The Hummingbirds' Foundation for M.E.

The Hummingbirds' Foundation for M.E. (HFME) is fighting for the recognition of M.E.,
and for patients to be accorded the same basic human rights as those with similar
disabling and potentially fatal neurological diseases such as M.S.

An important note:

Before reading the research/advocacy information given in the links below, please be aware of the following facts:

1. Myalgic Encephalomyelitis and ‘Chronic Fatigue Syndrome’ are not synonymous terms. The overwhelming majority of research on ‘CFS’ or ‘CFIDS’ or ‘ME/CFS’ or ‘CFS/ME’ or ‘ICD-CFS’ does not involve M.E. patients and is not relevant in any way to M.E. patients. If the M.E. community were to reject all ‘CFS’ labelled research as ‘only relating to ‘CFS’ patients’ (including research which describes those abnormalities/characteristics unique to M.E. patients), however, this would seem to support the myth that ‘CFS’ is just a ‘watered down’ definition of M.E. and that M.E. and ‘CFS’ are virtually the same thing and share many characteristics.

A very small number of ‘CFS’ studies refer in part to people with M.E. but it may not always be clear which parts refer to M.E. The
A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy paper is recommended reading and includes a checklist to help readers assess the relevance of individual ‘CFS’ studies to M.E. (if any) and explains some of the problems with this heterogeneous and skewed research.

In future, it is essential that M.E. research again be conducted using only M.E. defined patients and using only the term M.E. The bogus, financially-motivated disease category of ‘CFS’ must be abandoned.

2. The research referred to on this website varies considerably in quality. Some is of a high scientific standard and relates wholly to M.E. and uses the correct terminology. Other studies are included which may only have partial or minor possible relevance to M.E., use unscientific terms/concepts such as ‘CFS,’ ‘ME/CFS,’ ‘CFS/ME,’ ‘CFIDS’ or Myalgic ‘Encephalopathy’ and also include a significant amount of misinformation. Before reading this research it is also essential that the reader be aware of the most commonly used ‘CFS’ propaganda, as explained in A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy and in more detail in Putting research and articles on Myalgic Encephalomyelitis into context.

Neurological and cognitive research

The Nightingale Definition of Myalgic Encephalomyelitis (M.E.) by Dr Byron Hyde 2006

Preface

Since the Nightingale Research Foundation's publication in 1992 of its textbook, The Clinical and Scientific Basis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome, there has been a tendency by some individuals and organizations to assume that M.E. and CFS are the same illness. Over the course of two International Association of Chronic Fatigue Syndrome (IACFS, formerly the American Association of CFS) conferences, there have been suggestions that the name CFS be changed to M.E., while retaining the CFS definitions as a basis for such change. This does not seem to me to be a useful initiative: it would simply add credence to the mistaken assumption that M.E. and CFS represent the same disease processes. They do not.

M.E. is a clearly defined disease process. CFS by definition has always been a syndrome

At one of the meetings held to determine the 1994 U.S. Centers for Disease Control and Prevention (CDC) definition of CFS, in response to my question from the floor, Dr. Keiji Fukuda stated that numerous M.E. epidemics he cited the Los Angeles County Hospital epidemic of 1934, the Akureyri outbreak of 1947-48 and the 1955-58 Royal Free Hospitals epidemics-- were definitely not CFS epidemics. Dr. Fukuda was correct.

[Contains details of the many absnormalities seen in M.E., and explains how these can be tested for.]


A New and Simple Definition of Myalgic Encephalomyelitis and a New Simple Definition of Chronic Fatigue Syndrome & A Brief History of Myalgic Encephalomyelitis & An Irreverent History of Chronic Fatigue Syndrome by Dr Byron Hyde MD 2006

‘Do not for one minute believe that CFS is simply another name for Myalgic Encephalomyelitis (M.E.). It is not. Though CFS is based upon a typical M.E. epidemic, in my opinion it has always been a confused and distorted view of reality. The invention of Chronic Fatigue Syndrome has to be one of the most curious cases of inventive American scientific imperialism that one could imagine. It is my opinion that the CDC 1988 definition of CFS describes a non-existing chimera based upon inexperienced individuals who lack any historical knowledge of this disease process. The CDC definition is not a disease process.’

[Contains details of the many absnormalities seen in M.E.]


The Complexities of Diagnosis  by Dr Byron Hyde 2003

(Taken from: Handbook of Chronic Fatigue Syndrome by Leonard A. Jason, Patricia A. Fennell and Renée R. Taylor)

The physician and patient alike should remember that CFS is not a disease. It is a chronic fatigue state as described in four definitions starting with that published by Dr. Gary Holmes of the CDC and others in 1988 (Holmes, Kaplan, Gantz, et al., 1988; Holmes, Kaplan, Schonberger, et .al., 1988). The definition created by Lloyd, Hickie, Boughton, Spencer, and Wakefield (1990) is also widely used in Australia. There are two subsequent definitions. The Oxford definition of 1991 (Sharpe et al., 1991) and the 1994 NIH/CDC definitions (Fukuda et al., 1994) are basically, with a few modifications, copies of the first definition. Where the one essential characteristic of ME is acquired CNS dysfunction, that of CFS is primarily chronic fatigue. By assumption, this CFS fatigue can be acquired abruptly or gradually. Secondary symptoms and signs were then added to this primary fatigue anomaly. None of these secondary symptoms is individually essential for the definition and few are scientifically testable. Despite the list of signs and symptoms and test exclusions in these definitions, patients who conform to any of these four CFS definitions may still have an undiagnosed major illness, certain of which are potentially treatable.

Although the authors of these definitions have repeatedly stated that they are defining a syndrome and not a specific disease, patient, physician, and insurer alike have tended to treat this syndrome as a specific disease or illness, with at times a potentially specific treatment and a specific outcome. This has resulted in much confusion, and many physicians are now diagnosing CFS as though it were a specific illness. They either refer the patient to pharmaceutical, psychiatric, psychological, or social treatment or simply say, "You have CFS and nothing can be done about it."

[Contains details of the many absnormalities seen in M.E., and explains how these can be tested for.]


Brain problems in ME – is there a simple explanation? by Dr Elizabeth Dowsett

"A good memory demands normal functioning of almost all areas of the cerebral cortex, the basal nerve centres of the mid brain (eg the thalamus and hippocampus) and their interconnecting pathways through the brain stem. Fluctuations of metabolic activity in these areas (often made worse by physical and mental exhaustion) have been reported in SPECT scans of patients with ME,(2) the vast majority of whom complain of difficulty with short-term memory."

[Contains details of the many absnormalities seen in M.E..]


Time to put the exercise cure to rest? by Dr Elizabeth Dowsett

There is ample evidence that M.E. is primarily a neurological illness. It is classified as such under the WHO international classification of diseases (ICD 10, 1992) although non neurological complications affecting the liver, cardiac and skeletal muscle, endocrine and lymphoid tissues are also recognised. Apart from secondary infection, the commonest causes of relapse in this illness are physical or mental over exertion 1. And, on follow up over decades (rather than weeks or months), the average person so disabled is found to be functioning (as a student, employee or parent for example) dangerously near their energy limits. The prescription of increasing exercise is such a situation (or in the early stage of the illness when the patient desperately needs rest) can only be counter-productive.

[In other words - YES!]


The Late Effects of ME by Dr Elizabeth Dowsett

"The number likely to be affected by the post-polio syndrome has been calculated as between 200-270/100,000 currently[7], but no account has been taken of survivors from non-paralytic polio which could easily double that figure. Possible costing for ME support has been based on 3 times the cost of maintenance for multiple sclerosis on the supposition that ME is 3 times as common[4]. The only costs that we can be sure of are those derived from the failure of appropriate management, and of inappropriate assessments which waste vast sums of money and medical time while allowing patients to deteriorate unnecessarily.[16]

Research workers must be encouraged and appropriately funded to work in this field. However they should first be directed to papers published before 1988, the time at which all specialised experience about poliomyelitis and associated infections seem to have vanished mysteriously![11,12,13]"


Gray matter volume reduction in the chronic fatigue syndrome. de Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Toni I. F.C. Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, NL-6500 HB Nijmegen, The Netherlands.

