By Leonard A. Jason, Ph.D. and Meredyth Evans
DePaul University
The criteria for defining cases is an important topic in research and medicine. For chronic fatigue syndrome, it has been a vexing topic whether one considers CFS to be a new condition identified with the 1988 case definition (Holmes, et al.) or a new (if unwanted) name for a condition that has existed for decades, if not centuries, by other names. Here we will examine the cluster of symptoms known as post-exertional malaise (PEM) and its importance in defining the condition. PEM is also known as post-exertional relapse. It refers to the aggravation of various symptoms following even modest physical or mental exertion. (Editor’s note: Please see our series of articles on PEM by Jennifer M. Spotila, J.D., posted at http://bit.ly/pem-series)
The Fukuda et al. (1994) criteria as well as the empiric criteria (Reeves et al., 2005) for CFS do not require post-exertional malaise (PEM) to occur in all patients, rather PEM is one of eight symptoms, of which only four are required. However, according to a recent review article by Jason et al. (2012), the initial myalgic encephalomyelitis (ME) case definitions required PEM as an essential feature of this illness including Ramsay’s case criteria (Ramsay 1988), the London criteria (National Task Force Report on CFS/PVFS/ME, 1994), the Nightingale criteria (Hyde, 2007) and the Goudsmit et al. criteria (2009). Most definitions for ME note the characteristic delay in recovery of muscle strength after exertion ends. For example, Ramsay (1988) describes it as muscle fatigability that results from a minor degree of physical exercise with which three or more days elapse before full muscle power is restored. The London criteria (National Task Force Report on CFS/PVFS/ME, 1994) suggest that post-exertional malaise is precipitated by physical exertion, but also add the component of mental exertion as a precipitator of post-exertional malaise. The London criteria also suggest that exercise-induced fatigue should be relative to the patient’s previous exercise tolerance, but there is no specific time period for which full muscle power should be restored. The Nightingale criteria states that post-exertional malaise can be precipitated by both mental and physical activity; post-exertional malaise is defined as pain with rapid loss of muscle strength after moderate physical or mental activity, but also suggests that post-exertional malaise might be due to vascular dysfunction or peripheral nervous or spinal dysfunction (Hyde, 2007). Goudsmit et al. (2009) describes post-exertional malaise as a new onset of abnormal levels of muscle fatigability that is precipitated by minor levels of activity with symptoms getting worse during the next 24 to 48 hours. Our group (Jason et al., 2012) has recently tried to operationalize the ME criteria from Ramsay (1988), Hyde (2007), Goudsmit et al. (2009), and the “London” criteria mentioned in the National Task Force Report on CFS/PVFS/ME (1994).
In addition, the ME/CFS Canadian clinical case definition also required post-exertional malaise for diagnosis (Carruthers et al., 2003), and our group has tried to operationalize these criteria (Jason et al., 2012). This ME/CFS case definition has since been revised, and the recent ME-ICC criteria (Carruthers et al., 2011) require a person to have Post-Exertional Neuroimmune Exhaustion, which is characterized as marked, rapid physical and/or cognitive fatigability in response to exertion.
Many explanations for the effects of PEM have been offered, such as Dowsett et al. (1990) and Myhill, Booth, and McLaren-Howard’s (2009) suggestion of mitochondrial damage and/or inhibition of the oxidative metabolism, and Jammes, Steinberg, Mambrini, Brégeon, and Delliaux (2005), Pall (2007) and Twisk and Maes (2009) suggestion that PEM is a consequence of excessive (prolonged) oxidative stress after exertion. Research has yet to identify a single factor that can adequately explain the patient experience.
