Glasgow MP Carol Monaghan led a debate about the effect of the controversial flawed PACE Trial upon those living with Myalgic Encephalomyelitis (ME/CFS) in the UK and worldwide.
ME Association comment: Government-funded ME/CFS trial ‘one of greatest medical scandals of 21st century’
Action for ME summary: PACE trial Westminster debate – our summary
EM Action: Le PACE trial débattu au parlement anglais
ME Action: Westminster hall debate
Article extract:
What is pernicious anaemia?
Pernicious anaemia (PA) is the most common cause of B12 deficiency in the UK.
It is an autoimmune condition that causes the body’s immune system to attack cells in the stomach, limiting their ability to absorb B12. PA is generally treated with regular B12 injections.
For more information, see NHS Choices or the Pernicious Anemia Society.
Vitamin B12 and M.E.
Dr Shepherd, Hon. Medical Adviser, to the ME Association has talked previously with Martyn, and recognises the importance of excluding PA before a diagnosis of M.E. is made, and any treatment of M.E. with vitamin B12 is considered.
The ME Association has produced a leaflet that covers all aspects of vitamin B12 – causes of B12 deficiency, symptoms, blood tests, treatment, research into the possible link to M.E.
This leaflet can be downloaded or ordered from our online shop.
Summary of the key points:
NB Be aware that in Wales Health Boards work by different upper and lower levels of B12.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: what every family
physician needs to know, by Mary Dimmock, Susan Levine, MD, and Terri L. Wilder, MSW in Family Doctor (journal of New York State Academy of Family Physicians) Winter 2018 6:3 pp 23-25
The onset of ME/CFS is often sudden, typically following a viral or other type of infection but may occur following other types of physical trauma. In other cases the disease may develop gradually, over a period of weeks or months. Patients describe feeling `flulike’
symptoms chronically. In addition to the characteristic postexertional malaise (PEM), patients may also experience cognitive impairment, unrefreshing sleep, autonomic manifestations, such as heart rate variability and excessive sweating, and also experience
muscle and joint pain and sound, light, and chemical sensitivity.
Elevated antibody titers to viruses may be present, in addition to low levels of autoimmune serology. ME/CFS can present with a wide range of severity. Even in the same patient, the level of severity can change over time and from day to day as symptoms wax and wane. People with ME/CFS are unable to go about their daily activities in a predictable or consistent manner.
The IOM report stated that up to 70% of patients are unable to work and one quarter remain bed- or housebound (the latter however may be an underestimate). The IOM report stated that patients with ME/ CFS are more functionally impaired than those with ”type 2 diabetes mellitus, congestive heart failure, hypertension, depression, multiple
sclerosis, and end-stage renal disease.” Caring for severely disabled patients can put an enormous fiscal and emotional strain on family members and other caretakers.
Recovery is rare and as a result, patients can remain ill for decades. The IOM report estimated burden on the American economy is $17-24 billion annually in lost productivity and in direct medical costs.
Clinical Diagnosis
Previously, ME/CFS was considered a diagnosis of exclusion but the IOM criteria provide for the presence of certain “core” criteria in order to make the diagnosis of this disease.
The IOM clinical diagnostic criteria for ME/CFS require:
Sleep studies may identify co-morbid sleep apnea whereas the results of a tilt table test can confirm the presence of Postural Orthostatic Tachycardia Syndrome (POTS).
Neuropsychiatric testing typically shows impaired working memory and slowed information processing. Querying the patient’s response the day after activities that were previously tolerated can help determine the presence of post-exertional malaise (PEM).
The 2-day cardiopulmonary test (CPET) is used to measure anaerobic threshold, which is reduced in this disease and confirms the seminal finding of PEM.
A number of co-morbidities can be seen in ME/CFS, the most common of which include fibromyalgia, POTS, mast cell disturbances, and certain autoimmune disorders. These will need to be managed as appropriate for each condition.