The chronic fatigue syndrome (CFS) is a disabling disorder of unknown etiology. The symptomatology of CFS (central fatigue, impaired concentration, attention and memory) suggests that this disorder could be related to alterations at the level of the central nervous system. In this study, we have used an automated and unbiased morphometric technique to test whether CFS patients display structural cerebral abnormalities. We mapped structural cerebral morphology and volume in two cohorts of CFS patients (in total 28 patients) and healthy controls (in total 28 controls) from high-resolution structural magnetic resonance images, using voxel-based morphometry. Additionally, we recorded physical activity levels to explore the relation between severity of CFS symptoms and cerebral abnormalities. We observed significant reductions in global gray matter volume in both cohorts of CFS patients, as compared to matched control participants. Moreover, the decline in gray matter volume was linked to the reduction in physical activity, a core aspect of CFS. These findings suggest that the central nervous system plays a key role in the pathophysiology of CFS and point to a new objective and quantitative tool for clinical diagnosis of this disabling disorder.



The Presence of Cerebral Atrophy in CFS Comments by David Bell MD

Reference: de Lange F, Kalkman J, Bleijenberg G, Hagoort P, van der Meer J, Toni I. Gray matter volume reduction in the chronic fatigue syndrome. NeuroImage 2005;26:777-781.

In this study, the authors studied 28 patients with CFS and 28 healthy controls using an automated, “user-independent” magnetic resonance imaging (MRI) voxel-based morphometry (VBM) technique for measuring brain volume and tissue concentration. They were also able to quantify the activity reduction of the CFS patients using a technique called actinometry. For better control they restricted the study, both patients and controls, to women. They found that the volume of gray matter of the brain was significantly decreased in comparison to the healthy controls, (p < 0.001), and amounts to a reduction in brain tissue of 8% on average, and appears to be a global phenomenon rather than a local problem. The amount of brain tissue reduction was correlated to the severity of the activity limitation. Whether this is a cause or consequence of CFS is not known.

Reference: Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N. Mechanisms underlying fatigue: A voxel-based morphometric study of chronic fatigue syndrome. BMC Neurol 2004;4:14.

In this study MRI was used allowing “voxel-based morphometry” of 16 patients and 49 healthy age matched controls. CFS patients had reduced gray matter volume, primarily in the prefrontal cortex bilaterally. The authors state, “We observed a significant reduction in gray-matter volume in the bilateral prefrontal areas of CFS patients….In comparison to healthy controls, there was an average of 11.8% volume reduction in CFS patients.”


Brain MRI abnormalities exist in a subset of patients with CFS Lange G, DeLuca J, Maldjian JA, Lee H, Tiersky LA, Natelson BH Department of Psychiatry, UMDNJ-New Jersey Medical School, MSB E-561, 185 S. Orange Avenue, Newark, NJ, USA Journal of the Neurological Sciences (ISSN 0022-510X) 1999 Dec 1;171(1):3-7 NLM citation: PMID: 10567042

The authors studied MRI results in three groups: CFS-Psych, CFS-No psych, and healthy controls (HC). (Those designated CFS-Psych had been diagnosed with psychiatric illness since CFS onset). "The CFS-No Psych group showed a significantly larger number of brain abnormalities on T2 weighted images than the CFS-Psych and HC groups", with cerebral changes consisting mostly of "small, punctate, subcortical white matter hyperintensities, found predominantly in the frontal lobes." The authors conclude that this finding could explain the "more severe cognitive impairment previously reported in this subset of CFS patients."


Relationship Between SPECT Scans and Buspirone Tests in Patients with ME/CFS John Richardson, Durval Campos Costa Journal of Chronic Fatigue Syndrome 1998 vol.4 no.3 pp23-38

The purpose of this exercise was to study the relationship between the detail shown on the SPECT brain scans with those seen in the buspirone tests.

Thirty-nine patients are included in this study. These patients were selected from a large number who had been referred to Dr. Richardson from various parts of the country by their doctors because of a tentative diagnosis of ME/CFS. All the selected patients were confirmed by Dr. Richardson as suffering from ME/CFS taking into account the subjective scoring methods, clinical examination, virology and buspirone tests.

This study is an attempt to link together the results of the previously described techniques to investigate possible areas of impaired cellular function in brain which may have purely neuroneural effects or possibly neurohormonal effects.

All patients within this study displayed hypoperfusion in some brain area as shown by their SPECT scans. Thirty-five (90%) showed hypoperfusion in the regions comprising: Twenty-four (62%) in the Brain Stem; Twenty (51%) in the Caudate Nuclei. Nine (23%) showed hypoperfusion in both Brain Stem and Caudate Nuclei regions. Thirty (77%) cases demonstrated hyperprofusion in the regions comprising: Twenty-four (62%) in the Temporal Lobes; Twelve (31%) in the Parietal Lobes; Nine (23%) in the Frontal Lobes.

The significance of these results is to confirm that there is actual evidence of neurological dysfunction which results in the continuing morbidity in these ME/CFS patients.

The completion of this buspirone test and SPECT scan can be deemed to be basic complementary evidence for the positive diagnosis of ME/CFS.


Altered central nervous system signal during motor performance in chronic fatigue syndrome. Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. Department of Biomedical Engineering, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.


OBJECTIVE: The purpose of this study was to determine whether brain activity of chronic fatigue syndrome (CFS) patients during voluntary motor actions differs from that of healthy individuals. METHODS: Eight CFS patients and 8 age- and gender-matched healthy volunteers performed isometric handgrip contractions at 50% maximal voluntary contraction level. They first performed 50 contractions with a 10 s rest between adjacent trials--'Non-Fatigue' (NFT) task. Subsequently, the same number of contractions was performed with only a 5 s rest between trials--'Fatigue' (FT) task. Fifty-eight channels of surface EEG were recorded simultaneously from the scalp. Spectrum analysis was performed to estimate power of EEG frequency in different tasks. Motor activity-related cortical potential (MRCP) was derived by triggered averaging of EEG signals associated with the muscle contractions. RESULTS: Major findings include: (i) Motor performance of the CFS patients was poorer than the controls. (ii) Relative power of EEG theta frequency band (4-8 Hz) during performing the NFT and FT tasks was significantly greater in the CFS than control group (P < 0.05). (iii) The amplitude of MRCP negative potential (NP) for the combined NFT and FT tasks was higher in the CFS than control group (P < 0.05) (iv) Within the CFS group, the NP was greater for the FT than NFT task (P<0.01), whereas no such difference between the two tasks was found in the control group. CONCLUSIONS: These results clearly show that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue. SIGNIFICANCE: Physical activity-induced EEG signal changes may serve as physiological markers for more objective diagnosis of CFS.


Medical Neurobiology of CFS: May 7-9, 1993 by Jay Goldstein

It is widely documented that exercise is an exacerbator of CFIDS symptoms. Drs. Mena and Goldstein presented a series of SPECT scans which showed extreme hypoperfusion (reduced blood flow) in the brain following exercise. There appeared to be "holes" where blood would normally be flowing -- the degree of hypoperfusion was astonishing. Even 24 hours later, cerebral blood flow was severely reduced.

Cerebral hypoperfusion is not the only result of exercise intolerance. Drs. Lapp and Goldstein referenced irregular tidal volume rates common in PWCs. Hyperventilation and shallow breathing are frequent results of exertion. Normal controls breathe irregularly at the start of exercise, but respiration becomes regular over time. Dr. Lapp reported that PWCs breathed more regularly than controls at the outset, but during exercise their breathing was more variable. Dr. Goldstein concurred, "This phenomenon has never been described before in any population and, as of now anyway, we think that it's a diagnostic marker for CFS."

Neuroendocrine responses were often reversed or blunted in the Cheney-Lapp study. Cortisol, epinephrine, norepinephrine, DHEA levels and body temperature normally rise with exercise, but PWCs were found to have lower than expected measures of all of the above. Dr. Goldstein related this phenomenon to limbic dysfunction, as altered levels of interleukins and nitric oxide (NO) can result in altered neuroendocrine responses to exercise.

Dr. Lapp and Dr. Kathy Sietsema reported that PWCs reached anaerobic threshold much sooner than predicted. Anaerobic threshold (AT) is the point at which a healthy person becomes completely fatigued and cannot exercise any longer (commonly called "hitting the wall"). In the Cheney-Lapp study, PWCs continued exercising beyond the point of AT. Dr. Cheney has hypothesized that PWCs normally perform above AT in everyday activity due to a metabolic injury, and therefore are more accustomed to performing at this level than controls.


