ME/CFS: Past Present and Future by Dr. William Weir and Dr. Nigel Speight

https://pubmed.ncbi.nlm.nih.gov/34442121/

Synopsis of ME/CFS and Long Covid by Dr. William Weir (unpublished)

ME/CFS has, in the past, been the subject of considerable controversy. Long Covid, a strikingly similar condition, is now attracting the same controversy. Differing points of view as to their nature and causes are strongly held, from those who mistakenly believe that “they do not exist” to those who recognise them as genuine illnesses. In respect of ME/CFS, the then Chief Medical Officer (CMO) of England and Wales, Sir Kenneth Calman gave the following briefing on the 16th July 1998:

“I recognise (ME/)Chronic Fatigue Syndrome is a real entity. It is distressing, debilitating and affects a very large number of people. It poses a significant challenge to the medical profession”. (Ref: Report of the ME/CFS Working Group, January 2002, Page 1, Section 1.1).

This is supported by the 300 page landmark report by the American National Academy of Sciences and Institute of Health which reviewed approximately 9,000 peer reviewed studies into ME/CFS in 2015. The report states very clearly that: “ME/CFS is a serious, chronic, and systemic disease that frequently and dramatically limits the activities of affected patients”. (Ref: Report of the Institute of Medicine, Beyond Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: Redefining an Illness, Clinicians Guide, 10 February 2015, page 4).

The Communicable Disease Centre (CDC) of the United States also supports this view, reinforcing a suspicion that an infection is involved. Dr Elizabeth Unger, chief of the CDC’s Chronic Viral Diseases Branch, which runs their ME/CFS programme has said the following:

“ME/CFS is a biological illness, not a psychological disorder. Patients with ME/CFS are neither malingering nor seeking secondary gain. These patients have a variety of abnormalities that affect multiple systems…”

Long Covid is also beginning to look very similar to ME/CFS, if not identical (Ref: Komaroff et al). The defining features of both are an overwhelming sense of fatigue and chronic influenza-like malaise, typically exacerbated after physical or mental exertion. The fatigue is accompanied by a profound lack of energy, it is described as “like no other in type or severity, and is evidently very different from everyday tiredness.” (Ref: Report of the ME/CFS Working Group, January 2002, Page 37, Section 4.2.1.2). The fatigue itself is not always present, can be unpredictably variable from day to day and frequently follows a relapsing and remitting pattern. It is characteristically unrelieved by sleep. The incapacity due to this problem is now fully recognised by both the DWP and by NICE. In addition to the physical symptom of fatigue, a number of other symptoms are frequently present.

Common amongst these is cognitive impairment, which can manifest in a number of ways. It has been described thus: “In addition to general cognitive fatigue, other difficulties include reduced attention span, reported impairment of short term memory, word-finding difficulties, inability to plan or organise thoughts, spatial disorientation, and loss of powers of concentration” (Ref: Report of the ME/CFS Working Group, January 2002, Page 37, Section 4.2.1.2).

Other frequently observed symptoms are an extreme sensitivity to any sensory input (Ref: Report of the ME/CFS Working Group, January 2002, Page 37, Section 4.2.1.2), with severely affected patients finding relative comfort only in a darkened bedroom, isolated from even normal levels of environmental noise and light – reminiscent of patients with acute meningitis.

The precise cause or causes are unknown, but scientific research has demonstrated immune, endocrine, musculoskeletal and neurological abnormalities (Ref: Report of the ME/CFS Working Group, January 2002, Page 21 Section 3.3). Infections of various kinds seem to act as a trigger in some cases, particularly glandular fever, viral meningitis and viral hepatitis. To date no known infectious agent has been proven to be the cause of the ongoing illness.

Recent studies have provided further insight into the characteristic intolerance of exercise. It is this feature which is frequently attributed to psychological causes. It has now been shown that calibrated exercise on a bicycle ergometer on two consecutive days indicates clear differences in muscle metabolism between ME/CFS patients and healthy but sedentary, ie deconditioned, controls. In the ME/CFS patients, the “anaerobic threshold” lowers on the second exercise day, whereas it increases in the controls (Ref: Snell et al, Keller et al). The same is very likely with Long Covid.