Treatment
A noted above, there are no FDA approved treatments for ME/CFS. However, there are interventions that the family physician can provide to help patients with this disease. First and foremost, the family physician can explain post-exertional malaise and the associated aerobic metabolism impairment. For some people, exertion as minor as tooth brushing or eating can trigger PEM and a crash. People with ME/CFS should not exceed their “energy
envelope” and they should use an activity management approach called “pacing” to not exceed their limits.
Family physicians can also prescribe therapies that relieve symptoms, including those for sleep, pain, and orthostatic intolerance, including IV saline and Florinef. For patients with elevated viral titers, antiviral medications can help reduce symptoms. Patients often use earphones, earplugs, sunglasses, and eye masks to relieve the sensitivities to light and sound. Family physicians can also support patients by explaining the disease to the family and supporting applications for disability.
Social security accepts the 2-day CPET as objective evidence to support a disability claim. If this test is not easily available, a thorough explanation from the clinician caring for a patient with ME/CFS that describes the patients’ daily activities may suffice.
Conclusions
Family physicians have an important role to play in the diagnosis and care of people with ME/CFS. In May 2017, New York State Commissioner of Health Dr. Howard Zucker sent a letter to NYS physicians encouraging them to include ME/CFS as part of the differential diagnosis when evaluating patients with these symptoms.
The clinical diagnostic criteria published by the Institute of Medicine (IOM) are an important tool in this differential diagnosis that can result in faster and more accurate diagnosis. They can also provide the basis for treatment recommendations that can relieve symptoms and minimize postexertional crashes.
Most importantly, the family physician can validate the patient’s experience and ensure that the patient is not harmed by inappropriate treatment recommendations for exercise or talk therapy intended to convince the patient they are not ill.
A member of #MEAction Network Australia has written a primer, outlining the flaws in the graded exercise therapy (GET) research and explaining why GET is likely to be harmful for people with ME/CFS.
The primer has been endorsed by Emerge Australia Inc and infectious disease specialist, Dr John Whiting. It was submitted to the Australian Senate during the most recent Senate Estimates, in October 2017, has been sent to the President of the Royal Australian College
of General Practitioners, as well as several Australian politicians, and has been used by patient advocates in meetings with politicians in Australia and Ireland.
Now it is being made available for patients to download and give to their health professionals, or attach to their applications for disability support.
Key points in the primer:
The document also includes a two page summary at the beginning, for those who are unable to read the entire document.
This primer is available on Emerge Australia’s website
A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome: Systematic review; by Tiago Teodoro, Mark J Edwards, Jeremy D Isaacs in Journal of Neurology, Neurosurgery, and Psychiatry 2018 [Preprint: May 7, 2018]
Background:
Functional cognitive disorder (FCD) describes cognitive dysfunction in the absence of an organic cause. It is increasingly prevalent in healthcare settings yet its key neuropsychological features have not been reported in large patient cohorts. We hypothesised that cognitive profiles in fibromyalgia (FM), chronic fatigue syndrome (CFS) and functional neurological disorders (FNDs) would provide a template for characterising FCD.
Methods:
We conducted a systematic review of studies with cognition-related outcomes in FM, CFS and FND.
Results:
We selected 52 studies on FM, 95 on CFS and 39 on FND. We found a general discordance between high rates of subjective cognitive symptoms, including forgetfulness, distractibility and word-finding difficulties, and inconsistent objective neuropsychological deficits. Objective deficits were reported, including poor selective and divided attention, slow information processing and vulnerability to distraction. In some studies, cognitive performance was inversely correlated with pain, exertion and fatigue. Performance validity testing demonstrated poor effort in only a minority of subjects, and patients with CFS showed a heightened perception of effort.
Discussion:
The cognitive profiles of FM, CFS and non-cognitive FND are similar to the proposed features of FCD, suggesting common mechanistic underpinnings. Similar findings have been reported in patients with mild traumatic brain injury and whiplash. We hypothesise that pain, fatigue and excessive interoceptive monitoring produce a decrease in externally
directed attention. This increases susceptibility to distraction and slows information processing, interfering with cognitive function, in particular multitasking. Routine cognitive processes are experienced as unduly effortful.