Brainstem perfusion is impaired in chronic fatigue syndrome Costa DC, Tannock C, Brostoff J. Institute of Nuclear Medicine, University College London Medical School, London, UK. Quarterly Journal of Medicine 1995; 88(11): 767-73.

Abstract: We looked for brain perfusion abnormalities in patients with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). An initial pilot study revealed widespread reduction of regional brain perfusion in 24 ME/CFS patients, compared with 24 normal volunteers. Hypoperfusion of the brainstem (0.72 ± 0.05 vs. 0.80 ± 0.04, p <0.0001) was marked and constant. We then tested whether perfusion to the brainstem in ME/CFS patients differs from that in normals, patients with major depression, and others with epilepsy. Data from a total of 146 subjects were included in the present study: 40 normal volunteers, 67 patients with ME/CFS (24 in the pilot study, 16 with no psychiatric disorders, 13 with ME/CFS and depression, 14 with ME/CFS and other psychiatric disorders), 10 epileptics, 20 young depressed patients and 9 elderly depressed individuals. Brain perfusion ratios were calculated using 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) and single-photon emission tomography (SPECT) with a dedicated three-detector gamma camera computer/system (GE Neurocam). Brain-stem hypoperfusion was confirmed in all ME/CFS patients. Furthermore, the 16 ME/CFS patients with no psychiatric disorders and the initial 24 patients in the pilot study showed significantly lower brainstem perfusion (0.71 ± 0.03) than did depressed patients (0.77 ± 0.03; ANOVA, p < 0.0001). Patients with ME/CFS have a generalized reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem.


Abnormal Cerebral Perfusion in CFS Comments by David Bell MD

Reference: Schwartz R, Garada B, Komaroff A, Tice H, Gleit M, Jolesz F, et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. American Journal of Roentgenology 1994;162:935-941.

This paper was one of the first to look at the incidence of both the “high intensity” (bright) spots on the MRI scan and the brain blood flow abnormalities in patients with CFS. The authors implied that the SPECT seemed to correlate with the clinical picture.

There are now many papers on SPECT scans and cerebral perfusion studies. For a review I would suggest: Jason L, Corradi K, Torres-Harding S, Taylor R, King C. Chronic fatigue syndrome: the need for subtypes. Neuropsychology Review 2005;15(1):29-58

Comment: For many years patients with CFS have said that their cognitive symptoms are among the most disabling symptoms they experience. In the early 1990’s Dr. Sandman used the term “CFS dementia” and everyone was horrified, including me. But it is now clear that he was correct.

I would feel that the results mentioned above are linked to the poor prognosis seen in many of the CFS long term studies. For those persons with severe CFS persisting for more than five years, the likelihood of recovery is slim. I would assume that the neurological damage that causes the symptoms is also causing the cerebral atrophy, and that is not likely to be reversed.

What is causing this cerebral atrophy? We do not know is the simple answer. But for years we have seen abnormalities in the MRI scans, then SPECT scans showing reduced blood flow to the brain. Sometimes I hear neurologists say that the small “hyperintense” MRI lesions can be due to vascular or embolic phenomena (tiny blood clots or strokes), and this explanation is consistent with the reduced blood flow seen on studies. Like CFS, multiple strokes will cause cerebral atrophy.

Could it be that the reduced blood flow to the brain is the cause of the neurologic injury? Is there a hypercoagulable state causing these problems? Is there “sludging” of the blood flow in the brain because of reduced circulating blood volume? We don’t know and it is time that serious research is initiated on scale that occurred in multiple sclerosis years ago.

If the cerebral atrophy is due to reduced cerebral blood flow, it is theoretically preventable by opening the cerebral vessels and increasing the circulating blood volume. I can be criticized for speculating here, but I freely say that I do not know. But we need the studies to find out.

ME/CFS is a debilitating disease of the central nervous system that causes widespread disability. Unlike Alzheimer’s disease, ME/CFS affects young people in the prime of their life and affects children as well. It should no longer be considered a trivial problem.


Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome. Badawy AA, Morgan CJ, Llewelyn MB, Albuquerque SR, Farmer A
. Cardiff & Vale NHS Trust, Biomedical Research Laboratory, Whitchurch Hospital, Cardiff, Wales, UK. Abdulla.Badawy@cardiffandvale.wales.nhs.uk.

We assessed the serotonin status of patients with the chronic fatigue syndrome (CFS). Tryptophan (Trp) availability to the brain, expressed as the ratio of concentration of serum Trp to the sum of those of its five competitors (CAA), and other parameters of Trp disposition were compared in 23 patients with the CFS and 42 healthy controls. The serum [free Trp]/[CAA] ratio was 43% higher in CFS patients, due to a 48% higher [free Trp]. [Total Trp] was also significantly higher (by 19%) in CFS patients, and, although the [total Trp]/[CAA] ratio did not differ significantly between the control and patient groups, the difference became significant when the results were co-varied with age and gender. [CAA] was not significantly different between groups, but was significantly lower in females, compared to males, of the CFS patient group. We have established normal ranges for Trp disposition parameters and propose criteria for defining the serotonin-biosynthetic status in humans. We have provisionally identified two subgroups of CFS patients, one with normal serotonin and the other with a high serotonin status. The relevance of our findings to, and their implications for, the pharmacological and other therapies of the chronic fatigue syndrome are discussed.


In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Chaudhuri A, Behan PO
. Division of Clinical Neurosciences, Institute of Neurological Sciences, Southern General Hospital, University of Glasgow, 1345 Govan Road, Glasgow G51 4TF, UK. ac54p@udcf.gla.ac.uk

The pathogenic mechanisms of chronic fatigue syndrome (CFS) are not clearly known. Fatigue, poor short-term memory and muscle pain are the most disabling symptoms in CFS. Research data on magnetic resonance spectroscopy (MRS) of muscles and brain in CFS patients suggest a cellular metabolic abnormality in some cases. 31P MRS of skeletal muscles in a subset of patients indicate early intracellular acidosis in the exercising muscles. 1H MRS of the regional brain areas in CFS have shown increased peaks of choline derived from the cell membrane phospholipids. Cell membrane oxidative stress may offer a common explanation for the observed MRS changes in the muscles and brain of CFS patients and this may have important therapeutic implications. As a research tool, MRS may be used as an objective outcome measure in the intervention studies. In addition, regional brain 1H MRS has the potential for wider use to substantiate a clinical diagnosis of CFS from other disorders of unexplained chronic fatigue.


Relationship of brain MRI abnormalities and physical functional status in chronic fatigue syndrome. Cook DB, Lange G, DeLuca J, Natelson BH. Int J Neurosci 2001 Mar;107(1-2):1-6 Department of Neurosciences,; UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA. PMID: 11328679

Chronic Fatigue Syndrome (CFS) is an unexplained illness that is characterized by severe fatigue. Some have suggested that CFS is a "functional somatic syndrome" in which symptoms of fatigue are inappropriately attributed to a serious illness. However, brain magnetic resonance imaging (MRI) data suggest that there may be an organic abnormality associated with CFS.

To understand further the significance of brain MRI abnormalities, we examined the relationship between MRI identified brain abnormalities and self-reported physical functional status in 48 subjects with CFS who underwent brain MR imaging and completed the Medical Outcomes Study SF-36. Brain MR images were examined for the presence of abnormalities based on 5 general categories previously shown to be sensitive to differentiating CFS patients from healthy controls.

There were significant negative relationships between the presence of brain abnormalities and both the physical functioning (PF) (rho=-.31, p=.03), and physical component summary PCS (rho=-.32, p=.03) subscales of the SF-36. CFS patients with MRI identified brain abnormalities scored significantly lower on both PF (t(1,46) =2.3, p=.026) and the PCS (t(1,41) =2.4, p=.02) than CFS subjects without an identified brain abnormality. When adjusted for age differences only the PF analysis remained significant.

However, the effect sizes for both analyses were large indicating meaningful differences in perceived functional status between the groups.

These results demonstrate that the presence of brain abnormalities in CFS are significantly related to subjective reports of physical function and that CFS subjects with MRI brain abnormalities report being more physically impaired than those patients without brain abnormalities.


