Scheffers, Johnson, Grafman, Dale, & Straus, 1992; Schmaling, DiClementi, Cullum, & Jones, 1994). There are, in addition, differing conclusions regarding which cognitive domains are primarily affected in CFS. Some investigators have hypothesized that selective auditory processing deficits (DeLuca et al., 1993) or motor slowing (Marshall et al., 1997) underlie the impairments seen in CFS patients, whereas others have found deficits in areas such as memory and executive function, unrelated to sensory processing domain or speed (Marcel et al., 1996). In addition, the underlying cause of the cognitive deficits observed in CFS remains unclear. As a result of the high prevalence of depression and anxiety found among CFS patients, many studies have assessed psychiatric symptoms in the CFS patients to determine their relation to cognitive performance. Most of these studies have shown that cognitive deficits persist in CFS, even after adjusting for the presence of psychiatric symptomatology (Cope, Pernet, Kendall, & David, 1995; DeLuca, Johnson, Ellis, & Natelson, 1997; DeLuca et al., 1993; DiPino & Kane, 1996; Grafman et al., 1993; Marcel et al., 1996; Schmaling et al., 1994; Smith et al., 1993). Several studies have, however, compared patients with CFS to those with major depression and found that they did not differ from one another in terms of overall neuropsychological performance (De Luca et al., 1995; Marshall et al., 1997; Schmaling et al., 1994; Vollmer-Conna et al., 1997). It has also been suggested that a disorder of the immune system may, by itself, produce cognitive decline. To address this issue, studies have compared CFS patients to patients with multiple sclerosis (MS), particularly because of the presence of fatigue in both disorders. In one study, investigators found that patients with MS obtained lower scores on all test measures compared to CFS patients and controls (Krupp,

Sliwinski, Masur, Friedberg, & Coyle, 1994). Another study, however, reported that MS and CFS patients were not significantly different from one another, but both groups were more impaired than controls (DeLuca et al., 1993). To our knowledge, only one study has compared all three groups to one another (CFS vs. MS vs. depression) and to controls. This investigation reported that both the CFS and depression patients were significantly impaired in comparison to controls, but patients with MS did not differ statistically from either patient group or controls (DeLuca et al., 1995). To address the differences in outcome among the foregoing studies, we compared the neuropsychological performance of patients with CFS, MS, and depression. Psychiatric symptomatology, including depression and anxiety, were also evaluated in the same individuals to determine their relation to cognitive performance.

Method Participants A total of 101 patients participated in the study, all of whom provided informed consent consistent with institutional guidelines. Of these, 29 met the modified Centers for Disease Control (CDC) criteria for CFS (Schluederberg et al., 1992). Their mean age was 39.9 years. They had an average of 15.8 years of education. Their average duration of illness was 5.7 years. The CFS patients were recruited through the Chronic Fatigue Syndrome Cooperative Research Center at the Brigham and Women’s Hospital, Boston. Twenty-three out of the 29 patients were found to have either an abnormal Rhomberg or an abnormal tandem gait on neurologic examination, but no neurologic disease was diagnosed in any participant (such findings are seen in 10%–20% of CFS patients seen at Brigham and Women’s Hospital). Six patients had a history of depressive illness prior to the diagnosis of CFS, with 4 out of this group currently depressed. A total of 15 patients were on low doses (5–50 mg/day) of tricyclic antidepressant medication, primarily to treat coexisting sleep pathology. A total of 24 MS patients participated in the study. All MS patients met the case definition for clinically definite MS (Poser et al., 1983) and had the relapse-remitting form of MS. The mean age of the MS group was 39.6 years, and they had an average of 14.3 years of education. Their mean disability rating was 1.6 (range = 13

DALY ET AL.

0–4), based on the Expanded Disability Status Scale (Kurtzke, 1983). The MS patients were recruited from the MS Unit at Brigham and Women’s Hospital. Three of the MS patients had a history of psychiatric illness: 1 patient had a past history of depression, 1 patient reported a current depressive episode, and 1 patient had a history of bipolar disorder. All three of these participants were taking antidepressant medication and were medically stable. The depression group consisted of 23 patients. Their average age was 39.5 years, and they had a mean education of 14.1 years. Within this group, 20 patients had a history of major depressive disorder, and 3 had a diagnosis of bipolar disorder, depressed type. The diagnoses were based on clinical interviews obtained by research psychiatrists. Nineteen of the 23 patients in the depression group were currently on antidepressant medication, 9 were taking antipsychotic medication (e.g., Haldol, Melleril, or Stelazine), and 9 were on mood-stabilizing medication (e.g., lithium or carbamazepine). The depression patients were recruited from among inpatients and outpatients at the Brigham and Women’s Hospital, the Deaconess Medical Center, and the Freedom Trail Clinic at the Erich Lindemann Mental Health Center, Boston. A total of 25 control individuals participated in the study. Their mean age was 38.8 years, and they had an average of 16.3 years of education. They were recruited from advertisements in the local community. None had evidence of debilitating chronic fatigue within the past 6 months (first major criterion of the CDC case definition for CFS) or were suffering from any chronic organic or psychiatric illness that could produce chronic fatigue (second major criterion of the CDC case definition for CFS). All consecutively recruited participants who met study criteria agreed to participate. The participants in the four groups did not differ in terms of age. There was, however, a significant difference among the groups in terms of education (p < .003). Post hoc planned comparisons indicated that the CFS patients and the controls did not differ in mean educational level, but the MS and depression groups had significantly less education than the other two groups.

Neuropsychological Test Battery The participants were administered a neuropsychological test battery that contained a large number of standardized neuropsychological tests, as well as a bat14

tery of tasks adapted for administration by computer. The computerized battery was included because the patient groups examined in this study frequently complain of fatigue and slowness and computerized tasks can measure both speed and accuracy of response. The standard neuropsychological battery evaluated attention by means of the Digit Span Forward (Wechsler, 1945); language ability was assessed by the Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1982) and verbal fluency (Benton & Hamsher, 1976); memory was evaluated by the Russell version of the Wechsler Memory Scale (WMS; Russell, 1975; Wechsler, 1945) and a word list learning test (Weingartner, Cohen, Murphy, Martello, & Gerdt, 1981); set shifting and conceptualization (aspects of executive function) were assessed by means of the Stroop Interference Test (Stroop, 1935) and Proverb Interpretation (Gorham, 1956); spatial ability was evaluated by figure copying, as assessed by figures from the WMS (Wechsler, 1945) and cube copying from the Consortium to Establish a Registry for Alzheimer’s Disease battery (Morris et al.,1989); and overall IQ was estimated by means of the vocabulary subtest of the Wechsler Adult Intelligence Scale (Wechsler, 1958). The computerized battery evaluated comparable cognitive domains, using tasks adapted from standard neuropsychological procedures. A continuous performance task, which was based on standard tests of sustained attention (Rosvold, Mirsky, Sarason, Bransome, & Beck, 1956), was used to assess attentional capacity; an associate learning test measured verbal memory, and a pattern memory test assessed nonverbal memory (Warrington & James, 1967); spatial ability was evaluated by pattern matching (Acker, 1982) and a hand–eye coordination test (Hanninen, Eskilinen, & Nurminen, 1976); and set shifting was evaluated by a task that was an adaptation of a switching-attention test by Eckerman, Carrol, and Foree (1985).

Assessment of Psychiatric Symptoms Psychiatric symptomatology was evaluated by means of the Hopkins Symptom Checklist–Revised (SCL–90–R; Derogatis & Melisaratos, 1983). The SCL–90–R is a self-administered instrument that assesses a broad range of symptomatology and consists of nine subscales, including depression, anxiety, somatization, obsessive–compulsive symptoms, interpersonal sensitivity, hostility, phobic anxiety, paranoid ideation, and psychoticism.

NEUROPSYCHOLOGICAL FUNCTION WITH CFS, MS, AND DEPRESSION

Statistical Analysis Multivariate analysis of covariance (MANCOVA), analysis of covariance (ANCOVA), and analysis of variance (ANOVA) were used to compare the scores of the patient groups and the controls. When post hoc comparisons were performed following these analyses, Duncan’s multiple range test was used to adjust for multiple comparisons. In addition, an overall impairment rating (IR) was calculated for each participant to facilitate comparison with studies that have used a similar measure to contrast the performance of CFS patients to other patient groups (DeLuca et al., 1995; Krupp et al., 1994). The IR uses the standard deviation of the control group to determine the degree to which the patients differ from controls. The IR is calculated in the following manner: Scores for each test that were within 1 SD of the control group are assigned an IR of 0; scores between 1 and 2 SDs below the control group are assigned an IR of 1; scores between 2 and 3 SDs below the control group are assigned an IR of 2; and scores greater than 3 SDs below the control group receive an IR of 3. The IR scores for each test are then summed together for each participant and divided by the number of tasks the participant completed to give an overall IR for each participant. This summed IR was adjusted for any difference in education among the groups and used in subsequent analyses. It should be noted that 92 of 101 participants completed all of the tests in the battery. Of the remaining 9 participants, 7 completed all but one or two of the tests in the battery, and 1 participant completed 17 out of the 22 tests. Thus, the IR was based on the mean number of tests completed, rather than on the sum of the ratings assigned to each test. Multiple regression analysis was used to evaluate the relation between the cognitive measures and potential modifying factors of psychiatric symptomatology and medication.

Results The mean scores for each neuropsychological test were grouped according to cognitive domains, based on factor analysis, as follows: attention, memory, language, spatial ability, and executive function. These scores, adjusted for educational level, are shown in Table 1. A separate MANCOVA was performed for each of the five major cognitive domains (using educational level as the covariate) to determine whether the patient groups demonstrated selective impairments

within specific cognitive areas. Each of the five MANCOVAs included four or five primary test scores related to the domain in question. Education was used as a covariate because two of the four groups were significantly different in educational achievement, and individuals with lower levels of education tend to perform more poorly on cognitive tasks than those with higher levels of education. The MANCOVA for the cognitive domain of memory was statistically significant at the .01 level (F = 2.87, p > .001). In addition, the MANCOVAs for language and spatial ability were significant at the .05 level (F = 2.134, p = .016 and F = 1.855, p = .04, respectively). The results of the MANCOVAs are shown in Table 2. To further examine the specific cognitive tests within each of these three domains that differed among the groups, a series of post hoc planned comparisons, using ANCOVA, were performed, with years of education as the covariate. The results of the ANCOVAs are also shown in Table 2, which also summarizes the neuropsychological tests on which the patient groups differed from the controls. The post hoc planned comparisons within the memory domain demonstrated that on three out of four of the memory tests, all three patient groups were impaired in comparison to controls. These tests were the Mental Quotient (MQ) of the WMS, the Associate Learning task, and the List Learning task. Two of the three patient groups, the CFS group and the depression group, were significantly impaired in comparison to controls, on the nonverbal Pattern Recognition task. Only the MS group was not impaired in comparison to controls on this task. When memory performance was compared among the patient groups, the results varied depending on the task in question and the groups that were being compared. The CFS patients performed significantly better than the MS group on one of the memory tasks (the MQ subtest of the WMS). There was no statistical difference between the CFS and MS groups on the other three memory tasks (Associate Learning, List Learning, Pattern Recognition). In comparison to the depression patients, the CFS group performed better on two of the memory tasks (MQ of the WMS and Associate Learning) but showed no difference in performance on the other tasks (List Learning and Pattern Recognition). The depression and MS groups did not differ from one another on the memory tasks. The post hoc planned comparisons within the language domain indicated that the depression patients were the most impaired overall. This group was im15

DALY ET AL. Table 1.

Mean Test Scores Adjusted for Education: Controls and Patients With CFS, MS, and Depression

Test Name Attention Mental Control Digit Span Side Reaction Time Direction Reaction Time Continuous Performance Language Boston Naming Letter Fluency Category Fluency, Animals Category Fluency, Vegetables Memory WMS Memory Quotient List Immediate Recall List Learning Total Pattern Recognition Spatial Ability WMS Figure Copying Pattern Matching Eye–Hand Cube Copy Executive Function Proverbs Switching Direction Switching Sides Stroop Monitoring

CFSa

MSb

DEPc

Controld

8.12 7.41 429.41 540.97 404.19

7.62 7.19 464.87 598.43 398.18

6.92 7.45 489.66 610.98 421.23

8.02 6.88 406.93 547.84 389.32

56.24 47.68 19.51 14.70

56.39 42.21 19.15 15.15

52.89 40.68 18.06 13.96

55.01 46.46 22.33 16.30

121.97 7.45 64.25 6.52

116.87 7.03 56.37 5.72

117.24 7.41 50.87 5.99

130.82 8.51 78.26 5.29

13.11 19.90 2.53 2.44

12.76 19.33 2.46 2.64

12.64 19.52 2.70 2.43

12.80 19.64 2.49 2.71

13.61 692.84 855.80 0.84 4.65

12.55 718.98 869.92 1.47 4.79

13.49 810.11 926.92 1.62 5.23

13.06 638.80 777.09 2.94 5.33

Note: CFS = chronic fatigue syndrome; MS = multiple sclerosis; DEP = depression; WMS = Wechsler Memory Scale. a n = 29. bn = 24. cn = 23. dn = 25.

paired in comparison to the controls on all four of the language tests (Boston Naming, letter fluency, and the category fluency tests for animals and vegetables). The CFS and MS patients were only impaired in comparison to controls on the category fluency test for animals. When language performance was compared among the patient groups, the depression patients were impaired in comparison to the CFS and MS patients on one task (the Boston Naming Test). The depression patients were also impaired in comparison to the CFS group on the letter fluency task. However, on both of the category fluency tasks, the patient groups did not differ from one another. The post hoc planned comparisons within the spatial domain indicated, although several of the tests approached significance (contributing to the overall significance of the domain), only the cube copying task significantly differentiated the groups. On this task, the depressed patients were impaired in compari-

16

son to the controls. However, none of the patient groups were significantly different from one another on this task. ANOVA was then performed to examine the differences among the groups in the summed IR. This revealed an overall significant difference among the groups (F = 5.58, p < .0014). Post hoc planned comparisons demonstrated that the depression group and the MS group were significantly impaired in comparison to the controls. The CFS group was not impaired in comparison to the controls on this overall measure of impairment. The MS group and the CFS group were not significantly different from one another (see Figure 1). Psychiatric Symptomatology ANOVA was used to compare the degree of psychiatric symptomatology among the groups. All of the three patient groups had significantly higher total scores on the SCL–90–R in comparison to the controls.

NEUROPSYCHOLOGICAL FUNCTION WITH CFS, MS, AND DEPRESSION

cantly different from controls on 5 of the 10 subscales of the SCL–90–R. In addition, the depression patients had significantly higher scores than the CFS and MS patients on 7 out of 10 of the subscales of the SCL–90–R (they did not differ on the somatization, obsessive–compulsive, and hostility subscales). The CFS patients had higher mean scores than the MS patients on 6 of the 10 subscales, including depression, anxiety, phobic anxiety, somatization, obsessive–compulsive, and hostility. The MS patients had the lowest level of psychiatric symptomatology in comparison to the other patient groups. Because each of the patient groups was significantly more symptomatic in the area of depression, a separate MANCOVA was performed for each of the five cognitive domains, covarying the scores from the depression subscale of the SCL–90–R, in addition to education.

In addition, the SCL–90–R total score was significantly higher in the depression patients in comparison to the other patient groups (see Table 3). The depression and anxiety subscales were of particular interest, because these symptoms had been the focus of a number of previous studies in CFS patients. Each of the patient groups had significantly more symptoms of depression than controls, based on the depression subscale of the SCL–90–R. Two of the patient groups, the CFS patients and the depression patients (but not the MS patients), had more anxiety symptoms than controls. Overall, the depression group was more symptomatic than the other patient groups; they were significantly different from controls on all 10 of the subscales of the SCL–90–R. Among the patient groups, the MS patients reported the lowest level of psychiatric symptoms; they were signifiTable 2.

ANCOVAs and MANCOVAs for Controls and Patients With CFS, MS, and Depression ANCOVA

Test Name Attention Mental Controla Digit Span Side Reaction Time Direction Reaction Time Continuous Performance Language Boston Naminga Letter Fluencya Category Fluency, Animalsa, b, c Category Fluency, Vegetablesa Memory WMS Memory Quotienta, b, c List Immediate Recalla, b, c List Learning Totala, b, c Pattern Recognition Memoryb Spatial Ability WMS Figure Copying Pattern Matching Eye–Hand Coordination Cube Copya Executive Function Proverbs Switching Directiona, c Switching Sidesa Stroop Monitoringb, c

MANCOVA

F

p

4.57 1.39 1.07 1.76 2.01

.005 .252 .366 .160 .160

4.55 3.18 4.02 2.81

.005 .028 .010 .044

10.33 7.47 10.02 2.89

.0001 .0002 .0001 .0390

2.33 2.46 2.48 2.90

.080 .068 .067 .039

1.38 3.03 3.94 1.45 3.04

.250 .033 .011 .230 .033

p .22

.02

.001

.04

.33

Note: CFS = chronic fatigue syndrome; MS= multiple sclerosis; WMS = Wechsler Memory Scale. a Test differed significantly between the depressed group and the controls. bTest differed significantly between the chronic fatigue group and the controls. cTest differed significantly between the MS group and the controls.

17

DALY ET AL.

Post hoc planned comparisons between the patient groups and the controls within the memory domain revealed a very similar pattern of impairment to that found after covarying education alone. Once again, all three patient groups were significantly impaired in comparison to controls on three out of the four memory tasks (MQ of the WMS, List Learning, and Associate Learning). Two of the three patient groups (depression and CFS) were also impaired in comparison to controls on the Pattern Memory task. When the patient groups were compared with one another in memory performance with depression covaried, the differences among the groups were very similar to those following the covariance of education alone. The CFS group continued to have a significantly higher score on the MQ of the WMS than either the MS group or the depression group; the CFS group also continued to have significantly better scores on the Associate Learning task than the depression patients. The depression patient group did not differ significantly from the MS group on any of the memory tasks. The pattern of difference among the groups in the spatial domain was also relatively unchanged when depression was covaried. There continued to be a significant difference among the patient groups on the cube copying test when performance was adjusted for level of depression in addition to education. In the language domain, the differences among the groups were, however, attenuated following a statistical adjustment for level of depression in addition to education. All three groups continued to differ in comparison to controls on the category fluency test for animals, and the depression patients were also impaired in compari-

The same three cognitive domains that differed among the groups following the MANCOVA in which only education was covaried differed among the groups when depression scores were also covaried (i.e., memory, language, and spatial ability). In addition, the level of significance was similar. The MANCOVA for the cognitive domain of memory was statistically significant at the .01 level (F = 2.45, p < .005); the MANCOVAs for language and spatial ability were significant at the .05 level (F = 2.077, p < .019 and F = 2.03, p < .023, respectively).

Figure 1. This figure compares the mean summed IR scores in the four groups of participants (NC = normal controls; CFS = chronic fatigue syndrome; MS = multiple sclerosis; DEP = depression). The data were covaried for years of education. A significant difference compared to controls at p < .05 is indicated by (*) and a significant difference compared to CFS patients at p < .05 is indicated by (#).

Table 3.

Mean Total and Subscale Scores on SCL–90–R for Controls Versus Patients With CFS, MS, and Depression CFSa

SCL Variables Total SCL–90–R Depression Anxiety Phobic Anxiety Somatization Obsessive–Compulsive Interpersonal Sensitivity Hostility Paranoid Ideation Psychoticism Other

M

MSb SD

e

40.69 7.62e 4.45e 1.10e 7.66e 7.97e 3.21 1.86e 1.28 1.79e 3.76e

15.42 3.05 2.78 1.82 2.38 1.24 2.70 1.27 1.60 1.52 1.84

M

DEPc SD

e

34.17 6.38e 2.79 0.88 6.08e 6.67e 3.25 1.71 1.92 1.88e 2.63

16.71 3.25 2.43 1.42 2.22 2.26 2.40 1.65 2.04 2.09 1.61

M e

57.52 10.30e 7.09e 3.43e 6.43e 8.17e 6.74e 2.70e 3.17e 5.00e 4.48e

Controlsd SD

M

SD

22.15 4.02 2.81 2.37 4.21 2.01 2.53 2.01 2.23 2.78 2.04

16.92 3.16 1.76 0.08 1.64 3.20 2.68 0.92 1.12 0.68 1.68

12.66 2.93 1.76 0.28 1.29 2.87 2.50 0.86 1.20 1.28 1.22

Note: SCL–90–R = Sympton Checklist–Revised; CFS = chronic fatigue syndrome; MS = multiple sclerosis; DEP = depression. a n = 29. bn = 24. cn = 23. dn = 25. eSignificant difference compared to controls.

18

NEUROPSYCHOLOGICAL FUNCTION WITH CFS, MS, AND DEPRESSION

son to controls on the Boston Naming Test. The difference between the depression patients and the controls on the other fluency tasks (verbal fluency and category fluency for vegetables) were no longer significant when performance was adjusted by the level of depression. A series of regression analyses were also conducted to determine if the medications used by the participants had an impact on cognitive function, over and above that of the psychiatric symptoms of the participants. For each regression, the dependent variable was a cognitive test measure and the independent variables were the total score on the SCL–90–R and a code representing medication use (no medication = 0, antidepressant medication = 1, the number of other medications [i.e., antipsychotic, mood stabilizing, or tranquilizing medication] = 2–4). In no instance was medication use a significant predictor of cognitive test score beyond that contributed by psychiatric symptoms.