This may reflect a switch from an automatic to a less efficient controlled or explicit cognitive mode, a mechanism that has also been proposed for impaired motor control in FND. These experiences might then be overinterpreted due to memory perfectionism and heightened self-monitoring of cognitive performance.
[Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome] by Y Nakatomi, H Kuratsune, Y Watanabe in Brain Nerve. 2018 Jan;70(1):19-25 [Article in Japanese]
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by chronic, profound, disabling, and unexplained fatigue; cognitive impairment; and chronic widespread pain. By using positron emission tomography, our study demonstrated neuroinflammation in the brain of patients with ME/CFS.
Neuroinflammation was found to be widespread in the brain areas of the patients with ME/CFS and was associated with the severity of their neuropsychological symptoms. The ongoing research would lead to the establishment of objective diagnostic criteria and development of an appropriate therapy.
NB The researchers’ older paper is available in English.
Dr Montoya at Stanford announced at the end of 2017 that they plan to replicate the Japanese findings with even more sensitive tests.
Value of circulating cytokine profiling during submaximal exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Kegan J. Moneghetti, Mehdi Skhiri, Kévin Contrepois, Yukari Kobayashi, Holden Maecker, Mark Davis, Michael Snyder, Francois Haddad & Jose G. Montoya in Nature, Scientific Reports 8: 2779 (2018) [Published online 9 February 2018]
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion.
Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS.
Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling.
Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise.
Cardiac structure and exercise capacity were similar between groups. Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)).
The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1.
In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.
Scope blog post from Stanford Medicine, by Bruce Goldman, February 15, 2018: Exercise elevates blood signature difference between people with, without chronic fatigue syndrome
Health rising blog post, by Cort Johnson, 5 March 2018: Stanford Exercise Study Shows Different Immune Response in Chronic Fatigue Syndrome (ME/CFS)
Solve ME/CFS Initiative blog post: Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in ME/CFS, March 2018
Cerebral blood flow and heart rate variability in Chronic Fatigue Syndrome: a randomized
cross-over study, by Anneleen Malfliet, Roselien Pas, Raf Brouns, Joris De Win, Samar M Hatem, Mira Meeus, Kelly Ickmans, Robbert-Jan van Hooff, and Jo Nijs in heart 2018; 21:E13-E24
BACKGROUND:
Pain, fatigue, and concentration difficulties are typical features of chronic fatigue syndrome (CFS). The exact underlying mechanisms of these symptoms are still unknown, but available evidence suggests an important role for impaired pain modulation. As evidence also suggests that pain modulation is related to cardiovascular mechanisms, it seems logical to investigate whether cerebral blood flow (CBF) and heart rate variability (HRV) are altered in these patients.
OBJECTIVES:
We aimed to investigate the role of the cardiovascular system in pain modulation and symptoms of CFS; the response of CBF and HRV to physical stress and their relation to the change in temporal summation (TS) of pressure pain and self-reported symptoms was evaluated.
STUDY DESIGN: A controlled, randomized cross-over trial.
SETTING: University Hospital Brussels.
METHODS: Twenty CFS patients and 20 sedentary healthy controls were included in this study. In both of the groups, the change in TS of pressure pain, CBF (using transcranial Doppler), and HRV (using finger plethysmography) was examined during physical and emotional stress (to control for potential bias), as well as their association mutually and with self-reported symptoms of pain, fatigue, and concentrations difficulties.
RESULTS:
There was no significant interaction or group (F-values ranging from .100 to 1.862, P-values ranging from .754 to .181) effect in CBF or HRV parameters. HRV and CBF did change during physical exercise, but the changes did not differ between patients and controls. While pain scores during TS at the trapezius site reduced in the control group after the physical exercise protocol (P = .037), they did not change in the CFS group (P = .108), suggesting impaired pain modulation. There were no significant correlations between CBF, HRV, TS, and self-reported symptoms (all P-values of correlation analyses > .01).