SPECT Imaging of the Brain: Comparison of Findings in Patients with Chronic Fatigue Syndrome, AIDS Dementia Complex (ADC) and Major Unipolar Depression

Richard B. Schwartz, Anthony L Komaroff et al: Am. J. Roentgenology: 1994:162:943­-951

"This study shows that CFS (ME) shares some similarities on SPECT imaging with AIDS Dementia Complex acute changes in radionuclide uptake in the younger population may be caused by inflammatory processes at the cellular or micro vascular level .... the findings in CFS (ME) are consistent with the hypothesis that CFS (ME) ... results from a viral infection of neurons, glia or vasculature .....viral infection can provoke neurological dysfunction by interfering with intra-cellular mechanisms or membrane transport systems .... or by cerebral hypo perfusion due to vasculitis".


NeuroSPECT findings in children with chronic fatigue syndrome. Goldberg MD, Mena I, Darcourt J.Journal of Chronic Fatigue Syndrome 1997; 3(1): 61-67.

Abstract: BACKGROUND. NeuroSPECT studies have described specific abnormalities in cerebral perfusion in adults with criteria for Chronic Fatigue Syndrome. This reports findings in 13 children with criteria for Chronic Fatigue Syndrome. OBJECTIVE. NeuroSPECT findings in 13 CFS/CFIDS children. METHODS. Thirteen children meeting CDC criteria for CFS/CFIDS were evaluated using NeuroSPECT imaging utilizing Xenon 133 and Tc-99m-HMPAO (1). RESULTS. In 13 children, hypoperfusion was observed at 42 ± 10 ml/min/100g, p<0.0001 in the left temporal lobe and at 45 ± 11, p<.001 in right temporal lobe. Statistically significant hypoperfusion was also obsered in both parietal lobes and at 50 and 53 ml/min/100g, p< 0.05 in the frontal lobe of the right hemisphere. Quantitated HMPAO demonstrated bilateral orbitofrontal and anterior temporal hypoperfusion. There was also hypoperfusion in the dorsal aspects of both frontal lobes and both parietooccipital lobes. CONCLUSION. NeuroSPECT is presented as a quantifiable, reproducible tool that can allow us to document a cohort of children defined as CFS/CFIDS.


Divided attention deficits in patients with chronic fatigue syndrome. Ross S, Fantie B, Straus SF, Grafman J. Appl Neuropsychol 2001;8(1):4-1 Department of Psychology, American University, Washington, DC, USA. PMID: 11388122

Chronic fatigue syndrome (CFS) patients and controls were compared on a variety of mood state, personality, and neuropsychological measures, including memory, word finding, and attentional tasks that required participants to focus, sustain, or divide their attention, or to perform a combination of these functions.

CFS patients demonstrated a selective deficit on 3 measures of divided attention. Their performance on the other neuropsychological tests of intelligence, fluency, and memory was no different than that of normal controls despite their reports of generally diminished cognitive capacity.

There was an inverse relation between CFS patient fatigue severity and performance on 1 of the divided attention measures.

Given these findings, it is probable that CFS patients will report more cognitive difficulties in real-life situations that cause them to divide their effort or rapidly reallocate cognitive resources between 2 response channels (vision and audition).


The electroencephalogram as a diagnostic marker for Chronic Fatigue Syndrome (CFS) Myra Preston Ph.D. and Charles W. Lapp, M.D., Charlotte, North Carolina

Research efforts have failed to uncover a diagnostic marker for CFS. This study looks to the brain as the site of a possible diagnostic marker that would be sensitive and specific to the illness of CFS. The objective of this study is to differentiate CFS subjects from controls in a blinded fashion. To differentiate the two populations, we utilize an EEG pattern that was present in approximately 280 persons with CFS (PWCs), that we had previously studied in an unblinded fashion in the 24 months prior to this study. This brain abnormality was not present in other patient populations or controls.

Methods: We used a blinded protocol to collect raw EEG data in patients that met the CDC case definition of CFS. Controls were screened for current and/or potential exposure to health problems to insure that participants did not have prolonged fatigue or an acute illness. Results: PWCs were correctly identified with 80% sensitivity and 82% specificity compared to healthy controls. Four files utilized as an internal positive control were selected with 100% consistency. Conclusions: EEG data can be used to differentiate PWCs from controls with high sensitivity and specificity. The specific EEG signature seen in persons with CFS can be a diagnostic disorder for the disorder.


Objective evidence of cognitive complaints in Chronic Fatigue Syndrome: A BOLD fMRI study of verbal working memory. Lange G, Steffener J, Cook DB, Bly BM, Christodoulou C, Liu WC, Deluca J, Natelson BH. Neuroimage. 2005 Jun 1;26(2):513-24. Epub 2005 Apr 7. Department of Radiology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA. PMID: 15907308

Individuals with Chronic Fatigue Syndrome (CFS) often have difficulties with complex auditory information processing. In a series of two Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) studies, we compared BOLD signal changes between Controls and individuals with CFS who had documented difficulties in complex auditory information processing (Study 1) and those who did not (Study 2) in response to performance on a simple auditory monitoring and a complex auditory information processing task (mPASAT).

We hypothesized that under conditions of cognitive challenge: (1) individuals with CFS who have auditory information processing difficulties will utilize frontal and parietal brain regions to a greater extent than Controls and (2) these differences will be maintained even when objective difficulties in this domain are controlled for.

Using blocked design fMRI paradigms in both studies, we first presented the auditory monitoring task followed by the mPASAT. Within and between regions of interest (ROI), group analyses were performed for both studies with statistical parametric mapping (SPM99).

Findings showed that individuals with CFS are able to process challenging auditory information as accurately as Controls but utilize more extensive regions of the network associated with the verbal WM system. Individuals with CFS appear to have to exert greater effort to process auditory information as effectively as demographically similar healthy adults.

Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.


Cognitive Symptoms of CFS Comments by David Bell MD

Reference: Lange G, Streffner J, Cook D, Bly B, Christodoulou C, Liu W, et al. Objective evidence of cognitive complaints in chronic fatigue syndrome: A BOLD fMRI study of verbal working memory. NeuroImage 2005;26:513-524.

In this study, the authors, using blood oxygen level dependent (BOLD) functional MRI imaging show that CFS patients are able to process challenging information, but utilize more extensive cerebral networks and must exert greater effort to process auditory information. They state, “Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.”

Comment: Many standard neuropsychological testing results have been considered “normal” or “consistent with depression”, primarily because the areas studied were not the areas of impairment in CFS. If neuropsychological testing were to be done, the focus should be on ability to maintain attention, verbal processing speed, reaction times, and the ability to acquire new information. For a review of the neurocognitive studies, see Jason L, Corradi K, Torres-Harding S, Taylor R, King C. Chronic fatigue syndrome: the need for subtypes. Neuro-psychology Review 2005;15(1):29-58. Hopefully this study by Lange et al will put to rest the controversy of the presence of cognitive deficits in CFS, because they can be seen on fMRI.


Attention and Information Processing Efficiency in Patients with Chronic Fatigue Syndrome. Michiels V, de Gucht V, Cluydts R, Fischler B Free University of Brussels (VUB), Belgium Journal of Clinical and Experimental Neuropsychology (ISSN 1380-3395) 1999 Oct;21(5):709-729 NLM citation: PMID: 10572289

In a study of attentional tests and a verbal memory tasks administered to 29 people with Chronic Fatigue Syndrome and 22 healthy controls, the authors found evidence of a global non-modality-specific attentional dysfunction in patients with CFS.


Working memory deficits associated with chronic fatigue syndrome.Dobbs BM, Dobbs AR, Kiss I. J Int Neuropsychol Soc 2001 Mar;7(3):285-93 Department of Psychology, University of Alberta, Edmonton, Canada.
bdobbs@ualberta.caNLM Citation: PMID: 11311029

Cognitive impairments are among the most frequently reported and least investigated components of the chronic fatigue syndrome (CFS).

As part of a multifaceted study of the CFS, the present study investigated the cognitive functioning of chronic fatigue [syndrome] patients.

The performance of 20 CFS patients was compared to that of controls (N = 20) on 4 tests of working memory (WM). Digit Span Forward was used to assess the storage capacity of WM. Multiple aspects of central executive functioning were assessed using several standard measures: Digit Span Backward, and Trails A and Trails B. More recently developed measures of WM were used to assess control of processing under temporal demands (working memory task) and resistance to interference (a sustained attention task). Deficits were restricted to more demanding tasks, requiring resistance to interference and efficient switching between processing routines.