Exercise scientists have used standard bouts of acute exercise in attempts to better characterize the physiological experience of post-exertional malaise. Both maximal and sub-maximal exercise have been used within the ME/CFS population. For maximal exercise tests, participants are instructed at a prescribed rate (e.g. 60-70 revolutions per minute (rpm)) against a gradually increasing resistance to voluntional exhaustion or until the participant can no longer pedal at the prescribed rate (Cook et al., 2006). Standard criteria for peak effort are normally applied. For example, peak effort would be determined when participants meets two of the following four criteria as set by the American College of Sports Medicine (ACSM): a respiratory exchange ratio (CO2/O2) of at least 1.1, a change in oxygen consumption (VO2) of less than 200 ml with increasing work, achievement of 85 percent of age-predicted heart rate, and a rating of perceived exertion (RPE) of 17 or higher out of a total 20 on the Borg 6–20 category scale (Borg, 1978). Maximal exercise tests, when combined with metabolic measurement, are considered the gold standard for assessing an individual’s maximum oxygen consumption (VO2max) or aerobic fitness. Maximal exercise tests are brief (between 5-9 minutes in individuals with CFS) (Noonan & Dean, 2000), and repeated maximal exercise tests have been used in novel ways to demonstrate cardiorespiratory and metabolic differences between CFS/ME patients and healthy controls (VanNess, Stevens, Bateman, Stiles, & Snell, 2010). It should be noted that the measurement is only considered to be valid when a participant is able to reach a VO2max without succumbing to fatigue or musculoskeletal issues first, which can occur in a disabled population. Furthermore, completion of the maximal exercise tests, particularly when repeated over two days, involve a high level of motivation by the participant, and these procedures require specific equipment and trained professionals.
In comparison with maximal tests, submaximal tests can be used to predict aerobic capacity and determine the cardiorespiratory and symptom responses to exercise over longer durations (e.g., 25-30 minutes) compared to the maximal exercise test. Thus, rather than giving one all-out effort, the patient is asked to sustain a certain level of effort for a prescribed period of time. There are many different protocols for submaximal testing (see Noonan & Dean, 2000). An excellent example is the work conducted by Light and colleagues’ (2011) in their work on gene expression in response to exercise in individuals with ME/CFS and FM. Light and colleagues used a moderate “whole-body” test that required participants to increase their pedaling on a stationary bicycle until they were able to exert 70% percent of their age-predicted maximum heart rate. This level of exertion was then maintained for the next 20 minutes of the test. Submaximal tests are used by some researchers studying disabled populations such as ME/CFS due to the belief that they have higher generalizability with the natural level of exertion necessary for eliciting a deterioration of symptoms. In fact, Light and colleagues have found that their 25-minute submaximal exercise tests elicited a worsening of fatigue and pain symptoms in individuals with ME/CFS from 8 to 48 hours after exercise (2011). Post-exertional malaise can potentially be measured by increases in the expression for sensory, adrenergic and immune genes following moderate exercise (Light, White, Hughen, & Light, 2009).
It is important to note that PEM cannot be definitively established without the inclusion of the patients’ self-reported symptoms. Thus, there is a need to develop self-report methods for capturing the frequency, severity and duration of this cardinal symptom. Jason and colleagues (1999) found that in a group of individuals with ME/CFS, PEM ranged from 40.6-93.8% depending on how the question of this symptom was asked. This lack of uniformity in the way PEM is measured represents a significant problem for the scientific community studying this illness.
Many have looked to the Patient Reported Outcomes Measurement Information System (PROMIS), as one possible solution as it is a free database of standardized measures that assess patient reported health status. The PROMIS currently includes self-report questions related to the impact of fatigue on functioning, physical feelings of fatigue and limitations. However, the PROMIS does not investigate triggers/causes of fatigue or duration of fatigue. Also, the PROMIS lacks questions assessing fatigue that results from physical or mental exertion; thus lacking questions that tap into post-exertional malaise. Here are several PROMIS questions: In the past 7 days what was the level of your fatigue on most days? In the past 7 days how much mental energy did you have on average? In the past 7 days how often did you run out of energy? In the past 7 days how often did you experience extreme exhaustion?
Our group developed the ME/CFS Fatigue Types Questionnaire (MFTQ), which has good psychometric properties, and is designed to measure the different types of fatigue experienced by individuals with ME/CFS (Jason et al., 2009). We measured the experience of symptoms in a group of individuals with ME/CFS compared to a healthy group. We found that individuals with ME/CFS experienced several different types of fatigue including postexertional fatigue, wired fatigue, brain fog, energy fatigue and flu-like fatigue compared to the healthy group which only experienced just an overall, general type of fatigue. The MFTQ defined the factor called PEM as abnormal exhaustion following a bout of physical activity. Items from the PEM factor included:
- Dead, heavy feeling that occurs quickly after starting to exercise;
- Next day soreness or fatigue after non-strenuous, everyday activities;
- Mentally tired after the slightest effort;
- Physically drained or sick after mild activity; and,
- Minimum exercise makes you physically tired.
