The “Fatigue” Disorders

Multiple sclerosis (MS) ranks amongst the most fatiguing disorders known.  Fatigue is the most common symptom found in MS (75-95% of patients), and is a major research topic with ten studies in the last five months featuring fatigue in their titles.

fatigued woman

Both ME/CFS and MS are fatiguing disorders – but is their fatigue similar?

Like chronic fatigue syndrome, though, the fatigue in MS is a mystery.  In fact, in some ways, it’s even more than a mystery.  The fatigue in MS is, oddly enough, not correlated with disease severity.  People with MS can be fatigued before lesions start popping up in their brains.  Severe fatigue is often the first symptom to show up in MS.

Several types of fatigue are believed to occur in MS, one of  which – “lassitude” – may be unique to the disorder.  Lassitude refers to fatigue that occurs daily, that tends to worsen as the day goes on, is worse in hot and humid conditions, comes on easily and swiftly, and is more severe than normal fatigue.  [The coining of “lassitude”, which is right up there with “malaise” in its negative connotations, makes one wonder if the medical profession is capable of coming up with a fatigue-associated word that is not debasing in some way.]

MS has “lassitude” while ME/CFS has post-exertional malaise (PEM) – a term that was apparently coined specifically for ME/CFS.  That people with MS are advised to find energy-saving ways of walking and performing tasks suggests PEM is present. That they’re advised to develop an exercise program suggests it may not be.  Exercise studies, in fact, suggest that PEM is present in MS, but not nearly to the extent it is in Chronic Fatigue Syndrome.

Both ME/CFS and MS  are amongst the most fatiguing disorders found, but does the resemblance end there? Does the PEM present in ME/CFS mean the  fatigue found there is different or is it similar? Do some genes contribute to fatigue while others cause PEM? These are some of the question the White’s put to themselves in this 2012 study.

The Study

Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in chronic fatigue syndrome, multiple sclerosis and healthy controls. Andrea T. White, Ph.D.1,2, Alan R. Light, Ph.D.3,4, Ronald W. Hughen3, Timothy A.VanHaitsma, M.S.1, and Kathleen C. Light, Ph.D.3 Psychosom Med. 2012 January ; 74(1): 46–54. doi:10.1097/PSY.0b013e31824152ed.

In this study, 22 ME/CFS and 23 MS patients and 20 healthy controls engaged in moderate exercise for 25 minutes.  Just before, ½ 8, 24, and 48 hours after the exercise the expression of select genes in their blood was measured.  Their symptoms were assessed as well.

The Real Fatigue Disorder

The MS patients were indeed fatigued. In fact, their self-report fatigue scores before the exercise test were twice those of the people with ME/CFS (72-35). The pain scores at baseline, on the other hand, were significantly higher for ME/CFS patients than for MS patients.

The Post Exertional Malaise Disorder


Fatigue is present in both disorders – but only the ME/CFS patients got whacked by exercise

Despite their enormous fatigue, the MS patients mostly sailed through the exercise period. Their physical and mental fatigue did rise 8 hours after exercise, but both were back to baseline at 24 and 48 hours.  At no point did exercise increase their pain levels.

The ME/CFS patients, on the other hand, immediately experienced increased levels of physical and mental fatigue and pain after exercise – which were still present  8, 24, and even 48 hours later.

Simply looking at the symptoms indicated that MS is primarily a fatiguing disorder and that MS patients may experience more fatigue than ME/CFS patients.  They do experience some PEM, but nothing like what shows up in ME/CFS.

Fatigue is obviously present in Chronic Fatigue Syndrome, but it’s more of a post-exertional malaise disorder.  This study suggests Post-Exertional Relapse Syndrome would have been a better name for ME/CFS than Chronic Fatigue Syndrome.

But what do the genes say? Would these differences show up in the gene expression results?

They would….

The PEM Genes – Where ME/CFS  and MS  Part Ways.