LIMITATIONS:
Although effect sizes were medium to large, the study sample was relatively low. Also, the mild nature of the exercise bout is discussable. Nonetheless, this mild exercise was able to provoke endogenous pain modulation in the control group, which endorsed a proper execution of the cycling exercise. Moreover, mild exercises are more applicable to daily physical activities in CFS patients than vigorous exercises.
CONCLUSION:
These results seem to refute the previously suggested alterations of CBF/HRV in CFS patients. These cardiovascular parameters appear not to explain pain before, during, and following exercise.
Disclaimer: The study was funded by ME Research United Kingdom, a national charity funding biomedical research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. The funder did not have any influence in the study design, the collection or analysis of the data, or the conception of this manuscript.
An analysis of Dutch hallmark studies confirms the outcome of the PACE trial: cognitive behaviour therapy with a graded activity protocol is not effective for chronic fatigue syndrome and Myalgic Encephalomyelitis, by FNM. Twisk and LAMM Corsius in General Medicine Open Vol 1(3): 1-13 2017 [Published online 5 Feb 2018]
Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are considered to be enigmatic diseases. Several studies propose that the combination of cognitive behaviour therapy with a graded activity protocol (CBT+), justified by a so-called (bio)psychosocial (explanatory) model, is an effective treatment option for CFS (ME).
Objective: A critical review of five Dutch hallmark studies that allegedly support this claim.
Methods: An analysis of the five CBT+ studies with special attention to the patients studied, the criteria (subjective and objective measures and cut-off scores) used to select participants and to define improvement and recovery, the consistency of the definitions of caseness (being diagnosed as a CFS patient at entry) versus the definitions of improvement and recovery after CBT+, and the objective effects.
Results: The studies investigated suffer from various methodological flaws. Apart from these methodological shortcomings, the claim that CBT+ is an effective treatment option for CFS is not substantiated by the data reported. Some studies investigated CFS patients, other studies investigated CF patients, labelled as CFS patients, or combinations of CFS and CF patients. No study investigated the effect of CBT+ in a group of patients meeting the (original) diagnostic criteria for ME. The effects of CBT+ on subjective measures, for example fatigue and disability, if present, are insufficient to achieve normal values. Impressive recovery and improvement rates are based on very loose criteria for subjective measures. Cut-off scores for subjective measures used to define improvement and recovery in studies show overlap with cut-off scores for CFS caseness in one or more of the other studies. More importantly, looking at the objective measures, the proof of clinical improvement after CBT+ is lacking.
Conclusion: Solid evidence of effectiveness of CBT+ for CFS, let alone ME, is lacking in the five hallmark studies. The lack of objective improvement indicates CBT+ is ineffective. This finding confirms the outcome of the large-scale PACE-trial in the UK.
A molecular neurobiological approach to understanding the aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with treatment implications, by Jean A. Monro, Basant K. Puri in Mol Neurobiol (2018) pp1-12
Currently, a psychologically based model is widely held to be the basis for the aetiology and treatment of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) /systemic exertion intolerance disease (SEID).
However, an alternative, molecular neurobiological approach is possible and in this paper evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood–brain barrier and intestinal permeability, cytokines and infections, metabolism, structural and chemical brain changes, neurophysiological changes and calcium ion mobilisation.
Evidence is also detailed for biologically based potential therapeutic options, including: nutritional supplementation, for example in order to downregulate the nitric oxide-peroxynitrite cycle to prevent its perpetuation; antiviral therapy; and monoclonal antibody treatment.
It is concluded that there is strong evidence of a molecular neurobiological aetiology, and so it is suggested that biologically based therapeutic interventions should constitute a focus for future research into CFS/ME/SEID.
NB The treatment section of the paper discusses vitamin B12, hydroxocobalamin, CoQ10 and NADH supplementaton, melatonin, antiviral treatment and rituximab
More about Prof Basant Puri
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