Discussion These findings indicate that cognitive deficits are found in CFS patients and MS patients, but they are mild in comparison to those seen in depression. When the three patient groups are compared, the depression patients have the greatest overall level of impairment. The MS patients appeared to be slightly more impaired than the CFS patients, particularly with respect to the summed IR, but this difference was not significant. In addition, the depression patients had evidence of a different pattern of impairment across the five cognitive domains than either the CFS or MS patients. Although the CFS patients were only mildly impaired in comparison to the depression patients, there was evidence of impairment in comparison to controls. The CFS group was impaired on all four of the memory tasks compared to controls, including the nonverbal Pattern Recognition task. On one of the memory tasks, the MQ of the WMS, both the depression group and the MS group were significantly more impaired than the CFS patients. In addition, compared to the control participants, CFS patients were impaired on one of the language tasks (category fluency for animals), suggesting difficulties with both language skills and planning and organizational abilities related to executive function. These findings also clearly demonstrate that MS produces cognitive impairments. In agreement with numerous other studies, cognitive impairments were primarily found in the memory domain (Beatty & Monson 1991a, 1991b, 1994; Brassington & Marsh, 1998; D’Esposito et al., 1996; Diamond, DeLuca, Kim, &

Kelley, 1997; Grafman, Rao, Bernardin, & Leo, 1991; Litvan & Grafman, 1988; Minden & Schiffer, 1990; Penman, 1991; Rao, 1995). Impaired memory function has, in fact, been reported in 40% to 60% of patients (Rao et al., 1993). The summed IR, which evaluated performance across all cognitive domains, suggested that the MS patients were slightly more impaired than the CFS patients, although this difference did not reach statistical significance. Previous studies that have compared patients with CFS and MS have found differences in the level of impairment between the groups (e.g., DeLuca et al., 1995; Krupp et al., 1994), although this finding has not been uniformly reported (e.g., DeLuca et al., 1993). The depression patients, as previously mentioned, were impaired over a broad range of cognitive domains compared to the other two patient groups and had evidence of impairment in all five cognitive domains when compared to controls. Most of these differences remained after adjustment for degree of depressive symptomatology. In addition, the summed IR demonstrated that the depression patients were significantly more impaired overall, compared to CFS patients and to the controls, but they were not significantly different from the MS group. These findings are in agreement with many studies demonstrating that patients with depression can have substantial cognitive impairments (Byrne, 1977; Channon, Baker, & Robertson, 1993; Cornblatt, Lenzenweger, & Erlennmeyer-Kimmling, 1989; Elliot et al., 1996; Goodwin, 1997; Hertel & Rude, 1991; Lemelin & Baruch, 1998; Mialet, Pope, & Yurgelun-Todd, 1996; Paradiso, Lamberty, Garvey, & Robinson, 1997). In addition, many reports indicate that cognitive impairment persists in participants with depression even when their depression has remitted or levels of depression have been covaried (Abas, Sahakian, & Levy, 1990; Ferrier et al., 1991; Paradiso et al., 1997; Trichard et al., 1995). Our findings are, however, at variance with several previous reports in which patients with DEP were compared to CFS patients (DeLuca et al., 1995; Marshall et al., 1997; Schmaling et al., 1994; Vollmer-Conna et al., 1997). In these latter studies, the CFS patients were reported to be impaired to approximately the same degree as the patients with depression. One possible reason for the discrepancy between these previous studies and our study is that the patient groups examined may have differed in terms of severity of illness. In particular, the depression patients in this study were more depressed in comparison to those used in several previous reports. All of the participants in 19

DALY ET AL.

this study had either a diagnosis of major depressive disorder or bipolar disorder (depressive type), and the majority (19 of 23) were on antidepressant medication. In contrast, in previous studies comparing CFS and depression patients, the patients with depression were reported to have had either a diagnosis of dysthmia or depression, and only a minority were on antidepressant medication (DeLuca et al., 1995; Marshall et al., 1997; Schmaling et al., 1994). Likewise, in the one previous study comparing the three patient groups examined here, patients with CFS had symptoms of “moderate” severity and presented with cognitive complaints (DeLuca et al., 1995). The MS group in that study was specifically chosen to contrast patients with “mild” physical symptoms with patients with CFS, based on a specific cutoff on the Expanded Disability Status Scale (Kurtzke, 1983). In contrast, whereas we used similar research criteria to define the CFS and MS groups in our study, we did not select participants on the basis of the severity of physical disability or the presence of cognitive complaints. Moreover, numerous studies have demonstrated that the presence of cognitive impairments in MS can be unrelated to the physical disability measured by the Expanded Disability Status Scale (e.g., Rao, Leo, Bernardin, & Unverzagt, 1991). It therefore seems likely that our study included a more clinically heterogeneous group of participants with CFS and MS. There has been much discussion about the role that psychiatric symptomatology plays in the cognitive deficits observed in the patient groups. We assessed a broad range of psychiatric symptomatology in this study but found that the most consistent difference between the patient groups and the controls was the presence of depressive symptomatology. We therefore adjusted neuropsychological test scores for levels of depression. Our results support the view that the presence of depression cannot solely account for the cognitive differences among the patient groups or between the patient groups and the controls. In summary, our findings support the view that the cognitive deficits found in CFS cannot be attributed solely to the presence of depressive symptomatology in the patients. They are, for example, consistent with reports of brain alterations in CFS patients (e.g., Lange et al., 1999). Although the cognitive deficits of CFS patients appear somewhat similar to those of patients with MS, there was a trend in this study for the MS patients to be slightly more impaired. In addition, patients with depression were clearly more impaired than either of the other patient groups. These findings suggest that the de20

gree of cognitive impairment observed in CFS, MS, and depression is highly dependent on the criteria used to select the patients. Among a heterogeneous sample of CFS and MS patients, cognitive impairments will be present, but relatively mild in nature. The cognitive impairments seen among patients with depression appear, however, to vary greatly, depending on the severity of illness in the patients. Moreover, even after adjusting for level of depression, differences in degree of cognitive impairment among the groups are relatively unchanged. This suggests that the underlying causes of cognitive deficits in CFS, MS and depression vary.

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Original submission November 29, 1999 Accepted July 5, 2000

Applied Neuropsychology 2001, Vol. 8, No. 1, 23–30

Copyright 2001 by Lawrence Erlbaum Associates, Inc.

Quantitative Assessment of Cerebral Ventricular Volumes in Chronic Fatigue Syndrome

VOLUMETRIC ANALYSIS IN CHRONIC FATIGUE LANGE SYNDROME ET AL.

Gudrun Lange Departments of Psychiatry and Radiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA

Andrei I. Holodny Department of Radiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA

John DeLuca Departments of Neuroscience and Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA, and Kessler Medical Rehabilitation Research and Education Corporation, West Orange, New Jersey, USA

Huey-Jen Lee Department of Radiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA

Xiao-Hong Michelle Yan Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Jason Steffener Department of Psychiatry, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA

Benjamin H. Natelson Department of Neuroscience, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA Previous qualitative volumetric assessment of lateral ventricular enlargement in chronic fatigue syndrome (CFS) has provided evidence for subtle structural changes in the brains of some individuals with CFS. The aim of this pilot study was to determine whether a more sensitive quantitative assessment of the lateral ventricular system would support the previous qualitative findings. In this study, we compared the total lateral ventricular volume, as well as the right and left hemisphere subcomponents in 28 participants with CFS and 15 controls. Ventricular volumes in the CFS group were larger than in control groups, a difference that approached statistical significance. Group differences in ventricular asymmetry were not observed. The results of this study provide further evidence of subtle pathophysiological changes in the brains of participants with CFS. Key words: chronic fatigue syndrome, lateral ventricle, volumetric assessment, morphometry, brain pathology This study was supported in part by Grant U01–AI–32247 establishing a Chronic Fatigue Syndrome Cooperative Research Center at the New Jersey Medical School. Requests for reprints should be sent to Gudrun Lange, UMDNJ-New Jersey Medical School, Department of Psychiatry, ADMC 1410, 30 Bergen Street, Newark, NJ 07107, USA. E-mail: [email protected]

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LANGE ET AL.

Chronic fatigue syndrome (CFS) is a medically unexplained illness diagnosed by clinical case definition (Fukuda et al., 1994). Its characteristic features include severe fatigue, infectious and rheumatological symptoms, affective disturbances, and cognitive dysfunction. There is now converging evidence suggesting structural cerebral changes exist in persons with CFS. Specifically, small nonspecific MRI white matter lesions, primarily in the frontal lobes, have been reported in several studies. These white matter findings appear to occur most frequently in CFS patients without frank psychopathology (for a review, see Lange, Wang, DeLuca, & Natelson, 1998). In addition, a qualitative study reported ventricular enlargement in 36% of CFS participants with abnormal MRI scans (Natelson, Cohen, Brassloff, & Lee, 1993). The aim of this pilot study was to more rigorously examine whether lateral ventricular volume is increased in CFS patients compared to normal controls, utilizing a sensitive quantitative morphometric measurement technique. Lateral ventricular volume is one of the most common measurements in volumetric assessment of the brain. Enlargement of the ventricular system is nonspecific and generally regarded as an indirect measure of white matter loss, because much of the ventricular system is surrounded by white matter structures (i.e., Blatter et al., 1995; Coffey et al., 1993). As established in a variety of patient populations, quantitative volumetric analysis has been proven to be an excellent tool to measure even subtle volumetric changes (i.e., Gur et al., 1994; Holodny et al., 1998). Therefore, based on the initial qualitative findings by Natelson et al. (1993), it is hypothesized that participants with CFS will show quantitative evidence of volumetric enlargement of the lateral ventricle compared to healthy controls. Method For this pilot study, MRI data were obtained from 78 participants. The data of 25 participants had to be elimiTable 1.

nated from the subsequent volumetric analysis due to technically flawed MRI acquisitions. Successful quantitative volumetric analysis was conducted on the remaining 43 participants. Participants Participants were 28 CFS patients and 15 healthy controls who did not exercise regularly. CFS patients and controls were similar in age, years of formal education, gender distribution, and handedness (see Table 1). Participants with CFS were recruited either via self-referral based on media reports about the existence of the CFS Cooperative Research Center or by physician referral. All participants with CFS had a careful medical evaluation and were found to fulfill the most recent National Institute for Health and Centers for Disease Control case definition for CFS (Fukuda et al., 1994) with the following modifications: illness duration did not exceed 10 years at time of intake (M = 3 years, SD = 2.5 years, range = 1–8.5 years), there was no history of loss of consciousness for greater than 5 min, no history of psychiatric disorder in the 5 years prior to the onset of CFS, and no presence of current mania, schizophrenia, or eating disorders. Severity of CFS symptomatology was assessed by participants rating their level of discomfort on a Likert scale ranging from 0 (no discomfort at all) to 5 (extreme discomfort). Symptom ratings for 16 individual symptoms were then summed to express the overall degree of perceived severity of CFS symptomatology (M = 27, SD = 8.5, range = 14–46). Premorbid and current presence of Axis I psychiatric disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; American Psychiatric Association, 1987) was established by administering the computerized version of the structured Diagnostic Interview Schedule (Markus, Robins, & Bucholz, 1990). Based on this structured interview, the presence of an Axis I disorder (other than

Demographic Characteristics of Participants With CFS and Healthy, Sedentary Controls Participants With CFSa

Age Years of Formal Education Gender (% Female) Handedness (% Right) Note: CFS = chronic fatigue syndrome. a n = 28. bn = 15. cStudent’s t test. dFisher’s Exact Test.

24

Controlsb

M

SD

M

SD

p

39.1 15.7 79% 88%

9.3 2.8

37.7 14.4 87% 93%

6.6 1.8

nsc nsc nsd nsd

VOLUMETRIC ANALYSIS IN CHRONIC FATIGUE SYNDROME

the ones listed as exclusions) at any time since the onset of CFS was observed in 11 of the 28 participants with CFS. Of these, 8 participants suffered from major depressive disorder only; 1 individual had major depressive disorder plus generalized anxiety disorder; 1 had major depressive disorder plus multiple anxiety disorders (generalized anxiety disorder, panic disorder, agoraphobia, social phobia); and 1 was diagnosed with multiple anxiety disorders (generalized anxiety disorder, panic disorder). Controls were recruited by advertising in the local community and were paid for their participation. All healthy participants also underwent medical, cognitive, and psychiatric assessments, including the Diagnostic Interview Schedule, and were excluded if any of the following were present: medical problems, premorbid or current psychiatric history, and medication use other than birth control pills. All participants gave informed consent prior to participating in the study.

Imaging Procedure and Quantitative Volumetric Data Analysis All MRI data analyzed in this study were acquired on a 1.0 Tesla magnet (Picker HPG, Highland Heights, OH). Three-dimensional gradient-echo sequences were used to generate axial T1 weighted images with a 25-cm field of view, a 256 × 256 matrix, TR of 36 msec, TE of 15 msec, and a flip angle of 30 degrees. Fifty serial slices were obtained at a thickness of 3 mm without interslice gap. The scanner was calibrated before each MRI acquisition. All identifying patient information was removed from scans prior to the volumetric analysis. Volumes of different tissue types were measured using an algorithm for segmenting 3-D MRI brain images requiring minimal user involvement (Yan & Karp, 1995). Brain volume was extracted by a presegmentation algorithm with optimal thresholding, morphological operations, and the Chamfer distance. An adaptive Bayesian algorithm was then applied for segmenting 3-D MRI images into brain and cerebral spinal fluid (CSF). The algorithm models MRI images as collections of regions with slowly varying intensity plus a white Gaussian noise. Compartments are modeled by a Markov random field with the 3-D second-order neighborhood system, where different potentials are used for in-plane and axial directions to account for anisotropical images. This incorporates spatial interactions among adjacent label voxels, which reduce degradation due to poor signal-to-noise ratio and feature contrast. A cubic B-spline function models slowly varying mean intensity

of each compartment through least squares fitting. The spline helps overcome “shading” effects and reduces bias against small isolated regions (sulcal CSF). The algorithm is implemented iteratively and adaptively. Each iteration consists of (a) estimating mean intensities of each compartment through least squares fitting of a spline expression to the entire image and (b) estimation of compartment by maximizing the a posteriori probability density using the iterative conditional mode algorithm. Adaptation is achieved by gradually increasing the number of control points of the spline function. This optimizes estimates for both compartments and mean intensity for fixed number of control points. Combining spline representation and adaptation makes the segmentation more accurate and robust.

Morphometric Measurements of Regional Cerebral Volumes All measurements of regional cerebral volumes were made on axial T1-weighted MRI images. Brain structures were identified and manually outlined with the use of a trackball. The areas corresponding to pixel values reflecting white matter, gray matter, and CSF within the outline were calculated automatically. Total brain, consisting of the sum of the pixel values of gray matter, white matter, and CSF, was measured automatically in every slice from the foramen magnum to the vertex. The right and left lateral ventricles, consisting of the body, the anterior horns, the occipital horns, and the temporal horns, were outlined and measured in each slice in which they were present. Pixel values for parts of the right and left lateral ventricles were summed separately for each slice and then over all slices in which they were present to determine the pixel value for the complete right and left lateral ventricles. Complete right and left lateral ventricles were then summed to represent the pixel value for the lateral ventricular system. Volume (mm3) was determined by the following formula: (field of view/number of matrix pixels) × slice thickness, where field of view = 250 × 250 mm2, number of matrix pixels = 256 × 256, and slice thickness = 3 mm, summed over all slices in which the brain structure under examination appeared.

Reliability of Ventricular Volumetric Measurements Two raters were trained to perform quantitative volumetric measurements under the direction of a 25

LANGE ET AL.

neuroradiologist. Both raters were blind to group membership and other participant characteristics. To establish interrater reliability, a sample of 10 consecutive scans was analyzed by both raters. The intraclass correlation coefficient was computed for the right as well as left hemisphere lateral ventricular volume and was .99 for each subcomponent. Remaining scans were then analyzed by a single rater.

tal brain size by calculating the ventricle-to-brain ratio ([log ventricular volume/log total brain volume] × 100) separately for the lateral ventricular system, as well as the right and left ventricles for each participant, and then compared groups with a unidirectional Student’s t test.

Results Statistical Analysis In this pilot study, the main hypothesis was unidirectional and predicted increased lateral ventricular CSF in the CFS group based on previously published data. Because the distribution of the raw volume data of the CFS group was significantly skewed in the positive direction (ratio of skewness to its standard error > 2.0 for each dependent variable), assumptions of normality were violated and, specifically by using a directional test, could increase the possibility of Type II error. Instead of using a less powerful nonparametric test statistic for this type of data, we chose to normalize the distribution by log transforming the data set to be able to conduct a more powerful parametric test. Thus, by using logn transformed data, the distribution was normalized (ratio of skewness to its standard error < 2.0 for each dependent variable) by rescaling the unit of measurement (mm3) without compromising power. Between-group differences in total lateral ventricular volume, as well as the volumes of the left and right lateral ventricles, were then analyzed using a one-tailed Student’s t test. The frequency of occurrence of ventricular asymmetry in CFS and control groups was assessed using a two-tailed Fisher’s Exact Test. In addition, we examined within-group differences in volume of the right versus left ventricles with a two-tailed Student’s paired t test. We chose bidirectional statistical analyses for these two asymmetry measures because, based on the literature, it could not be predicted that participants with CFS have either a greater likelihood of ventricular asymmetry or unequal ventricular size than controls. Using Pearson bivariate correlation with a significant level set at .05, log ventricular volumes were then correlated with presence of concurrent Axis I disorder, duration of illness, and overall severity of CFS symptoms. Because participant characteristics, such as age, handedness, and sex, did not differ statistically across the CFS and control groups, we did not control for these variables in the volumetric analysis of this pilot study. However, in a secondary analysis we did control for to26

Group differences in total ventricular volume are illustrated in Figure 1. Figure 2 provides an illustration of ventricular differences between participants with CFS and controls. Compared to control groups, the CFS group showed a larger mean volume of the lateral ventricular system (p < .057; see Table 2). The same trend was observed for the analysis of the right and left lateral ventricles with the CFS group showing ventricular enlargement relative to controls (see Table 2). Effect sizes were calculated for all three variables (Cohen, 1988) (a) to obtain another estimate of the degree of departure of lateral ventricular volume of participants with CFS from the null hypothesis and (b) to ascertain the degree of power to avoid Type II error. Effects for all three dependent measures were of medium size (d =. 50, r = .231); that is, expressed in terms of correlation, 54% of the variance for each variable was accounted

Figure 1. In the equivalent quantile–quantile plot shown, logn of total ventricular volume of CFS versus controls are ranked from smallest to largest and then plotted. If the two groups were drawn from the same population pool, data should lie along the line of identity (x = y). Note that the data lie to the right of the line of identity, corroborating the statistic that participants with CFS have greater total ventricular volume than controls.

VOLUMETRIC ANALYSIS IN CHRONIC FATIGUE SYNDROME

Figure 2. Examples of ventricular size in two contiguous slices in a participant with CFS (left) and a control participant (right) shown according to radiologic convention.

Table 2.

Logn Transformed Volumes of the Entire Lateral Ventricular System as Well as the Left and Right Lateral Ventricles Separately Participants With CFSa

Entire Lateral Ventricular System Left Lateral Ventricle Right Lateral Ventricle

Controlsb

M

SD

M

SD

t (df = 41)

p (One-Tailed)

10.45 9.77 9.71

.52 .49 .60

10.19 9.54 9.43

.46 .43 .53

–1.61 –1.51 –1.53

.057 .069 .066

Note: CFS = chronic fatigue syndrome. a n = 28. bn = 15.

for by group membership. The power to detect unidirectional group differences in this effect size range with unequal sample sizes was only 46%. The near statistically significant relation between CFS and control groups was maintained even after controlling for total brain volume by calculating ventricle-to-brain ratios (see Table 3).

We also considered whether groups would differ in the frequency of lateral ventricular asymmetry or whether the ventricular subcomponents within each group may have different mean volumes. The frequency of occurrence of ventricular asymmetry was similar between participants with CFS and controls (Fisher’s Exact Test, two-tailed, p = .322). As shown in 27

LANGE ET AL. Table 3. Logn Transformed Volumes of VBRs for the Entire Lateral Ventricular System as Well as the Left and Right Lateral Ventricles Separately Participants With CFSa VBR Entire Lateral Ventricular System Left Lateral Ventricle Right Lateral Ventricle

Controlsb

M

SD

M

SD

t (df = 41)

p (One-Tailed)

68.36 63.92 63.54

3.32 3.12 3.86

66.73 62.48 61.74

3.07 2.90 3.50

–1.57 –1.47 –1.50

.061 .074 .070

Note: VBR = ventricle-to-brain ratio; CFS = chronic fatigue syndrome. a n = 28. bn = 15.

Figure 3, both the CFS and control groups tended to have larger left than right ventricles, which is consistent with previous reports in normal adults (e.g., Zipursky, Lim, & Pfefferbaum, 1990). In addition, no significant mean differences were found between the size of right and left lateral ventricles within groups.

