Study Measures

Participants completed the following questionnaires about their general health at study entry:

1. Pediatric Quality of Life Inventory (PedsQL): The PedsQL is a brief, 23-item, multidimensional child self-report instrument for measuring HRQOL (22). The 23-item assessment examines how much of a problem the child has experienced in the past month with health and activities, feelings, ability to get along with others (which includes social relations, and stamina), and school functioning (cognition, attendance). Responses to each item range from 0 (never) to 4 (almost always). Raw scores are transformed to total scores that range from 0 to 100, with higher scores indicating better quality of life. Five subscales within the PedsQL address physical, emotional, social, school, and psychosocial functioning. The questionnaire is available in age-appropriate formats (Child Report for ages 8–12, Teen Report for 13–18, or Young Adult for 18–24 years). This instrument is reliable, valid and commonly used in pediatric ME/CFS and other pediatric chronic illness populations (10, 11, 23, 24).

2. Functional Disability Inventory (FDI): This one-page, 15-item self-report instrument for children and adolescents asks whether in the past 2 weeks respondents had any physical trouble or difficulty doing specific activities, such as walking up stairs, being at school all day, walking the length of a football field, or going shopping (25). Responses are scored as: 0 = no trouble, 1 = a little trouble, 2 = some trouble, 3 = a lot of trouble, 4 = impossible. The total score ranges from zero (no difficulty with any activity) to 60 (all activities impossible). The FDI has good reliability and validity. It has been used to study a variety of pediatric health problems, including chronic pain and ME/CFS (8, 26, 27).

3. Wood Mental Fatigue Inventory (WMFI): This questionnaire asks subjects to rate the frequency of nine mental fatigue symptoms in the past month on a Likert scale ranging from not at all (0) to very much (4). Higher scores indicate worse cognitive difficulty (28). This measure has been shown to discriminate effectively between ME/CFS patients who are ill and ME/CFS patients who have recovered (29), to correlate with overall well-being in adolescents and adults with ME/CFS (30), and to correlate with the degree of reported brain fog among those with postural tachycardia syndrome (31).

4. Child Depression Inventory (CDI): This 27 item, self-administered instrument measures the mood of the respondent over the preceding 2 weeks (18). The measure assesses behavioral and cognitive signs of depression, applicable to pediatric populations aged 7–17 years. Scores on the 27 items are ranked from 0 (best) to 2 (worst). T-scores of 65 or higher are considered clinically significant (19).

5. Beck Depression Inventory II (BDI): This self-administered, 21-item scale of depression has been validated in adolescents age 13 and older (20). Respondents rank the severity of individual symptoms of depression (including sadness, loss of pleasures, guilty feelings, self-dislike, indecisiveness, loss of energy, concentration difficulty, and fatigue) on a 0–3 scale. Scores of 14–19, 20–28, and 29–63 indicate mild, moderate, and severe depression, respectively (21).

6. PedsQL Multidimensional Fatigue Scale (MFS): This brief, one-page questionnaire measures how much of a problem individuals have had with specific tasks that reflect general fatigue, sleep and rest, and cognitive fatigue, and total fatigue over the preceding month (32). The questionnaire is valid for patients aged 13–18, as well as for college-aged populations (33). Responses on the 18 items range from 0, never a problem, to 4, almost always a problem. As with the PedsQL, the MFS raw scores are transformed to a 0 to 100 scale, with higher scores indicating less fatigue.

7. ME/CFS Symptom Assessment: All participants responded to a study questionnaire that assessed the frequency of Fukuda criteria CFS symptoms as well as lightheadedness in the 2 weeks before study enrollment. Possible responses for the frequency of lightheadedness, fatigue, body aches, joint aches, headaches, or trouble thinking, remembering, or concentrating, were: (a) all day long, every day, (b) several times a day, every day, (c) once or twice a day, every day, (d) several times a week, but not every day, (e) once or twice a week, (f) I haven't had [this symptom]. For the frequency of sore throats and tender glands, possible responses were: (a) every day, (b) more than 5 days but not every day, (c) a few days (2–5), (d) once, or (e) I have not had [this symptom]. For post-exertional malaise (PEM), we focused on physical activity as the trigger, and asked: “In the last 2 weeks, after mild exercise how often have you felt prolonged fatigue or a feeling of illness that lasts longer than 24 h?” Possible responses were (a) 4 or more times, (b) 2 to 3 times, (c) once, (d) never. For unrefreshing sleep, we asked, “In the last 2 weeks, upon awakening after a night's sleep how frequently have you felt refreshed?” Possible responses included (a) all of the time, (b) most of the time, (c) some of the time, (d) none of the time.

Other Measurement Criteria

Prevalence of Fukuda Features

Using cut-points that were closest to symptoms being present at least half the time, Table 2 shows the rank order of the prevalence of Fukuda criteria symptoms for the 55 with ME/CFS and the 55 HC. As expected, those with ME/CFS had greater self-reported prevalence of all symptoms compared to HC. Of note, those with ME/CFS were most likely to report fatigue, unrefreshing sleep, PEM, and cognitive impairment, and were least likely to report sore throat, joint aches, and tender glands. Among controls, 15–20% endorsed unrefreshing sleep, body and joint pain, lightheadedness, and headaches several times per week.

