ME and CFS References

De Lange, FP., Koers, A., Kalkman, JS and Bleijenberg, G., Hagoort, P, van de Meer, JWM and Toni, I. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain, 2008, June 28th. DOI:10.1093/brain/awn140.

CFS is a disabling disorder, characterized by persistent or relapsing fatigue. Recent studies have detected a decrease in cortical grey matter volume in patients with CFS, but it is unclear whether this cerebral atrophy constitutes a cause or a consequence of the disease. Cognitive behavioural therapy (CBT) is an effective behavioural intervention for CFS, which combines a rehabilitative approach of a graded increase in physical activity with a psychological approach that addresses thoughts and beliefs about CFS which may impair recovery. Here, we test the hypothesis that cerebral atrophy may be a reversible state that can ameliorate with successful CBT. We have quantified cerebral structural changes in 22 patients with CFS (CDC criteria ’94) that underwent 16 sessions of CBT, and 22 healthy control participants.

At baseline, CFS patients had significantly lower global grey matter volume than healthy control participants, particularly the passive patients. CBT intervention led to a significant improvement in health status, physical activity and cognitive performance. Crucially, CFS patients showed a significant increase in grey matter volume, localized in the lateral prefrontal cortex. This change in cerebral volume was related to improvements in cognitive speed in the CFS patients. However, grey matter volume in the patient group remained lower than that of the controls (p=.03), and there was less change amongst the older participants.

The mean actometer score at baseline was 63.5, at follow-up, it was 73.2 (p<.01) and there was a trend of patients becoming more physically active following CBT (p=.056). However, the increase in activity level was only marginally correlated with the increase in grey volume matter (r=.3, p=.086). There was no significant relation between the latter and changes in subjective ratings such as fatigue and functional impairment. Moreover, CBT had no consistent effect on cognitive performance. “Not all patients benefited from CBT”.

Our findings indicate that the cerebral atrophy associated with CFS is partially reversed after effective CBT. This result provides an example of macroscopic cortical plasticity in the adult human brain, demonstrating a surprisingly dynamic relation between behavioural state and cerebral anatomy. Furthermore, our results reveal a possible neurobiological substrate of psychotherapeutic treatment.

[Ed. Note: There are no data on levels of stress before and after treatment. Hence, it is not possible to assess if a reduction of stress reversed the original changes in grey matter volume.]

ENDOCRINOLOGY AND NEUROENDOCRINOLOGY

Hyde, B., Leveille, J and Vaudry, S and Green, T. Thyroid malignancy association with cortical & subcortical brain SPECT changes in patients presenting with a myalgic encephalomyelitis/chronic fatigue syndrome. Alasbimn Journal, 2007, 10 (38), AJ38-2.

Thyroid malignancy in ME/CFS patients greatly exceeds the normal incidence of thyroid malignancy in any known subgroup. The thyroid malignancy incidence in the ME/CFS group may exceed 6,000/100,000. As part of their investigation, ME/CFS patients should be examined by thyroid ultrasound for evidence of thyroid pathology and malignancy. Thyroid pathology may be missed in this group of patients if investigation relies only upon serum testing for TSH, FT3, FT4, microsomal and thyroglobulin antibodies, which are usually normal. Thyroid uptake scans tend also to be normal and may also miss malignant lesions. A newly recognized syndrome may exist in ME/CFS patients characterized by: (a) thyroid malignancy, (b) persistent abnormal cortical and subcortical SPECT brain scans (NeuroSPECT), (c) failure of thyroidectomy surgery and hormone replacement to correct the fatigue syndrome, and (d) an unusual high incidence of cervical vertebrae osteoarthritic changes. ME/CFS patients with treated non-malignant thyroid disease and abnormal NeuroSPECT scans may also fail to improve despite adequate thyroid hormone replacement.

In the past 100 patients whom I have investigated for ME/CFS, with or without associated Fibromyalgia Syndrome (FS), I have found that 6% of these patients had thyroid malignancy. In each of these patients the diagnosis was made by ultrasonography and needle biopsy under ultrasonography. This was followed by surgical removal of the thyroid, and each case the malignancy was confirmed. These findings would suggest that 6% of the ME/CFS patients seen, or 6,000 cases per 100,000, had a confirmed thyroid malignancy. Unfortunately, these figures may be conservative since we are in the process of obtaining needle biopsies on six further cases of these first 100 patients. In addition, we have not yet performed thyroid ultra-sound on all 100 cases. We are in the process of further investigation of those patients who had not yet been investigated by thyroid ultrasound.