In another study, the above five PEM items from the MFTQ were confirmed as having the best diagnostic sensitivity and specificity (Jason, Evans, Brown, et al. 2011). The MFTQ PEM factor is distinct for patients with ME/CFS from the Emotional Distress factor of the Profile of Fatigue-Related Symptoms (Ray et al., 1992), which measures mood states such as depression, anxiety, and anger. In addition, as another indicator of construct validity, the Fatigue Severity Scale (Krupp et al. 1989), a measure of the impact fatigue has on one’s functional ability, demonstrated stronger relationships for the MFTQ Post-Exertional factor in the ME/CFS group than the control group. These five PEM items have been included in a new diagnostic measure: the DePaul Symptom Questionnaire (DSQ), developed by our group at DePaul University to help classify people with all the major case definitions, and we currently are collecting data using this instrument.
Our research group feels that post-exertional malaise is a cardinal feature of ME; the definition recognizes post-exertional malaise as prolonged restoration of muscle power following either mental or physical exertion.
References
Borg, G. (1978). Subjective aspects of physical and mental load. Ergonomics, 21, 215-220.
Carruthers, B. M., Jain, A., de Meirleir, K. L., Peterson, D. L., Klimas, N. G., Lerner, A., & … van de Sande, M. I. (2003). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols.Journal Of Chronic Fatigue Syndrome, 11(1), 7-115. doi:10.1300/J092v11n01_02
Carruthers, B. M., van de Sande, M. I., De Meirleir, K. L., Klimas, N. G., Broderick, G., Mitchell, T., . . . Stevens, S. (2011). Myalgic encephalomyelitis: International consensus criteria. Journal of Internal Medicine, 270(4), 327-338. doi: 10.1111/j.1365-2796.2011.02428.x.
Cook, D.B., Nagelkirk, P.R., Poluri, A., Mores, J., & Natelson, B.H. (2006). The influence of aerobic fitness and fibromyalgia on cardiorespiratory and perceptual responses to exercise in patients with chronic fatigue syndrome. Arthritis and Rheumatism, 54(10), 3351-3362. DOI 10.1002/art.22124
Dowsett, E.G., Ramsay, A.M., McCartney, R.A., & E.J. Bell, 1990. Myalgic encephalomyelitis-a persistent enteroviral infection? Postgraduate Medical Journal, 66, 526-530. PMID: 2170962
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.
Goudsmit, E., Shepherd, C., Dancey, C.P., & Howes, S. (2009). ME: Chronic fatigue syndrome or a distinct clinical entity? Health Psychology Update, 18, 26-31. PMID: 19576714
Hyde, B.M. (2007). The Nightingale Definition of Myalgic Encephalomyelitis (M.E.), The Nightingale Research Foundation, Ottawa, Canada.
Jammes, Y., Steinberg, J.G., Mambrini, O., Bre´ Geon, F., & Delliaux, S. (2005). Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response toincremental exercise. Journal of Internal Medicine 257, 299-310.
Jason, L.A., Damrongvachiraphan, D., Hunnell, J., Bartgis, L., Brown, A., Evans, M., & Brown, M., (2012). Myalgic Encephalomyelitis: Case definitions. Autonomic Control of Physiological State and Function, 1, 1-14. doi:10.4303/acpsf/K11060. Available at: http://www.ashdin.com/journals/ACPSF/K110601.pdf Accessed Dec. 18, 2011.