The overall results clearly implicate deficits in the control aspects of central executive function in CFS.


Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome.
LaManca JJ, Sisto SA, DeLuca J, Johnson SK, Lange G, Pareja J, Cook S, Natelson BH
. Chronic Fatigue Syndrome Cooperative Research Center, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, USA.

The purpose of this study was to determine the effect of exhaustive exercise on cognitive performance of patients with chronic fatigue syndrome (CFS) and sedentary healthy controls (CON). Subjects were 19 women with CFS and 20 CON. A test battery consisting of 4 cognitive tests (CTB) was given pre-, immediately post-, and 24 hours post-treadmill exercise to exhaustion. No differences were seen on the CTB pre-exercise. CFS patients improved at a slower rate than CON on the Symbol Digit Modalities Test (SDMT), Stroop Word Test (SWT), and Stroop Color Test (SCT). When compared with CON, a lower number of correct responses was seen for the CFS immediately postexercise on the SDMT (61 +/- 3 vs 66 +/- 2), SWT (137 +/- 6 vs 146 +/- 6), and SCT (99 +/- 4 vs 107 +/- 3), and 24 hours postexercise on the SDMT (64 +/- 3 vs 69 +/- 2), SWT (134 +/- 7 vs 148 +/- 5), and SCT (101 +/- 4 vs 106 +/- 3). We conclude that after physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals.


Relationships of cognitive difficulties to immune measures, depression and illness burden in CFS. Lutgendorf S, Klimas NG, Antoni M, Brickman A, Fletcher MA  University of Miami School of Medicine, Miami, Florida, USA. Journal of Chronic Fatigue Syndrome 1995; 1(2): 23-41.

Abstract: OBJECTIVE. We related the subjective assessment of cognitive difficulties with lymphocyte phenotypes, cell-mediated immunity (CMI), cytokine and neopterin levels in patients with chronic fatigue syndrome (CFS), in order to determine if CFS patients complaining of greater cognitive difficulties would show greater impairments in cell-mediated immunity and a greater degree of immune system dysregulation, and to determine if these cognitive difficulties would correlate with the other non-affective measures of CFS-associated illness burden. We also assessed whether these relationships would hold independent of depression in two ways, by statistically covarying depression severity scores and by comparing subsets of CFS patients with and without a concurrent diagnosis of major depressive disorder. DESIGN. A case series of CFS patients. SETTING. Outpatient tertiary referral clinic at the University of Miami School of Medicine, Miami, FL.  PATIENTS. Consecutive sample of 65 patients who were referred as CFS to the University of Miami Diagnostic Immunology Clinic, who met the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of CFS and consented to participate.  MAIN MEASURES. Self-assessment of cognitive difficulties, depression and illness burden, clinician-assessed depression and CFS symptoms, lymphocyte phenotype, proliferative response to mitogens, serum levels of cytokines and neopterin.

RESULTS. Among CFS patients, high Cognitive Difficulty Scale (CDS) scores were significantly related to lower lymphocyte proliferative responses to mitogens, higher neopterin levels, and higher CD4 and lower CD8 lymphocyte counts. These relationships, with the exception of T cell subset percentages, were maintained when depression severity was used as a co-variate. High CDS scores were also significantly related to lower Karnofsky scores, and greater illness burden as measured by the Sickness Impact Profile. Evidence is presented that CFS patients with higher cognitive difficulty scores have more immune and clinical dysfunction than those with less cognitive difficulty, and that these relationships are independent of depression . These observations provide support for the concept that although both cognitive difficulties and immunologic abnormalities, such as immune activation and impaired cell-mediated immunity, may represent secondary sequelae to the same event(s), they are not likey to be secondary sequelae to depression.


Attention and information processing efficiency in patients with Chronic Fatigue Syndrome.Michiels V; de Gucht V; Cluydts R; Fischler B Free University of Brussels (VUB), Belgium.J Clin Exp Neuropsychol 1999 Oct; 21(5):709-29 (ISSN: 0168-8634)

In this study a battery of attentional tests and a verbal memory task were administered to outpatients with Chronic Fatigue Syndrome (CFS) in order to evaluate aspects of attention that have not been explored in this group to date. In addition, this study was designed to further examine memory function and to extend the few reports investigating the rate of cognitive processing independent of motor speed and the possibility of a modality-specific impairment of information processing. Twenty-nine patients with CFS and 22 healthy controls matched for age, gender, intelligence, and education were included in this study. The results show that patients with CFS do not seem to be impaired for modification of phasic arousal level, nor for visual selective attention requiring shifting of attention in the visuospatial field. The results further support the presence of reduced information processing speed and efficiency, and strengthen the evidence of a global non-modality-specific attentional dysfunction in patients with CFS. In this study the poor performance of patients with CFS on recall of verbal information was due to poor initial storage rather than to a retrieval failure.
Unique NLM Identifier: 20042376


Impaired associative learning in chronic fatigue syndrome. Servatius RJ; Tapp WN; Bergen MT; Pollet CA; Drastal SD; Tiersky LA; Desai P; Natelson BH New Jersey Medical School, Department of Neuroscience, East Orange 07019, USA.Neuroreport 1998 Apr 20;9(6):1153-7 (ISSN: 0959-4965)

Patients with chronic fatigue syndrome (CFS) report cognitive difficulties (impaired attention, memory and reasoning). Neuropsychological tests have failed to consistently find cognitive impairments to the degree reported by CFS patients. We tested patients with CFS and sedentary controls in protocols designed to measure sensory reactivity and acquisition of the classically conditioned eyeblink response. Patients with CFS exhibited normal sensitivity and responsivity to acoustic stimuli. However, CFS patients displayed impaired acquisition of the eyeblink response using a delayed-type conditioning paradigm. Sensitivity and responsivity to the airpuff stimulus were normal. In the absence of sensory/motor abnormalities, impaired acquisition of the classically conditioned eyeblink response indicates an associative deficit. These data suggest organic brain dysfunction within a defined neural substrate in CFS patients.

Unique NLM Identifier: 98263991 Grant ID: UOI-AI32247-AI-NIAID


Detection of Intracranial Abnormalities in Patients with Chronic Fatigue Syndrome: comparison of MR Imaging and SPECT. Schwartz, R. B.,Garada,B.M., Komaroff A. L. et al:
American Journal of Roentgenology 1994:162:935-941

"in addition to CNS lupus, other inflammatory vascular.. conditions can appear similar to CFS (ME) clinically and radiologically……As with any chronic inflammatory condition affecting the CNS, the T2-bright foci on MR in CFS (ME) may represent perivascular cellular infiltrate and / or reactive demyelination of the surrounding white matter. Alternatively, these abnormalities may reflect the result of a vasculopathy specifically involving the small vessels of the cerebral white matter; indeed, the distribution of lesions on MR in CFS (ME) is similar to that observed in occlusive arteriolar disease of any origin. The cortical defects measured with SPECT likewise may result from decreased flow through cortical arterioles owing to vasculitis. Specifically, on the basis of our observations, the white matter abnormalities seen on MR images may represent ... chronic demyelination, which appears to be irreversible".


Grief in M.E. sufferers

Grief is the most common cause of mood change in CFS. The change in quality of life with CFS is profound; patients must adapt every aspect of existence and often resist acceptance of this unwanted change22,23. Grief cannot begin until a diagnosis is made and other diagnoses are ruled out. Diagnosis frees the patient to begin the process of grieving. Grief is not a disorder. It is a normal developmental process which enables people to deal with overwhelming loss. It is an understandable reaction to a serious, uncertain, stigmatizing and chronic disorder. Grief is therefore common during the initial post diagnostic period and may recur each time there are new changes in health or life situation.


A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Ablashi DV, Salahuddin SZ, Saxinger C, Biddle R, et al. Annals of Internal Medicine 1992; 116(2): 103-13.