Discussion The results of this quantitative volumetric study support earlier qualitative findings of ventricular enlargement in individuals with CFS (Natelson et al., 1993). On average, there was a marginally significant trend toward enlargement of the lateral ventricles in the CFS group relative to age, gender, handedness, and education-matched controls. In addition, the statistical significance of the finding was not diminished by controlling for individual differences in total brain volume (ventricle-to-brain ratio). It has been argued that by removing this additional source of variance, the precision of the volumetric measurement is increased and the correlation with validity criteria, such as diagnostic status, is improved (Mathalon, Sullivan, Rawler, & Pfefferbaum, 1993). This is the first study to quantitatively document ventricular enlargement in CFS patients. Ventricular enlargement is a nonspecific finding. Its pathophysiological significance is unclear and has been linked to a variety of causes, including white matter loss in patients with vascular problems (Gorelick et al., 1992), Alzheimer’s disease (Murphy et al., 1993), and traumatic brain injury (e.g., Gale, Sterling, Bigler, & Blatter, 1995); gray matter loss in schizophrenics (e.g., Pfefferbaum & Marsh, 1995); and reversible metabolic abnormalities in participants suffering from anorexia nervosa and Cushing’s disease (Heinz, Martinez, & Haenggeli, 1977). Given the preliminary nature of this study, future volumetric studies in patients with CFS need to replicate and extend the scope of this initial 28

Figure 3. Frequency of ventricular asymmetry in controls and participants with CFS. The correlation between the mean volume of the lateral ventricular system, as well as left and right ventricles separately, with current Axis I disorder, duration of illness, and degree of severity of CFS symptoms was analyzed in participants with CFS only. None of the relations examined was significant.

work. Given the increasing number of studies showing cerebral pathology in CFS using structural (Buchwald et al., 1992; Lange et al., 1999; Natelson et al., 1993) and functional (SPECT [Costa, Tannock, & Brostoff, 1995; Schwartz et al., 1994] and PET [Tirelli et al., 1998]) neuroimaging tools, volumetric studies provide an additional technique for quantifying changes in the brain. Future volumetric studies should focus on understanding the possibly subtle involvement of specific gray and white matter structures in CFS. This preliminary investigation utilized a quantitative method for volumetric analysis (Yan & Karp, 1995). This type of probe is very sensitive in detecting even subtle changes in ventricular volume, and we were thus able to find the modest ventricular enlargement in participants with CFS versus controls. However, due to

VOLUMETRIC ANALYSIS IN CHRONIC FATIGUE SYNDROME

limitations in sample size, we only had 46% power to detect a true difference at the .05 level (one-tailed). Thus, this study was underpowered, failing to appropriately guard against false negative claims. To ensure appropriate power to detect a medium effect size at the .05 level of significance (one-tailed), roughly double the current sample size would be necessary (Cohen, 1988). Therefore, a follow-up study with a larger sample of participants with CFS and controls is necessary to confirm the important findings of this quantitative volumetric study. Because we were also interested in the functional significance of these findings, we examined the relation between increased ventricular volume in participants with CFS and factors such as presence of coexisting psychiatric diagnoses, duration of illness, and overall degree of perceived severity of CFS symptoms. None of these factors explained a significant portion of the variance in the volumetric measurements. It is possible, however, that an increase in ventricular CSF may be related to specific CFS symptoms or to objective cognitive function, which were not evaluated in this work. Again, these possibilities should be examined in a larger follow-up study. In conclusion, although the reasons for changes in ventricular size in CFS are unclear, findings of this carefully conducted study may have marked significance in the understanding of the pathophysiology of CFS. If these findings are replicated, this would suggest that at least a subset of CFS patients may have underlying brain pathology producing subtle cerebral loss. Significantly increased lateral ventricular volume in the group of participants with CFS would further add to the growing body of evidence suggesting the existence of an underlying neurological disease process (e.g., DeLuca, Johnson, Beldowicz, & Natelson, 1995; DeLuca, Johnson, Ellis, & Natelson, 1997; Natelson et al., 1993).

References American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders (3rd ed., rev.). Washington, DC: Author. Blatter, D. D., Bigler, E. D., Gale, S. D., Johnson, S. C., Anderson, C. V., Burnett, B. M., Parker, N., Kurth, S., & Horn, S. D. (1995). Quantitative volumetric analysis of brain MR: Normative database spanning 5 decades of life. American Journal of Neuroradiology, 16, 241–251. Buchwald, D., Cheney, P. R., Peterson, D. L, Henry, B., Wormsley, S. B., Geiger, A., Ablashi, D. V., Salahuddin, S. Z., Saxinger, C., Biddle, R., Kikinis, R., Jolesz, T. A., Folks, T.,

Balachandran, N., Peter, J. B., Gallo, R. C., & Komaroff, A. L. (1992). A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpes virus type 6 infection. Annals of Internal Medicine, 116, 103–113. Coffey, C. E., Wilinson, W. E., Weiner, R. D., Parashos, J. A., Djang, W. T., Webb, M. C., Figiel, G. S., & Spritzer, C. E. (1993). Quantitative cerebral anatomy in depression. A controlled magnetic resonance imaging study. Archives of General Psychiatry, 50, 7–16. Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Lawrence Erlbaum Associates, Inc. Costa, D. C., Tannock, C., & Brostoff, J. (1995). Brainstem perfusion is impaired in chronic fatigue syndrome. Quarterly Journal of Medicine, 88, 767–773. DeLuca J., Johnson, S., Beldowicz, D., & Natelson, B. H. (1995). Neuropsychological impairments in chronic fatigue syndrome, multiple sclerosis, and depression. Journal of Neurology, Neurosurgery, and Psychiatry, 58, 38–43. DeLuca, J., Johnson, S. K., Ellis, S. P., & Natelson, B. H. (1997). Cognitive functioning is impaired in patients with chronic fatigue syndrome devoid of psychiatric disease. Journal of Neurology, Neurosurgery, and Psychiatry, 62, 151–155. Fukuda, K., Straus, S. T., Hickie, I., Sharpe, M. C., Dobbins, J. G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121, 953–959. Gale, S. D., Sterling, C. J., Bigler, E. D., & Blatter, D. D. (1995). Trauma-induced degenerative changes in brain injury: A morphometric analysis of three patients with preinjury and postinjury MR scans. Journal of Neurotrauma, 12, 151–158. Gorelick, P. B., Chatterjee, A., Patel, D., Flowerdew, G., Dollear, W., Taber, J., & Harris, Y. (1992). Cranial computed tomographic observations in multi-infarct dementia: A controlled study. Stroke, 23, 804–811. Gur, R. E., Mozley, P. D., Shtasel, D. L., Cannon, T. D., Gallacher, F., Turesky, B., Grossman, R., & Gur, R. C. (1994). Clinical subtypes of schizophrenia: Differences in brain and CSF volume. American Journal of Psychiatry, 151, 343–350. Heinz, E. R., Martinez, J., & Haenggeli, A. (1977). Reversibility of cerebral atrophy in anorexia nervosa and Cushing’s syndrome. Journal of Computer Assisted Tomography, 1, 415–418. Holodny, A. I., Waxman, R., George, A. E., Rusinek, H., Kalnin, A. J., & de Leon, M. (1998). MR differential diagnosis of normal-pressure hydrocephalus and Alzheimer disease: Significance of perihippocampal fissures. American Journal of Neuroradiology, 19, 813–819. Lange, G., DeLuca, J., Maldjian, J. A., Lee, H., Tiersky, L. A., & Natelson, B. H. (1999). Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. Journal of Neurological Sciences, 171, 3–7. Lange, G., Wang, S., DeLuca, J., & Natelson, B. H. (1998). Neuroimaging in chronic fatigue syndrome. American Journal of Medicine, 105, 50S–53S. Markus, S., Robins, L. N., & Bucholz, K. (1990). Quick diagnostic interview schedule 3R version 1. St. Louis, MO: Washington University School of Medicine. Mathalon, D. H., Sullivan, E. V., Rawles, J. M., & Pfefferbaum, A. (1993). Correction for head size in brain-imaging measurements. Psychiatry Research: Neuroimaging, 50, 121–139.

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LANGE ET AL. Murphy, D. G., DeCarli, C. D., Daly, E., Gillette, J. A., McIntosh, A. R., Haxby, J. V., Teichberg, D., Schapiro, M. B., Rapoport, S. I., & Horwitz, B. (1993). Volumetric magnetic resonance imaging in men with dementia of the Alzheimer type: Correlations with disease severity. Biological Psychiatry, 34, 612–621. Natelson, B. H., Cohen, J. M., Brassloff, I., & Lee, H.-J. (1993). A controlled study of brain magnetic resonance imaging in patients with the chronic fatigue syndrome. Journal of Neurological Sciences, 120, 213–217. Pfefferbaum, A., & Marsh, L. (1995). Structural brain imaging in schizophrenia. Clinical Neuroscience, 3, 105–111. Schwartz, R. B., Garada, B. M., Komaroff, A. L., Tice, H. M., Gleit, M., Jolesz, F. A., & Holman, B. L. (1994). Detection of intracranial abnormalities in patients with chronic fatigue syndrome: Comparison of MR imaging and SPECT. American Journal of Radiology, 162, 935–941.

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Tirelli, U., Chierichetti, F., Tavio, M., Simonelli, C., Bianchin, G., Zanco, P., & Ferlin, G. (1998). Brain positron emission tomography (PET) in chronic fatigue syndrome: Preliminary data. American Journal of Medicine, 105, 54S–58S. Yan, M. X. H., & Karp, J. S. (1995). An adaptive Bayesian approach to three-dimensional MR brain segmentation. In Y. Bizais, C. Barillot, & R. DiPaol (Eds.), Information processing in medical imaging (pp. 201–213). Dordrecht, The Netherlands: Kluwer. Zipursky, R. B., Lim, K. O., & Pfefferbaum, A. (1990). Volumtric assessment of cerebral asymmetry from CT scans. Psychiatry Research, 35, 71–89.

Original submission July 13, 1999 Accepted September 29, 1999

Applied Neuropsychology 2001, Vol. 8, No. 1, 31–40

Copyright 2001 by Lawrence Erlbaum Associates, Inc.

Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?

EXERCISE CLAYPOOLE AND COGNITION ET AL.

Keith Claypoole Departments of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA

Roderick Mahurin Department of Neurology, University of Washington, Seattle, Washington, USA

Mary E. Fischer Department of Epidemiology and Biostatistics, University of Illinois, Chicago, Chicago, Illinois, USA

Jack Goldberg Department of Epidemiology, University of Washington, Seattle, Washington, USA, and the Vietnam Era Twin Registry, Hines, Illinois, USA

Karen B. Schmaling Departments of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA

Robert B. Schoene, Suzanne Ashton, and Dedra Buchwald Department of Medicine, University of Washington, Seattle, Washington, USA This study examined the effects of exhaustive exercise on cognitive functioning among 21 monozygotic twin pairs discordant for chronic fatigue syndrome (CFS). The co-twin control design adjusts for genetic and family environmental factors not generally accounted for in more traditional research designs of neuropsychological function. Participants pedaled a cycle ergometer to exhaustion; maximum oxygen output capacity (VO2 max) as well as perceived exertion were recorded. Neuropsychological tests of brief attention and concentration, speed of visual motor information processing, verbal learning and recognition memory, and word and category fluency were administered with alternate forms to participants pre- and postexercise. The preexercise neuropsychological test performance of CFS twins tended to be slightly below that of the healthy twin controls on all measures. However, twins with CFS did not demonstrate differential decrements in neuropsychological functioning after exercise relative to their healthy co-twins. Because exercise does not appear to diminish cognitive function, rehabilitative treatment approaches incorporating exercise are not contraindicated in CFS. Key words: twins, chronic fatigue syndrome, cognition, neuropsychological function

This work was supported by Grant U19–AI38429 from the National Institute of Allergy and Infectious Diseases to Dedra Buchwald. We would like to thank the participants in the University of Washington Chronic Fatigue Twin Registry for their cooperation, patience, and goodwill, and Dr. Leigh Sawyer, Program Officer, National Institute of Allergy and Infectious Diseases, for her encouragement and support. We also wish to acknowledge our External Advisory Committee, who with sage advice and ongoing encouragement, improved our scientific efforts. Finally, we acknowledge Tom Erickson for his psychometric expertise and Niloofar Afari for support of this investigation. Requests for reprints should be sent to Dedra Buchwald, Chronic Fatigue Center Cooperative Research Center, 325 Ninth Avenue, Seattle, WA 98104, USA. E-mail: [email protected]

31

CLAYPOOLE ET AL.

Impaired cognitive functioning is one of the most common symptoms of chronic fatigue syndrome (CFS) with up to 95% of patients reporting decreased attention, concentration, and memory abilities (Komaroff & Buchwald, 1991). Complaints of postexertional malaise and illness exacerbation also are prominent among patients with CFS. In fact, nearly 70% report worsening of CFS symptoms after physical exertion, including increased difficulties with cognitive processing (Komaroff & Buchwald, 1991). However, little research has been conducted to identify and quantify such subjective exercise-induced neuropsychological impairments. Formal neuropsychological assessments of CFS patients have most consistently demonstrated intact intellectual and executive abilities. However, difficulties in the areas of attention, short-term or working memory, and, most commonly, reduced information-processing speed (Grafman et al., 1993; Joyce, Blumenthal, & Wessely, 1996; Krupp, Sliwinski, Masur, Friedberg, & Coyle, 1994; McDonald, Cope, & David, 1993) have been documented. Furthermore, a reduction in information processing or lack of “spare capacity” has been hypothesized to diminish performance on cognitive tasks requiring processing resources that exceed the available capacity (Wearden & Appleby, 1996). If reduced information-processing resources are characteristic of CFS, then impairments of neuropsychological functioning could become apparent when demands on cognition, such as those imposed by strenuous exertion, exceed the processing capacity of CFS patients. Several recent studies have examined the influence of exercise on cognition in CFS. One small investigation reported that compared to depressed controls, a group of 10 CFS patients experienced a decrease in focused and sustained attention after an exercise treadmill test; a reduction in sustained attention was also observed relative to the healthy group (Blackwood, MacHale, Power, Goodwin, & Lawrie, 1998). Other investigators have administered the Symbol Digit Modalities Test, the Stroop Color and Word Test, the Oral Trail Making Test, and the Serial 13s Test before and after treadmill exercise to exhaustion in 19 participants with CFS and 20 sedentary healthy controls (LaManca et al., 1998). No group differences on preexercise test results were observed, but postexercise the participants with CFS improved at a slower rate on the Stroop Color and Word Test and the Symbol Digits Modality Test. Taken together, such studies suggest that after physically demanding exercise, persons with CFS may experience impaired cognitive processing. These reports of cognitive compromise following exhaustive exercise in CFS prompted our investigation 32

into the relation of exercise and neuropsychological performance. We used a co-twin control study of monozygotic twins discordant for CFS to evaluate brief attention span and concentration or working memory, verbal learning and recognition memory, visual motor information-processing speed, and verbal and category fluency before and after exhaustive exercise in both twins. The use of illness-discordant monozygotic twins adjusts for genetic and family environmental factors not generally accounted for in more traditional research designs of neuropsychological function among CFS patients. Given the excellent control afforded by this methodology, and the genetic influence on exercise capacity (Bouchard, Dionne, Simoneau, & Boulay, 1992) and fatigue (Hickie, Kirk, & Martin, 1999), we examined whether CFS twins would have a different neuropsychological response to exercise than their healthy co-twins.

Method Participant Recruitment A total of 600 twins were mailed an intake questionnaire; 426 (71%) were returned, and complete data were available for both members of 193 twin pairs. Twins were recruited through patient support group newsletters (58%), practitioners and researchers familiar with CFS (11%), electronic bulletin board notices for CFS (15%), twin organizations and researchers (6%), relatives and friends (3%), and other sources (8%). Each twin completed a mailed questionnaire that collected extensive data on demographics; zygosity; lifestyle and habits; psychiatric and physical health conditions; and a section on the nature, extent, and consequences of fatigue along with a checklist of the symptoms of CFS (Fukuda et al., 1994). For the nonfatigued twin, a control version of questions was used that did not reference fatigue. A more comprehensive description of the CFS twin registry can be found elsewhere (Buchwald et al., 1999). Psychiatric Disorders To determine current and lifetime psychiatric diagnoses, the Diagnostic Interview Schedule, Version III-A (Robins & Heltzer, 1985) was administered via telephone interview to registry participants. The Diagnostic Interview Schedule assigns current and lifetime diagnoses by computer algorithm based on the criteria of the Diagnostic and Statistical Manual of Mental Dis-

EXERCISE AND COGNITION

orders (3rd ed., rev.; American Psychiatric Association, 1987). A trained research assistant administered modules on major depression, dysthymia, generalized anxiety, panic, agoraphobia, posttraumatic stress disorder, mania, bipolar affective disorders, schizophrenia, eating disorders, somatization, and substance abuse or dependence. Besides the Centers for Disease Control and Prevention (CDC) defined exclusionary psychiatric disorders, no psychotic symptoms in the schizophrenia section were acceptable. Melancholia was scored without symptoms attributable to CFS.

1979), then confirmed with analysis of restriction fragment length polymorphisms. DNA samples were extracted and digested with the restriction endonuclease HaeIII. The restriction fragments were separated by molecular size in agarose gel, southern blotted onto nylon membrane, and hybridized with a variable number of tandem repeat probes. Following six probes, the probability of monozygosity can be presented with 99.9% certainty.

Participant Selection

After at least a 2-hr fast and explanation of procedures, spirometry was performed on participants with a Medical Graphics Pulmonary Function System. Forced and slow vital capacity breaths were measured until three reproducible values were achieved, as prescribed by the American Thoracic Society (1995) Guidelines. A maximum voluntary ventilation was also performed. Participants were then instrumented with a 12-lead electrocardiogram and a finger-pulse oximeter, placed on a cycle ergometer, and connected to a Medical Graphics Cardio-2 exercise system by a mouthpiece with nose clips in place. The system was calibrated with gases of known concentration and the pneumotachogram with a 3-liter calibration syringe. Measurements of metabolic rate (VO2, VCO2), minute ventilation (VE, BTPS), and heart rate (bpm) were made on a breath-by-breath basis at rest and during the course of exercise. After unloaded pedaling for a total of 4 min, the workload for participants was increased by a computer program at 20 watts/min in a ramp protocol. All participants were encouraged to provide a full effort to exhaustion. Blood pressure and perceived exertion using the 6- to 20-point Borg scale (Borg, 1970) were determined at baseline and approximately four times during exercise. Following exhaustion on the stationary cycle, the participants remained seated for 5 min, during which time recovery data were collected with continuous electrocardiographic monitoring and metabolic measurements. From these measurements, maximum oxygen consumption (VO2 max) and ventilation were determined for all twins.

From the twin registry, 22 sets of monozygotic twins discordant for CFS were chosen for a 7-day in-person evaluation based on registry information and additional telephone screenings. Twins were required to (a) be at least 18 years of age; (b) be reared together; (c) be discordant for CFS (one twin met the CDC CFS criteria at the time of evaluation and the unaffected twin was healthy); (d) discontinue alcohol, caffeine, and all medications known to affect sleep or cognition at least 2 weeks prior to the evaluation; and (e) travel to Seattle together. CFS criteria were determined according to participant responses to the CFS symptom checklist and the diagnoses generated by the Diagnostic Interview Schedule. The same inclusion and exclusion criteria (e.g., body mass index, psychiatric disorder) and review processes were applied to the fatigued and healthy twins. Thus, a healthy twin with a history of melancholic depression would preclude the study of the twin pair, even if the co-twin met other study eligibility criteria. Participants’ medical records for the last 5 years were reviewed by a physician knowledgeable about CFS for potentially exclusionary medical conditions, including head trauma that was recurrent or accompanied by more than 5 min of loss of consciousness. A psychologist and an infectious disease specialist also independently reviewed participants’ medical charts to verify illness and health status and approve twins for participation. Thyroid function tests were obtained for twins on replacement therapy if recent results were not available. Prior to the scheduled visit, we confirmed that the ill twin still met CFS criteria and that the control twin was healthy and not fatigued. Zygosity Monozygosity was initially determined using previously validated self-report methods (Eisen, Neuman, Goldberg, Rice, & True, 1989; Torgersen,

Exercise Challenge and Perceived Exertion

Neuropsychological Measures Neuropsychological tests with alternate or parallel forms (Lezak, 1995) were administered in a standardized manner by a trained examiner at baseline, just prior to exercise, and within 20 min postexercise challenge. Four primary measures (yielding seven test scores) were included in this brief, equivalent test form 33

CLAYPOOLE ET AL.

battery. The Wechsler Adult Intelligence Scale–Revised (WAIS–R; Wechsler, 1981) Digit Span Forward and Backward subtests were administered to examine brief auditory attention span and the more effortful concentration and working memory. The Hopkins Verbal Learning Test consisting of three trials of free recall of a 12-item semantically categorized word list (with a yes–no recognition format) evaluated verbal learning and memory. The Digit Vigilance Test evaluated visual motor speed of information processing. This number cancellation task, originally included in the Lafayette Clinic Repeatable Neuropsychological Test Battery, consists of two pages with a total of 59 rows of 35 digits. On the alternate forms, the target number is either 6 or 9, yielding equal time scores. Finally, word fluency was assessed with the Controlled Oral Word Association Test (COWAT) and category fluency with animal naming. We administered the standard COWAT three 60-sec trials of verbal fluency for equivalent three-letter versions of CFL and PRW. The animal naming task involved a single 60-sec trial.