The expression levels of two genes (P2X4/TRPVI) that bounced up immediately after exercise in the ME/CFS group, and then stayed elevated for 48 hours were associated with post-exertional malaise. One of them, P2X4, was directly associated with both the increased fatigue and pain experienced after exercise in the ME/CFS patients.  These are muscle metabolite sensing genes that assess the levels of factors associated with muscle fatigue and damage.

A “Well-Regulated Sensory Pathway”

After exercise the MS patients looked more like healthy controls than the ME/CFS patients.  The levels of the metabolite sensing genes actually dropped in both the MS and healthy controls eight hours after exercise and then rebounded to normal levels. The Lights  called this response evidence of a “well-regulated sensory pathway” .

A Not So Well Regulated Sensory Pathway


“Well regulated” was not the how the authors characterized the sensory pathways in the ME/CFS patients

That sensory pathway looks more than a little dysregulated in ME/CFS.

The Lights suggested that even normal levels of muscle metabolites may be sparking an overexpression of metabolite-sensing genes in people with ME/CFS.  Those genes are there to alert the central nervous system that the muscles are overworked and that it’s time to induce fatigue and pain to keep them from being injured.

Metabolite receptors that are going bananas after even small amounts of exercise could easily explain the fatigue and pain ME/CFS patients experience after exercise.

It’s also possible that they simply reflect the fact that exercise is harming the muscles in ME/CFS. The authors noted that the Newton pH studies suggest just that – that sympathetic nervous system problems may be either increasing proton buildup or the ability to remove protons and other metabolites from the muscles.

The Fatigue Genes

Increased increased levels of adrenergic receptors suggested that sympathetic nervous system dysregulation was contributing to fatigue in both disorders.  One of the receptors is involved in directing blood flows to the muscles. Reduced blood flows to the muscles could be interfering with oxygen transport and with the removal of metabolites.


Genes that detect damaging muscle metabolites appeared tied to post-exertional malaise in ME/CFS

Bye-bye Fatigue?

These findings suggest that a variety of distinct symptoms have been shoved under the fatigue label – but that if researchers take the time to really articulate those symptoms they can say a lot about a disease.

There’s nary a mention of PEM in MS. Nowhere in the description of “lassitude” are the effects of exertion cited. Post-exertion problems, on the other hand, permeate the ME/CFS literature.

The findings also have implications for research.  The omnipresent fatigue and moderate and transient PEM suggest MS patients can be profitably studied when they’re at rest. The moderate fatigue and enormous PEM found in ME/CFS, on the other hand, suggests that pushing their systems with exertion is the best way to uncover what’s going on.

Conclusion – the Fatigue Disorder and the PEM Disorder

Despite both disorders being associated with high rates of fatigue, people ME/CFS and multiple sclerosis had very different responses to exercise – and display very different types of fatigue. The fatigue in MS is omnipresent but is not greatly affected by exercise.  The fatigue in ME/CFS is.

Both the symptom and gene expression results suggest multiple sclerosis is primarily a fatiguing disorder that has a moderate post-exertional malaise overlay, while Chronic Fatigue Syndrome is more of a post-exertional relapse disorder with moderate (at least compared to MS) rates of fatigue.


The word fatigue doesn’t begin to describe the different kinds of exhaustion present in disease

The MS patients fatigue levels increased shortly after exercise but then diminished quickly.  At no point did the pain levels of MS patients increase.

Fatigue in the ME/CFS patients was lower than in the MS patients at baseline, but exercise caused their pain and fatigue levels to increase rapidly and remain elevated even up to 48 hours after exercise.

Gene involving muscle metabolites and the sympathetic nervous system were associated with PEM in ME/CFS. Increases in genes associated with sympathetic nervous system activity were associated with increased fatigue after exercise in both disorders.  Muscle metabolite-detecting genes appear to play a key role in producing post-exertional malaise in ME/CFS.

  • Next up – Dane Cook and the Lights take on exercise in ME/CFS


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