Abstract: OBJECTIVE: To conduct neurologic, immunologic, and virologic studies in patients with a chronic debilitating illness of acute onset. DESIGN: Cohort study with comparison to matched, healthy control subjects. PATIENTS: We studied 259 patients who sought care in one medical practice; 29% of the patients were regularly bedridden or shut-in. MAIN OUTCOME MEASURES: Detailed medical history, physical examination, conventional hematologic and chemistry testing, magnetic resonance imaging (MRI) studies, lymphocyte phenotyping studies, and assays for active infection of patients' lymphocytes with human herpesvirus type 6 (HHV-6). MAIN RESULTS: Patients had a higher mean (± SD) CD4/CD8 T-cell ratio than matched healthy controls (3.16 ± 1.5 compared with 2.3 ± 1.0, respectively; P less than 0.003). Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with edema or demyelination in 78% of patients (95% CI, 72% to 86%) and in 21% of controls (CI, 11% to 36%) (P less than 10(-9)). Primary cell culture of lymphocytes showed active replication of HHV-6 in 79 of 113 patients (70%; CI, 61% to 78%) and in 8 of 40 controls (20%; CI, 9% to 36%) (P less than 10(-8], a finding confirmed by assays using monoclonal antibodies specific for HHV-6 proteins and by polymerase chain reaction assays specific for HHV-6 DNA. CONCLUSIONS: Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system. The active replication of HHV-6 most likely represents reactivation of latent infection, perhaps due to immunologic dysfunction. Our study did not directly address whether HHV-6, a lymphotropic and gliotropic virus, plays a role in producing the symptoms or the immunologic and neurologic dysfunction seen in this illness. Whether the findings in our patients, who came from a relatively small geographic area, will be generalizable to other patients with a similar syndrome remains to be seen.


Brainstem perfusion is impaired in chronic fatigue syndrome. Costa DC, Tannock C, Brostoff J. Quarterly Journal of Medicine 1995; 88(11): 767-73.

Abstract: We looked for brain perfusion abnormalities in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). An initial pilot study revealed widespread reduction of regional brain perfusion in 24 ME/CFS patients, compared with 24 normal volunteers. Hypoperfusion of the brainstem (0.72 ± 0.05 vs. 0.80 ± 0.04, p <0.0001) was marked and constant. We then tested whether perfusion to the brainstem in ME/CFS patients differs from that in normals, patients with major depression, and others with epilepsy. Data from a total of 146 subjects were included in the present study: 40 normal volunteers, 67 patients with ME/CFS (24 in the pilot study, 16 with no psychiatric disorders, 13 with ME/CFS and depression, 14 with ME/CFS and other psychiatric disorders), 10 epileptics, 20 young depressed patients and 9 elderly depressed individuals. Brain perfusion ratios were calculated using 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) and single-photon emission tomography (SPECT) with a dedicated three-detector gamma camera computer/system (GE Neurocam). Brain-stem hypoperfusion was confirmed in all ME/CFS patients. Furthermore, the 16 ME/CFS patients with no psychiatric disorders and the initial 24 patients in the pilot study showed significantly lower brainstem perfusion (0.71 ± 0.03) than did depressed patients (0.77 ± 0.03; ANOVA, p < 0.0001). Patients with ME/CFS have a generalized reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem.


Assesment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Ichise M, Salit IE, Abbey SE, Chung DG, Gray B, Kirsh JC, Freedman M. Nuclear Medicine Communications 1992; 13(10): 767-72.

Abstract: Chronic fatigue syndrome (CFS) is a severely disabling illness of uncertain aetiology. It is characterized by a chronic, sustained or fluctuating sense of debilitating fatigue without any other known underlying medical conditions. It is also associated with both somatic and neuropsychological symptoms. Both physical and laboratory findings are usually unremarkable. Regional cerebral blood flow (rCBF) was assessed in 60 clinically defined CFS patients and 14 normal control (NC) subjects using 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO) single photon emission computed tomography (SPECT). Compared with the NC group, the CFS group showed significantly lower cortical/cerebellar rCBF ratios, throughout multiple brain regions (P <0.05). Forty-eight CFS subjects (80%) showed at least one or more rCBF ratios significantly less than normal values. The major cerebral regions involved were frontal (38 cases, 63%), temporal (21 cases, 35%), parietal (32 cases, 53%) and occipital lobes (23 cases, 38%). The rCBF ratios of basal ganglia (24 cases, 40%) were also reduced. 99Tcm-HMPAO brain SPECT provided objective evidence for functional impairment of the brain in the majority of the CFS subjects. The findings may not be diagnostic of CFS but 99Tcm-HMPAO SPECT may play an important role in clarifying the pathoaetiology of CFS. Further studies are warranted.


Gait abnormalities in chronic fatigue syndrome. Natelson BH, Sisto SA, Tapp WN. Journal of the Neurological Sciences 1995; 131(2): 156-61.

Abstract: To evaluate our clinical impression that patients with the chronic fatigue syndrome (CFS) did not walk normally, we assessed gait kinematics at slow walking speeds (i.e., 0.45, 0.89 and 1.34 m/sec) and 30 m run time speeds on CFS patients and on a comparison group of sedentary controls. Run time was significantly slower for CFS than control subjects (p <0.001). There was a significant interaction (p < 0.01) between group and speed for maximum hip angle during stance and swing phase with hip angle being significantly larger at 1.34 m/sec for CFS than controls subjects for both cases (p < 0.05). Knee flexion during stance and swing phases was significantly larger for controls than CFS subjects at 0.45 m/sec (p < 0.01). Ratio of stride length divided by leg length was significantly larger for the control subjects than for the CFS subjects with differences occurring at 0.45 and 0.89 m/sec (p < 0.01) but not 1.34 m/sec. The data indicate that CFS patients have gait abnormalities when compared to sedentary controls. These could be due to balance problems, muscle weakness, or central nervous system dysfunction; deciding which will require further research. Evaluation of gait may be a useful tool to measure outcome following therapeutic interventions.


A controlled study of brain magnetic resonance imaging in patients with the chronic fatigue syndrome. Natelson BH, Cohen JM, Brassloff I, Lee HJ. Journal of the Neurological Sciences 1993; 120(2): 213-7.

Abstract: Two neuroradiologists compared the brain MR scans of 52 patients with the CDC criteria for the chronic fatigue syndrome (CFS) with those of 52 age and sex matched controls who had undergone imaging because of histories of head trauma or headache. CFS patients had significantly more abnormal scans than controls—27% vs 2%. Abnormalities seen were foci of increased white matter T2 signal in 9 CFS patients and one control and ventricular or sulcal enlargement in 5 CFS patients. Follow up of patients with subcortical signal hyperintensities revealed 3 who had symptoms suggestive of other known medical causes of what appeared to be CFS. The data indicate that some CFS patients have some organic problem manifesting itself on neuroimaging. But, finding MR abnormalities should warn the physician that the patient's symptoms may be secondary to some other medical illness and not simply primary CFS.


Cognitive functioning is impaired in patients with chronic fatigue syndrome devoid of psychiatric disease. Deluca J, Johnson SK, Ellis SP, Natelson BH. Journal of Neurology Neurosurgery and Psychiatry 1997; 62: 151-55.

Abstract: OBJECTIVE: To examine the effect of the presence or absence of psychiatric disease on cognitive functioning in chronic fatigue syndrome. METHODS: Thirty six patients with chronic fatigue syndrome and 31 healthy controls who did not exercise regularly were studied. Subgroups within the chronic fatigue syndrome sample were formed based on the presence or absence of comorbid axis I psychiatric disorders. Patients with psychiatric disorders preceding the onset chronic fatigue syndrome were excluded. Subjects were administered a battery of standardised neuropsychological tests as well as a structured psychiatric interview. RESULTS: Patients with chronic fatigue syndrome without psychiatric comorbidity were impaired relative to controls and patients with chronic fatigue syndrome with concurrent psychiatric disease on tests of memory, attention, and information processing. CONCLUSION: Impaired cognition in chronic fatigue syndrome cannot be explained solely by the presence of a psychiatric condition.


Information processing efficiency in chronic fatigue syndrome and multiple sclerosis. DeLuca J, Johnson SK, Natelson BH. Archives of Neurology 1993; 50(3): 301-4.