Statistical Analysis Initial analyses compared demographic and exercise measures between CFS and healthy twins. The mean level for each cognitive test in CFS and healthy twins was graphed both before and after exercise testing. The analysis was primarily directed at detecting whether exercise alters the pattern of the relation between CFS status and neuropsychological functioning over time. A random effects regression model (Hedecker & Gibbons, 1996) was used to explicitly test for the interaction between CFS status and time (pre- vs. postexercise) for each test. This model is especially suited for the analysis of twin data because it accounts for both the paired and repeated measurement structure of the data and avoids the problems inherent in piecemeal hypothesis testing for the effects of group and time. The specific model we used included random effects for the pair and the pre- and postexercise measurements within an individual. The analysis was conducted in a hierarchical fashion. First, we fit a “full” model that contained the effects of group, time, and the Group × Time interaction. If the estimated Group × Time interaction parameter was statistically significant, no further modeling was performed. However, if the interaction term was not significant (p ≥ .05) we fit a “reduced” model that included only the main effects of group and time. Formal statistical testing was based on separate F tests for the Group × Time interaction effect as well as the main ef34

fects of group and time. Finally, we expanded the regression model to include the effects of the difference between the initial and final Borg scores (as a measure of changes in perceived fatigue) and our measure of exercise capacity (VO2 max). Analyses were conducted using SPSS for Windows version 6.1.4 and SAS for Windows version 6.2.

Results Of 193 twin pairs, 119 (62%) were discordant for at least 6 months of fatigue; 67 (56%) of these were monozygotic and had complete data available. Among these 67 monozygotic, chronic fatigue discordant pairs, 14 were excluded for psychiatric illness, 4 for medical disorders, and 1 for a body mass index > 45. In an additional 9 pairs, the fatigued twin did not meet CFS symptom criteria, 4 pairs were excluded because the nonfatigued twin had an exclusionary condition, and 9 pairs were excluded for a variety of other reasons (e.g., recent death of the co-twin, inadequate English, pregnancy). This process left 29 eligible twin pairs in which the ill twin met strict criteria for CFS and his or her co-twin was healthy and denied fatigue. Of these, 22 (76%) completed the study, 1 (3%) refused, 2 (7%) could not be scheduled, and 4 (14%) were unable to discontinue potentially interfering medications. One set that participated in the study did not complete the test procedure according to the protocol and was excluded from the analysis. Table 1 provides basic demographic information on our CFS and healthy control twins. The mean age at the time of examination for the 21 twin pairs was 41; 19 pairs were female and 2 pairs were male, and all were White. There were no significant differences among the CFS and healthy twins with respect to marital status or years of education, although the healthy twins were more likely to be employed (p = .006). The CFS twins had an average duration of illness of 7.2 years. Mean VO2 max was slightly lower in the CFS twins (18.9) compared with their healthy co-twins (20.5), although this difference is not nominally significant (p = .056). Our measure of exercise fatigue perception, the Borg scale, was very similar pre- and postexercise for the CFS and healthy twins. The mean WAIS–R Digit Forward raw score prior to exercise was 8.33 in the CFS twins and 8.62 in the healthy twins; following exercise these mean values were 8.24 and 8.52, respectively. There was no evidence of a Group × Time interaction effect, F(1, 40) = 0.00, p = 1.00, suggesting that exercise did not alter the

EXERCISE AND COGNITION

effects analysis, the healthy twins had a higher mean raw score on the Digit Span Backwards subtest, F(1, 41) = 12.19, p = .001, with consistently higher scores both before and after exercise. There was no evidence of a time effect on these test scores, F(1, 41) = 0.69, p = .41. The mean total words learned on the Hopkins Verbal Learning Test prior to exercise in the CFS twins was 26.1 and 27.4 in the healthy twins; postexercise these values were 24.6 and 26.8, respectively. For this verbal learning measure, there was no differential effect of ex-

association between CFS status and performance on this subtest. In the reduced model, which contained only the main effects of group and time, there were no significant mean differences between the CFS twins and healthy controls, F(1, 41) = 0.34, p = .56, and there were no pre- versus postexercise differences over time, F(1, 41) = 0.09, p = .76. Figure 1 presents the baseline and postexercise WAIS–R Digit Span Backwards performance in CFS and healthy twins. For the Digit Span Backwards raw score, the Group × Time interaction was not significant, F(1, 40) = 0.39, p = .53. In the main Table 1.

Demographic and Clinical Characteristics of Monozygotic Twins Discordant for CFS CFS Twinsa

Characteristic Demographic Age (Years) Female Education (Years) White Married Employed Clinical Fatigue Duration (Years) Peak Oxygen Capacity (VO2 max, cc/kg/min) Borgb Preexercise Postexercise Current Major Depression Acute Onset With Flu

Healthy Twinsa

M

SD

n

%

M

SD

n

%

41.2 — 14.1 — — —

10.0 — 2.2 — — —

— 19 — 21 12 9

— 90 — 100 57 43

41.2 — 14.6 — — —

10.0 — 2.2 — — —

— 19 — 21 12 19

— 90 — 100 57 90

7.2 18.9

4.2 4.8

— —

— —

— 20.5

— 4.4

— —

— —

6.2 18.5 — —

0.4 1.2 — —

— — 4 10

— — 19 48

6.2 17.4 — —

0.5 2.7 — —

— — 0 —

— — 0 —

Note: CFS = chronic fatigue syndrome. a n = 21. bn = 18 twin pairs in Borg analysis.

Figure 1.

Wechsler Adult Intelligence Scale–Revised Digit Span subtest: Digits Backwards.

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CLAYPOOLE ET AL.

ercise and the Group × Time interaction test was not significant, F(1, 40) = 0.50, p = .48. When the main effects model was fit to these data, there was no difference between CFS and healthy twins, F(1, 41) = 2.71, p = .11, and there was no difference between the mean pre- to posttest scores, F(1, 41) = 2.78, p = .10. Figure 2 presents the results for the Hopkins recognition memory score or Discrimination Index, calculated by subtracting the number of false positives from the true positives. This measure demonstrated a nonsignificant interaction effect between group and time, F(1, 40) = 3.34, p = .08. A main effects model indicated a significant downward trend in the Discrimination Index with time, F(1, 41) = 4.95, p = .03, and a nonsignificant group effect, F(1, 41) = 1.24, p = .27.

Figure 2.

Hopkins Verbal Learning Test Discrimination Index.

Figure 3.

36

The results from the Digit Vigilance Test, calculated as the total time for pages 1 and 2 in seconds, are presented in Figure 3. There was no evidence of a Group × Time interaction effect, F(1, 40) = 0.03, p = .87; the main effects model showed no significant differences in scores between CFS and healthy twins, F(1, 41) = 0.03, p = .86, or between the pre- and posttest scores, F(1, 41) = 2.86, p = .10. Analysis of word fluency, as evaluated by the COWAT and shown in Figure 4, failed to demonstrate a differential or interaction effect between CFS and healthy twins produced by exhaustive exercise, F(1, 40) = 0.12, p = .73. In the main effects model, there was a significant group effect with CFS twins demonstrating consistently lower performance than their healthy co-twins, F(1, 41) = 6.15, p = .02.

Digit Vigilance Test total time.

EXERCISE AND COGNITION

Figure 4.

Verbal fluency: Controlled Oral Word Association Test.

Figure 5.

Category fluency: Animal Naming.

The effects of time demonstrated a significant improvement in scores for both CFS and healthy twins, F(1, 41) = 12.66, p = .001. Figure 5 illustrates the significant Group × Time interaction effect observed for category fluency, F(1, 40) = 6.48, p = .01, indicating that the postexercise performance of healthy twins improved more than that of CFS twins by generating ~2.5 more animal names in 1 min. The main effects for group and time are derived from the full model that includes the significant Group × Time interaction term; in this context the significance of group, F(1, 40) = 5.37, p = .03,

and time, F(1, 40) = 12.48, p = .001, is of minor importance. Finally, we fit a series of random effects regression models that accounted for the effects of each participant’s perceived degree of increased fatigue after exercise (Borg change score from pre- to postexercise) and their peak oxygen consumption (VO2 max) on the association between CFS status and cognitive function before and after exhaustive exertion. The results of these regression models are not presented because in no case did we observe any confounding influence of Borg

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scores or VO2 max on the relation between CFS and neuropsychological functioning.

Discussion This study found no evidence of a consistent pattern of impaired cognitive functioning following exhaustive exertion in twins with CFS compared to their healthy twin siblings. Tests of brief attention span and concentration and working memory, speed of visual motor information processing, verbal learning capacity, and verbal fluency were similar both before and after exhaustive exercise. In general, the preexercise neuropsychological test performance of CFS twins tended to be slightly below that of the healthy twin controls on all of the measures examined. Only category fluency showed a significant effect of exercise attributable to CFS with a trend (p < .10) toward a significant Group × Time effect for the Hopkins Discrimination Index. However, in the case of category fluency, the effect was observed because the healthy twins showed a modest improvement after exertion whereas the CFS twins’ performance remained fairly stable. For the Discrimination Index, the healthy twins declined postexercise and the CFS twins were unchanged. In other words, the interactions were a consequence of exercise effects in the healthy twins with virtually undetectable exercise effects in the CFS twins. Moreover, the observed effects in the healthy twins were in different directions for the two tests. Although other investigators have demonstrated significant group differences between healthy and ill participants (DeLuca, Johnson, Ellis, & Natelson, 1997a, 1997b; Riccio, Thompson, Wilson, Morgan, & Lant, 1992; Tiersky, Johnson, Lange, Natelson, & DeLuca, 1997), we found that the preexercise neuropsychological test performance of CFS twins tended to be only slightly below that of the healthy twin controls. It may be that our rigorous screening process resulted in a sample of both healthy and CFS twins that was, relative to other studies, more free of nonexclusionary psychiatric and medical conditions that could confound the interpretation of neuropsychological performance. Taken together, our findings suggest that comparing neuropsychological test performance pre- and postexercise challenge is unlikely to reveal meaningful pathophysiological correlates of CFS. Although initially promising, the minimal quantitative alteration in cognitive functioning before and after exercise among the CFS twins argues against the potential for identifying patients on the basis of a brief, 38

noninvasive measure of cognitive functioning. Furthermore, CFS patients seen in a typical referral setting would probably have greater psychiatric or medical comorbidity that would further minimize the utility of exercise challenge testing as a clinical discriminator. There may be several explanations for the lack of a differential effect of exercise challenge on cognitive functioning in this sample of twins. One possibility is that the healthy twins have a susceptibility to CFS and their cognitive functioning was therefore already altered, even in the absence of fatigue. Although we cannot address this question directly, this did not seem to be the case, because the average test performance of the healthy twins was well within or above the normal range (Brandt, 1991; Lezak, 1995; Mitrushina, Boone, & D’Elia, 1999). Another plausible explanation is that our participants did not exercise strenuously enough to exceed the theoretical threshold for cognitive processing capacity at which a compromise could be demonstrated. However, all twins exercised to exhaustion using a standard protocol; moreover adjusting for VO2 max or Borg scores had no impact on the findings. A third alternative is that our neuropsychological test measures may not have been adequately sensitive to detect subtle deficits of cognition associated with exercise in CFS. Nevertheless, our test battery, although necessarily brief, examined domains of neuropsychological functioning comparable to those used in prior studies of cognitive performance after exercise in CFS (Blackwood et al., 1998; LaManca et al., 1998). However, we relied on instruments with alternate test forms rather than administer the same measure repeatedly to minimize practice effects. Although twin studies have been considered to be especially well suited to the study of illnesses of unclear etiology and those for which the appropriate comparison groups are poorly defined (Hubric & Robinette, 1984), our co-twin control methodology has several notable limitations. The solicitation methods we used to identify the monozygotic twin pairs discordant for CFS were not ideal, and the resulting sample of volunteer pairs may have potential ascertainment problems. The more desirable strategy of systematically identifying and randomly selecting twins from a well-defined population-based twin registry is not readily accomplished in the United States. Thus, how representative the twins in our study were of either monozygotic twins in general or of persons with CFS is difficult to gauge. However, the sociodemographic and clinical characteristics of our ill twins were similar to those of previously reported individuals with CFS (DeLuca, Johnson, Beldowicz, & Natelson, 1995; Schmaling, DiClementi, Cullum, & Jones, 1994; Tiersky et al., 1997).

EXERCISE AND COGNITION

A strength of the co-twin control research design in examining the effects of exercise on cognition in CFS is that monozygotic twins provide an excellent match for cognitive ability structures that are under genetic control (Brandt, Welsh, Breitner, Helms, & Christian, 1993; Finkel & McGue, 1993). Although some studies have confirmed a lack of significant neuropsychological differences in monozygotic twins (Campana, Macciardi, Gambini, & Scarone, 1996), others have utilized the co-twin methodology to detect subtle differences in cognition. For example, when examining the effects of minimal alcohol consumption on neuropsychological abilities among monozygotic twins discordant for alcohol use, one study demonstrated decreased visual-spatial ability, vocabulary, category sorting, and tactual performance among the alcohol-consuming twins (Gurling, Curtis, & Murray, 1991). The issue of well-matched controls may be especially germane in light of the varied control groups used by other investigators, including healthy controls (Blackwood et al., 1998; LaManca et al., 1998), depressed individuals (Blackwood et al., 1998; DeLuca et al., 1995), and patients with multiple sclerosis (DeLuca et al., 1995; DeLuca, Johnson, & Natelson, 1993; Krupp et al., 1994) and mild traumatic brain injury (Tiersky, Cicerone, Natelson, & DeLuca, 1998). On the other hand, although our monozygotic co-twin design provided excellent controls, the absence of a nongenetic or dizygotic control group in our study design did not allow us to examine the role of genetic influence in the phenomenon under study. In conclusion, this study highlights the importance of selecting appropriate control groups in studies of cognitive functioning in CFS. Our results indicate that monozygotic twins with CFS are unlikely to experience a significant or dramatic decline in objectively measured neuropsychological functioning after an exercise challenge compared to their healthy co-twins. These findings have relevance to persons with CFS engaged in exercise as well as rehabilitative treatment approaches involving progressive exercise regimens designed to counteract the deconditioning aspects of CFS (Fulcher & White, 1997). Our data suggest that such strategies to increase physical activity need not be restricted by concerns that exertion will induce cognitive impairments among CFS patients. References American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders (3rd ed., rev.). Washington DC: Author.

American Thoracic Society. (1995). Standardization of spirometry, 1994 update. American Journal of Respiratory and Critical Care Medicine, 152, 1107–1136. Blackwood, S. K., MacHale, S. M., Power, M. J., Goodwin, G. M., & Lawrie, S. M. (1998). Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression. Journal of Neurology, Neurosurgery, and Psychiatry, 65, 541–546. Borg, G. (1970). Perceived exertion as an indicator of somatic stress. Scandinavian Journal of Rehabilitation Medicine, 2, 92–98. Bouchard, C., Dionne, F. T., Simoneau, J. A., & Boulay, M. R. (1992). Genetics of aerobic and anaerobic performances. Exercise and Sports Scientific Review, 20, 27–58. Brandt, J. (1991). The Hopkins Verbal Learning Test: Development of a new memory test with six equivalent forms. The Clinical Neuropsychologist, 5,125–142. Brandt, J., Welsh, K. A., Breitner, J. C., Helms, M., & Christian, J, C. (1993). Hereditary influences on cognitive functioning in older men. Archives of Neurology, 50, 599–603. Buchwald, D. S., Herrell, R., Ashton, S., Belcourt, M., Schmaling, K., & Goldberg, J. (1999). The chronic fatigue twin registry: Method of construction, composition and zygosity assignment. Twin Research, 2, 203–211. Campana, A., Macciardi, F., Gambini, O., & Scarone, S. (1996). The Wisconsin Card Sorting Test (WCST) performance in normal twins: A twin study. Neuropsychobiology, 34, 14–17. DeLuca, J., Johnson, S. K., Beldowicz, D., & Natelson, B. H. (1995). Neuropsychological impairments in chronic fatigue syndrome, multiple sclerosis, and depression. Journal of Neurology, Neurosurgery, and Psychiatry, 58, 38–43. DeLuca, J., Johnson, S. K., Ellis, S. P., & Natelson, B. H. (1997a). Cognitive functioning is impaired in patients with chronic fatigue syndrome devoid of psychiatric disease. Journal of Neurology, Neurosurgery, and Psychiatry, 62, 151–155. DeLuca, J., Johnson, S. K., Ellis, S. P., & Natelson, B. H. (1997b). Sudden vs gradual onset of chronic fatigue syndrome differentiates individuals on cognitive and psychiatric measures. Journal of Psychiatric Research, 31, 83–90. DeLuca, J., Johnson, S. K., & Natelson, B. H. (1993). Information processing efficiency in chronic fatigue syndrome and multiple sclerosis. Archives of Neurology, 50, 301–304. Eisen, S. A., Neuman, R., Goldberg, J., Rice, J., & True, W. (1989). Determining zygosity in the Vietnam Era Twin Registry: An approach using questionnaires. Clinical Genetics, 35, 423–432. Finkel, D., & McGue, M. (1993). The origins of individual differences in memory among the elderly: A behavior genetic analysis. Psychology and Aging, 8, 527–537. Fukuda, K., Straus, S. E., Hickie, I., Sharpe, M. C., Dobbins, J. G., Komaroff, A., & the International Chronic Fatigue Syndrome Case Definition Study Group. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121, 953–959. Fulcher, K., & White, P. D. (1997). Randomized controlled trial of graded exercise in patients with the chronic fatigue syndrome. British Medical Journal, 314, 1647–1652. Grafman, J., Schwartz, V., Dale, J. K., Scheffers, M., Houser, C., & Straus, S. E. (1993). Analysis of neuropsychological functioning in patients with chronic fatigue syndrome. Journal of Neurology, Neurosurgery, and Psychiatry, 56, 684–689.

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CLAYPOOLE ET AL. Gurling, H. M., Curtis, D., & Murray, R. M. (1991). Psychological deficit from excessive alcohol consumption: Evidence from a co-twin study. British Journal of the Addictions, 86, 151–155. Hedeker, D., & Gibbons, R. D. (1996). MIXREG: A computer program for mixed-effects regression analysis with autocorrelated errors. Computer Methods and Programs in Biomedicine, 49, 229–252. Hickie, I., Kirk, K., & Martin, N. (1999). Unique genetic and environmental determinants of prolonged fatigue: A twin study. Psychological Medicine, 29, 259–268. Hubric, Z., & Robinette, C. D. (1984). The study of human twins in medical research. New England Journal of Medicine, 310, 435–441. Joyce, E., Blumenthal, S., & Wessely, S. (1996). Memory, attention, and executive function in chronic fatigue syndrome. Journal of Neurology, Neurosurgery, and Psychiatry, 60, 495–503. Komaroff, A. L., & Buchwald, D. (1991). Symptoms and signs in chronic fatigue syndrome. Reviews of Infectious Diseases, 13, S8–S11. Krupp, L. B., Sliwinski, M., Masur, D. M., Friedberg, F., & Coyle, P. K. (1994). Cognitive functioning and depression in patients with chronic fatigue syndrome and multiple sclerosis. Archives of Neurology, 51, 705–710. LaManca, J. J., Sisto, S. A., DeLuca, J., Johnson, S. K., Lange, G., Pareja, J., Cook, S., & Natelson, B. H. (1998). Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. American Journal of Medicine, 105, 59S–65S. Lezak, M. D. (1995). Neuropsychological assessment (3rd ed.). New York: Oxford University Press. McDonald, E., Cope, H., & David, A. (1993). Cognitive impairment in patients with chronic fatigue: A preliminary study. Journal of Neurology, Neurosurgery, and Psychiatry, 56, 812–815. Mitrushina, M. N., Boone, K. B., & D’Elia, L. F. (1999). Handbook of normative data for neuropsychological assessment. New York: Oxford University Press.

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Riccio, M., Thompson, C., Wilson, B., Morgan, D. J. R., & Lant, A. F. (1992). Neuropsychological and psychiatric abnormalities in myalgic encephalomyelitis: A preliminary report. British Journal of Clinical Psychology, 31, 111–120. Robins, L. N., & Helzer, J. E. (1985). Diagnostic Interview Schedule (DIS): Version III-A. St. Louis, MO: Department of Psychiatry, Washington University School of Medicine. Schmaling, K. B., DiClementi, J. D., Cullum, C. M., & Jones, J. F. (1994). Cognitive functioning in chronic fatigue syndrome and depression: A preliminary comparison. Psychosomatic Medicine, 56, 383–388. Tiersky, L. A., Cicerone, K. D., Natelson, B. H., & DeLuca, J. (1998). Neuropsychological functioning in chronic fatigue syndrome and mild traumatic brain injury: A comparison. The Clinical Neuropsychologist, 12, 503–512. Tiersky, L. A., Johnson, S. K., Lange, G., Natelson, B. H., & DeLuca, J. (1997). Neuropsychology of chronic fatigue syndrome: A critical review. Journal of Clinical and Experimental Neuropsychology, 19, 560–586. Torgersen, S. (1979). The determination of twin zygosity by means of a mailed questionnaire. Acta Geneticae Medicae et Gemellologiae (Roma), 28, 225–236. Wearden, A., & Appleby, L. (1996). Research on cognitive complaints and cognitive functioning in patients with chronic fatigue syndrome (CFS): What conclusions can we draw? Psychosomatic Research, 41, 197–211. Wechsler, D. (1981). Wechsler Adult Intelligence Scale–Revised manual (WAIS–R). New York: Harcourt Brace.

