Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Redefining an Illness (2015) / Chapter Skim
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4 Review of the Evidence on Major ME/CFS Symptoms and Manifestations
4 Review of the Evidence on Major ME/CFS Symptoms and Manifestations
Pages 71-140
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From page 71... ...
, sleep-related symptoms, neuro cognitive manifestations, and orthostatic intolerance and autonomic dysfunction in ME/CFS. LIMITATIONS OF THE RESEARCH BASE One of the most significant challenges to achieving a better understanding of ME/CFS results from the methodological limitations of the current research base.
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From page 72... ...
The majority of published studies compared a small number of ME/CFS patients with healthy controls. Control groups including people with other illnesses, sedentary individuals, or people who meet different case definitions of ME/CFS have not commonly been used.
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, which often is attributed to deprivation of sleep, primary sleep disorders, or sedating medications (Hossain et al., 2005)
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From page 74... ...
found that those with ME/CFS frequently report the occurrence of several distinct fatigue states that may diverge from commonplace perceptions of fatigue among the general population. They examined dimensions of fatigue in ME/CFS using a unique 22-item ME/CFS Fatigue Types Questionnaire administered to 130 patients and 251 healthy controls.
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From page 75... ...
Early studies used this tool to distinguish ME/CFS from major depression, multiple sclerosis, acute infectious mononucleosis, hypertension, congestive heart failure, type II diabetes mellitus, acute myocardial infarction, unexplained chronic fatigue, and healthy controls (Buchwald et al., 1996; Komaroff et al., 1996a)
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Jason and colleagues (2011c) found that impairments in VT, social functioning, and RP had the greatest sensitivity and specificity in identifying patients who met the Fukuda definition of ME/CFS.
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The challenge in understanding this acquired chronic debility, unfortunately named "chronic fatigue syndrome" for more than two decades, will be to unravel those complexities.
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But, I have no help 2 Personal communication; public comments submitted to the IOM Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for meeting 1, 2014.
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. After maximal exercise 3 Personal communication; public comments submitted to the IOM Committee on the Diag nostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for meeting 3, 2014.
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compared 236 ME/CFS patients with 86 healthy controls who completed the DePaul Symptom Questionnaire, rating the frequency and severity of 54 symptoms. Patient data were obtained from the SolveCFS BioBank, which includes patients diagnosed by a licensed physician using either the Fukuda definition or the CCC.
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From page 81... ...
Assessment of PEM in ME/CFS PEM can be assessed subjectively by clinical history. It also can be assessed by standardized symptom questionnaires specific to ME/CFS and by comparison of self-reported symptoms and objective measures (such as functional impairment)
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From page 82... ...
Objective Measures of PEM Emerging evidence for objective indicators that may help us understand the presentation of PEM in ME/CFS patients centers on the two commonly reported domains in the PEM complex: recovery after physical exertion and cognitive function. Objective assessment of cognitive function is discussed in the section on neurocognitive manifestations later in this chapter.
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From page 83... ...
. Although some ME/CFS subjects show very low VO2max results on a single CPET, others may show results similar to or only slightly lower than those of healthy sedentary controls (Cook et al., 2012; De Becker et al., 2000; Farquhar et al., 2002; Inbar et al., 2001; Sargent et al., 2002; VanNess et al., 2007)
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. For example, one study asked ME/CFS subjects and healthy controls to complete computerized tests of memory, at
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After an exercise stressor, ME/CFS patients compared with healthy controls demonstrated delayed recovery of muscle function and pH (Jones et al., 2010, 2012; Paul et al., 1999) , increased depression or mood disturbances (Arroll et al., 2014; Meyer et al., 2013)
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Subjective reports of PEM and prolonged recovery are supported by objective evidence, including failure to normally reproduce exercise test results (2-day CPET) and impaired cognitive function.
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. A cross-sectional study of randomly selected patients found that sleep-related symptoms may become less frequent over the course of the illness (Nisenbaum et al., 92% 68% 65% 58% 47% Controls CFS 22% 21% 16% 15% 14% 10% 4% Unrefreshing Problems falling Need to Problems staying Waking up early Sleeping all sleep asleep nap daily asleep day/awake all night FIGURE 4-2 Percentage of ME/CFS patients and healthy controls reporting sleeprelated symptoms of at least moderate severity that occurred at least half of the time during the past 6 months.
