Though there are as yet no readily available, well-accepted, objective diagnostic tests for ME and CFS, work is ongoing in several key areas to develop one.
One objective measure, the 2-day CPET, is gaining acceptance and has been used with success in legal presentations. A drawback to this measure is its potential for harming patients.
And there are good subjective or self-reported diagnostic measures, though these are of limited value in clinical diagnosis.
In its response to the recent NIH solicitation for input into new research strategies for ME/CFS, the International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (IACFS/ME) documented emerging opportunities, research needs, and continuing challenges, but in particular highlighted promising work on developing a diagostic test or biological marker for the illness.
The IACFS/ME authors — Lily Chu, Fred Friedberg, Staci Stevens, Steve Krafchick, and Jon Kaiser — noted: “Some tests might not be suitable for clinical use but might provide a gold standard test for research purposes [and] may also provide clues to the pathophysiology of this disease and even to future treatments.”
They identified 9 key areas of investigation requiring urgent need of government support and funding.
Tap the tabs below to read more on each of these key areas of investigation into testing for ME and CFS.
Low natural killer cell activity (NKCA)
In a review of 17 studies, Strayer et al. found that 88% of studies suggested ME/CFS patients tended to have lower natural killer cell activity than healthy controls.
The IACFS/ME submission noted that low NKCA “…was downgraded as a requirement for the Institute of Medicine’s SEID criteria for two main reasons: a) low NKCA can occur for reasons other than ME/CFS and b) it was not clear what percentage of ME/CFS patients have low NKCA.
“However, no diagnostic test in medicine is 100% sensitive and specific: clinicians just need a test to be sensitive and specific enough. Test results coupled with history, physical exam, and clinical course together make the diagnosis.”
We encourage NIH to support research that a) can confirm or refute the finding of low NKCA in a larger population of ME/CFS patients and b) elucidate such a test’s operating characteristics (i.e. sensitivity, specificity, positive predictive value, negative predictive value).
2-day repeated cardiopulmonary exercise testing
Post-exertional malaise is considered to be a cardinal and disabling symptom of ME/CFS by both clinicians and patients. A major feature of post-exertional malaise is the inability to repeat the same frequency, intensity, or type of activity from one day to the next or repeatedly, regularly. 2-day CPET may be able to detect and quantify this symptom.
Healthy and even sick individuals are able to reproduce certain cardiometabolic parameters within a 7% margin of error when physically exercised on two separate days; three separate groups have shown this is not the case for ME/CFS patients.
Patients with ME/CFS performed worse than controls in a controlled repeated exercise study, were discriminated against in currently applied metabolic and workload measurements, could not reproduce VO2peak which indicated functional impairment and had diminished cardiopulmonary capacity during post-exertional malaise.
One or more of four cardiometabolic parameters can decrease from 8% to 55% from the first day’s value to the second day’s value.
The authors noted: “Further studies of 2-day repeated cardiopulmonary testing in larger populations can confirm if this test can be used as an objective marker of PEM and/ or as a gold standard test for ME/CFS.
“Most studies have not specifically inquired subjects about presence, onset, and duration of PEM and linked cardiometablic changes to the time course of symptoms so future studies should try to correct this gap.
Researchers should be aware not every ME/CFS subject will have the physical capacity to undergo CPET nor be willing to risk the adverse effects of CPET.
“Tests which can detect PEM in patients unable to or concerned about undergoing CPET should be devised. For comparison purposes, both sick and healthy controls should be recruited for studies.”
Neuropsychological testing related to information processing
Neurocognitive symptoms are common in ME/CFS and may be more disabling than physical fatigue or pain. This manifests in patients’ lives in a variety of ways, for example, being unable to drive, understand/ participate in a conversation, or read and remember a book.
When tested formally, diminished information processing speed, appears to be a common characteristic that distinguishes subjects from healthy or sick controls. Some subjects may perform normally with no time limits but abnormalities are particularly unmasked under time pressure.
Furthermore, some researchers believe that slowed information processing speed is at the root of other neurocognitive symptoms such as poor attention and memory. Validated tests of information processing that have already shown abnormalities in some subjects, such as the simple/ complex reaction time tests in the CANTAB or CalCap batteries, the Paced Auditory Serial Addition Test (PASAT), or visual information processing tests, could be applied to larger populations of subjects to confirm this finding.
Objective findings should also be linked to 28 subjective symptoms. Confounding factors such as medication, sleep deprivation, and co-morbid depression will need to be accounted for in such studies.
The authors recommended that: “Other than time restrictions, researchers should also consider testing patients after they have experienced cognitive loading (e.g. a day of work or school) or chart the course of the cognitive performance over time.”
Patients also report postexertional malaise due to cognitive activity. In one study, patients took an average of 57 hours to recover from a 3-hour cognitive battery whereas healthy controls had recovered their energy in 7 hours.