In lay terms, the anaerobic threshold is the point at which muscles exercising at maximum level switch to a metabolic pathway which does not use oxygen. This allows for a final burst of energy, followed within a few seconds by a sensation of exhaustion and hyperventilation due to the lactic acid released by the anaerobic pathway. High anaerobic thresholds are characteristic of athletes, particularly those doing endurance events which enables them to run long distances without hitting their anaerobic threshold. In non-athletic but healthy people, repeated daily exercise causes the anaerobic threshold to rise, the result being increasing physical fitness. This does not happen in ME/CFS (and Long Covid), and misguided attempts to force exercise on ME/CFS (and Long Covid) patients has exactly the opposite effect. In many instances, enforced exercise renders the ME/CFS (and Long Covid) sufferer exhausted and bedbound for prolonged periods – because they repeatedly breach their anaerobic threshold with minimal levels of exertion. The resulting incapacity is sometimes inappropriately attributed to psychological causes, for which there is no scientific evidence base whatsoever.

As previously stated, exercise lowers the anaerobic threshold exclusively in ME/CFS and Long Covid patients. A sensation of ‘air hunger’ is frequently reported by patients who are approaching their anaerobic threshold at modest/minimal levels of physical activity, because of the increasing buildup of lactic acid – which requires additional oxygen to metabolise it. Post exertional malaise is also one of the clinical expressions of this. This observation has been repeated in more than one academic centre (Ref: Keller et al) It is also supported by a study of biopsied muscle from ME/CFS patients and healthy controls. Repeated electrical stimulation of isolated muscle cells from ME/CFS patients in vitro reveals impairments of metabolism which are not seen in the healthy controls (Ref: Brown et al). Biopsied muscle fibres are self-evidently separate from the owner’s psyche, safely excluding any influence from this source. In severely affected patients the effect of an extremely low anaerobic threshold is severe exercise intolerance which manifests as profound exhaustion, even with the minimal effort of getting out of bed, eating and swallowing, or talking for short periods.

Other conditions which are often associated with ME/CFS and Long Covid must also be mentioned. These are Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS). POTS is characteristically manifest with changes of posture, particularly on sitting or standing up from the horizontal. It is probably due to a combination of a reduced blood volume and dysfunction of the vascular reflexes which normally control blood pressure with changes of posture (Ref: Stewart et al). Reduced circulating blood volume has been shown to be due to low levels of circulating cortisol and/or ADH, (Ref: Demitrack et al, De Bellis et al) a well-recognised feature in ME/CFS. Deficient function of the hypopituitary-adrenal axis has been recognised as the cause, with pathologically serious reduction of capillary perfusion (Ref Wirth and Lohn). In the first instance, severely affected patients can be helped significantly by increasing their blood volume either by glucose/electrolyte mixture taken orally, or by intravenous normal saline; the quantities required are often well in excess of 2 litres per day. Replacement of the deficient pituitary hormones is an obvious necessity following appropriate investigation. A final point to make about a chronically reduced circulating blood volume: the effect on capillary blood flow, lasting for months, sometimes even years, will mean that the tissues are subject to a chronic level of hypoxia and undernutrition from which recovery is slow – but only if the blood volume is restored.

MCAS has been discovered relatively recently, with a range of different symptoms. (Ref: Frieri et al) It is due to a tendency for mast cells to discharge inappropriately when “triggered” by normally harmless proteins, or allergens. Triggering results in the release of various substances, particularly histamine. Mast cells are part of the immune system and typically are found in the skin, lungs and the lining of the intestine. Depending on where the triggering occurs, MCAS can manifest as itching, asthma, or in severe cases, anaphylactic shock. Another manifestation being increasingly recognised comprises food intolerance, due to mast cells in the intestinal lining being triggered by normally harmless substances in food. Sometimes this is severe enough to cause persistent and severe abdominal pain, nausea and vomiting, leading to life threatening malnutrition because food intake is drastically reduced. Mast cell stabilisers such as Nalcrom, also antihistamines, can be life-saving in this situation, but sometimes the last resort is Total Parenteral Nutrition (TPN), which bypasses the gut altogether.