HRQOL Comparisons Between ME/CFS Participants and Healthy Controls

Of the 55 with ME/CFS, 21 (38%) had changed from regular schooling due to their symptoms: seven (13%) had switched from full-time to part-time schooling, and 14 (25%) had received home tutoring. Figure 1 shows that the PedsQL total and subscale scores were significantly lower for those with ME/CFS than for healthy individuals (all P < 0.001). As displayed in Table 3, the scores on all other measures showed significantly worse HRQOL for those with ME/CFS than for healthy controls (P < 0.001).

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Figure 1

PedsQL total and subscale scores for those with ME/CFS and healthy controls.

The study design excluded controls if they met criteria for depression, invalidating comparisons with the ME/CFS group. Of those with ME/CFS, 54/55 completed the BDI, the mean (SD) score for which was 15.3 (7.6). Forty-three percent had scores <14, 31% had scores from 14 to 19, 20% had scores from 20 to 28, and 6% had scores of 29 or higher. One child who was too young to complete the BDI had a normal CDI score. There was a significant negative correlation of the BDI with the PedsQL total score (r = −0.68; P < 0.001). Seven of the 46 (15%) who completed the CDI had T-scores in the clinically significant range of ≥65.

HRQOL Comparisons With Other Pediatric ME/CFS Studies

Table 4 illustrates the scores for the ME/CFS participants and HC from other studies that use the PedsQL to measure HRQOL in this illness. The PedsQL total score was slightly lower for the study populations from Norway and Australia than for our cohort. The relative pattern of subscale results was similar for those with ME/CFS participants in all studies, identifying relatively lower results for school function, and physical function than for social or emotional function.

The mean (SD) FDI score in this study was 21 (10), which was similar to the means of 24.0 (9.2) and 23.1 (9.2) for the 60 Norwegian ME/CFS adolescents in each group randomized to clonidine or placebo, respectively (27). Among 68 HC in that study, the mean FDI score was 1.6 (3.1). These results were also similar to the mean score of 24 in a sample of 20 with ME/CFS reported from the UK (8).

Relationship of PEM, Cognitive Impairment, and Lightheadedness to HRQOL

To further investigate the interaction between the proposed core ME/CFS criteria and HRQOL, we examined whether greater frequencies of PEM, cognitive impairment, and lightheadedness were associated with worse scores on the various measures. Figure 2A shows that those reporting more frequent PEM in the preceding 2 weeks had significantly lower scores on the PedsQL (ANOVA F score = 10.73; P = 0.0001). Post-hoc comparisons using the Bonferroni test indicated that PedsQL scores were lower in those reporting PEM at least four times in 2 weeks than those reporting PEM 0-1 time (P < 0.001) or 2–3 times (P = 0.001), but not significantly different between those reporting PEM 2–3 times and 0–1 time (P = 0.78).

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Figure 2

HRQOL measured by (A), Peds QL total score, and (B), FDI, according to self-reported frequency of post-exertional malaise (PEM) in the preceding 2 weeks.

A significant association was also present for the relationship between the frequency of PEM in the past 2 weeks and scores on the FDI (Figure 2B) (ANOVA F score = 26.1; P < 0.0001). Post-hoc comparisons using the Bonferroni test indicated that FDI score was lower in those reporting PEM at least four times in 2 weeks than those reporting PEM 0–1 time (P < 0.001) or 2–3 times (P < 0.001), but not significantly different between those reporting PEM 2–3 times and 0–1 time (P = 0.18).

As shown in Figure 3A, the relationship of cognitive impairment with the PedsQL total score was weaker (ANOVA F score = 4.55; P = 0.02), as was the relation between the frequency of lightheadedness and the PedsQL total score (Figure 3B; ANOVA F score = 2.72; P = 0.08).

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Figure 3

HRQOL measured by PedsQL total score according to (A), self-reported frequency of trouble thinking and concentrating, and (B), self-reported frequency of lightheadedness, both in the preceding 2 weeks.

Measuring the IOM Criteria

Table 5 shows the prevalence of impaired function, unrefreshing sleep, PEM, cognitive impairment, and orthostatic intolerance according to the methods we used for operationalizing the IOM criteria. Along with self-reported frequency of unrefreshing sleep, PEM, and the other core symptoms, we defined a substantial impairment in function as a questionnaire score that was 2 SD worse than the mean of healthy controls for the PedsQL (scores of 70 or below) or the FDI (scores of eight or higher). To supplement the self-reported frequency of trouble thinking and concentrating, we also used score of 2 SD worse than the mean for healthy controls on the WMFI (scores >8) or the MFS (scores of <63).

