The cause of the severe fatigue found in diseases like chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and multiple sclerosis (MS) constitutes one of the great mysteries of medicine. For years fatigue was thought of as a minor symptom but researchers are beginning to recognize that severe fatigue is one of the most functionally debilitating symptoms that can occur.

Exhausted-womanSevere fatigue is finally getting some attention in some disorders and one of them is multiple sclerosis (MS).

A recent review paper examining the roots of severe fatigue in MS provided an opportunity to see how fatigue is being produced in it and whether fatigue might be produced in similar ways in ME/CFS and FM.


Multiple sclerosis and fatigue: A review on the contribution of inflammation and immune-mediated neurodegeneration. Robert Patejdl, Chris K. Penner b, Thomas K. Noacka, Uwe K. Zettl Autoimmunity Reviews xxx (2015) xxx–xxx

Fatigue in MS is often the first symptom to show up and is one of the most debilitating symptoms that many MS patients experience. The cause of the movement problems in MS is fairly clear but the cause of the fatigue in MS is something of a mystery.

The Central Nervous System – Multiple Sclerosis

The extent of the central nervous system lesions (nerve demyelination) found in MS tracks very well with the progression of the disease. Severe fatigue, however, can show up before the lesions are most prominent or before significant movement issues occur. This early occurrence of severe fatigue is probably why some people with ME/CFS and probably fibromyalgia are either misdiagnosed with MS or are given brain scans to determine if they have it.

Brain-puzzleThe fatigue in MS is not correlated with the extent of the CNS lesions but may be associated with where lesions are found. The association of lesions in the prefrontal, temporal, and hypothalamic regions of the brain with fatigue suggests that damage to these regions causes fatigue.
Several hypotheses have been generated to explain why these lesions are causing fatigue

  1. Compensation – The loss of signal strength between cortical regions causes other parts of the brain to jump in to compensate. This use of extra brain matter is inefficient, and increases metabolic needs – and fatigue is a natural result.
  2. Brain stem damage in MS impairs the activation of the cerebral cortex which is connected to the thalamus and basal ganglia. The thalamus is the seat of alertness and the basal ganglia affects “reward” (which is tightly tied to fatigue), the autonomic nervous system and movement.
  3. Motor region – Lesions in the motor region are associated with quick fatigability in MS during physical exercises.
  4. HPA Axis – Lesions in the hypothalamus in MS patients affect circadian and endocrine factors. The disruption of the circadian rhythm can impact sleep – causing fatigue, and endocrine factors regulate metabolic and immune processes.

The authors suggested that each of these hypotheses are probably too limited in their scope. They proposed that the fatigue in MS probably results from a broad breakdown of a master subcortical network in the brain that governs alertness, energy production, etc. This suggests that different regions of the brain that keep us alert are simply not communicating well with each other.

This hypothesis suggests that the thalamus may play a key role as it controls the activation of the cerebral cortex. Both fatigue and thalamic atrophy occur early in MS.

The Central Nervous System – ME/CFS/FM

Patients with CFS activate more wider area of activated frontal regions…. in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. Mizuno et. Al. 2015

Lesions in different parts of the brain are associated with fatigue in MS. Those same lesions are not usually found in FM and ME/CFS. Some studies suggest, however, that the same areas of the brain may be impacted.

Compensatory, Less Efficient Brain Functioning Causes Fatigue – several studies suggest the mental fatigue found in ME/CFS may result from a similar compensatory response as seen in MS. In ME/CFS more brain regions than normal are required to complete a task. This is believed to result in less efficient brain activity, greater use of brain resources for simple tasks, and ultimately fatigue.

Brain Stem Damage – Barndem’s fascinating 2011 study suggested brainstem damage in ME/CFS was producing altered autonomic nervous system functioning. The greatest damage was found in the reticular activation system which activates the cerebral cortex via the thalamus. Similar to MS, Barnden’s findings suggested that reduced activation of the cerebral cortex and other upper brain regions was present.

reduce brain activation chronic fatigue syndrome

Reduced brain activation was found in one (unpublished) ME/CFS study

The Zinn’s fascinating EEG studies highlighted in the Stanford Chronic Fatigue Syndrome Symposium suggested that reduced activation of the cortex was highly associated with fatigue in ME/CFS. They characterized ME/CFS as a “global expression of central nervous system hypoactivation”; i.e. it appeared that significant parts of ME/CFS patients’ brain were underactivated. Their results suggested that reduced “arousal” from the brainstem may be to blame. In the Stanford newsletter from early this year, Dr. Montoya stated that the paper was in publication. It has not been published yet.