Abstract: OBJECTIVE—To compare the cognitive performance of subjects with chronic fatigue syndrome (CFS), multiple sclerosis (MS), and healthy controls. All subjects were matched for age, education, and verbal intelligence, as previous neuropsychological studies of CFS had not used appropriate control groups. DESIGN—Case-control design. All subjects were given a neuropsychological battery and the test scores were compared among the groups. SETTING—Subjects with CFS and subjects with MS were recruited from private and institutional practice and from the community. Healthy subjects were recruited from the community. PATIENTS/OTHER PARTICIPANTS—Twelve subjects (all female) with CFS participated in the study. Chronic fatigue syndrome was diagnosed in these patients in accordance with the requirements outlined by the Centers for Disease Control as modified subsequently to not exclude patients with concurrent depression and/or anxiety. All subjects with CFS were referred for a neuropsychological examination to assess persistent cognitive complaints. Eleven subjects (10 female, one male) with the diagnosis of clinically stable MS were chosen from clinics and the community because of complaints of mild to moderate cognitive impairment. The subjects with MS and 11 healthy volunteers (10 female, one male) were matched to the group with CFS by age, education, and estimated verbal intelligence (based on the Vocabulary subtest of the Wechsler Adult Intelligence Scale-Revised). The subjects with MS had a mean Kurtzke Expanded Disability Status Scale score of 4.95 (SD, 1.95; range, 2.0 to 7.5). As a result of the matching procedure, there were no differences among the three groups in age (F[2,31] = 0.32), education (F[2,31] = 0.80), and verbal intelligence (F[2,31] = 0.31). INTERVENTIONS—None. MAIN OUTCOME MEASURES—These measures included the Beck Depression Inventory (BDI), the Paced Auditory Serial Addition Test (PASAT), Digit Span Test, and the Similarities Test of Verbal Abstract Reasoning. CONCLUSIONS—These results indicate that subjects with CSF and subjects with MS show significant impairment on a test of complex concentration when compared with appropriate controls. The data suggest that subjects with CFS and subjects with MS have difficulty on tasks that require the simultaneous processing of complex cognitive information.


AACFS CONFERENCE REPORT - JANUARY 2001

On MRI there are small areas of high signal in the white matter,.. SPECT scans are more physiologic and show a "tattered" signal in CFS. A functional MRI gives a better picture of the physiology. The brain appears to be working harder than in a healthy person doing the same task. Other parts of the brain seem to be brought in to "help".


Selective impairment of auditory processing in chronic fatigue syndrome: a comparison with multiple sclerosis and healthy controls. Johnson SK, DeLuca J, Diamond BJ, Natelson BH. Perceptual and Motor Skills 1996; 83: 51-62.

Abstract: The most consistent deficit observed in individuals with Chronic Fatigue Syndrome has been in efficiency of information processing. To examine the possibility of a modality-specific impairment, the present study examined subjects with Chronic Fatigue Syndrome, multiple sclerosis, and healthy controls on an auditory-versus visual-paced serial-addition test. 20 subjects with Chronic Fatigue Syndrome, 20 subjects with clinically definite Multiple Sclerosis, and 20 sedentary healthy controls were compared. One-half of the subjects in each group were administered the Paced Auditory Serial Addition Test and the other half were administered the Paced Visual Serial Addition Test. The group with Chronic Fatigue Syndrome was differentially impaired on the auditory relative to the visual processing task. The group with Multiple Sclerosis was equally impaired on both versions of the task. The results are discussed within the framework of Baddeley's model of working memory.


Cognitive functioning of patients with chronic fatigue syndrome. Johnson SK, DeLuca J, Fiedler N, Natelson BH. Clinical Infectious Diseases 1994; 18(Supp 1): S84-5.

Abstract: Neuropsychological problems are a distressing and frequent component of the symptom complex associated with chronic fatigue syndrome. Objective assessment of these difficulties is essential to understanding the nature of this illness. Results of the studies discussed in this paper suggest that impaired information processing, rather than primary memory dysfunction, may be at the root of the cognitive problems that afflict so many patients with CFS.


Relationships of cognitive difficulties to immune measures, depression and illness burden in CFS. Lutgendorf S, Klimas NG, Antoni M, Brickman A, Fletcher MA. Journal of Chronic Fatigue Syndrome 1995; 1(2): 23-41.

Abstract: OBJECTIVE. We related the subjective assessment of cognitive difficulties with lymphocyte phenotypes, cell-mediated immunity (CMI), cytokine and neopterin levels in patients with chronic fatigue syndrome (CFS), in order to determine if CFS patients complaining of greater cognitive difficulties would show greater impairments in cell-mediated immunity and a greater degree of immune system dysregulation, and to determine if these cognitive difficulties would correlate with the other non-affective measures of CFS-associated illness burden. We also assessed whether these relationships would hold independent of depression in two ways, by statistically covarying depression severity scores and by comparing subsets of CFS patients with and without a concurrent diagnosis of major depressive disorder. DESIGN. A case series of CFS patients. SETTING. Outpatient tertiary referral clinic at the Unversity of Miami School of Medicine, Miami, FL. PATIENTS. Consecutive sample of 65 patients who were referred as CFS to the University of Miami Diagnostic Immunology Clinic, who met the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of CFS and consented to participate. MAIN MEASURES. Self-assessment of cognitive difficulties, depression and illness burden, clinician-assessed depression and CFS symptoms, lymphocyte phenotype, proliferative response to mitogens, serum levels of cytokines and neopterin. RESULTS. Among CFS patients, high Cognitive Difficulty Scale (CDS) scores were significantly related to lower lymphocyte proliferative responses to mitogens, higher neopterin levels, and higher CD4 and lower CD8 lymphocyte counts. These relationships, with the exception of T cell subset percentages, were maintained when depression severity was used as a co-variate. High CDS scores were also significantly related to lower Karnofsky scores, and greater illness burden as measured by the Sickness Impact Profile. Evidence is presented that CFS patients with higher cognitive difficulty scores have more immune and clinical dysfunction than those with less cognitive difficulty, and that these relationships are independent of depression. These observations provide support for the concept that although both cognitive difficulties and immunologic abnormalities, such as immune activation and impaired cell-mediated immunity, may represent secondary sequelae to the same event(s), they are not likey to be secondary sequelae to depression.


Cognitive deficits in patients with chronic fatigue syndrome. Marcel B, Komaroff AL, Fagioli LR, Kornish RJ, Albert MS. Biological Psychiatry 1996; 40(6): 535-41.

Abstract: Twenty-nine subjects with chronic fatigue syndrome (CFS) and 25 healthy control subjects were administered a lengthy neuropsychological battery that included standard neuropsychological tests and a computerized set of tasks that spanned the same areas of ability. The primary significant differences between patients and controls were found on tests of learning and memory. These differences remained when the degree of psychiatric symptomatology in the subjects was covaried. Patients on and off psychoactive medications did not differ in their performance on these tasks. These results suggest that at least a subset of CFS patients may experience significant impairments in learning and memory.


Cognitive functioning in patients with chronic fatigue syndrome. Michiels V. Cluydts R, Fischler B, Hoffman G, LeBon O, De Meirleir K. Journal of Clinical and Experimental Neuropsychology 1996; 18(5): 666-677.

Abstract: A comprehensive battery of neuropsychological tests was administered to 35 outpatients suffering from Chronic Fatigue Syndrome (CFS). They were compared to 33 normal controls matched for age, gender, intelligence, and education. The patients displayed psychomotor slowing and impaired attention. The learning rate of verbal and visual material for patients with CFS was slower, and delayed recall of verbal and visual information was impaired. Because there was a high variability in cognitive impairment within the CFS group, it would be inappropriate to generalize results to the entire CFS population. Two neuropsychological variables indicating aspects of psychomotor performance and verbal memory were found to discriminate best between patients and controls.


Sensory and cognitive event-related potentials in myalgic encephalomyelitis. Prasher D, Smith A, Findley L. Journal of Neurology Neurosurgery and Psychiatry 1990; 53: 247-53.

Abstract: Myalgic Encephalomyelitis (ME) is a form of post viral fatigue syndrome resulting in myalgia and fluctuating fatiguability. Symptoms reflecting central nervous system dysfunction are common and include muscle weakness, headache, sensory disturbances, poor short term memory and impairment of concentration. In view of the fact that sensory and cognitive disturbances are experienced by many patients objective evidence was sought with multi-modality sensory evoked potentials and auditory event-related cognitive potentials in a group of ME patients both with and without the enteroviral antigen, VP1 test positive. The auditory brainstem, median nerve somatosensory and pattern reversal checkerboard visual potentials were normal for all 37 patients tested. In contrast to the sensory potentials significant differences in the mean latencies of the cognitive potential N2 and P3 were found. Reaction times were also significantly prolonged but the performance in terms of error was not significantly affected. No significant difference emerged in any of the parameters for the VP1 test. P3 was abnormal in latency or amplitude in 36% of the VP1 positive patients for the frequency discrimination task and 48% for the more difficult duration discrimination task. The abnormalities indicate attentional deficits in some patients and slower speed of information processing in others. The prolonged latencies observed in these patients have not been observed in patients with depression in many other studies.