Tilt table testing
Orthostatic intolerance (OI) is very common in ME/CFS, affecting up to 80% of patients. Consequently, OI symptoms were included as part of the IOM definition. OI can also exacerbate post-exertional malaise and impacts function significantly and independently. If identified, there are effective treatments available for OI.
Tilt table testing is the gold standard for diagnosing different types of OI yet the full benefits of using tilt table testing to diagnose and help guide treatment in ME/CFS has not been fully explored.
“Studies exploring the prevalence of OI symptoms, the prevalence of positive tilt table tests, and the correlation of symptoms with objective tilt table testing would be informative not only for diagnostic purposes but for treatment purposes,” noted the authors.
ME/CFS patients experience many symptoms that may be related to the neurological system. Aside from problems with cognition and sleep, clinicians have also observed ataxia, muscle weakness, sensory hypersensitivity, visual issues, neuropathic pain, and bowel and bladder issues.
These symptoms may be related to infection and/or inflammation of nervous tissue. In a series of autopsies, patients were found to have inflammation of the dorsal root columns of the spinal cord while a neuroimaging study with a small sample size showed widespread inflammation in the brain which was correlated with neuropsychological symptoms.
These studies warrant further follow-up, according to the IACFS/ME authors.
Unrefreshing sleep, heart rate variability, and sympathetic predominance
Unrefreshing sleep is experienced by over 90% of ME/CFS patients and remains an issue even in patients who are able to fall and stay asleep, uninterrupted, for prolonged periods. Patients frequently report that upon awakening, they feel as if they had not slept at all.
Routine polysomnography of has not revealed any striking differences between patients and healthy controls.
In contrast, a review showed that the autonomic system of ME/CFS patients, as measured by heart rate variability, might be overactivated and that this might be leading to poor sleep. One study found that higher heart rate and reduced heart rate variability persist during sleep and another that heart rate variability correlated with sleepiness in patients.
The IACFS/ME submission noted: “This is an area that would benefit from further investigation. Patients selected for such studies should report current unrefreshing sleep despite, often with the use of medications, no problems falling asleep or staying asleep.”
Natelson et al. found abnormalities primarily in those reporting being sleepier in the morning. Those who felt less sleepy in the morning were no or little different from healthy controls. Furthermore, physical activity the prior day improved sleep in a “less-sleepy-AM” group while it had no benefit or even disrupted the sleep of those in the “more-sleepyAM” group.
A number of past studies have shown that family members of patients are at higher risk than the general population for developing ME/CFS, with one study suggesting the illness was inheritable and another noted that the illness runs in families where more than one person is affected.
The authors noted: “Studies of pedigrees, coupled with technologies such as genetic analysis or human leukocyte antigen (HLA) testing, could help identify markers for the disease and lead to an understanding of its pathophysiology.”
Such studies could also stimulate work examining prevention of ME/CFS in at-risk family members or members of the general public.
Energy metabolism issues and lactate processing in muscle and brain
Several studies suggest that patients have problems with energy metabolism. Four different studies of 2-day repeated cardiopulmonary exercise testing show that the anaerobic threshold, the time when production of lactic acid exceeds its removal, decreases by 7% to 26% on the second day in patients. Accumulation of lactic acid results in muscle pain and fatigue (refer also here, here and here.
Consequently, it is not surprising that patients report being able to accomplish an activity one day but not being able to repeat it again later.
Supporting this fall in anaerobic threshold are other studies documenting issues with lactate processing.
Shungu et al. in a series of studies found high levels of lactate in the cerebrospinal fluid of patients. One study found ventricular cerebrospinal fluid lactate is increased in cfs compared with generalized anxiety disorder, another found increased ventricular lactate in cfs compared with major depressive disorder.
Newton et al. found that, after an exercise challenge, the muscles of some ME/CFS patients retained 20 times the acid amount of healthy controls. Her group also linked low cerebral blood flow, which might encourage anaerobic metabolism and higher levels of lactate, with muscle pH.
These studies suggest an underlying mechanism that could account for both physical and cognitive fatigue in patients.
Up to 80% of patients report a post-infectious trigger close to the beginning of the onset of their illness.
Prospective studies have shown that, following infection with a wide variety of microbes (e.g. Epstein-Barr virus, Coxiella Burnetti, Girardia, influenza), approximately 10% of patients come down with ME/CFS. One study found that 60% of patients with long-lasting post-infectious fatigue after giardiasis were diagnosed with CFS.
Because current diagnostic criteria require that patients must be sick for at least 6 months prior to diagnosis, researchers may be missing the early stage of the illness. One study already suggests that the immune system of patients who have been sick less than 3 years differs from those who have been sick longer.