Of other disturbances of physiological function which can be treated, thyroid function impairment should be mentioned (Ref: Ruiz-Nunez et al). Thyroxine is usually regarded as the correct treatment for hypothyroidism, but requires the patient to convert thyroxine (T4 – which is inert) to tri-iodothyronine (T3 – which is active). In some ME/CFS patients there would appear to be a block to this conversion process.

As the name implies it tends to be an illness of long duration, with some patients remaining ill and incapacitated for several decades (Ref: Report of the CFS/ME Working Group, January 2002, Page 7, Section 1.4.3). Diagnosis is arrived at by undertaking a careful history and physical examination. As yet, there is no convenient laboratory blood test with which to identify the condition. Other conditions which may cause similar symptoms clearly have to be excluded and laboratory investigation is often required to do this. Treatment remains both unsatisfactory and a bone of contention. What is not in doubt is that there are no “magic bullets” currently available which will restore complete wellbeing overnight. Management primarily consists of advice to avoid both inactivity and overactivity, to keep active within the individual patient’s (often meagre) limits and to maintain a non-stressful daily agenda – “pacing”. What activity is possible should be kept below the patient’s anaerobic threshold at all times, and severely affected patients often have to spend most of the time resting in bed; attempts to mobilise them too soon can be disastrous. Cognitive Behavioural Therapy (CBT) has been advocated by some authorities as being of help but there is little evidence for this. Graded Exercise Therapy (GET) is potentially disastrous because of the potential for exceeding a perilously low anaerobic threshold.

It cannot be more strongly emphasised that exertion, both physical or mental, beyond an individual sufferer’s severely reduced anaerobic threshold causes an exacerbation of symptoms – post exertional malaise. This is characteristically delayed by hours, and sometimes for a day or more.

Emotional stress often has the same effect; if overexertion and/or emotional stress is prolonged, this will have a negative impact on prognosis. It should also be re-emphasised that a sufferer from either ME/CFS or Long Covid will be very vulnerable to the stress arising from light or noise above their threshold of tolerance, which, as stated above, can be abnormally low.

Finally, ME/CFS and Long Covid sufferers do not necessarily look unwell, but symptoms such as fatigue, dizziness, and cognitive dysfunction are often invisible to the uninformed witness. Furthermore the delay between activity and post-exertional malaise usually means that sufferers may appear normal on a relatively “good” day when they may push themselves beyond their narrow limit, but the following day they suffer a characteristic crash with further disabling symptoms lasting for days and sometimes weeks. In summary, properly focused scientific research will eventually define the pathology involved, followed by development of an effective treatment. The dogma which insists that ME/CFS and Long Covid have a purely psychological basis will need to be buried first.

W R C Weir, FRCP, FRCP (Edin)

References

Report of the CFS/ME working group: Report to the Chief Medical Officer published January 2002.

Komaroff, et al: Will Covid19 lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Front. Med. 2020, 7, 606824.

Snell et al: Discriminative value of metabolic and workload measurements for identifying chronic fatigue syndrome. Phys Ther 2013 Nov;93(11):1484-92.

Keller et al: Inability of ME/CFS AND LONG COVID patients to reproduce VO2 peak indicates functional impairment. J Transl Med. 2014; 12: 104.

Brown et al: Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with Chronic Fatigue Syndrome. PloS One Apr 2015; 10(4).

Report of the Institute of Medicine: Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, Clinicians Guide, 10 February 2015.

Stewart et al: Reduced central blood volume and cardiac output and increased vascular resistance during static handgrip exercise in postural tachycardia syndrome. Am J PhysiolHeart Circ Physiol 2007 Sep; 293(3): H1908-17.

Frieri et al: Mast cell activation syndrome: a review. Curr Allergy Asthma Resp 2013 Feb; 13(1): 27-32.

Wirth  and  Löhn Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Evolving from the Post COVID-19 Syndrome Medicina (Kaunas). 2024 Feb; 60(2): 194.

Ruiz-Nunez et al Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study. Front Endocrinol (Lausanne). 2018; 9: 97.