Memory deficits associated with chronic fatigue immune dysfunction syndrome. Sandman CA, Barron JL, Nackoul K, Goldstein J, Fidler F. Biological Psychiatry 1993; 33(8-9): 618-23.

Abstract: Performance on tests of memory in 39 patients who met Center for Disease Control (CDC) criteria for chronic fatigue immune dysfunction syndrome (CFIDS) was compared with 23 depressed patients (DSM-III-R) and 129 healthy controls. Although the CFIDS patients had normal neuropsychological profiles, they significantly overestimated their ability (metamemory), performed significantly worse on tests of recall as context increased (e.g., recognition), made more errors when rehearsal was prevented, and had delayed mental scanning as memory load increased. The overall pattern indicated that CFIDS patients had a significant memory deficit, far worse than implied by CDC criteria. The pattern for CFIDS patients was consistent with temporal-limbic dysfunction and significantly different than depressed patients and control subjects.


The psychiatric status of patients with the chronic fatigue syndrome. Hickie I, Lloyd A, Wakefield D, Parker G. British Journal of Psychiatry 1990; 156: 534-40.

Abstract: The prevalence of psychiatric disorder in 48 patients with chronic fatigue syndrome (CFS) was determined. Twenty-two had had a major depressive (non-endogenous) episode during the course of their illness, while seven had a current major (non-endogenous) depression. The pre-morbid prevalence of major depression (12.5%) and of total psychiatric disorder (24.5%) was no higher than general community estimates. The pattern of psychiatric symptoms in the CFS patients was significantly different to that of 48 patients with non-endogenous depression, but was comparable with that observed in other medical disorders. Patients with CFS were not excessively hypochondriacal. We conclude that psychological disturbance is likely to be a consequence of, rather than an antecedent risk factor to the syndrome.


The role of mitochondria in the pathogenesis of neurodegenerative diseases. Manfredi G, Beal MF Department of Neurology and Neuroscience, Weill Medical College of Cornell University and the New York Hospital, Cornell Medical Center, New York 10021, USA. gim2004@mail.med.cornell.edu Brain Pathol 2000 Jul;10(3):462-72

A growing body of evidence indicates that mitochondrial dysfunction may play an important role in the pathogenesis of many neurodegenerative disorders. Because mitochondrial metabolism is not only the principal source of high energy intermediates, but also of free radicals, it has been suggested that inherited or acquired mitochondrial defects could be the cause of neuronal degeneration as a consequence of energy defects and oxidative damage. Mitochondrial respiratory chain dysfunction has been reported in association with primary mitochondrial DNA abnormalities, and also as a consequence of mutations in nuclear genes directly involved in mitochondrial functions, such as SURF1, frataxin, and paraplegin. Defects of oxidative phosphorylation and increased free radical production have also been observed in diseases that are not due to primary mitochondrial abnormalities. In these cases, the mitochondrial dysfunction is likely to be an epiphenomenon, which, nevertheless, could be of importance in precipitating a cascade of events leading to cell death. In either case, understanding the role of mitochondria in the pathogenesis of neurodegenerative diseases could be important for the development of therapeutic strategies in these disorders.


Politics, science, and the emergence of a new disease. Jason LE, Richman JA, Friedberg F, et al.  American Psychologist 1997; 52(9): 973-983.

Abstract: Chronic fatigue syndrome (CFS) emerged as a diagnostic category during the last decade. Initial research suggested that CFS was a relatively rare disorder with a high level of psychiatric comorbidity. Many physicians minimized the seriousness of this disorder and also interpreted the syndrome as being equivalent to a psychiatric disorder. These attitudes had negative consequences for the treatment of CFS. By the mid-1990s, findings from more representative epidemiological studies indicated considerably higher CFS prevalence rates. However, the use of the revised CFS case definition might have produced heterogeneous patient groups, possibly including some patients with pure psychiatric disorders. Social scientists have the expertise to more precisely define this syndrome and to develop appropriate and sensitive research strategies for understanding this disease.


In honour of International ME Awareness day An article lists the symptoms of brain injury noting how many of them are seen in ME/ICD-CFS also.


Brain SPECT Abstracts (Choose CFS on the pull down menu)


Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. Schwartz RB, Garada BM, Komaroff AL, Tice HM, Gleit M, Jolesz FA, Holman BL. American Journal of Roentgenology 1994; 162(4): 935-41.

Abstract: OBJECTIVE. Chronic fatigue syndrome is a recently characterized condition of unknown origin that is manifested by fatigue, flulike complaints, and neurologic signs and symptoms, including persistent headache, impaired cognitive abilities, mood disorders, and sensorimotor disturbances. This syndrome can be difficult to diagnose clinically or by standard neuroradiologic tests. We performed MR imaging and single-photon emission computed tomography (SPECT) in patients with chronic fatigue syndrome to compare the usefulness of functional and anatomic imaging in the detection of intracranial abnormalities. SUBJECTS AND METHODS. Sixteen patients who fulfilled the Centers for Disease Control, British, and/or Australian criteria for chronic fatigue syndrome had MR and SPECT examinations within a 10-week period. Axial MR and SPECT scans were analyzed as to the number and location of focal abnormalities by using analysis of variance with the Student-Newman-Keuls option. MR imaging findings in patients with chronic fatigue syndrome were compared with those in 15 age-matched control subjects, and SPECT findings in the patients with chronic fatigue syndrome were compared with those in 14 age-matched control subjects by using Fisher's exact test. The findings on MR and SPECT scans in the same patients were compared by using the Wilcoxon matched-pairs signed-ranks test. RESULTS. MR abnormalities consisted of foci of T2-bright signal in the periventricular and subcortical white matter and in the centrum semiovale; there were 2.06 foci per patient, vs 0.80 foci per control subject. MR abnormalities were present in eight (50%) of 16 patients, compared with three (20%) of 15 age-matched control subjects. Neither of these differences reached significance, although the power of the study to detect differences between groups was small. Patients with chronic fatigue syndrome had significantly more defects throughout the cerebral cortex on SPECT scans than did normal subjects (7.31 vs 0.43 defects per subject, p <.001). SPECT abnormalities were present in 13 (81%) of 16 patients, vs three (21%) of 14 control subjects (p < .01). SPECT scans showed significantly more abnormalities than did MR scans in patients with chronic fatigue syndrome (p < .025). In the few patients who had repeat SPECT and MR studies, the number of SPECT abnormalities appeared to correlate with clinical status, whereas MR changes were irreversible. CONCLUSION. SPECT abnormalities occur more frequently and in greater numbers than MR abnormalities do in patients with chronic fatigue syndrome. SPECT may prove to be useful in following the clinical progress of patients with this syndrome.


Chronic fatigue syndrome: neurological findings may be related to blood-brain barrier permeability.Bested AC, Saunders PR, Logan AC.Med Hypotheses 2001 Jul;57(2):231-7 Environmental Health Clinic, Sunnybrook and Women's College, Health Sciences Centre, Toronto, Canada PMID: 11461179

Despite volumes of international research, the etiology of chronic fatigue syndrome (CFS) remains elusive. There is, however, considerable evidence that CFS is a disorder involving the central nervous system (CNS). It is our hypothesis that altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and symptoms found in CFS.

To support this hypothesis we have examined agents that can increase the blood-brain barrier permeability (BBBP) and those that may be involved in CFS.

The factors which can compromise the normal BBBP in CFS include viruses, cytokines, 5-hydroxytryptamine, peroxynitrite, nitric oxide, stress, glutathione depletion, essential fatty acid deficiency, and N-methyl-D-aspartate overactivity.

It is possible that breakdown of normal BBBP leads to CNS cellular dysfunction and disruptions of neuronal transmission in CFS. Abnormal changes in BBBP have been linked to a number of disorders involving the CNS; based on review of the literature we conclude that the BBB integrity in CFS warrants investigation.

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