Original submission September 24, 1999 Accepted March 27, 2000

Applied Neuropsychology 2001, Vol. 8, No. 1, 41–50

Copyright 2001 by Lawrence Erlbaum Associates, Inc.

Longitudinal Assessment of Neuropsychological Functioning, Psychiatric Status, Functional Disability and Employment Status in Chronic Fatigue Syndrome

LONGITUDINAL ASSESSMENT IN CHRONIC FATIGUE TIERSKY SYNDROME ET AL.

Lana A. Tiersky School of Psychology, Fairleigh Dickinson University, Teaneck, New Jersey, USA, Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA, and Chronic Fatigue Syndrome Center, Newark, New Jersey, USA

John DeLuca Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA, Chronic Fatigue Syndrome Center, Newark, New Jersey, USA, and Kessler Medical Research, Rehabilitation and Education Corporation, West Orange, New Jersey, USA

Nancy Hill Chronic Fatigue Syndrome Center, Newark, New Jersey, USA

Sunil K. Dhar Department of Mathematical Sciences and the Center for Applied Mathematics and Statistics, New Jersey Institute of Technology, Newark, New Jersey, USA

Susan K. Johnson Department of Psychology, University of North Carolina-Charlotte, Charlotte, North Carolina, USA

Gudrun Lange Chronic Fatigue Syndrome Center, Newark, New Jersey, USA, and Departments of Radiology and Psychiatry, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA

Gabrielle Rappolt Chronic Fatigue Syndrome Center, Newark, New Jersey, USA

Benjamin H. Natelson Chronic Fatigue Syndrome Center, Newark, New Jersey, USA, and Department of Neurosciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA The longitudinal course of subjective and objective neuropsychological functioning, psychological functioning, disability level, and employment status in chronic fatigue syndrome (CFS) was examined. The relations among several key outcomes at follow-up, as well as the baseline

This research was supported by Grants U0I–AI32247 and R01–MH52810 from the National Institutes of Health. Requests for reprints should be sent to Lana A. Tiersky, School of Psychology, Fairleigh Dickinson University, 1000 River Road, Mail Stop T-WH1-01, Teaneck, NJ 07666, USA.

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characteristics that predict change (e.g., improvement), were also evaluated. The study sample consisted of 35 individuals who met the 1988 and 1994 CFS case definition criteria of the Centers for Disease Control (CDC) at intake. Participants were evaluated a mean of 41.9 (SEM = 1.7) months following their initial visit (range = 24–63 months). Results indicated that objective and subjective attention abilities, mood, level of fatigue, and disability improve over time in individuals with CFS. Moreover, improvements in these areas were found to be interrelated at follow-up. Finally, psychiatric status, age, and between-test duration were significant predictors of outcome. Overall, the prognosis for CFS appears to be poor, as the majority of participants remained functionally impaired over time and were unemployed at follow-up, despite the noted improvements. Key words: chronic fatigue, neuropsychological assessment, follow-up Although numerous cross-sectional studies document the extent and nature of cognitive impairment, psychological distress, disability, and unemployment in chronic fatigue syndrome (CFS), it remains unclear how these factors change over time (Tiersky, Johnson, Lange, Natelson, & DeLuca, 1997; Wessely, Hotopf, & Sharpe, 1998). Few longitudinal studies have been completed, and even fewer have used CFS samples defined by recognized clinical criteria (Joyce, Hotopf, & Wessely, 1997). Thus, the purpose of this investigation was to evaluate these variables over time in a group of CFS patients diagnosed according to case definition criteria. A key feature of CFS is subjective and objective cognitive impairment. It is estimated that between 74% and 95% of CFS patients complain of some type of cognitive deficit (Komaroff & Buchwald, 1991; Vercoulen et al., 1998). In addition, studies of objective neuropsychological functioning in CFS consistently document impairment in information-processing speed, divided auditory attention, and memory (for reviews, see DiPino & Kane, 1996; Moss-Morris, Petrie, Large, & Kydd, 1996; Tiersky et al., 1997). Given its centrality, it is important to examine the longitudinal course of cognitive functioning in CFS, as it likely affects the overall prognosis of the illness. Only two longitudinal studies have examined change in subjective or objective cognitive abilities in individuals diagnosed with CFS or chronic fatigue. One study investigated cognitive functioning in 14 patients with chronic fatigue over the course of an average of 6 months. In this study, chronic fatigue was defined as scoring above a certain cutoff point on a measure of fatigue and demonstrating fatigue for at least 6 months. Although limited by the small sample size and short duration of follow-up, this study found that the patients significantly improved on a block design task, a supraspan learning task, and a verbal paired associates

42

task (Cope, Pernet, Kendall, & David, 1995). In the second study, Vercoulen et al. (1996) found that subjective concentration difficulties significantly decreased over time in individuals who rated themselves as recovered from CFS or generally improved. Clearly, little is known about the longitudinal course of subjective and objective cognitive impairment in CFS. When examining the course of an illness, it is important to look at factors that affect prognosis. Although no study has investigated the effect of baseline level of objective neuropsychological impairment on final outcome, two studies have investigated how initial level of subjective cognitive impairment affects prognosis (Ray, Jefferies, & Weir, 1997; Vercoulen et al., 1996). The findings of these studies are mixed. One study reported that higher scores on a measure of cognitive problems at baseline predicted higher levels of fatigue at follow-up (Ray et al., 1997). Vercoulen et al. (1996), however, did not find that baseline level of cognitive difficulty affected prognosis. In addition, it remains an open question whether objective neuropsychological abilities affect outcome. It is possible that objective neuropsychological abilities contribute to overall prognosis in CFS, because neuropsychological impairment was found to be related to functional disability in a cross-sectional study (Christodoulou et al., 1998). Psychiatric comorbidity is common in CFS (Wessely et al., 1998), but its status over time has not been extensively investigated. One study that examined the natural course of CFS found that self-reported symptoms of depression and general psychological well-being significantly improve over time in some CFS patients (Vercoulen et al., 1996). Although few studies have examined the course of psychiatric disturbance in CFS, several have attempted to relate psychiatric status at baseline to health status at follow-up. The majority of studies have found that psychological status at initial evaluation is not related to improvement in

LONGITUDINAL ASSESSMENT IN CHRONIC FATIGUE SYNDROME

CFS symptoms, fatigue, or self-rated functional impairment at outcome (Hill, Tiersky, Scavalla, Lavietes, & Natelson, 1999; Ray et al. 1997; Vercoulen et al., 1996; Wilson et al., 1994). Bombardier and Buchwald (1995), however, found that having a dysthymic disorder at initial evaluation predicted general improvement but accounted for only 2% of the variance. Moreover, studies that have looked at the relation between general improvement and psychiatric status at follow-up have found that improvement in health status is related to improvement in psychiatric functioning (Hill et al., 1999; Vercoulen et al., 1996; Wilson et al., 1994). Thus, we know little about the longitudinal course of psychiatric symptoms in CFS other than that as health status improves, psychiatric status does as well. Functional disability is also often observed in CFS, but only a few authors have examined the course of disability over time (Ray et al., 1997; Vercoulen et al., 1996; Wilson et al., 1994). In general these studies show that although functional disability tends to significantly improve, many patients remain disabled at follow-up. For instance, Wilson et al. found that at follow-up 32% of participants were unable to perform any significant physical activity and Vercoulen et al. found that at follow-up only 3% of the total sample was performing at the level of healthy participants on a measure of functional ability. In addition, studies that have examined the factors that predict disability in CFS conclude that illness duration, levels of baseline fatigue (Ray et al., 1997), as well as baseline scores on measures of illness beliefs such as “disease conviction” are related to functional impairment at follow-up (Wilson et al., 1994). Thus, it appears that individuals with CFS remain disabled over time and that illness beliefs, illness duration, and initial fatigue level play some role in this outcome. Although unemployment is common in CFS (Wessely et al., 1998), only two studies have examined employment status over time in individuals with CFS. Both Hill et al. (1999) and Vercoulen et al. (1996) found no significant change in employment status from baseline to follow-up in individuals with CFS. Moreover, little is known about what predicts employment status at follow-up. Specifically, Bombardier and Buchwald (1995) found that demographic, clinical, or psychiatric variables were not predictive of return to work. Thus, it appears that employment status does not change in CFS over time. Still, the baseline factors that contribute to this outcome are not yet identified. The purpose of this investigation was to examine change in subjective and objective neuropsychological functioning, psychological functioning, disability sta-

tus, and employment status in CFS over the course of several years. Change in CFS severity and fatigue was also examined to provide descriptive information pertaining to severity of illness in the sample. In addition to examining change over time, the baseline characteristics that predict improvement in objective neuropsychological functioning and disability, as well as employment status at follow-up, were evaluated. Finally, the relations among key outcomes were studied to determine if long-term performances were interrelated. Thus, we also investigated the relations among neuropsychological functioning, disability level, fatigue, and mood at follow-up.

Method Participants At study entry, 47 individuals who were participants in the New Jersey Fatigue Research Center and who completed a comprehensive neuropsychological and psychological evaluation were invited to participate in the longitudinal investigation. In addition to meeting the 1988 and 1994 CFS case definition, participants also had to meet the following inclusion and exclusion criteria at study entry: (a) onset of CFS within the 4 years prior to the initial evaluation, (b) presence of symptoms of at least moderate severity at intake, (c) no history of psychiatric disorder in the 5 years prior to intake, (d) no substance abuse history, and (e) no loss of consciousness greater than 5 min. All 47 individuals who participated in the initial baseline evaluation (Time 1) were later contacted to participate in the follow-up psychological and neuropsychological evaluations (Time 2). The following procedures were utilized to contact patients at Time 2. First, all participants who participated at Time 1 were contacted by phone to schedule an appointment for the Time 2 evaluation. Participants who were unable to return in person at Time 2, but who were willing to participate in the study, were sent questionnaire measures to complete. Individuals who were unwilling to participate at Time 2, as well as those who could not be reached by phone, were sent a follow-up letter to request participation. Those individuals who could not be contacted or who refused to participate were considered lost to follow-up or nonresponders. Of those participants contacted, 35 (74.5%) participated at Time 2. These participants were designated as responders. Two responders (4%) only completed questionnaire measures that allowed us to rate CFS se43

TIERSKY ET AL.

verity because they lived geographically too distant to complete the in-person evaluations. Twelve (25.5%) of the 47 individuals declined to participate or could not be contacted and were designated nonresponders. Participants were reevaluated a mean of 41.9 (SEM = 1.7) months following their initial visit (range = 24–63 months). At Time 1, the mean age of the responders was 35.5 (SEM = 1.6) years, the mean level of education was 14.8 (SEM = .40) years, and the mean duration of illness was 25.9 (SEM = 2.5) months. At Time 2, the mean age of the responders was 38.9 (SEM = 1.5) years, and the mean educational level, which did not significantly change over time (p > .05), was 14.8 (SEM = .40) years. Some of the individuals who participated in this investigation were also included in an earlier investigation of longitudinal functioning in CFS (Hill et al., 1999).

Procedure Initial baseline evaluation (Time 1). At Time 1, all participants underwent a comprehensive psychological and physical assessment. During the physical assessment, a medical history was obtained by a physician’s assistant or nurse practitioner trained in the diagnosis of CFS. At this time, the severity of each individual’s CFS was rated by the clinician using a 6-point scale. The CFS severity category rankings are listed in Table 1. CFS severity was rated based on level of reduction in activity and number and severity of minor symptoms rated from 0 (symptom is no problem) to 5 (sympTable 1. Rating 1 2 3

4

5

6 Note:

44

CFS Severity Rating Scale Definition of Numeric Rating ≥ 50% reduction in activity and 7 symptoms rated as at least substantial (severe CFS) ≥ 50% reduction in activity and 4–6 symptoms rated as at least substantial < 50% reduction in activity and 4 or more symptoms rated as at least substantial (at least 3 symptoms rated as very severe) < 50% reduction in activity and 4 or more symptoms rated as at least substantial (no more than 2 symptoms may be rated as very severe) ≥ 50% reduction in activity (must be at least substantial) and 4 or more symptoms rated less than substantial Substantial reduction in activity and 4 or more symptoms rated less than substantial

CFS = chronic fatigue syndrome.

tom is a very severe problem). Information pertaining to psychiatric status was obtained using the Quick Diagnostic Interview Schedule for the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev. [DSM–III–R]; American Psychiatric Association, 1987), a structured computerized diagnostic interview that was administered by trained personnel (Marcus, Robins, & Bucholz, 1990). A psychiatric disorder was considered concurrent if the onset of the disorder occurred following the onset of CFS. Thus, participants who were diagnosed with a concurrent Axis I disorder(s) at Time 1 were noted to have the disorder concurrent with CFS. In addition, lifetime history of psychiatric illness was also evaluated. Axis II status was determined based on the participants’ responses on the Personality Diagnostic Questionnaire–Revised, which is a self-report questionnaire (Hyler & Rieder, 1987). At Time 1, participants also completed a neuropsychological evaluation that included the following measures: The California Verbal Learning Test (CVLT; Delis, Dramer, Kaplan, & Ober, 1987); the Paced Auditory Serial Addition Task (PASAT; Gronwall, 1977); the Rey–Osterreith Complex Figure Test, Immediate Recall (ROCF–I) and Delayed Recall (ROCF–D) subtests (Corwin & Bylsma, 1993); the Wechsler Adult Intelligence Scale–Revised (WAIS–R) Digit Span Forward and WAIS–R Digit Span Backward subtests (Wechsler, 1981); the Meta-Memory Questionnaire (Mateer, Sohlberg, & Crinean, 1987); the Beck Depression Inventory (BDI; Beck, Ward, Medelson, Mock, & Erbaugh, 1961); and the State–Trait Anxiety Inventory–Form X (Spielberger, Gorsuch, & Lushene, 1983). All measures were administered according to published procedures. In addition, at Time 1 participants completed the Fatigue Rating Scale (Krupp, LaRocca, Muir-Nash, & Steinberg, 1989), which is a self-report measure. A self-report measure of magnitude of disability due to illness, the CFS Disability Scale (CDS), was also completed. The CDS is a modification of the Karnofsky Performance Index (Wilson et al., 1994) in which the areas of mild to moderate disability are expanded. Moreover, it uses a scoring system whereby each disability rating is defined within a 10-point band. The CDS has been utilized in other studies examining functional ability in CFS (Natelson et al., 1995). Employment status (i.e., employed full time or part time or unemployed or retired due to health) was also determined during the initial evaluation. Follow-up evaluation (Time 2). All participants who returned in person at Time 2 underwent both a

LONGITUDINAL ASSESSMENT IN CHRONIC FATIGUE SYNDROME

physical assessment and a neuropsychological evaluation. At this time, a follow-up psychiatric interview was completed, and a follow-up medical history was also obtained. The procedures for administration of the Time 2 assessments were the same as those followed at Time 1 except that lifetime history of disease or psychopathology was not reassessed during the medical history and psychiatric interview. A trained physician’s assistant or nurse practitioner rated CFS severity during the follow-up evaluation.

Analyses Due to the non-normal distributions of the data, Wilcoxon matched-pair sign-rank tests were used to examine the significance of change over time for the continuous variables. McNemar’s binomial probability test was utilized to examine change over time for the dichotomous variables. When normality assumptions for two independent samples were not satisfied, Mann–Whitney U tests were utilized to compare group differences within Time 1. A proportion test (the Z test) was used to examine improvement in CFS severity. Because the sample size was large (n > 30), the Central Limit Theorem was invoked to validate the use of the Z test. Spearman’s rank correlation coefficients were computed to determine the level of association among the variables because they were non-normal in distribution as well. Logistic regression analyses were completed to predict improvement in disability level and neuropsychological functioning, as well as employment status at Time 2. Improvement in disability was defined as a 10-point decrease in disability level as measured by the CDS. The improved group, therefore, consisted of participants whose CDS scores improved by at least 10 points at Time 2. Those participants who did not demonstrate such an improvement were considered not improved. Ten points was chosen as the criteria for improvement because each 10-point band of scores on the CDS defines a different disability category. Improvement in neuropsychological functioning was defined as a 1-point decrease on the impairment index from Time 1 to Time 3. Thus, participants who decreased by 1 point on the impairment index from Time 1 to Time 2 were placed in the improved category, and those that did not demonstrate such a decrease in impairment were considered not improved. Improvement in CFS severity was defined as a 1-point increase in CFS category (i.e., a lessening of symptoms). Thus, those participants who improved by at

least 1 point from Time 1 to Time 2 on the measure of clinician-rated CFS severity were placed in the improved category, and those that did not demonstrate any positive change in symptoms were categorized as not improved. The following were used as predictor variables in all of the regression analyses: duration of illness, illness severity, duration of time lapsed between baseline and follow-up evaluation (“between test duration”), presence of a concurrent psychiatric diagnosis, age, gender, and education at Time 1. To predict improvement in level of neuropsychological functioning, also included in the model was disability status at Time 1. To predict improvement in disability status, level of neuropsychological impairment at Time 1 was also included. Finally, to predict employment status at Time 2, level of neuropsychological impairment and disability status at Time 1 were included in the model. A backward stepwise elimination method was used to complete all of the logistic regression analyses. Specifically, all of the predictor variables were included in the initial model. Then, the variable whose coefficient was the least significant, including that of the constant, was removed from the model one step at a time. To examine overall neuropsychological functioning, a neuropsychological impairment index was created that was similar to that utilized in other studies of cognitive functioning in CFS (Christodoulou et al., 1998). This index was created by summing the number of tests a participant failed. A test was considered failed if the individual performed 2 or more SD below the mean of a healthy control group on a given test. The data on the healthy comparison group have been published elsewhere (DeLuca, Johnson, Beldowicz, & Natelson, 1995). The measures included in the index were the following: CVLT total score (CVLT–T), long-delay free recall (CVLT–LDF), and short-delay free recall (CVLT–SDF); PASAT total score; ROCF–I and ROCF–D; and WAIS–R Digit Span Forward and WAIS–R Digit Span Backward subtests.

Results Comparison Between Responders and Nonresponders on Time 1 Measures To examine for the possibility of a sampling bias, the Time 1 performance of the responders (n = 35) was compared to those who did not respond (nonresponders, n = 12). There were no significant differences in age, education, illness severity, illness duration, employment status, gender, level of depression, or 45

TIERSKY ET AL.

concurrent psychiatric status between responders and nonresponders at Time 1 (all p >. 05). However, the nonresponders demonstrated lower levels of anxiety (responders: Mdn = 38, range = 21–78; nonresponders: Mdn = 27, range = 20–74; p = .02) and less disability at Time 1 than the responders (responders: Mdn = 30, range = 20–60; nonresponders: Mdn = 45; range = 20–70; p = .03) The median disability level of the nonresponder group corresponded to a disability ranking identified by the following characteristics: not confined to the house, unable to perform strenuous duties, and able to perform light-duty desk work 3 to 4 hr a day but requires rest periods. In contrast, the median disability level of the responder group corresponded to a disability ranking identified by the following characteristics: usually confined to house, unable to perform any strenuous tasks, and able to perform desk work 2 to 3 hr a day but requires rest periods. Finally, there were no significant differences between the groups in level of neuropsychological functioning at Time 1 (all p >. 05).

Change From Time 1 to Time 2

CFS severity and fatigue. At Time 1, all participants met both the 1988 and 1994 CDC case definition criteria for CFS, and 97% of the participants demonstrated severe CFS (see Table 1 for a definition of severe CFS). At Time 2, only 1 participant no longer met either the 1988 or 1994 CDC criteria. Moreover, clinician-rated CFS severity did not significantly improve from Time 1 to Time 2 (p = .40). Specifically, 57% of the CFS participants demonstrated improvement over time, whereas 43% did not. At follow-up, all of the participants designated as not improved continued to demonstrate severe CFS. Moreover, 45% of the improved participants continued to rate some of their symptoms as at least a substantial problem. Finally, although no change in CFS severity was observed, the participants did demonstrate an improvement in level of fatigue over time (p = .01; see Table 2). Neuropsychological status. As demonstrated in Table 3, significant improvement from Time 1 to Time 2 was noted on some of the neuropsychological variables. Notably, a significant positive change in performance was observed on the PASAT, a measure of complex information processing (p = .01) as well as on the Meta-Memory Test, a self-report measure of attentional and memory functioning (p = .01). No other significant changes were found. 46

Table 2. Performance of Responders on Psychological, Illness-Related, and Disability Measures at Time 1 and Time 2 Time 1

BDI STAI Fatigue CDS

Time 2

Mdn

Range

Mdn

Range

p

13 38 60 30

4–30 21–78 49–63 20–60

10 39 57 40

0–33 23–67 17–63 20–100

.02 .66 .01 .01

Note: BDI = Beck Depression Inventory; STAI = State–Trait Anxiety Inventory; Fatigue = Fatigue Rating Scale; CDS = CFS Disability Scale.