Several studies have also found evidence of brainstem problems in FM.

Reduced Activation of the Motor Region – The ability of repetitive transcranial magnetic stimulation (rTMS) to increase motor cortex activation and significantly decrease the pain of FM patients suggests that motor cortex activation is reduced in FM as well. Reduced motor performance in ME/CFS patients suggests they have problems controlling voluntary muscle activities.

Neuroendocrine Changes – Several studies suggest that HPA axis changes contribute to the fatigue in MS but they do so in way opposite to ME/CFS. Reduced activation of the HPA axis contributes to the fatigue in ME/CFS and FM while increased activation does so in MS.

Thalamus – Several studies suggest problems with the thalamus exist in FM. Thalamus issues in FM have been associated with alpha-delta sleep problems, reduced pain inhibition and increased stress.

The Central Nervous System in ME/CFS/FM and MS – MS patients have lesions. ME/CFS and FM patients may have some lesions but not nearly to the extent as MS. Studies suggest, though, that similar parts of the brain that have been associated with increased fatigue are affected in both disorders.


Multiple Sclerosis

The fact that similar types of fatigue occur in MS, infections, systemic autoimmune diseases, and malignant tumors suggests that inflammation and cytokines probably contribute to the severe fatigue often seen in MS. Cytokines are important drivers of the flu-like symptoms (“sickness behavior”) produced during an infection – and associated with MS. Some of them can affect central nervous system functioning. It makes sense that they would play a role.

The existing data does not, however, suggest that inflammatory factors found in the blood contribute strongly to the fatigue found in MS. (The same is true, by the way, for rheumatoid arthritis – another inflammatory disease.)

That’s odd because markers of inflammation in the blood are associated with disease progression in MS. One study, though, found that the immune cells in fatigued MS patients were producing fewer cytokines than normal. Other studies have produced contradictory findings regarding cytokines and fatigue. Sometimes cytokines are increased and sometimes they are not.

The upshot is that while it’s clear that pro-inflammatory cytokines in the brain contribute strongly to MS the role that cytokines in the periphery or blood contribute is unclear.

Chronic Fatigue Syndrome (ME/CFS)

The cytokine situation in ME/CFS is, as always, complicated. A recent review found consistent evidence of one cytokine abnormality in ME/CFS (TGF-b). While natural killer cytotoxicity is consistently reduced in ME/CFS the cytokine results one might expect to result from that have not consistently shown up.

The immune situation in ME/CFS and MS is complicated

The immune situation in ME/CFS and MS is complicated

A recent study comparing healthy controls and moderately and severely ill ME/CFS patients demonstrates how complicated the cytokine issue is. Of the approximately 25 immune factors measured (IL-1ra, Il-1b, IL-2, IL-4, IL-5, IL-6, IL-6, IL-1, Il-8, IL-9, IL-10, IL-12p70, IL-13, IL-17, FGF, eotaxin, G-CSF, GM-CSF, IP-10, PDGF-BB, IFN-y, TNF-α and VEGF) only six were different between one or more of the groups

When they did differ they often didn’t differ in the direction one might have expected. One would expect that pro-inflammatory cytokines would be lowest in the healthy controls, higher in the moderate patients, and highest in the severely ill patients. That pattern, however, rarely occurred.

In fact, the most common pattern to emerge (4/6) in the few cytokines that were different, was that the severely ill patients looked more like the healthy controls than the moderately ill patients.

  • A pro-inflammatory chemokine (RANTES) was significantly higher in the moderate ME/CFS patients than both the healthy controls and the severely ill patients.
  • An important regulatory pro-inflammatory cytokine IL-1b is strongly associated with fatigue in RA patients. In fact, the authors of a recent animal study proposed that IL-1B is a required factor in immunologically produced fatigue in the brain. IL-1b, though, was not increased in the severely ill patients but was in the moderately ill patients. With regards to IL-1B, the severely ill ME/CFS patients looked more like the healthy controls than the moderate ill patients.
  • Il-6 was decreased in the moderate patients relative to both the healthy controls and the severely ill patients. Again – the severely ill patients looked more like the healthy controls than the moderately ill patients.
  • IFN-y was significantly increased in the severely ill patients relative to the moderately ill ME/CFS patient but again – not relative to the healthy controls (!).
  • Only with IL-7 and 8 did the pattern expected show up; these cytokines were highest in the most severely ill.