Jason, L.A., Evans, M., Porter, N., Brown, M., Brown, A., Hunnell, J. & Friedberg, F. (2010). The development of a revised canadian myalgic encephalomyelitis chronic fatigue syndrome case definition. American Journal of Biochemistry and Biotechnology, 6(2). 120-135. Retrieved from http://www.scipub.org/fulltext/ajbb/ajbb62120-135.pdf
Jason, L., Evans, M., Brown, M., Porter, N., Brown, A., Hunnell, J., Anderson, V., & Lerch, A. (2011). Fatigue scales and chronic fatigue syndrome: Issues of sensitivity and specificity. Disability Studies Quarterly, 31. Retrieved from http://www.dsq-sds.org/article/view/1375/1540
Jason, L. A., Jessen, T., Porter, N., Boulton, A., Njoku, M. G., & Friedberg, F. (2009). Examining types of fatigue among individuals with ME/CFS. Disability Studies Quarterly, 29. (available at: http://www.dsq-sds.org/article/view/938/1113).
Jason, L.A., C.P. King, J.A. Richman, R.R. Taylor and S.R. Torres et al., (1999). US case definition of chronic fatigue syndrome: Diagnostic and theoretical issues. Journal of Chronic Fatigue Syndrom., 5, 3-33. DOI: 10.1300/J092v05n03_02
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(3A), 59S-65S.
Light, A.R., Bateman, L., Jo, D., Hughen, R.W. (2011). Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. Journal of Internal Medicine, ;271(1):64-81.
Light, A.R., White, A.T., Hughen, R.W., Light, K.C., (2009). Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. The Journal of Pain, 10(10), 1099-1112.
Lloyd, A.R., I. Hickie, C.R. Boughton, O. Spencer, & D. Wakefield, (1990). Prevalence of chronic fatigue syndrome in an Australian population. Medical Journal of Australia. 153, 522-528. PMID: 2233474
Meeus, M. Roussel, N.A., Truijen, S., & Nijs, J., (2010). Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study. Journal of Rehabilitation Medicine, 42, 884–890.
Myhill, S., Booth, N.E., McLaren-Howard, J. (2009). Chronic fatigue syndrome and mitochondrial dysfunction. International Journal of Clinical and Experimental Medicine,2(1):1-16.
Noonan, V. & Dean, E. (2000). Submaximal exercise testing: clinical application and interpretation. Physical Therapy, 80, 782-807.
Pall, ML (2007). ”Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO-cycle”. Medical hypotheses (0306-9877),69(4), p. 821
Ramsay, A. M. (1988). Myalgic Encephalomyelitis and Postviral Fatigue States: The Saga of Royal Free Disease, Gower Publishing Corporation, London, 2nd ed.
Reeves, W. C., Wagner, D., Nisenbaum, R., Jones, J. F., Gurbaxani, B., Solomon, L., et al. (2005). Chronic fatigue syndrome – A clinical empirical approach to its definition and study. BMC Medicine, 3:19. doi:10.1186/1741-7015-3-19. (available at: http://www.biomedcentral.com/content/pdf/1741-7015-3-19.pdf )
Report from National Task Force on Chronic Fatigue Syndrome (CFS) Post Viral Fatigue Syndrome (PVFS) Myalgic Encephalomyelitis (ME) September 1994 p15
Twisk F, Maes M (2009). A review on Cognitive Behavorial Therapy (CBT) and Graded Exercise Therapy (GET) in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS): CBT/GET is not only ineffective and not evidence–based, but also potentially harmful for many patients with ME/CFS. Neuroendocrinology Letters, 30(3), 284–99.
VanNess, J.M., Stevens, S.R., Bateman, L., Stiles, T.L., Snell, C.R. (2010). Postexertional malaise in women with chronic with chronic fatigue syndrome. Journal of Women’s Health, 19(2), 239-244.
Whiteside, A., Hansen, S., Chaudhuri, A. (2004). Exercise lowers pain threshold in chronic fatigue syndrome. Pain, 109, 497-499.
About the Authors:
Leonard Jason, Ph.D., is the director of the Center for Community Research at DeP
aul University. He has been involved in ME/CFS research since 1990 and has published 219 papers on the topic, many of which address the issue of case definition and other epidemiologic issues. Dr. Jason is second from the right in this photograph of the CFS Research Team, part of the Center for Community Research.
Meredyth Evans (first from left) is a graduate student at DePaul University who just completed her master’s thesis investigating psychometric properties of varying time intervals for assessing ME/CFS symptoms.