Table 3. Performance of Responders on Neuropsychological Measures at Time 1 and Time 2

CVLT–T CVLT–SDFR CVLT–LDFR ROCF–I ROCF–D W–DSF W–DSB PASAT MMQ

Time 1

Time 2

Mdn Range

Mdn Range

p

52 30–76 11 4–16 10 4–16 34 4–64 35 3–64 9 6–14 9 3–13 128 60–177 73 38–136

54 29–75 11 3–16 12 2–16 35 0–66 36 3–63 9 5–12 7 3–12 137 75–189 67 32–111

.89 .76 .31 .40 .47 .84 .26 .01 .01

Note: CVLT = California Verbal Learning Test; CVLT–T = total score; CVLT–LDF = long-delay free recall; CVLT–SDF = short-delay free recall; PASAT = Paced Auditory Serial Addition Test total score; ROCF–I = Rey–Osterreith Complex Figure Test, immediate recall; ROCF–D = delayed recall; W–DSF = Wechsler Adult Intelligence Scale–Revised Digit Span Forward–total Digits; W–DSB = Digit Span Backward–total Digits; MMQ = Meta-Memory Questionnaire total score.

Concurrent psychiatric status. No significant change in the proportion of concurrent Axis I or Axis II (all p >. 05) disorders in the sample was observed over time. Specifically, at both Time 1 and Time 2, 34% of the participants met the criteria for a concurrent Axis I disorder. In addition, no change in Axis II performance was observed with a prevalence of 45% during both time periods. Despite the lack of change in the proportion of concurrent Axis I and Axis II disorders in the sample over time, a significant improvement was noted on a measure of mood, the BDI (p = .02; see Table 2). Disability and employment status. As illustrated in Table 2, initial level of disability significantly

LONGITUDINAL ASSESSMENT IN CHRONIC FATIGUE SYNDROME

diminished at follow-up (p = .01). At Time 2, the median level of functioning on the disability measure corresponded to a disability ranking characterized by: not confined to the house, unable to perform strenuous duties, able to perform light-duty desk work 3 to 4 hr a day but requires rest periods. The sample did not change significantly from Time 1 to Time 2 in employment status (p >. 05). Specifically, 68% of the participants were unemployed at both time periods.

Table 5. Correlations Among Fatigue, CFS Severity, Disability, Mood, and Objective and Subjective Neuropsychological Functioning at Time 2

Fatigue CDS BDI Neuro MMQ

Fatigue

CDS

BDI

Neuro

–.78* .60* .44** .69*

–.57* –.66* –.84*

.53* .55*

.59*

MMQ

Note: Fatigue = Krupp Fatigue Rating Scale; CDS = CFS Disability rating scale; BDI = Beck Depression Inventory; Neuro = level of neuropsychological impairment (total number of tests failed); MMQ = Meta-Memory Questionnaire total score. *p < .01. **p < .02.

Predicting Time 2 Performance From Time 1 Performance Predicting neuropsychological performance. As illustrated in Table 4, between-test duration was the only variable that significantly predicted improvement in neuropsychological functioning when the baseline log odds were set to zero, c2(1, N = 25) = 8.16, p = .01. This model demonstrates that the longer the duration of time lapsed between baseline and follow-up evaluations, the lower the odds of improvement in neuropsychological functioning.

Predicting disability. Concurrent psychiatric history at Time 1 and age at Time 1 predicted improvement in level of disability when the baseline log odds were set to zero, c2(2, N = 32) = 9.63, p = .01 (see Table 4). As Table 4 illustrates, the positive coefficient for the variable measuring psychiatric status indicates that having a concurrent psychiatric diagnosis at Time 1 contributes to higher odds in favor of improvement in disability. The negative coefficient for the variable measuring age reflects that there is a trend for older age

Table 4. Logistic Regression Models for Neuropsychological Improvement, Improvement in Disability, and Time 2 Employment Status

at baseline to contribute to lower odds of improvement in disability status. Predicting employment status. Concurrent psychiatric status and age at Time 1 significantly predicted employment at Time 2, when the baseline log odds were set to zero (a = 0), c2(2, N = 35) = 13.50, p = .01 (see Table 4). This model demonstrates that being older at baseline lowers the odds of being employed at Time 2 and that having a concurrent psychiatric diagnosis at intake contributes to higher odds in favor of being employed at Time 2.

Interrelated Variables at Time 2 The relations at Time 2 among the variables that significantly changed over time were also examined. As is illustrated in Table 5, improvement in level of fatigue, mood, disability level, neuropsychological functioning, and subjective attention and memory abilities were all interrelated.

Discussion Predictors Neuropsychological Improvement Between-Test Duration Disability Improvement Age Psychiatric Status Time 2 Employment Status Age Psychiatric Status

Beta

SE

Wald c2(1)

–.03

0.01

6.57

.01

–.03 2.61

0.01 0.93

3.40 7.40

.07 .01

–.05 1.93

0.02 0.83

8.95 5.44

.01 .02

p

This study was designed to examine long-term change in neuropsychological functioning, psychiatric status, disability, and employment status in individuals with CFS. Disability level, depression, fatigue, subjective attention and memory, and complex information processing were found to improve. Moreover, when compared to standard normative values, CFS participants improved to the extent that at Time 2 they were functioning in the normal to near-normal range in two of these areas. Specifically, on the PASAT, participants 47

TIERSKY ET AL.

performed in the average range at Time 2 (Brittain, La Marche, Reeder, Roth, & Thomas, 1991). Likewise, the level of depression demonstrated by the sample at Time 2 fell in the mild to minimal range (Beck et al., 1961). Thus, these findings are consistent with prior studies (for a review, see Joyce et al., 1997). Despite the observed improvement, the majority of the participants continued to demonstrate CFS symptoms, were unemployed (68%), and remained functionally impaired at Time 2. Only a single individual was found to no longer meet the 1988 or 1994 CFS criteria at follow-up. Moreover, the median CDS score at Time 2 indicated that participants were not able to perform strenuous duties and were only able to perform light-duty desk work for 3 to 4 hr a day. The CDS score indicated that even this amount of work required rest periods. This level of disability and illness suggests a poor overall prognosis in CFS. It is possible that the participants in this investigation were more functionally disabled at Time 2 than participants included in other studies. For instance, we found higher unemployment rates in our study at Time 2 as compared to other authors (i.e., Bombardier & Buchwald, 1995; Vercoulen et al., 1996). In addition, Wilson et al. (1994) reported higher levels of functioning at follow-up in their investigation, which used the clinician-rated Karnofsky Performance Index. They found CFS participants to be functioning at a level between “cares for self, unable to carry on normal activity or to do active work” and “normal activity with effort.” This comparison between studies must be interpreted cautiously, however, as the measures used to evaluate outcome differed (i.e., a self-report measure of disability was used in our investigation, and a clinician rating of disability was utilized in the study by Wilson et al.). This discrepancy highlights the need for a future investigation to examine long-term disability level in individuals with CFS using both self-report as well as objective criteria, such as the Karnofsky Performance Index. Based on the results of this investigation, it also appears that having a concurrent psychiatric disorder at intake (or Time 1) is positively related to long-term outcome. Patients diagnosed with a psychiatric disorder concurrent with their illness onset demonstrated greater odds of improvement in level of disability than those with no history of a concurrent psychiatric disorder. Participants with a concurrent psychiatric diagnosis at intake were also more likely to be employed at follow-up than those without such a history. One reason patients with a concurrent psychiatric history may demonstrate better outcomes from CFS 48

sufferers with no such history is that the etiology of their CFS symptoms may differ. Psychiatric disorders such as depression have a variable course in which symptoms fluctuate, and often a natural remission in symptoms occurs (American Psychiatric Association, 1987). Thus, it is possible that the more favorable course observed in participants with CFS and a psychiatric history reflects an underlying psychiatric etiology. Participants with CFS with no psychiatric history, however, may have another cause for their symptoms. For instance, it is possible that participants with CFS and no psychiatric history have a neurologic cause to the illness, the consequence of which is a chronic and intractable course. Two studies provide some support for this notion (DeLuca, Johnson, Ellis, & Natelson, 1997; Lange et al., 1999). Specifically, Lange et al. (1999) found that CFS sufferers with no psychiatric history demonstrated a greater number of MRI abnormalities than CFS patients with a concurrent psychiatric history. In addition, DeLuca et al. (1997) found that CFS sufferers with no psychiatric history demonstrated greater neuropsychological impairment than those with a positive psychiatric history. Future research should investigate the possible differences in illness course in CFS sufferers with differing psychiatric histories or illness etiologies. Moreover, the fact that some individuals with CFS develop psychiatric disorders and others do not suggests differences in coping style and adaptation. Thus, it is also possible that the factors that maintain the illness are different in CFS participants with a psychiatric history as compared to those with no psychiatric history. For example, participants with CFS and no psychiatric history may accommodate to their illness more readily and thus not develop an emotional disorder. CFS patients with no concurrent psychiatric disorders may also be more behaviorally disengaged as evidenced by the fact that they are more likely to be unemployed than those with a psychiatric history. Illness accommodation and behavioral disengagement have both been found to predict poor outcome in some participants with CFS (Ray et al., 1997). A future investigation should examine changes over time in these cognitive variables in CFS participants with differing psychiatric histories. In contrast to the findings of this investigation, other authors have not found that psychiatric status at intake predicts employment status or improvement in functioning at follow-up (Bombardier & Buchwald, 1995; Hill et al., 1999; Ray et al. 1997; Vercoulen, 1996; Wilson et al., 1994). These discrepant findings may be due to methodological differences, such as the use of differ-

LONGITUDINAL ASSESSMENT IN CHRONIC FATIGUE SYNDROME

ent outcome measures or the use of different measures to evaluate psychiatric distress. For example, Vercoulen et al. (1996) and Wilson et al. (1994) used self-reported change as a final outcome variable. Other primary outcomes have included self-reported fatigue and functional impairment (Ray et al., 1997; Vercoulen et al., 1996); clinician-rated functional impairment (Wilson et al., 1994); change in immunological parameters (Wilson et al., 1994); clinician-rated improvement (Hill et al., 1999); and return to work (Bombardier & Buchwald, 1995). Measures of psychiatric status at baseline have included a variety of measures such as the Hospital Anxiety and Depression Scale (Ray et al., 1997), the neuroticism subtest of the Eysenck Personality Inventory, and the Diagnostic Interview Schedule for the DSM–III–R (American Psychiatric Association, 1987; Bombardier & Buchwald, 1995; Hill et al., 1999). Thus, due to the use of differing measures, it is difficult to directly compare the studies. Demographic factors also appear to be related to long-term outcome. In this study it was found that older patients at intake had a higher risk of unemployment at Time 2, a finding that has been observed by other authors (for a review, see Joyce et al., 1997). There was also a trend for older patients to have lower odds of improvement on the disability measure. One limitation of our investigation is that the duration between baseline and follow-up testing was not constant for all participants. This limitation was addressed by including between-test duration as a variable in the regression analyses. This allowed us to examine how elapsed time may have affected our three main outcomes: neuropsychological impairment, disability, and employment. We found that between-test duration only impacted neuropsychological functioning. Specifically, the longer the duration between baseline and follow-up testing, the lower the odds of detecting improvement. Given this finding, it is possible that our repeated measures analyses did not capture significant changes on some of the neuropsychological measures. Finally, the findings of our investigation have two main clinical implications. Given that participants demonstrate some improvement in neuropsychological functioning, periodic reevaluation appears warranted so that level of functioning can be most accurately estimated. Reevaluation can also provide information about whether interventions such as psychotherapy or vocational rehabilitation are indicated. In addition, as is consistent with the findings of other authors, we noted that many areas of functioning improved concurrently (Ray et al., 1997). These related improvements suggest

that treatment targeted toward improving one or a few of the areas may result in improvement in the other domains. For instance, cognitive behavioral therapy (CBT), which has been found to improve overall level of disability and mood in CFS patients (Deale, Chalder, Marks, & Wessely, 1997; Sharpe et al., 1996), may also result in an improvement in level of neuropsychological impairment. A topic for future research is whether CBT can improve cognitive functioning in CFS.

References American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders (3rd ed., rev.). Washington, DC: Author. Beck, A. T., Ward, C. H., Mendelson, M., Mock, J., & Erbaugh, J. (1961). An inventory for measuring depression. Archives of General Psychiatry, 4, 561–571. Bombardier, C. H., & Buchwald, D. (1995). Outcome and prognosis of patients with chronic fatigue vs. chronic fatigue syndrome. Archives of Internal Medicine, 155, 2105–2110. Brittain, J. L., La Marche, J. A., Reeder, K. P., Roth, D. L., & Boll, T. J. (1991). Effects of age and IQ on Paced Auditory Serial Addition Task (PASAT) performance. The Clinical Neuropsychologist, 5, 163–175. Christodoulou, C., DeLuca, J., Lange, G., Johnson, S. K., Sisto, S. A., Korn, L., & Natelson, B. H. (1998). Relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome. Journal of Neurology, Neurosurgery, and Psychiatry, 64, 431–434. Cope, H., Pernet, A., Kendall, B., & David, A. (1995). Cognitive functioning and magnetic resonance imaging in chronic fatigue. British Journal of Psychiatry, 167, 86–94. Corwin, J., & Bylsma, F. W. (1993). Translations of excerpts from Andre Rey’s “Psychological examination of traumatic encephalopathy” and P. A. Osterreith’s “The Complex Figure Copy Test.” The Clinical Neuropsychologist, 7, 3–15. Deale, A., Chalder, T., Marks, I., & Wessely, S. (1997). Cognitive behavior therapy for chronic fatigue syndrome: A randomized controlled trial. American Journal of Psychiatry, 154, 408–414. Delis, D. C., Dramer, J. H., Kaplan, E., & Ober, B. A. (1987). California Verbal Learning Test: Adult version. San Antonio, TX: Psychological Corporation. DeLuca, J., Johnson, S. K., Beldowicz, D., & Natelson, B. H. (1995). Neuropsychological impairments in chronic fatigue syndrome, multiple sclerosis, and depression. Journal of Neurology, Neurosurgery, and Psychiatry, 58, 38–43. DeLuca, J., Johnson, S. K., Ellis, S. P., & Natelson, B. H. (1997). Cognitive functioning is impaired in patients with chronic fatigue syndrome devoid of psychiatric disease. Journal of Neurology, Neurosurgery, and Psychiatry, 62, 151–155. DiPino, K. R., & Kane, L. R. (1996). Neurocognitive functioning in chronic fatigue syndrome. Neuropsychology Review, 6, 47–60. Gronwall, D. (1977). Paced Auditory Serial Addition Task: A measure of recovery from concussion. Perceptual Motor Skills, 44, 367–373.

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TIERSKY ET AL. Hill, N. F., Tiersky, L. A., Scavalla, V. R., Lavietes, M., & Natelson, B. H. (1999). Natural history of severe chronic fatigue syndrome. Archives of Physical Medicine and Rehabilitation, 80, 1–5. Hyler, S. E., & Rieder, R. O. (1987). PDQ–R. New York: New York State Psychiatric Institute. Joyce, J., Hotopf, M., & Wessely, S. (1997). The prognosis of chronic fatigue and chronic fatigue syndrome: A systematic review. Quarterly Journal of Medicine, 90, 223–233. Komaroff, A. L., & Buchwald, D. (1991). Symptoms and signs in chronic fatigue syndrome. Reviews of Infectious Diseases, 13, S8–S11. Krupp, L. B., LaRocca, N. G., Muir-Nash, J., & Steinberg, A. D. (1989). The fatigue severity scale: Application to patients with multiple sclerosis and systemic lupus erythematosus. Archives of Neurology, 46, 1121–1123. Lange, G., DeLuca, J., Maldjian, J. A., Lee, H.-J., Tiersky, L. A., & Natelson, B. H. (1999). Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. Journal of Neurological Sciences, 171, 3–7. Marcus, S., Robins, L. N., & Bucholz, K. (1990). Quick Diagnostic Interview Schedule III–R, Version 1. St Louis, MO: Washington University School of Medicine. Mateer, C. A., Sohlberg, M. M., & Crinean, J. (1987). Focus on clinical research: Perceptions of memory function in individuals with closed-head injury. Journal of Head Trauma Rehabilitation, 2, 74–84. Moss-Morris, R., Petrie, K. J., Large, R. G., & Kydd, R. R. (1996). Neuropsychological deficits in chronic fatigue syndrome: Artifact or reality? Journal of Neurology, Neurosurgery, and Psychiatry, 60, 474–477. Natelson, B. H., Johnson, S. K., DeLuca, J. Sisto, S., Ellis, S. P., Hill, N., & Bergen, M. T. (1995). Reducing heterogeneity in chronic fatigue syndrome: A comparison with depression and multiple sclerosis. Clinical Infectious Diseases, 21, 1204–1210. Ray, C., Jefferies, S., & Weir, W. R. C. (1997). Coping and other predictors of outcome in chronic fatigue syndrome: A 1-year follow-up. Journal of Psychosomatic Research, 43, 405–415. Sharpe, M., Hawton, K., Simkin, S., Surawy, C., Hackmann, A., Klimes, I., Peto, T., Warrell, D., & Seagroatt, V. (1996). Cognitive behavior therapy for the chronic fatigue syndrome: A randomized controlled trial. British Medical Journal, 312, 22–26. Spielberger, C. D., Gorsuch, R., & Lushene, R. (1983). The State–Trait Anxiety Inventory (STAI) test manual. Palo Alto, CA: Consulting Psychologists Press. Tiersky, L. A., Johnson, S. K., Lange, G., Natelson, B. H., & DeLuca, J. (1997). Neuropsychology of chronic fatigue syndrome: A critical review. Journal of Clinical and Experimental Neuropsychology, 19, 560–586. Vercoulen, J. H. M. M., Bazelmans, E., Swanink, C. M. A., Galama, J. M. D., Fennis, J. F. M, Van der Meer, J. W. M., & Bleijenberg, G. (1998). Evaluating neuropsychological impairment in chronic fatigue syndrome. Journal of Clinical and Experimental Neuropsychology, 20, 144–156. Vercoulen, J. H. M. M., Swanink, C. M. A., Ferris, J. F. M., Galama, J. M. D., Van der Meer, J. W. M., & Bleijenberg, G. (1996).

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Prognosis in chronic fatigue syndrome: A prospective study on the natural course. Journal of Neurology, Neurosurgery, and Psychiatry, 60, 489–494. Wechsler, D. (1981). Wechsler Adult Intelligence Scale–Revised manual. New York: Psychological Corporation. Wessely, S., Hotopf, M., & Sharpe, M. (1998). Chronic fatigue and its syndromes. Oxford, England: Oxford University Press. Wilson, A., Hickie, I., Lloyd, A., Hadzi-Pavlovic, D., Boughton, C., Dwyer, J., & Wakefield, D. (1994). Longitudinal study of outcome of chronic fatigue syndrome. British Medical Journal, 308, 756–759.

Original submission November 15, 1999 Accepted June 19, 2000

Appendix Management of Missing Values When creating the impairment index, the following methods were used to statistically manage missing values. The test variable PASAT total score had nine missing observations at Time 1 because the participants were not administered the measure. Values for these nine missing data points were computed using an optimal regression model that included the remaining seven cognitive measures (i.e., CVLT–T, CVLT–LDF, CVLT–SDF, ROCF–I, ROCF–D, WAIS–R Digit Span Forward and Digit Span Backward subtests). Specifically, to generate the scores for the nine missing values, all seven of the cognitive variables were entered in the multiple linear regression model, and a stepwise backward elimination procedure was performed. The final model, which was selected on the basis of having the smallest sum of square error (SSE), included the following predictor variables: ROCF–I, CVLT–SDF, and ROCF–D (SSE = 25.55). An analysis of variance showed that this regression model was significant with p = .00. Although the model coefficients corresponding to ROCF–I and CVL–SDF were not significant (p = .21 and .22, respectively), they were kept in the final model because the objective of getting the model with the smallest SSE, which yields the best prediction, was met with their inclusion. Thus, the final model used to predict PASAT total score for the nine missing vales was the following: PASAT (score) = 76.68 + 1.67 × ROCF–D (score) + 1.90 × CVL–SDF (score) – .96 × ROCF–I (score).

Applied Neuropsychology 2001, Vol. 8, No. 1, 51–64

Copyright 2001 by Lawrence Erlbaum Associates, Inc.