Since duration of illness was not correlated with illness severity, the findings – immune upregulation in the moderately ill and immune downregulation in the severely ill – did not necessarily track with those from the CFI immune study.

It should be noted that similar difficulties with cytokine studies have shown up in MS.

Conclusion – The immune system is complicated and capturing its effects in the blood has not been easy either in ME/CFS or MS.

Post-exertional Malaise

Fatigue and post-exertional malaise are different. Fatigue is not necessarily associated with exercise or activity while PEM, of course, strongly is.

Alan Light found markedly different symptom presentations and gene expression levels in ME/CFS vs MS patients after exercise. The MS patients entered the exercise feeling very fatigued, got worse after the exercise but then quickly rebounded with a day or two.

The ME/CFS patients entered the exercise study feeling less fatigued but crashed severely after the exercise and did not rebound quickly. Exercise also triggered few changes in gene expression in the MS patients (they were similar to controls) but dramatic changes in the ME/CFS patients.

Conclusion – Both diseases feature fatigue but the physiological responses to exercise appear to be very different in each. Light’s paper suggests that the PEM in ME/CFS may indeed be a very unusual occurrence.


The FDA has approved no less that thirteen drugs to treat MS, at least one of which, Copaxone (glatiramer acetate) appears to be able to reliably reduce fatigue. (Health Rising will cover Copaxone more in a blog about a person with ME/CFS who was diagnosed with MS and whose fatigue diminished markedly while she was on Copaxone). The monoclonal antibody Natalizumab also appears to be able to decrease fatigue in some MS patients.

Fatigue is common in rheumatic disorders such as rheumatoid arthritis, Sjogren’s Syndrome and systemic lupus. Because the medications used in these disorders often focus in altering immune functioning they present possibilities for ME/CFS/FM patients.

Immune altering drugs

Immune altering drugs have worked better in altering pain than fatigue in other diseases. Newer drugs may work better.

An overview of these immune altering drugs (methotrexate and leflunomide, biologics (infliximab, adalimumab, etanercept, golimumab and certolizumab), anti-IL-6 (tocilizumab), immunoglobulins (abatacept) and Rituximab) found that, at least in rheumatoid arthritis they may improve pain but generally have had small effects on fatigue.

The review concluded that “fatigue is a multi-factorial symptom related to pain, functioning and psychological factors, but does not seem to be related exclusively to inflammation, which is reflected by joint disease activity”

Note that Rituximab – currently under investigation in ME/CFS – is in this list. If Rituximab turns out to have large effects on fatigue in ME/CFS it will change how people understand Rituximab and how it works.

Some new biologic drugs appear to be more effective in fighting fatigue. The first IL-17 antibody – Secukinumab and tofacitinib, an oral Janus kinase inhibitor both improved fatigue significantly.   Secukinumab improved physical functioning in patients with psoriatic arthritis. The success of Secukinumab is intriguing given the interest in IL-17 in ME/CFS.

Conclusion – in general immune targeted drugs do not appear to be particularly effective at reducing fatigue in other diseases. We know that Ampligen and Rituximab can be very effective in reducing fatigue in some ME/CFS patients. Further studies are needed to know how many and which ones.


Central nervous system problems appear to track best with fatigue production in ME/CFS, FM and MS at this point. Brainstem and the midbrain issues which interfere with activation of the cerebral cortex and other parts of the brain, in particular, appear to be present in both ME/CFS and MS. The thalamus and basal ganglia may feature prominently in fatigue production in these diseases.

People with ME/CFS or MS also appear to use more brain regions than normal to accomplish tasks – an inherently fatiguing process. Since the demyelinating lesions found in MS do not occur in ME/CFS/FM, other issues (low grade inflammation?) are probably affecting brain regions in these diseases.

Evidence that inflammation in the periphery (the body as opposed to the brain) is contributing to the fatigue in MS, RA and ME/CFS is inconsistent. HPA axis problems, on the other hand, appear to contribute to fatigue in both ME/CFS and MS (albeit in different directions.)

Inflammation reducing drugs can effectively relieve pain in rheumatological diseases but have had only small effects on fatigue. Some newer immune modulating drugs appear to be more effective. The field of immune altering drugs is growing rapidly and we should expect more drugs to enter the market as time goes on.

Both ME/CFS and MS patients experience fatigue but people with multiple sclerosis do not  experience the extent of post-exertional malaise present in ME/CFS.

Finally one ME/CFS patient’s successful experience with an MS drug suggests that the treatment options known to reduce fatigue in MS might be able to reduce fatigue in ME/CFS.

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