Of those with ME/CFS, 82% reported a frequency of cognitive impairment (difficulty thinking and concentrating) of at least several times per week vs. just 2% of healthy controls. Combining the self-reported symptom frequency with a WMFI or MFS cognitive subscale >2 SD worse than the mean for healthy controls identified six additional ME/CFS participants and five additional controls as meeting the criteria for trouble thinking and concentrating. As expected, there was a strong negative correlation between the WMFI scores and the cognitive subscale of the PedsQL MFS (r = −0.90; P < 0.001).

Lightheadedness at least several times per week was endorsed by 42/55 (76%) of those with ME/CFS. Four others who reported lightheadedness 1–2 times per week or less met other criteria for orthostatic intolerance: two had been diagnosed with NMH before study entry and were being treated with fludrocortisone at the time of the symptom questionnaire, and two others had a history of recurrent syncope in the presence of a structurally normal heart and were being treated with an increased intake of sodium and fluids at the time of questionnaire completion. Among the nine remaining participants with ME/CFS whose questionnaire responses indicated a frequency of lightheadedness of 1–2 times per week or less, one adolescent reported a discrepant history during the clinical interview, describing a daily “head rush” (identical to lightheadedness) with postural changes. She was therefore re-classified. Thus, 84% met the study criteria for orthostatic intolerance using the criteria of frequent lightheadedness and a prior diagnosis or treatment of orthostatic intolerance.

The remaining eight participants underwent a 10 min passive standing test; four were receiving no vasoactive medications at the time of testing, and four were being treated with one or more medications that had some potential to affect the HR and BP responses to orthostatic testing (amitriptyline for headaches [n = 1], stimulant medications for attention deficit disorder [n = 1], selective serotonin or serotonin/norepinephrine reuptake inhibitors for anxiety or low mood [n = 2], and oral contraceptives [n = 1]). Of the four medication-naïve participants, two developed POTS during the 10-min standing test, each with a 50 beat per min increase in HR while upright, and a third became presyncopal at the 6-min point of upright posture, consistent with NMH. All four had worsening or provocation of their typical chronic orthostatic or ME/CFS symptoms during the period of standing (most commonly increased fatigue, lightheadedness, and warmth). Of the four who were being treated with vasoactive medications, three developed POTS and increased symptoms, and the fourth reported increased orthostatic symptoms only during the passive standing test. In all, 96% had evidence of orthostatic intolerance if those who developed POTS or NMH during the standing test were added.

Implications for Measuring Orthostatic Intolerance

An important aspect of the study methodology was that we included a comprehensive evaluation of orthostatic intolerance, incorporating the self-reported frequency of lightheadedness as well as a detailed clinical history and, where necessary, orthostatic testing. Although significantly more ME/CFS participants described lightheadedness several times per week or more compared to healthy controls [76 vs. 15%, P < 0.001], the prevalence of orthostatic intolerance increased to 84% when a history of recurrent syncope or prior positive orthostatic testing was included. A further 12% developed POTS or NMH in response to a 10-min passive standing test in clinic, all of whom reported provocation of their usual ME/CFS symptoms when standing. There is as yet no consensus on which of these criteria should be considered valid for confirming orthostatic intolerance. Among the caveats about orthostatic testing that need to be considered are that (1) the response to head-up tilt table testing can be abnormal in otherwise healthy individuals, some of whom develop hypotension or syncope during the procedure (30, 39), (2) as the current HR criteria for POTS are defined, approximately 5% of healthy adolescents would have at least a 40 bpm increase in heart rate during 10 min upright (39), some of whom might endorse chronic lightheadedness in daily life. We are unsure how many healthy individuals would develop increased orthostatic symptoms during a 10-min passive standing test, although the available data from tilt testing suggests this would be infrequent. Singer et al. reported that 8/106 (8%) of healthy controls developed orthostatic symptoms during a 10 min head-up tilt test, none of whom had a history of syncope or orthostatic symptoms (39). Moreover, chronic fatigue was reported by only 5% of the healthy controls in our study. Because healthy controls have a low prevalence of chronic orthostatic symptoms in daily life, and a low prevalence of orthostatic symptoms provoked during upright tilt, we would assume a similarly low rate of provocation of orthostatic symptoms in healthy adolescents during passive standing tests. These caveats notwithstanding, our results illustrate the potential for the prevalence of orthostatic intolerance to be underestimated if it is only measured by self-reported lightheadedness. Other questions that ask about orthostatic provocation of fatigue, PEM, difficulty thinking and concentrating, headache, pain, nausea, and warmth deserve further study to determine whether they add to the yield of lightheadedness as a reflection of orthostatic intolerance in ME/CFS. Taken together, the findings from this study provide further support for the inclusion of orthostatic intolerance in the case definition of ME/CFS, as was recommended in the IOM report.

We thank the many patients and healthy volunteers who made this study possible. PR is supported by the Sunshine Natural Well-being Foundation Professorship. We thank Drs. C. (Linda) M. C. van Campen, and Frans C. Visser of the Stichting CardioZorg, Hoofddorp, The Netherlands, for their helpful comments on the manuscript.