Cytokine and Other Immunologic Markers in Chronic Fatigue Syndrome and Their Relation to Neuropsychological Factors

IMMUNOLOGY AND NEUROPSYCHOLOGY PATARCA-MONTERO, OF CHRONIC ANTONI, FLETCHER, FATIGUE SYNDROME & KLIMAS

Roberto Patarca-Montero, Michael Antoni, Mary Ann Fletcher, and Nancy G. Klimas E. M. Papper Laboratory of Clinical Immunology, Center for Behavioral Medicine Research, Miami Veterans Administration Medical Center, University of Miami School of Medicine, Miami, Florida, USA The literature is reviewed and data are presented that relate to a model we have developed to account for the perpetuation of the perplexing disorder currently termed chronic fatigue syndrome (CFS). In patients with CFS there is chronic lymphocyte overactivation with cytokine abnormalities that include perturbations in plasma levels of proinflammatory cytokines and decrease in the ratio of Type 1 to Type 2 cytokines produced by lymphocytes in vitro following mitogen stimulation. The initiation of the syndrome is frequently sudden and often follows an acute viral illness. Our model for the subsequent chronicity of this disorder holds that the interaction of psychological factors (distress associated with either CFS-related symptoms or other stressful life events) and the immunologic dysfunction contribute to (a) CFS-related physical symptoms (e.g., perception of fatigue and cognitive difficulties, fever, muscle and joint pain) and increases in illness burden and (b) impaired immune surveillance associated with cytotoxic lymphocytes with resulting activation of latent herpes viruses. Key words: chronic fatigue syndrome, cytokines, proinflammatory cytokines, Type 1 and Type 2 cytokines, immune activation, cognitive difficulties, natural killer cells attempt is made to relate these immunological data to the available psychological and neuropsychological variables where possible. Previously, Klimas, Salvato, Morgan, and Fletcher (1990) as well as Evans (1991) outlined multifactorial models for possible etiologic factors involved in CFS, including virus infections, other viruses, and mental stress and reactivation of herpes viruses as risk factors. Here we present a model for maintenance and exacerbation of CFS. Our model proposes cytokine dysregulation (due to a heterogeneous and largely unknown set of causes) characterized by episodic increased proinflammatory cytokines in plasma and by a shift in the ratio of Type 1 to Type 2 cytokines produced in vitro following mitogen stimulation of peripheral blood lymphocytes. These soluble mediators affect immune function and may underlie many of the pathological manifestations seen in CFS (Patarca, Sandler, Walling, Klimas, & Fletcher, 1995). However, this review of the world literature reveals a lack of unanimity of opinion in regard to the nature and extent of immunological abnormalities in CFS. A relevant recent review by Vollmer-Conna, Lloyd, Hickie,

The aim of this report is to integrate the findings of our research group concerning the immunology and psychology of chronic fatigue syndrome (CFS) with those of other researchers and to formulate a model describing how multiple biological and psychological factors may relate to the maintenance of the neuropsychological symptoms and illness burden associated with CFS. Although our aim is to relate the immunological and neuropsychological findings in CFS, it should be recognized that there are very few studies that have attempted to relate these variables with CFS patients. As such, most of this review focuses on immunological factors. Every

This work was supported, in part, by a grant from the CFIDS Association of America, by National Institutes of Health Center Grant 1UD1–AI 45940–02, and by funds from Neoprobe Corporation and Ciratech Corporation. Requests for reprints should be sent to Nancy G. Klimas, E. M. Papper Laboratory of Clinical Immunology, Center for Behavioral Medicine Research, Miami Veterans Administration Medical Center, University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101, USA.

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and Wakefield (1998) on the immunopathogenesis of CFS concludes that neuropsychiatric symptoms in CFS patients may be more closely related to disordered cytokine production by glial cells within the central nervous system (CNS) than to circulating cytokines. However, the requirement for more invasive sampling techniques has limited the number of such studies in CFS patients. Most studies have been done using peripheral blood samples, although our laboratory has reported on results with surgically excised lymph nodes (Klimas & Fletcher, 1999).

Cytokines and CFS The cause of CFS remains to be elucidated; however, the data published from this laboratory, as well as those from other laboratories around the world, suggest that the syndrome is associated with immunologic abnormalities. A clear picture has not been achieved because of the noticeable variability in the nature and magnitude of the findings reported by different groups and because of the paucity of prospective longitudinal studies of CFS. For instance, Buchwald, Werner, Pearlman, and Kith (1997) concluded that although a subset of CFS patients with immune system activation can be identified, serum markers of inflammation and immune activation are of limited diagnostic usefulness in the evaluation of patients with CFS because changes in their values may reflect an intercurrent, transient, common condition, such as an upper respiratory infection, or may be the result of an ongoing illness-associated process. On the other hand, Patarca and colleagues (Patarca, Klimas, Garcia, Pons, & Fletcher, 1995; Patarca, Klimas, Sandler, Garcia, & Fletcher, 1995) found that CFS patients can be categorized based on immunological findings—particularly cytokines. It is also worth noting that although the degree of overlap between distributions of soluble immune mediators in CFS and controls has fueled criticism on the validity or clinical significance of immune abnormalities in CFS, the latter degree of overlap is not unique to CFS and is also present for instance in sepsis syndrome and HIV-associated disease, clinical entities where studies of immune abnormalities are providing insight into pathophysiology (Goldie et al., 1995).

Proinflammatory Cytokines in CFS Linde and coworkers (1992) reported elevations of serum interleukin-1-alpha (IL-1α) in CFS patients. 52

Patarca, Lugtendorf, Antoni, Klimas, and Fletcher (1994) found elevated levels of IL-1α but not of IL-1β in 17% of 70 patients studied. When the cohort was examined as to severity of symptoms, it was noted that the top quartile in terms of disability had the highest level of IL-1. Curiously, use of reverse transcriptase-coupled polymerase chain reaction (RT-PCR) revealed IL-1β but not IL-1α messenger ribonucleic acid (mRNA) in peripheral blood mononuclear cells (PBMCs) of several CFS patients with highly elevated levels of IL-1α. RT-PCR of fractionated cell populations showed that lymphocytes accounted for the IL-1β mRNA detected in PBMCs. No IL-1 mRNA was apparent in control participants. That IL-1α mRNA was not detectable by RT-PCR in either PBMCs or granulocytes suggests that serum IL-1α in CFS patients is probably derived from a source other than peripheral blood cells. Other potential sources are tissue macrophages, endothelial cells, lymph node cells, fibroblasts, CNS microglia, astrocytes, and dermal dendritic cells (Dinarello, 1991). Rasmussen and his coworkers (1994) found no difference in serum IL-α among 21 patients diagnosed with CFS and 21 healthy controls. Several studies, in addition to the one previously described by Patarca and colleagues (1994), found no difference in the circulating levels of IL-β in CFS patients compared to controls (Linde et al., 1992; Rasmussen et al., 1994; Straus, Dale, Peter, & Dinarello, 1989). Swanink and coworkers (1996) in a study of 76 CFS patients and 69 healthy controls found no obvious difference in the levels of circulating cytokines, and in ex vivo production of IL-1α and IL-1 receptor antagonist (IL-1Ra). Although endotoxin-stimulated ex vivo production of tumor necrosis factor-alpha (TNF-α) and IL-1β was significantly lower in the CFS patients, none of the immunologic test results correlated with fatigue severity or psychologic well-being scores. Swanink et al. concluded that these immunologic tests cannot be used as diagnostic tools in individual CFS patients. Twenty-eight percent of CFS patients studied by Patarca and colleagues (1994) had elevations in serum levels of TNF-α and TNF-β. Expression of TNF-α in CFS patients was evident at the mRNA level, which suggested de novo synthesis rather than release of a preformed inducible surface TNF-α protein on activation of monocytes and CD4+ T cells (Kriegler, Perez, DeFay, Albert, & Lu, 1988). The levels of spontaneously (unstimulated) produced TNF-α by nonadherent lymphocytes were also significantly increased as compared to simultaneously studied matched controls by Gupta, Aggarwal, See, and Starr (1997). A study by Dreisbach, Hendrickson, Beezhold, Riesenberg, and Sklar (1998)

IMMUNOLOGY AND NEUROPSYCHOLOGY OF CHRONIC FATIGUE SYNDROME

suggests that TNF-α may be involved in the pathogenesis of postdialysis fatigue. In contrast to the studies previously discussed, Rasmussen et al. (1994) and Peakman, Deale, Field, Mahalingam, and Wessely (1997) found no difference in the levels of TNF-α or β in CFS patients These discrepancies are likely due to the fact that TNF levels decrease precipitously if the serum or plasma is not frozen within 30 min from collection (Patarca, Sandler, et al., 1995). CFS patients have higher levels of soluble tumor necrosis factors receptor type I (sTNF-RI) or sCD120a and sTNF-RII or sCD120b (Patarca, Klimas, Garcia, et al., 1995; Patarca, Klimas, Sandler, et al., 1995). Levels of sTNF-Rs are negatively correlated with the natural killer cell cytotoxicity (NKCC) and lymphoproliferative activities in blood samples from patients with CFS, an observation that is consistent with the activities of these soluble mediators. TNF-α’s proinflammatory effects may be mediated by induction of gene expression for neutrophil activating protein-1 and macrophage inflammatory proteins resulting in neutrophil migration and degranulation (Dinarello, 1992). Thus, it is reasonable that TNF elevations may also be associated with markers of macrophage activation such as serum neopterin elevations (Patarca, Bell, & Fletcher, 1997). Our work also suggests that TNF mRNAs in CFS patients are produced by activated lymphocytes: TNF proteins correlate significantly (p < .01) with percentages of activated cluster designation (CD)2+CD26+ T cells among CFS patients but not controls. Thus immune system dysregulation or overactivation in CFS patients may be best reflected in a combination of measures that includes cytokine and soluble cytokine receptor levels, serum neopterin to index macrophage activation, and enumeration of activated subsets (e.g., CD8+HLA-DR+, CD8+CD38+, and CD26+CD2+ percentages). Chronic T-cell activation can lead to decreased lymphocyte proliferative responsiveness to specific and nonspecific stimuli and to decreased NKCC (Klimas et al., 1990). Thus, chronic lymphocyte activation with elevated expression of lymphocyte activation markers may relate to impairments in cell-mediated immune functions—proliferative and cytotoxic responses of lymphocytes—that have been observed in CFS (Lloyd, Hickie, Hickie, Dwyer, & Wakefield, 1992; Lloyd, Wakefield, & Hickie, 1993). The types of soluble immune mediator dysfunctions in CFS patients reported by some investigators certainly may be regarded as potentially important in the pathophysiology of the syndrome. Knowledge is accumulating on cytokine–nervous system interactions that may be mediated by endocrine mechanisms

(Berkenbosch, VanOers, del Rey, Tilders, & Besedovsky, 1987; Besedovsky, del Ray, Sorkin, & Dinarello, 1986; Demitrack & Dale, 1991; Kamilaris et al., 1987; Kling et al., 1991; Lowry, Reder, & Gormley, 1988; Uehara, Gottschall, Dahl, & Arimura, 1987). For example, the proinflammatory cytokine IL-1 interacts with cortiocotropin-releasing hormone at the hypothalamus and subsequent hypothalamic pituitary adrenal (HPA) axis activation is hypothesized to follow (Besedovsky et al., 1986). This interaction between cytokines and the HPA axis may act to downregulate inflammatory processes and limit the clonal expansion of antigen-specific lymphoid cells. Conversely, states characterized by dysregulation of the HPA axis and hypocortisolemia may be associated with sustained elevations in cytokines and subsequent physical symptoms (e.g., fatigue) related to pyrogenic and proinflammatory agents (Sternberg, 1993). Glucocorticoid insufficiency is associated with extreme fatigue, onset precipitated by stressors, myalgias, exacerbation of allergic responses, and sleep disturbances (Demitrack & Crofford, 1998; Moldofsky, 1995). It is plausible that persistent cytokine elevations may also contribute to HPA axis dysregulation and that subsequent endocrine abnormalities may relate to some of the physical symptoms of CFS. Of course, the picture is complicated by the possibility that HPA abnormalities may be secondary to the affective disturbance or distress responses of CFS patients that are in turn interacting with the appearance of the physical symptoms just mentioned (Scott & Dinan, 1998; Scott, Medbak, & Dinan, 1998; Visser et al., 1998). The signs and symptoms of CFS, which include fatigue, myalgia, and low-grade fever, are similar to those experienced by patients infused with cytokines such as IL-1. Elevated serum levels of IL-1α found in a significant number of CFS patients could underlie several of the clinical symptoms. IL-1 can gain access to the brain through the preoptic nucleus of the hypothalamus, where it induces fever and the release of adrenocorticotropin hormone (ACTH)- releasing factor (Arnason, 1991; Berkenbosch et al., 1987; Besedowsky et al., 1986; Sapolsky, Rivier, Yamamoto, Plotsky, & Vale, 1987), which in turn would lead to release of ACTH and cortisol. The observation that cortisol levels tend to be low in CFS patients regardless of IL-1α levels suggests a role of a defective hypothalamic feedback loop in the pathogenesis of CFS (Demitrack & Crofford, 1998; Demitrack & Dale, 1991). Besides its effects on the HPA axis, IL-1 has other effects on the pituitary; it has been shown to augment release of prolactin and growth hormone and to inhibit 53

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release of thyrotropin and luteinizing hormone (Bernton, Beach, Holaday, Smallridge, & Fein, 1987; Rettori, Gimeno, Karara, Gonzalez, & McCann, 1991). The growth hormone deficiency state associated with CFS may also be a reflection of a defect in the hypothalamic feedback loop that renders it inadequately responsive to IL-1 (Allain et al., 1997; Buskila, 1999). IL-1 and TNF provoke slow-wave sleep when placed in the lateral ventricles of experimental animals (Shoham, Davenne, Cady, Dinarello, & Krueger, 1987). The inordinate fatigue, lassitude, and excessive sleepiness associated with CFS (Holmes et al., 1988; Moldovsky, 1989) could well be a consequence of the direct action of these cytokines on neurons. IL-1 induces prostaglandin (PGE2, PGI2) synthesis by endothelial and smooth muscle cells (Dejana et al., 1987). These substances are potent vasodilators, and IL-1 administration in animals and humans produces significant hypotension. IL-1 has a natriuretic effect (Caverrzasio, Rizzoli, & Dayer, 1987) and may affect plasma volume, thereby also underlying the cardiovascular manifestations of CFS. TNF-α is implicated in CNS pathology in that it has been associated with demyelination (Beutler & Cerami, 1988). CFS is a condition that affects women in disproportionate numbers and that is often exacerbated in the premenstrual period and following physical exertion. Cannon and co-workers (1997) found that isolated PBMCs from healthy women, but not CFS patients, exhibited significant menstrual-cycle-related differences in IL-1β secretion that were related to estradiol and progesterone levels. IL-1Ra secretion for CFS patients was twofold higher than controls during the follicular phase, 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. The only changes that may be attributable to exertion occurred in the control participants during the follicular phase, who exhibited an increase in IL-1β secretion 48 hr after the stress. These results suggest that an abnormality exists in IL-1β secretion in CFS patients that may be related to altered sensitivity to estradiol and progesterone. Furthermore, the increased release of IL-1Ra and sIL-1RII by cells from CFS patients is consistent with the hypothesis that CFS is associated with chronic, low-level activation of the immune system (Klimas et al., 1990). Rodent studies show that infection-derived sickness behavior, a collection of symptoms reminiscent of those experienced by CFS patients, is caused by the effects on the brain of proinflammatory cytokines, including IL-1, IL-6, and TNF-α (Dantzer, 2000). The 54

hypothesis that expression of proinflammatory cytokines within the CNS plays a role in the pathogenesis of immunologically mediated fatigue is underscored by the study by Sheng, Hu, Lampkin, Peterson, and Chao (1996), who, using two strains of mice with differential patterns of cytokine expression in response to an injection challenge with Corynebacterium parvum, demonstrated that elevated IL-1 and TNF cytokine mRNA expression in the CNS corresponded to development of fatigue. Injection of antibodies specific to either IL-1 or TNF did not alter immunologically induced fatigue, suggesting a lack of involvement of these cytokines produced outside of the CNS.

Type 1 Cytokines in CFS Serum IL-2 levels were found to be elevated in CFS patients compared with controls in one study (Chenry, Dorman, & Bell, 1989), decreased in two studies (Gold et al., 1990; Kibler, Lucas, Hicks, Poulos, & Jones, 1985), and no difference was reported in three studies (Linde et al., 1992; Patarca et al., 1994; Strauss et al., 1989). Rasmussen and coworkers (1994) reported a higher production of IL-2 by stimulated peripheral blood cells from CFS patients as compared to controls. Symptoms of depression and elevated plasma levels of several cytokines are induced in cancer patients undergoing immunotherapy with IL-2 (Neveu et al., 2000). Cheney and coworkers (1989) found no obvious relation between IL-2 serum levels and severity or duration of illness in CFS. Elevated levels of soluble interleukin-2 receptor (sIL-2R), a marker of lymphoid cell activation, have been found in a number of pathological conditions, including viral infections, autoimmune diseases, and lymphoproliferative and hematological malignancies (Pui, 1989). Twelve percent of CFS patients studied by Patarca and coworkers (1994) had elevated levels of sIL-2R. The latter observation is consistent with the increased proportion of activated T cells and the reduced levels of IL-2 or decreased NKCC activity found in several studies of CFS patients discussed previously. Linde and coworkers (1992) found no elevation in sIL-2R levels in CFS patients. The interferons (IFN) are a multigenic family with pleiotropic properties and diverse cellular origin. Data from six studies indicate that circulating IFNs are present in 3% or less of patients studied (Aoki, Usuda, Miyakashi, Tamura, & Herberman, 1987; Borysiewicz et al., 1986; Buchwald & Komaroff, 1991; Ho-Yen, Carrington, & Armstrong, 1988; Jones & Strauss,

IMMUNOLOGY AND NEUROPSYCHOLOGY OF CHRONIC FATIGUE SYNDROME

1987; Lloyd, Hanna, & Wakefield, 1988). Vojdani, Ghoneum, Choppa, Magtoto, and Lapp (1997) found elevated IFN-α levels in CFS patients. Fatigue occurs in more than 70% of patients treated with IFN-α. IFN-α therapy-associated fatigue is often the dominant dose-limiting side effect, worsening with continued therapy, and accompanied by significant depression. Although the direct cause of IFN-α-induced fatigue is unknown, it is possible that neuromuscular fatigue, similar to that observed in patients with postpolio syndrome, may also be one component of this syndrome. The induction of proinflammatory cytokines observed in patients treated with IFN-α is consistent with a possible mechanism of neuromuscular pathology that could manifest as fatigue. A study by Davis et al. (1998) also revealed that IFN-α/β is at least partially responsible for the early fatigue induced by polyI:C during prolonged treadmill running in mice. IFN-γ is an immunoregulatory substance, enhancing both NK cell cytotoxicity (Targan & Stebbing, 1982) and causing inhibition of suppressor T lymphocyte activity (Knop, Stremer, Nauman, deMaeyer, & Macher, 1982). Two groups have found impaired IFN-γ production on mitogenic stimulation of PBNCs from CFS patients (Klimas et al., 1990; Visser et al., 1998). Shown in Figure 1 are results from our laboratory comparing IFN-γ production by CFS patients and controls in vitro following stimulation of whole blood cultures with either phytohemagglutinin (PHA) or pokeweed mitogen (PWM). In contrast with the findings on lymphocyte activation, four groups reported no difference in the levels of

Figure 1.

circulating plasma IFN-γ (Linde et al., 1992; Peakman et al., 1997; Strauss et al., 1989; Visser et al., 1998). Overall, the results are in favor of a Th2 shift—but a shift that is not apparent by measuring plasma cytokine levels.

Type 2 Cytokines, IL-4, IL-5, IL-6, and IL-10 in CFS Visser and colleagues (1998) reported that although CD4 T cells from CFS patients produce less IFN-γ than cells from controls, IL-4 production and cell proliferation are comparable. With CD4 T cells from CFS patients (compared with cells from controls), a 10- to 20-fold lower dexamethasone (DEX) concentration was needed to achieve 50% inhibition of IL-4 production and proliferation, indicating an increased sensitivity to DEX in CFS patients. In contrast to IL-4, IFN-γ production in patients and controls was equally sensitive to DEX. A differential sensitivity of cytokines or CD4 T cell subsets to glucocorticoids may explain an altered immunologic function in CFS patients. IL-4 acts as a growth factor for various types of lymphoid cells, including B, T, and cytotoxic T cells (Paul & Ohara, 1987), and it has been shown to be involved in immunoglobulin isotype selection in vivo (Keuhn, Rajewsky, & Mueller, 1991). Although activated T cells are the major source of IL-4 production, mast cells can also produce it, and IL-4 has been associated with allergic and autoimmune reactions (Paul & Ohara, 1987). It is also noteworthy that many of the effects of IL-4 are antagonized by IFN-γ, and the decreased pro-

Type 1 cytokine (interferon gamma) production in response to mitogens.