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Oxidative stress is just one of the many abormalities induced/intensified by (mental and physical) exertion that could account for PEM. As substantiated in Twisk and Maes (2009):
Exertion induces post-exertional malaise with a decreased physical performance/aerobic capacity, increased muscoskeletal pain, neurocognitive impairment, “fatigue”, and weakness, and a long lasting “recovery” time.
This can be explained by findings that exertion may amplify pre-existing pathophysiological abnormalities underpinning ME/CFS, such as inflammation, immune dysfunction, oxidative and nitrosative stress, channelopathy, defective stress response mechanisms and a hypoactive hypothalamic-pituitary-adrenal (HPA) axis.
Using Fukuda et al. (1994) criteria and PEM, “fatigue”, and a subjective feeling of infection as discriminatory symptoms
we recently established that
ME, “CFS” (Fukuda/not-ME) and CF are distinct diagnostic categories.
ME patients have significantly higher scores on concentration difficulties and a subjective experience of infection, and higher levels of IL-1, TNFα, and neopterin than patients with “CFS”.
Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: Results of supervised learning techniques applied on clinical and inflammatory data.
Psychiatry Res. 2012 Apr 20. doi: 10.1016/j.psychres.2012.03.031.
Maes M, Twisk FNM, Johnson C.
http://www.sciencedirect.com/science/article/pii/S0165178112001400
It is time to leave the CFS label and “fatigue” behind us and
to make a clear distinction between ME patients (those with PEM and e.g. cognitive impairment) and “CFS” patients (those without PEM).
Aside from the practical implications of e.g. reassessing everyone with a current diagnosis of ‘CFS’ and/or ‘CFS/ME’ is ‘PEM’ the only distinguishing symptom (assuming there are indeed two distinct conditions)?
Are you suggesting for example that ‘ME’ could comprise PEM and cognitive dysfunction and that CFS could also include cognitive dysfunction without PEM?
I can kind of see ‘CFS’ being replaced by ‘ME’ but if PEM etc. is/are taken away, then presumably there will be no Syndrome within ‘CFS’. So it would in effect become Chronic Fatigue?
I do support the attempts to better quantify the symptoms as well as attempts to place a biological marker behind them – I just can’t see there is enough at present for Health Authorities to accept we are talking about two distinct diseases.
Surely we need to arrive at research that demonstrates significant differences. Accepted research defining ‘each’ condition markedly. And where does the latest PENE fit in with any of this? It seems we still have several theories about what causes PEM as well as competing definitions.
Don’t get me wrong. It would be terrific one day to arrive at a consensus view for my condition. I think though we need to bring the authorities along with us or else, well, what strides are made will not be accepted.
This talk about ‘CFS’ and ‘ME’ still causes division in the ‘community’. ‘CFS’ has become an often derided term and unfortunately this can – and does – lead to accusations of ‘CFS’ patients being somehow inferior simply because their physician has used that exact term.
I’m also not convinced that PEM is unique to either CFS/ME or ME but I am happy to be shown that it is or informed that it doesn’t have to be.
I suspect PEM is a feature of other e.g. neurological conditions like for example Multiple Sclerosis; but agree that this feature does need to be better understood and quantified.
A patient saying ‘I have PEM’ is not, I wouldn’t have thought, a satisfactory means of identifying them as having a distinct disease especially when PEM cannot currently be quantified and may even be ‘fluctuating’.
One cannot render a syndrome devoid of its original intent: to discover the illness of its prototypes.
If the members of the original CFS cohort had post-exertion malaise, altering the CFS definition in such a way as to remove the prototypes from having their own syndrome in order to confer it on some other condition is a bizarrely outrageous breach of medical ethics, and is antithetical to the scientific method.
And to the law of gravity and good taste.
OK, maybe not the last two, but definitely to science.
There are days I could read and debate this, but today isn’t one of those days.
There are days I could exercise well and recover well …..last year when I stuck to my plan……during the move late last year all my plans and rules went out the window as I ran out of supplements, money and energy and still over did it…..only now – APRIL – am I getting back on track.