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From page 88... ...
Similarly, another BOX 4-1 Sleep-Related Symptoms in Case Definitions and Diagnostic Criteria for ME/CFS 1994 Fukuda Case Definition of CFS (Fukuda et al., 1994) • Unrefreshing sleep is a minor criterion (not required)
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From page 89... ...
One study found that more patients fulfilling the Fukuda definition reported greater difficulty staying asleep than those fulfilling the CCC ( ason J et al., 2004) , while a second study reported no significant differences in sleep-related symptom scores between patients fulfilling the Fukuda definition and those fulfilling the ME-ICC (Jason et al., 2014)
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From page 90... ...
In a study using the DePaul Symptom Questionnaire, for example, 65 percent of healthy controls reported unrefreshing sleep that occurred with mild severity at least a little of the time, yet only 16 percent of healthy controls reported unrefreshing sleep that occurred with moderate severity at least half of the time (Jason et al., 2013b)
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From page 91... ...
Most studies used healthy controls as a comparison group, and several compared twin pairs in which one twin was diagnosed with ME/CFS and the other was healthy. Fewer studies used controls affected by other illnesses.
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From page 92... ...
Continuous positive airway pressure (CPAP) is a common treatment for SDB, and while it has been shown to reduce fatigue and sleepiness in people with obstructive sleep apnea (Tomfohr et al., 2011)
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One study found mean sleep latency to be greater in ME/CFS patients than in healthy controls (Bailes et al., 2006)
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There is growing evidence that ME/CFS patients experience abnormal sleep continuation compared with healthy controls. In one study, ME/CFS patients had higher levels of microarousal, despite the study's exclusion of sleep disorders normally associated with microarousals (Neu et al., 2008)
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As an example, ME/CFS patients who also had postural orthostatic tachycardia syndrome (POTS) were found to have reduced daytime hypersomnolence compared with those without POTS (Lewis et al., 2013)
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In several case definitions and diagnostic criteria for ME/CFS, primary treatable sleep disorders such as sleep apnea and narcolepsy are listed as exclusionary criteria for an ME/CFS diagnosis. However, there is evidence to suggest that primary sleep disorders should be considered important comorbid conditions in the differential diagnosis and that sleep complaints are complex.
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found that a greater percentage of ME/CFS patients than healthy controls reported neurocognitive symptoms of at least moderate severity that occurred at least half of the time (see Figure 4-3)
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98 BEYOND ME/CFS 80% 73% 69% 68% 66% 55% ME/CFS Controls 7% 7% 5% 2% 2% 2% Problems Difficulty Difficulty Slowness of Absent- Difficulty remembering expressing paying thought mindedness understanding thoughts attention FIGURE 4-3 Percentage of ME/CFS patients and healthy controls reporting neurocognitive manifestations of at least moderate severity that occurred at least half of the time during the past 6 months. NOTE: All patients fulfilled the Fukuda definition for CFS.
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. A metaanalysis of studies of cognitive functioning by Cockshell and Mathias (2010)
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. Memory Impairment In objective neuropsychological testing, individuals meeting criteria for ME/CFS have displayed deficits in working memory compared with healthy controls.
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However, mental fatigue is an important correlate of working memory in ME/CFS patients, with a populationbased sample of these patients showing a clear association between subjec
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and complex (PASAT) information processing speed showed moderate to large significant impairments in persons with ME/CFS compared with healthy controls (Cockshell and Mathias, 2010)
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. Several studies also have shown impairments C in executive attention relative to healthy controls, with ME/CFS patients demonstrating greater difficulty concentrating on a particular element when confronted with potential distractions (Hou et al., 2014; Hutchinson and Badham, 2013)
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. However, there are significant differences in the movement time of reaction time tests between people with ME/CFS and healthy controls (Cockshell and Mathias, 2010)
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. In another study, ME/CFS patients who were not medicated were reliably differentiated from healthy controls and those with depression using EEG spectral coherence (Duffy et al., 2011)
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. These objective findings based on multiple technologies support the concept that ME/CFS patients, at least those meeting Fukuda definition, have objective brain differences from healthy controls.
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. The most prevalent forms of orthostatic intolerance in the general population, as well as among those with ME/CFS, are POTS and neurally mediated hypotension (NMH)
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. Autonomic symp 7 Personal communication; public comments submitted to the IOM Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for meeting 3, 2014.