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duction of the latter may underlie a predominance of IL-4 over IFN-γ effects. The levels of spontaneously produced IL-6 by both adherent monocytes and nonadherent lymphocytes were significantly increased in CFS patients as compared to controls (Gupta et al., 1997). The abnormality of IL-6 was also observed at mRNA level. In the same patients, spontaneously produced IL-10 by both adherent monocytes and nonadherent lymphocytes and by PHA-activated nonadherent monocytes were decreased. In terms of circulating IL-6, Buchwald and coworkers (1997) found that IL-6 was elevated among febrile CFS patients compared to those without this finding and therefore considered it an epiphenomenon possibly secondary to infection. Of possible interest in this regard is the observation of Patarca and Fletcher (1998) that IL-6 was greatly elevated in a patient with hypothermia. Chao and coworkers (Chao, Gallagher, Phair, & Peterson, 1990; Chao et al., 1991) also found elevated plasma IL-6 in CFS patients, but other groups found no difference (Buchwald et al., 1997; Linde et al., 1992; Patarca et al., 1994; Peakman et al., 1997). CFS patients have higher levels of sIL-6R (Patarca, Klimas, Garcia, et al., 1995), and sIL-6R enhances the effects of IL-6. Most of the cell types that produce IL-6 do so in response to stimuli such as IL-1 and TNF, among others (Mizel, 1989). Excessive IL-6 production has been associated with polyclonal B-cell activation, resulting in hypegammaglogulinemia and autoantibody production (Van Snick, 1989). As is the case with IL-4, IL-6 may contribute to activation of CD5-bearing B cells, leading to autoimmune manifestations. IL-6 also synergizes with IL-1 in inflammatory reactions and may exacerbate many of the features described previously for IL-1. Study of cytokine production by stimulated PBMCs from patients with a closely related syndrome to CFS, the post-Q-fever fatigue syndrome (QFS; inappropriate fatigue, myalgia and arthralgia, night sweats, changes in mood and sleep patterns following about 20% of laboratory-proven, acute primary Q-fever cases), showed an accentuated release of IL-6 that was significantly in excess of medians for all four control groups (resolving QFS, acute primary Q-fever without subsequent QFS, healthy Q-fever vaccines, and healthy controls). Levels of induced IL-6 significantly correlated with total symptom scores and scores for other key symptoms (Penttila et al., 1998). Prior studies from this laboratory suggested a CFS-associated shift in the cytotoxic cell and macrophage-oriented predominant Type 1 response (IL-γ) to a B cell- and mainly IgE-oriented Type 2 re56

sponse with elevated IL-5 (Klimas, Patarca, & Fletcher, 1996). Conti, Magrini, Valesini, and Bonini (1996) provided evidence for eosinophil activation in CFS by demonstrating elevated serum levels of eosinophil cationic protein (ECP). In the CFS population they studied, the prevalence of radioabsorbentest (RAST) positivity to one or more allergens was 77%, whereas no control showed positive RAST. Twelve of the 14 CFS patients with increased ECP serum levels were RAST-positive. However, CFS RAST-positive patients had no significantly higher ECP serum levels than CFS RAST-negative patients. It remains to be determined whether eosinophil activation has a pathogenetic role in CFS or whether a common immunologic background may exist for both atopy and CFS. Although a higher prevalence of allergy (Steinberg, Pheley, & Peterson, 1996) and delayed type hypersensitivity (Lloyd et al., 1992; Lloyd, Wakefield, Boughton, & Dwer, 1989) can be detected in CFS patients, a trial with antihistamine treatment did not provide significant improvement (Steinberg et al., 1996), and other authors such as Mawle and coworkers (1997) found no significant difference in the incidence of delayed type hypersensitivity and allergic responses among CFS patients. Baraniuk, Clauw, and Gaumond (1998) found that 30% of CFS patients had positive skin tests suggesting the potential for allergic rhinitis complaints, and 46% had nonallergic rhinitis. They suggested that whereas atopy may coexist in some CFS participants, it is unlikely that it plays a causal role in CFS pathogenesis. Borish et al. (1998) proposed that in at least a large subgroup of participants with CFS with allergies, the concomitant influences of immune activation brought on by allergic inflammation in an individual with the appropriate psychologic profile may interact to produce the symptoms of CFS. Borok (1998) suggested that food intolerance, in a genetically predisposed group of people, causes symptoms akin to both the major and minor criteria of CFS, and it should be screened for to avoid confusion. Although the controversy of atopy and CFS continues, it may be possible that these two conditions share some common denominators that are worth pursuing, particularly in light of the proposed Type 2 cytokine predominant pattern. Low NKCC has been reported in studies of CFS (Caliguri, Murray, & Buchwald, 1987; Klimas et al., 1990; Salvato, Klimas, Ashman, & Fletcher, 1988; Tarsis, Klimas, Baron, & Fletcher, 1987) as well as another condition resembling CFS—low NK syndrome (LNKS; Aoki et al., 1987). Poor NK cell function may be related to a shift in the Type 1 to Type 2 cytokine pattern of lymphocytes from CFS. Downregulation of

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the Type 1 cytokines with subsequent impairment of NKCC may result in persistent activation of ubiquitous viruses—particularly herpes viruses, a theory that is supported by the elevation of leukocyte 2’5’ oligoadenylate synthetase, an IFN-induced enzyme in lymphocytes of CFS patients (Morag, Tobi, Ravid, Ravel, & Schattner, 1982). Pursuing the hypothesis that the low-grade fever and fatigue in LNKS—a condition resembling CFS in many but not all ways—may be abrogated by interventions that normalize NK functioning, one group has tested the effects of immunopotentiators with patients diagnosed with LNKS. They found in single-blind trials (contents of medication were not revealed to patients) that although the administration of antipyretics, nonsteroidal anti-inflammatory drugs, or antibiotics had no detectable effects on fever, lentinan, a glucon extracted from Japanese mushrooms, improved clinical symptoms and increased NKCC and antibody-dependent cellular cytotoxicity in patients with LNKS (Miyakoski, Aoki, & Mizukoshi, 1984). Although preliminary, this is one of the only studies to document parallel improvement in CFS-like clinical symptoms and NKCC following an experimental manipulation. However, this study did not focus specifically on CDC-diagnosed CFS patients. The decreased NKCC and lymphoproliferative activities and increased allergic and autoimmune manifestations in CFS would be compatible with the hypothesis that the immune system of affected individuals is biased toward a Type 2 type, or humoral immunity-oriented cytokine pattern (Rook & Zumla, 1997). The factors that could lead to a Type 2 shift and to mood changes associated with immunoendocrine changes among CFS patients are unknown. Vaccines and stressful stimuli have been shown to lead to long-term, nonspecific shifts in cytokine balance. Therapeutic regimens that induce a systemic Type1 bias are being tested, including poly(I)-poly (C12U; Vojdami & Lapp, 1999) and ex vivo activation of lymph node cells (Klimas & Fletcher, 1999).

current case definition for CFS and the following inclusion criteria: (a) a history of acute onset; (b) a Karnofsky score < 80 (Karnofsky, Abelmann, Craver, & Burchenal, 1948); (c) evidence of immune dysfunction in three or more of the following: > 1 SD above controls for elevated sTNF-RI in serum, elevated sTNF-RI in PHA stimulated blood culture or elevated IL-5 in PHA stimulated blood culture; or lymphocyte activation (CD2+CD26+ cells > 50%); or low NKCC (< 20%). The lymph node cells were cultured for 10 to 12 days with anti-CD3 and IL-2. These cells were then reinfused into the donor, who was monitored for safety and possible clinical benefit. There were no adverse events noted in this Phase 1 clinical trial. Of 13 participants, 2 had palpable lymph nodes that proved fibrotic with no viable cells. Of the remaining 11 participants, all successfully underwent expansion and reinfusion. Of the 11 participants, 9 had cognitive improvement. There was a trend toward significant change in speed of visual scanning (Trail Making Test A). Shown in Figure 2 is the significant increase in the patients’ ability to mentally track and rapidly shift cognitive set as measured by Trail Making Test B (Army Individual Test Battery, 1944). Measures of severity of illness also demonstrated improvement. There was a significant increase in Karnofski scores (see Figure 3) and in the Quality of Life scale (see Figure 4) from the Sickness Impact Profile (SIP; Bergner et al., 1982). There was a significant decrease in IL-5 production by PHA-stimulated blood cultures observed at 1 week, which persisted for several weeks postinfusion (Figure 5). PHA induced IFN-γ did not change. But, because of the drop in IL-5, there was a trend toward a decrease in

Experimental Therapy Results in an Apparent Shift in the Cytokine Pattern from Type 1 to Type 2 Recently we completed a safety and feasibility study using lymph node extraction, ex vivo cell culture, followed by autologous cell reinfusion as a treatment strategy in CFS patients (Klimas & Fletcher, 1999). Lymph nodes were obtained from patients who met the

Figure 2. Effect of adoptive lymph node cell transfer on Trail Making Test B for 11 CFS patients at baseline and 24 weeks posttransfer.

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the ratio of IFN-γ/IL-5 starting at Week 1 and persisting for at least 12 weeks. The lack of adverse effects from this experimental approach to immunomodulation in CFS and the favorable clinical and immunologic results observed in the small number of patients studied suggest that further clinical trials are warranted.

Cytokines, Other Immune Markers, Stressors, and Symptoms

Figure 3. Effect of adoptive lymph node cell transfer on Karnofski scores for 11 CFS patients at baseline and 12 weeks posttransfer.

Figure 4. Effect of adoptive lymph node cell transfer on Quality of Life scale for 11 CFS patients at baseline and 12 weeks posttransfer.

Figure 5. IL-5 production following PHA changes 12 weeks from transfer of autologous lymph node cells.

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Our model holds that the interaction of psychological factors (distress associated with either CFS-related symptoms or other stressful life events) and immunologic dysfunction (indicated in signs of chronic overactivation with cytokine abnormalities) contribute to (a) CFS-related physical symptoms (e.g., fatigue, joint pain, cognitive difficulties, fever) and increases in illness burden; and (b) dysfunction in the immune system’s ability to survey viruses, including latent herpes viruses (indicated in impaired NKCC). As discussed previously, there is a decrease in the ratio of Type 1/Type 2 cytokines produced by lymphocytes in vitro following mitogen stimulation in CFS patients. This type of dysfunction should be expected to result in impaired immune surveillance associated with cytotoxic lymphocytes. For example, Cohen, Tyrrell, and Smith (1991) found an association among psychosocial stressors, immunomodulation, and the incidence and progression of rhinovirus infections in healthy normals. Here, the rates of respiratory infections and clinical colds increased in a dose–response fashion with increases in psychological stress across all five of the cold viruses studied. If viruses related to upper respiratory infections are not well controlled by immune surveillance mechanisms (e.g., NKCC) in CFS patients who are exposed to stressors, then patients may suffer more frequent and protracted upper respiratory infections that are accompanied by prolonged elevations in proinflammatory cytokines. Stress-associated reactivation of latent herpes viruses may also play a role in modulating the production of cytokines that underlie CFS symptom exacerbations. Alternatively, distress increases may more directly influence cytokine dysregulation, by way of neuroendocrine changes, which in turn intensify physical symptoms. Important for all of these possible paths, further increases in distress as a “reaction” to mounting symptoms create a vicious cycle. Such a recursive system may act as a positive feedback loop, thereby accounting for the

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chronic nature of CFS and its refraction to interventions focusing solely on symptom reduction. Our conceptual model for CFS was supported by data in our lab showing that distress levels in response to the stressor Hurricane Andrew were positively correlated with alterations in NK cells and elevated (compared to prestorm values) circulating levels of the cytokines; exacerbation in CFS symptoms; and increases in SIP-based illness burden scores among 49 CFS patients (Lutgendorf et al., 1995). We found that CFS patients living in a hurricane exposure area (Dade County) had significantly greater severity of CFS symptom relapses (using clinician-rated fatigue levels and ability to engage in work-related activities) and significantly greater increases in illness burden as compared to age- and gender-matched CFS patients from the same clinical practice living in an adjacent geographical region that was not in the storm’s path, Broward County and Palm Beach County. We also found that pre–post hurricane NKCC changes were associated with pre–post storm symptom severity changes, including patient-reported cognitive symptoms (r = –.54, p < .01), muscle weakness (r = –.61, p < .01), and muscle pain (r = –.43, p < .05). These data suggested that stressor-induced decrements in NKCC were associated with greater increases in the severity of perceived cognitive difficulties, muscle weakness, and pain symptoms. A final regression analysis on NKCC indicated that appraisals of greater storm impact and low social support predicted the greatest pre–post storm decrements in NKCC (total R2 = .35, p < .01). Avoidance coping predicted higher levels of IL-6. Higher degrees of negative emotions conveyed through essays predicted greater SIP total, physical, and psychosocial symptoms and displayed a trend toward higher IL-6 levels. In another cohort of 30 CFS patients given a comprehensive immunologic and psychosocial evaluation, Hamilton Depression scale, and Profile of Mood States (POMS; McNair, Lore, & Droppleman, 1971), depression subscale scores were negatively correlated with mitogenic response to PWM, as well as B cell number (ps < .05; Klimas, Patarca, & Fletcher, 1992). The POMS Fatigue and Anxiety scores were negatively correlated with NK cell number, and NKCC, whereas the POMS Vigor subscale was correlated positively with both PHA and PWM responses. NKCC was negatively correlated with the use of avoidant, passive aggressive, and self-defeating coping styles. We also studied the association among CFS physical symptoms, illness burden, and lymphocyte activation

markers in 27 newly recruited CFS patients (Wagner, Helder, Klimas, Antoni, & Keller, 1999). Elevations in T-helper and inducer cells were associated with a greater frequency and severity of tender lymph nodes, greater severity of memory, and concentration difficulties and headaches (rs = .35 to .46). Greater numbers of activated T cells (CD2+CD3+CD26+) were associated with a greater frequency of tender lymph nodes (r = .52) and cognitive difficulties (r = .34), whereas more activated cytotoxic and suppressor cells (CD38+HLADR+CD8+) were associated with greater severity of tender lymph nodes (r = .45), fatigue (r = .34), and sleep problems (r = .34). Conversely, lower percentage of regulatory cells such as CD3+CD8 cells was associated with a greater number of cognitive difficulties (r = –.61), greater SIP-Total (r = –.47), SIP Physical Impairment (r = –.39), and an increased frequency (r = –.43) and severity of memory problems (r = –.43), increased frequency of headaches (r = –.70), and increased severity of fatigue (r = –.39). A multiple regression equation predicted 29% of the variance in fatigue severity from higher CD38+HLADR+CD8+ cells (r = .41) and lower CD3+CD8+ cells (r = –.41).Thus, among CFS patients the degree of cellular immune activation is associated with the severity of CFS-related physical symptoms, cognitive complaints, and perceived illness burden. Our laboratory found that other indexes of immune system dysregulation—greater serum neopterin levels and reduced lymphocyte proliferative responses to mitogens—are related to the severity of perception of cognitive difficulties in CFS patients (Lutgendorf, Klimas, Antoni, Brickman, & Fletcher, 1995). The Cognitive Difficulties Scale (CDS) was used (McNair & Kahn, 1983). This is a 39-item self-report behavioral questionnaire assessing the extent of everyday difficulties in attention, concentration, and memory. We determined that the CDS tapped objective cognitive difficulties in short-term memory, sustained attention, and ability to deal with interference. For example, correlations showed that higher CDS scores were significantly associated with poorer performance on a 90-min delayed recall task (r = –.28, p < .01). Patients with greater CDS scores also showed greater impairment on the Karnofsky scale (p < .03). Importantly, we demonstrated that higher scores were associated with greater physical illness burden and that these findings held after statistically controlling for a Diagnostic and Statistical Manual of Mental Disorders (3rd ed.; American Psychiatric Association, 1981) diagnosis of major depressive disorder and after controlling for degree of depressed affect as measured on psychiatric interview. In 59

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a sample of 65 CFS patients, we observed that decreased lymphocyte proliferative responses to the mitogens PHA (Figure 6) and PWM were associated with increased cognitive difficulties and greater SIP physical illness burden, and these relations were significant after controlling for SCID-based major depression disorder and interviewer-rated depression severity (Hamilton Depression scale). Subsequent analyses of this sample revealed that TNF-α levels were associated with other signs of immune system dysregulation: elevated B-lymphoctyes (CD20) and activated T-cell counts (CD2+CD3+CD26+). Thus elevations in immunoregulatory cytokines appear to be associated with alterations in lymphocyte activation markers and cellular immune system functioning.

Conclusions The data summarized herein indicate that CFS is associated with immune abnormalities that can potentially account for neuropsychopathological symptomatology. What is needed, however, are studies that begin to relate the kinds of immunological abnormalities previously outlined with psychological and neuropsychological functioning. Assessment of immune status reveals a heterogeneity among CFS patients that allows their categorization, thus systematizing the study of the interactions among immune, psychological, and physiological parameters in this disorder. The study of immune status at different levels also provides an integrated view of this complex syndrome and is opening doors for deciphering its cause and for developing rational treatment protocols. Future re-

Figure 6. Lymphocyte proliferation in response to PHA: Mean (± SD) net CPM in CFS patients scoring above or below the mean on cognitive difficulties scale.

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search should further elucidate the cellular basis for immune dysfunction in CFS and its implications. Other compartments such as the CNS have to be assessed using similar techniques to those used with peripheral blood. Further studies are needed that probe the relations between immunologic dysfunction and the neuropsychopathology of CFS. Neuropsychology should play a key role in the conduct of such future studies. References Allain, T. J., Bearn, J. A., Coskeran, P., Jones, J., Checkley, A., Butler, J., Wessely, S., & Miell, J. P. (1997). Changes in growth hormone, insulin, insulin-like growth factors, and IGF-binding protein-1 in chronic fatigue syndrome. Biological Psychiatry, 41, 567–573. American Psychiatric Association. (1981). Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: Author. Aoki, T., Usuda, Y., Miyakashi, H., Tamura, K., & Herberman, R. B. (1987). Low natural syndrome: Clinical and immunologic features. Natural Immunity and Cell Growth Regulation, 6, 116–128. Army Individual Test Battery. (1944). Trail Making Test (A and B) manual of directions and scoring. Washington, DC: War Department, Adjutant General’s Office. Arnason, B. G. W. (1991). Nervous system–immune system communication. Reviews in Infectious Diseases, 13, S134–S137. Baraniuk, J. N., Clauw, D. J., & Gaumond, E. (1998). Rhinitis symptoms in chronic fatigue syndrome. Annals of Allergy, Asthma and Immunology, 81, 359–365. Bergner, M., Bobbitt, R. A., Carter, W. B., & Gilson, B. S. (1982). The Sickness Impact Profile: Development and final revision of a health status measure. Medical Care, 19, 787–805. Berkenbosch, F., VanOers, J., del Rey, A., Tilders, F., & Besedovsky, H. (1987). Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science, 238, 524–526. Bernton, E. W., Beach, J., Holaday, J. W., Smallridge, R. C., & Fein, H. G. (1987). Release of multiple hormones by a direct action of interleukin-1 on pituitary cells. Science, 238, 519–521. Besedovsky, H., del Ray, A., Sorkin, E., & Dinarello, C. A. (1986). Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science, 233, 652–654. Beutler, B., & Cerami, A. (1988). Cachectin (tumor necrosis factor): A macrophage hormone governing cellular metabolism and inflammatory response. Endocrinology Reviews, 9, 57–66. Borish, L., Schmaling, K., DiClementi, J. D., Streib, J., Negri, J., & Jones, J. F. (1998). Chronic fatigue syndrome: Identification of distinct subgroups on the basis of allergy and psychologic variables. Journal of Allergy and Clinical Immunology, 102, 222–230. Borok, G. (1998). Chronic fatigue syndrome: An atopic state. Journal of Chronic Fatigue Syndrome, 4, 39–58. Borysiewicz, L. K., Haworth, S. J., Cohen, J., Munin, J., Rickinson, A., & Sissons, J. G. (1986). Epstein–Barr virus—Specific immune defects in patients with persistent symptoms following infectious mononucleosis. Quarterly Journal of Medicine, 58, 111–121.

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Original submission October 29, 1999 Accepted July 20, 2000

Appendix Definitions Chronic fatigue syndrome (CFS). A disorder of unknown etiology characterized by severe disabling fatigue of at least 6 months duration and associated with self-reported muscle pain and both objective and subjective disturbances of cognition and sleep. Frequently, patients with CFS have immune activation and associated immune dysfunction. Cytokines. Small molecular weight glycopeptides produced by lymphocytes, monocytes, and other cells that modulate immune, neuron, and endocrine cells. Proinflammatory cytokines. The major cytokines associated with inflammation and fever are tumor necrosis factor-alpha (TNF-a) and interleukin-1-alpha and beta (IL-1-a and b), which are produced by monocytes and lymphocytes in response to infection, trauma, or stress. Type 1 cytokines. Lymphocytes are the major source of IL-2, IL-12 and interferon-gamma (IFN-g), which are cytokines associated with enhancement of cellular immunity including T cell proliferation and cytolytic activity of both T cells and natural killer cells. 63

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Type 2 cytokines. Also produced by lymphocytes, cytokines such as IL-4, IL-5, IL-6 and IL-10 can stimulate B cell activity, promote humoral (antibody) immunity but also allergic reaction. Cognitive Difficulties Scale (CDS). A self-report behavioral questionnaire assessing the extent of everyday difficulties in attention, concentration, and memory. Sickness Impact Profile (SIP). A behavioral-based inventory that assesses the degree to which individuals report that various aspects of their daily activities have been compromised by their illness.

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Natural killer (NK) cells. Large, granular lymphocytes that have the ability to kill target cells, including virus-infected cells and tumor cells but not normal cells. Immune activation. Exposure of lymphocytes and monocytes to antigen, to stress hormones, or to cytokines can result in cell proliferation, in expression of phenotypic markers on their cell surfaces, such as CD26, CD38 or HLA/DR, in release of soluble substances such as other cytokines, b-2-microglobulin or neopterin. Chronic immune activation can result in loss of immune function.