I’m convinced there is a PEM phase where we need to stay under 50% of ability to allow recovery but there is also a doing well phase when we have the nutrients and capacity to do so that we can push ourselves more significantly and capacity increases and PEM decreases.
I’ll read the article through more closely on a better day ….. thanks for addressing this as it is something I’ve been ad hoc self experimenting and it is great to not be alone on this issue.
Could Dr Jason, or anyone else who knows, explain what ‘wired energy’ is?
Hi, UK Citizen,
This is awfully late in responding to your question about “wired energy,” and I hope you’ve heard from someone else before now. I can only offer my experience of “wired energy,” which feels a lot like being anxious. Often I have too much energy to go to sleep, but it’s a “wired” kind of energy, that is, it does not feel that it is in any way under my control, nor can I focus it on accomplishing a task. When I’m experiencing this kind of energy, it’s hard to concentrate, to read, sometimes even to watch TV. It is as if the energy has me, rather than the other way around. I may feel exhausted, but no matter how tired I feel, this “wired energy” won’t let me sleep, nor truly rest. Hope this helps.
Get education & information about how to treat CFS/ME into the medical schools, using the most recent definitions:
http://www.iacfsme.org/Portals/0/PDF/PrimerFinal3.pdf
Emphasize the importance of how to avoid triggering Post-Exertional-Malaise.
Post-Exertional-Malaise is the main presenting symptom of my CFS/ME.
Once you get doctors educated, then you can refine the definitions all you want.
I have spent the last decade trying to educate my doctors, who really really want me to have fibromyalgia (which I do not have) so that they can prescribe tricyclics (which makes my CFS worse.)
I have just co-authored ‘Ramsay’s Disease – ME – And the Unfortunate Creation of CFS’ with Les Simpson, a researcher in hematology (the physical properties of blood – not included in medical studies, so its implications in chronic illnesses fails to be recognised). The title of the book reflects Les’s conviction that ME needs to be singled out from other illnesses on the basis of Ramsay’s criteria, so it is a pleasure to read that Professor Jason has reached the same conclusion!
The struggle to account for the range and complexity of symptoms in ME could be immensely simplified if the results of Simpson’s research were acknowledged and included in our efforts to understand this illness. Micrographs of immediately fixed red blood cells clearly show a predominance of non-discocytic erythrocytes in many chronic illnesses, including ME. (Immediate fixation is essential – when washed in saline and left before being photographed, the cells revert to the biconcave discocyte form. In last year’s Invest in ME Conference, the importance of Les’ work was dismissed by a speaker on the basis of a small study in which this essential feature of his research protocol had not been followed.) When the erythrocyte population consists largely of non-deformable shapes, tissues and organs most sensitive to the consequent loss of oxygen and build up of waste products. This can account for the dysfunction of the aerobic muscle metabolism (the low VO2) – resulting in the fact that even minimal exercise for the ME patient equates to a weight-lifting session for a person with normally functioning muscles. It also accounts for the problems in cognitive and endocrine functioning, producing ‘brain fog’ and PEM after cognitive effort, as well as the symptoms which are indicative of endocrine dysfunction.
It should be emphasised that this type of change in the shape population of the erythrocytes occurs in other chronic conditions as well. It does not explain the cause or causes of ME, it only describes a mechanism which can explain the symptoms. Simpson suggests simple supplements to improve blood flow, but does not claim that these will cure ME, only that they may effect an improvement in patient well-being.
The reported occurrence of psychiatric problems, notably depression, in ME patients can, I believe, often be attributed to the design of questionnaires purporting to diagnose depression which include categories which are the physical symptoms of ME, and not symptoms of a mood disorder – the Beck Inventory is an outstanding example. ‘Fatigue’ is not a symptom of depression. Sadness to the point of ‘apathy’ is. How long would it take you (anyone!) to tell the difference between a person who is steeped in misery and can’t be bothered to do anything, and a person who is desperate to do things, tries, finds out they just can’t, and gets upset about it? That only becomes difficult if you want to accuse the person with ME of ‘having depression’. But people with ME are likely to become, realistically, not neurotically, depressed about being so incapacitated.