“Since the CDC first defined this group of illnesses as Chronic Fatigue Syndrome in 1988, and through the further definitions of CFS, all physicians attempting a new definition have insisted that CFS is a syndrome and not a disease. Unfortunately, even those defining the illness have tended to treat CFS as a disease and speak of it as a disease, rather than investigating the entire patient as to the causes of their fatigue syndrome. There has been some movement to consider these syndromes as the same. They are not. ME is essentially an acute onset, post-viral illness with CNS, organ and immune system implications or pathologies. ME has a clearly defined incubation period of 4 to 6 days, and is well known to occur in epidemics. CFS is essentially defined by a persisting fatigue state of six months or more in a patient who rapidly exhausts both physical and cognitive abilities, and who is slow to recover to decreased baseline ability. CFS can have either an acute or gradual onset, has no known incubation period, and has no organ associated pathology other than the immune system. ME has the attributes of a disease process, whereas CFS is clearly a syndrome.”

http://www.alasbimnjournal.cl/alasbimn/index.php?option=com_content&task=category&sectionid=7&id=27&Itemid=94

Papadopoulos, A., Ebrecht, M., Roberts, ADL., Poon, L., Rohleder, N and Cleare, AJ. Glucocorticoid receptor mediated negative feedback in chronic fatigue syndrome using the low dose (0.5 mg) dexamethasone suppression test. Journal of Affective Disorders, 2008 Jun 21. [Epub ahead of print]. DOI:10.1016/j.jad.2008.05.001.

CFS is associated with hypocortisolism, but it is not yet clear the extent to which enhanced negative feedback may underlie this finding. We undertook a low-dose dexamethasone (0.5 mg) suppression test in 18 CFS patients (Oxford and CDC ’94 criteria, 9 with co-morbid depression) and 20 matched, healthy controls. We measured salivary cortisol levels at 0800 h, 1200 h, 1600 h and 2000 h before and after the administration of 0.5 mg of dexamethasone.

Basal cortisol output was raised in this group of CFS patients compared to controls. Overall, the percentage suppression following dexamethasone administration was no different between CFS (mean+sem: 80.4+4.4%) and controls (76.2+4.9%). However, the sub-group of patients with CFS and comorbid depression (n=9) showed a significant hypersuppression of salivary cortisol in response to dexamethasone (89.0+1.9%; p<0.05 v controls).

The sub-group analysis was on small numbers and should be considered preliminary. Dexamethasone probes only glucocorticoid medicated negative feedback but does not probe mineralocorticoid feedback, the other main physiological feedback mechanism. We found partial support for the hypothesis of enhanced negative feedback in CFS but only in patients with comorbid depression and also in the context of a sample of patients with elevated basal cortisol levels, which is an atypical finding in the literature.

[Ed. Note: The subjects were due to take an experimental drug halfway through the experiment. The study gives no details of current or chronic stress, which may have influenced the results.]

PHYSIOLOGY AND BIOCHEMISTRY

Paul, L., Rafferty, D., Wood, L and Maclaren, W. Gait characteristics of subjects with chronic fatigue syndrome and controls at self-selected and matched velocities. Journal of NeuroEngineering and Rehabilitation, 2008. 5:16. [Epub ahead of print].

DOI: 10.1186/1743-0003-5-16.

Gait abnormalities have been reported in individuals with CFS, however no studies exist to date investigating the kinematics of individuals with CFS in over-ground gait. The aim of this study was to compare the over-ground gait pattern (sagittal kinematics and temporal and spatial) of individuals with CFS and control subjects at their self-selected and at matched velocities.

Twelve individuals with CFS (physician diagnosed and selected from support groups) and 12 matched controls participated in the study. Each subject walked along a 7.2m walkway three times at each of three velocities: self-selected, relatively slow (0.45 ms-1) and a relatively fast (1.34 ms-1). A motion analysis system was used to investigate the sagittal plane joint kinematics and temporal spatial parameters of gait.

At self-selected velocity there were significant differences between the two groups for all the temporal and spatial parameters measured, including gait velocity (p=0.002). For the kinematic variables, the significant differences were related to both ankles during swing and the right ankle during stance. At the relatively slower velocity, the kinematic differences were replicated. However, the step distances decreased in the CFS population for the temporal and spatial parameters. When the gait pattern of the individuals with CFS at the relatively fast walking velocity (1.30 + 0.24ms-1) was compared to the control subjects at their self-selected velocity (1.32 + 0.15ms-1) the gait pattern of the two groups was very similar, with the exception of both ankles during swing.

The self-selected gait velocity and/or pattern of individuals with CFS may be used to monitor the disease process or evaluate therapeutic intervention. These differences may be a reflection of the relatively low self-selected gait velocity of individuals with CFS rather than a manifestation of the condition itself.

www.jneuroengrehab.com/content/pdf/1743-0003-5-16.pdf

PSYCHOLOGY AND PSYCHIATRY

Friedberg, F and Sohl, SJ. Memory for fatigue in chronic fatigue syndrome: The relation between weekly recall and momentary ratings. International Journal of Behavioral Medicine, 2008, 15, 1, 29-33.

Understanding how patients with CFS recall their fatigue is important because fatigue is a core clinical dimension of this poorly understood illness. This study assessed the associations between momentary fatigue ratings and weekly recall of fatigue in 71 participants with CFS (CDC criteria ’94 and 2003).

During the three-week data collection period, fatigue intensity was recorded six times a day in electronic diaries. At the end of each week, participants were asked to recall their fatigue intensity for that week. Statistical analyses were done with t-tests and Pearson's and intraclass correlations.

