Comment by MERGE

Neil Abbot
Director of Operations
MERGE
ME Research Group for Education and Support (Charity no. 1080201)
The Gateway, North Methven St, Perth PH1 5PP, UK
ENERGISING ME RESEARCH

There is no doubt that central nervous system symptoms are part of the ME/CFS spectrum; indeed, they are as characteristic as the post-exercise malaise, myalgia or the myriad of other symptoms that people experience. They were discussed in the famous review by Acheson in 1959 (1) http://www.meresearch.org.uk/melibrary/information/index.html#acheson and, half a century later, they form a key element of the Canadian definition of ME/CFS (2003) which insists that patients must have at least two of a list of six "neurological/cognitive manifestations", including impairment of concentration and short-term memory, difficulty with information processing, and disorientation or confusion (2).

To date, no-one has established for certain what causes the cognitive dysfunction in ME/CFS, though a variety of structural and functional studies have been undertaken to try to elucidate the matter. SPECT imaging of the brain showed promise initially, and demonstrated areas of low blood flow in multiple brain areas in ME patients - the work of Schwartz et al (3) and Costa et al (4) was seminal in this regard. However, the initial findings were not confirmed by other studies, and one investigation that compared 11 pairs of twins discordant for ME/CFS found no differences in regional cerebral blood flow (5). In separate but possibly related work, four studies have reported an increase in the number of subcortical "white matter hyperintensities" - areas of bright intensity on MRI scans - in ME/CFS patients, though it seems that such phenomena are not specific for this illness and that similar areas can be found in at least some clinically healthy middle-aged adults. As usual in ME/CFS research, however, the issue of the meaning research results is clouded by differences in ME/CFS diagnostic definition between studies. The jury is still out on the meaning of these reports, however, and 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.

The paper by de Lange et al. in the July 2005 issue of the journal, Neuroimage, is an intriguing step toward this goal. Impressively, after observing significant structural abnormalities in one group of ME/CFS patients, the authors tested the reliability of their observation by investigating a second independent group - and the final report therefore concerns two separate groups of women with ME/CFS (a younger and an older group), as well as matched controls. In addition, the use of voxel-based morphometry - still a relatively novel technique which, in the past 5 years, has been applied to various illnesses, including Alzheimer's disease, depression and epilepsy - has allowed the objective automated analysis of the high-resolution images of the brain, an important advance given the limitations of the human-observer-rating techniques used in the past.

Overall, de Lange et al. report a significant 8% (95% Confidence Interval 5-11%; P < 0.001) reduction in gray matter volume compared with healthy controls. Moreover, the reductions were related to level of physical activity in the ME/CFS patients but not in the control group, and importantly were unrelated to age or duration of illness. The authors comment that their results "corroborate and complement previous studies that observed cerebral abnormalities associated with CFS" (3,6,7,8). Significantly, these results accord with the findings of a recent study by Okada et al 2004 (9) http://www.biomedcentral.com/1471-2377/4/14, also using voxel-based morphometry, from the National Institute for Physiological Sciences, Aichi, Japan. Examining 16 patients and 49 age-matched healthy control subjects, this research group reported an average 11.8% reduction in gray-matter volume in the bilateral prefrontal cortex, a volume reduction which paralleled the severity of the fatigue of the patients.

Why should gray matter be reduced in ME/CFS? de Lange et al speculate that reduced gray matter volume might be the "cause" of the illness and the ensuing physical inactivity, and remark that an alternative scenario - that gray matter reduction is a consequence of the reduced physical activity - is not immediately compatible with the fact that the volume reduction is not correlated with duration of ME/CFS. Alternatively, oxidative stress may be involved: the finding from animal work that metabolically active gray matter of the brain appears more susceptible to oxidative stress than white matter, and is the likely primary target of oxidative stress at all ages (10), seems to sit easily with the number of reports that have now linked ME/CFS with raised levels of oxidative stress in the tissues (e.g., see http://www.meresearch.org.uk/melibrary/publications/advances.html#frdama ge).

However, the truth is that whether gray matter reduction is a primary feature of ME/CFS, related to the underlying pathophysiology, or a finding secondary to other processes remains to be discovered. But the report of the phenomenon by two separate research groups is interesting, more so because (unusually) both research groups have found correlations between loss of gray matter and patients' symptoms.

References 1. Acheson ED. The clinical syndrome variously called benign myalgic encephalomyelitis, Icelandic disease and epidemic neuromyasthenia. American Journal of Medicine 1959; 26(4): 569-595.
2. 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.
3. 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
4. Costa DC, et al. Brainstem perfusion is impaired in chronic fatigue syndrome. Quarterly Journal of Medicine 1995;88:767-73
5. Lewis DH, et al. Monozygotic twins discordant for chronic fatigue syndrome: Regional cerebral blood flow SPECT. Radiology 2001; 219: 766-773.
6. Buchwald, D, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med 1992; 116: 103-113.
7. Lange, G et al. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J Neurol Sci 1999; 171: 3- 7.
8. Natelson BH, et al. A controlled study of brain magnetic resonance imaging in patients with the chronic fatigue syndrome. J Neurol. Sci 1993; 120: 213-217.
9. Okada T et al. Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome. BMC Neurol 2004; 4(1): 14.
10. Youssef JA et al. Age-independent, gray matter-localized, brain-enhanced oxidative stress in male fischer 344 rats: brain levels of F2-isoprostanes and F4-neuroprostanes. Free Radical Biology and Medicine 2003; 34(12): 1631-1635.