In historical publications on ‘epidemics’ of ME, symptoms consistent with central nervous system pathology were reported with regularity, and were as characteristic as the post-exercise malaise, myalgia or the range of other symptoms that patients experienced. Prof. Donald Acheson in his famous review (1) discussed such symptoms, pointing out that they were more consistent with cerebral damage than with other, psychoneurosis-based explanations prevalent at the time. Almost 50 years later, ‘neurological/cognitive manifestations’ form a key element of the Canadian Consensus definition of ME/CFS (2003) which insists that patients must have at least two of a list of six cognitive symptoms, including impairment of concentration and short-term memory, difficulty with information processing, and disorientation or confusion (2). Such symptoms can impact greatly on quality of life and employment; a high proportion of people with ME/CFS are unemployed, costing approx £3.4 billion annually in the UK in treatments, lost taxes and benefit payments.
It has not yet been established for certain what causes the prominent cognitive dysfunctions in the illness, but factors which might contribute include vascular insufficiency, metabolic dysregulation, or an ongoing infectious process. To date, a variety of structural and functional studies have been undertaken to try to identify physiological changes, but, as the Table below shows, the number of discrete studies is small, and the results have been mixed although nevertheless tantalising.
|Year||Author||Technology||Main finding compared with controls (quote)|
|2006||Yoshiuchi K||Xenon-CT||Reduced absolute cortical blood flow in rather broad areas|
|2005||de Lange FP||MRI||Significant reductions in global gray matter volume in both cohorts of CFS patients|
|2004||Okada T||MRI||Reduced gray-matter volume in the bilateral prefrontal cortex|
|2003||Schmaling KB||SPECT||Pattern of diffuse regional cerebral blood flow in comparison with the more focal pattern of regional cerebral blood flow seen among healthy subjects|
|2001||Cooke DB||MRI||Presence of brain abnormalities in CFS are significantly related to subjective reports of physical function|
|2001||Lange G||MRI||Ventricular volumes in the CFS group were larger than in control groups, a difference that approached statistical significance|
|2001||Lewis DH||SPECT||Results did not provide evidence of a distinctive pattern of resting rCBF abnormalities|
|2000||Tomada||SPECT||The various clinical symptoms in CFS patients may be closely related to an abnormal brain function|
|1999||Lange G||MRI||Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome|
|1998||Abu-Judeh HH||SPECT||Thirteen patients had abnormal SPET brain perfusion scans and five had normal scans|
|1996||Fischler B||SPECT||A pathophysiological role of frontal blood flow in the cognitive impairment and physical activity limitations in CFS is hypothesized|
|1995||Costa DC||SPECT||Brainstem perfusion is impaired in chronic fatigue syndrome|
|1994||Peterson PK||SPECT||Findings were not significantly different from those in the control group|
|1994||Schwartz RB||SPECT and MRI||SPECT abnormalities occur more frequently and in greater numbers than MR abnormalities do in patients with CFS|
|1992||Ichise M||SPECT||SPECT provided objective evidence for functional impairment of the brain in the majority of the CFS subjects|
As regards brain blood flow, SPECT imaging seemed a promising technique initially, and areas of low blood flow in multiple brain areas in CFS patients were observed — the work of Ichise et al (3), Schwartz et al (4) and Costa et al (5) was seminal in this regard. However, other studies have had different results, and the value of SPECT imaging technologies for the diagnosis of ME/CFS (or any subgroups within that rubric) remains unproven scientifically.
In separate but possibly related work, there are reports of subcortical “white matter hyperintensities” — areas of bright intensity — on MRI scans in CFS patients (e.g., Natelson et al (6) and Lange et al (7)), but such phenomena are not necessarily specific for this illness, are age-related, and can be found in at least some clinically healthy middle-aged adults.
Considering brain biochemistry, three recent research studies employing magnetic resonance spectroscopy have shown changes in the chemistry of the brain in patients with CFS, especially in relation to raised free choline levels; however, numbers of patients studied have been relatively small.
Voxel-based morphometry allows for objective, automated analysis of high-resolution images of the brain, and this technique has recently been used on CFS patients revealing gray matter volume reduction (Okada et al (8) and Lange et al (9)). Significant reductions (11.8 and 8% in each study, respectively) have been reported in the brains of CFS patients compared with healthy controls, reductions apparently unrelated to age or duration of illness. The jury is still out, however, on whether gray matter reduction is a primary feature of the ME/CFS spectrum and on whether it is related to the underlying pathophysiology, or is a finding secondary to other processes.
As well as the investigations above, a range of studies have reported cognitive deficits in CFS patients; these include impairments in attention, verbal and visual memory, concentration, acquiring new information, and psychomotor function, further suggesting deficits in basic motor or cognitive functioning.
Of course, as with all research on the full spectrum of ME/CFS patients, specific methodological factors complicate the interpretation of individual research results. The primary problem concerns differences in ME/CFS criteria used in various studies, and the fact that most definitions are so wide that they contain a variety of patient groups — from plain chronic fatigue to frank post-infectious myalgic encephalomyelitis. Sample size is yet another confounding problem (most of these studies have relatively few subjects), and the nature of the control groups can also be problematic. In addition, other factors specific to neurocognitive research might exist (a complication well-discussed in the review by Lange (10)); for example, the various studies have used different neuropsychological tests, different technologies (for instance, SPECT cameras can range from single to triple-head, and MRI scanners have a range of field strengths), and various but distinct data processing methodologies.
Clearly, the body of evidence pointing to brain abnormalities in ME/CFS is tentative, and we cannot yet make definitive statements about the meaning of the body of literature quoted above. As can be seen from the list of studies in the Table, however, it is entirely possible that well-conducted, objective, structural and functional studies in clearly defined or subgrouped ME/CFS patients might yet be able to provide diagnostic information in place of the present deduction or guesswork about what might be going on in the brain.
For this reason, ME Research UK welcomes applications from established researchers using state-of-the-art MRI technologies to carry out such studies.
(Those not cited can be supplied on request.)
- Acheson ED. The clinical syndrome variously called benign myalgic encephalomyelitis, Icelandic disease and epidemic neuromyasthenia. American Journal of Medicine 1959; 26(4): 569–95. Download pdf version here
- Carruthers BM et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome 2003; 11: 7–115.
- Ichise M et al. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nucl Med Commun 1992; 13(10): 767–72.
- Schwartz RB et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. AJR Am J Roentgenol 1994; 162: 935–41.
- Costa DC et al. Brainstem perfusion is impaired in chronic fatigue syndrome. Quarterly Journal of Medicine 1995; 88: 767–73.
- Natelson BH et al. A controlled study of brain magnetic resonance imaging in patients with the chronic fatigue syndrome. J Neurol Sci 1993; 120: 213–17.
- Lange G et al. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J Neurol Sci 1999; 171: 3–7.
- Okada T et al. Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome. BMC Neurol 2004; 4(1): 14.
- Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Tonia I. Gray matter volume reduction in the chronic fatigue syndrome. NeuroImage 2005; 26: 777–81.
- Lange G. Is CFS a Brain Disorder? CFIDS Chronicle: The Science and Research of CFS, 2006.