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evaluated 21 monozygotic twins discordant for CFS. Symptoms of orthostatic intolerance in the week before head-up tilt testing were graded on a 0 (none)
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The Fukuda definition of CFS includes no mention of disorders in the regulation of heart rate and blood pressure in the differential diagnosis or management of ME/CFS symptoms (Fukuda et al., 1994)
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. Objective Measures Orthostatic vital signs -- measured by taking heart rate and blood pressure in supine, sitting, and standing positions -- often are measured within 2 minutes or less, and thus are insufficient to identify most forms of chronic orthostatic intolerance.
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Passive tilt testing provokes a larger heart rate change in those with postural orthostatic tachycardia syndrome (POTS) than does active standing beyond 5 minutes of upright posture (Plash et al., 2013)
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The most common forms of orthostatic intolerance are described in Box 4-3. Several studies reviewed were conducted by the same group of investigators.
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; • duration of the orthostatic stress; and • criteria for abnormal response to orthostatic stress (earlier studies tended to report only rates of NMH, without reporting rates of BOX 4-3 Common Orthostatic Intolerance Syndromes Postural orthostatic tachycardia syndrome (POTS) POTS is defined by a heart rate increase between the supine position and 10 minutes of standing of more than 30 beats per minute (bpm)
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recruited participants based on the presence of autonomic symptoms. Of the 14 studies with healthy controls in which orthostatic testing lasted longer than 10 minutes, only 2 did not report a higher prevalence of either POTS or NMH among those with ME/CFS compared with controls (Duprez et al., 1998; Jones et al., 2005)
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From page 116... ...
Symptoms reported during orthostatic testing The literature review identified five studies reporting orthostatic or ME/CFS symptoms following standing or tilt table testing. Upright posture was associated with provocation of fatigue symptoms and higher rates of lightheadedness, nausea, and warmth in 55-100 percent of subjects with ME/CFS (Bou-Holaigah et al., 1995; Hollingsworth et al., 2010; Naschitz et al., 2000; Streeten et al., 2000)
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, however, found no differences in daytime or nighttime blood pressure in ME/CFS patients. Of interest, although blood pressure did not differ in that study, there were significant differences in heart rate between ME/CFS cases and healthy controls throughout the 24-hour period.
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From page 118... ...
examined the prevalence of the ME/CFS symptoms of the Fukuda definition among those with POTS who did not satisfy the criteria for ME/CFS, comparing this group with those who had POTS together with ME/CFS. Those with POTS alone often reported an elevated prevalence of severe fatigue, unrefreshing sleep, impaired memory or concentration, muscle pain, and post-exertional fatigue, although they did not have a sufficient number of symptoms to satisfy the Fukuda definition.
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2007. The impact of a 4-hour sleep delay on slow wave activity in twins discordant for chronic fatigue syndrome.
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2002. Joint hyper mobility is more common in children with chronic fatigue syndrome than in healthy controls.
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2007. Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: A population-based study.
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2011. Cognitive deficits in patients with chronic fatigue syndrome compared to those with major depressive disorder and healthy controls.
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1997. Neuropsychological functioning in a pre-screened sample of chronic fatigue syndrome patients.
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2011. EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients: A case control study.
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2012. Impaired blood pressure variability in chronic fatigue syndrome: A potential bio marker.
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2008. Postural orthostatic tachycardia syn drome is an under-recognized condition in chronic fatigue syndrome.
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2013a. Contrasting chronic fatigue syndrome versus myalgic encephalomyelitis/chronic fatigue syndrome.
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2013. The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome.
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In Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. American Journal of Medicine 101(3)
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2013. Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome.
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2014. Endogenous pain modulation in response to exercise in patients with rheumatoid arthritis, patients with chronic fatigue syndrome and comorbid fibromyalgia, and healthy controls: A dou ble-blind randomized controlled trial.
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2007. Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome.
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2012. Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycar dia syndrome.
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2000. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome.
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2001. Fludro cortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: A randomized controlled trial.
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2012. Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome.
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2013. Heart rate variability during sleep and subsequent sleepiness in patients with chronic fatigue syndrome.
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2012. Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls.
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2003. A measure of heart rate variability is sensitive to orthostatic challenge in women with chronic fatigue syndrome.
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