Average weekly recall of fatigue intensity was significantly higher than average momentary ratings. Furthermore, moderate to high Pearson's correlations and intraclass correlations (consistency and absolute agreement) between recall and momentary fatigue ratings were found. Conclusion: Individuals with CFS recalled consistently higher levels of fatigue in comparison to real-time momentary ratings, yet the level of agreement between the two measures was moderate to high. These findings may have implications for the conduct of office examinations for CFS.

Geisser, ME., Strader Donnell, C., Petzke, F., Gracely, RH., Clauw, DJ and Williams, DA. Comorbid somatic symptoms and functional status in patients with fibromyalgia and chronic fatigue syndrome: Sensory amplification as a common mechanism. Psychosomatics, 2008, 49, 3, 235-242.

Somatic symptoms are common in conditions such as fibromyalgia (FM) and CFS. The authors investigated a potential shared pathologic mechanism: a generalized perceptual abnormality where there is heightened responsiveness to varied sensory stimulation, namely pain following pressure on the thumb plus perceived exertion following exercise.

A composite measure of sensory sensitivity was created from the pressure stimulation and exertion scores and compared with measures of somatic symptoms, co-morbid psychological disturbances, and self-reported physical functioning (SF-36) in 38 patients with FM and/or CFS (CDC criteria ’94).

The amplification scores were not significantly related to fatigue. Both individual measures were significantly correlated with pain but neither correlated with depression, or strongly with functioning. More detailed analysis revealed that sensory amplification influenced physical functioning indirectly through pain intensity, and physical symptoms and fatigue also independently contributed to physical functioning.

“These findings support the hypothesis that physical symptoms other than the hallmark symptoms of pain and fatigue significantly contribute to the poor physical functioning in FM and CFS... The lack of association between sensory amplification and fatigue, the hallmark symptom of CFS, raises several possibilities. Although many of the co-morbidities are shared between FM and CFS, making them appear to be similar, it is possible that the hallmark symptoms emanate from distinctly different mechanisms. It is also possible that the lack of relationship between sensory amplification and fatigue is in part due to the chronicity of symptoms in this sample.” Sensory amplification may be an underlying pathophysiologic mechanism in these disorders that is relatively independent of depression and depressive symptoms.

Majer, M., Welberg, LAM., Capuron, L., Miller, AH., Pagnoni, G and Reeves, WC. Neuropsychological performance in persons with chronic fatigue syndrome: Results from a population-based study. Psychosomatic Medicine, 2008 Jul 7. [Epub ahead of print].

DOI:10.1097/PSY.0b013e31817b9793.

The aim of this study was to examine the neuropsychological function characterized in subjects with CFS at the same time controlling for relevant confounding factors. CFS is associated with symptoms of neuropsychological dysfunction. Objective measures of neuropsychological performance have yielded inconsistent results possibly due to sample selection bias, diagnostic heterogeneity, co-morbid psychiatric disorders, and medication usage.

People with CFS, (CDC criteria ’94, n=58) and well controls (n=104) from a population-based sample were evaluated, using standardized symptom severity criteria. Subjects who had major psychiatric disorders or took medications known to influence cognition were excluded. Neuropsychological function was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Compared with controls, CFS subjects exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task. CFS subjects also exhibited alterations in working memory as manifested by a less efficient search strategy on the spatial working memory task, fewer % correct responses on the spatial recognition task, and prolonged latency to a correct response on the pattern recognition task. A significantly higher percentage of CFS subjects versus controls exhibited evidence of neuropsychological impairment in tasks of motor speed and spatial working memory. Impairment in CFS subjects versus control subjects ranged from 20% versus 4.8% in five-choice movement time (p=.002) to 27.8% versus 10.6% in search strategy on the spatial working memory task (p=.006).

These results confirm and quantify alterations in motor speed and working memory in CFS subjects independent of co-morbid psychiatric disease and medication usage.

[Ed. Note: “Alterations in basal ganglia circuits that interact with cortical brain regions may also contribute to neuropsychological findings in CFS subjects including alterations in working memory”.]

Allen, PR. Chronic fatigue syndrome: implications for women and their health care providers during the childbearing years. Journal of Midwifery & Women’s Health, 2008, 53, 289-301.

Caseras, X., Mataix-Cols, D., Rimes, KA., Giampietro, V., Brammer, M., Zelaya, F., Chalder, T and Godfrey, E. The neural correlates of fatigue: An exploratory imaginal fatigue provocation study in chronic fatigue syndrome. Psychological Medicine, 2008, 38, 7, 941-951.

Fatigue is the central symptom in CFS and yet very little is known about its neural correlates. The aim of this study was to explore the functional brain response, using functional magnetic resonance imaging (fMRI), to the imaginal experience of fatigue in CFS patients and con-trols.

We compared the blood oxygen level dependent (BOLD) responses of 12 CFS patients (CDC criteria ’94) and 11 healthy controls to a novel fatigue provocation procedure designed to mimic real-life situations (e.g. carrying heavy bags home). A non-fatiguing anxiety-provoking condition (e.g. imagine standing on the edge of a high cliff) was also included to control for the non-specific effects of negative affect. Subjects then rated fatigue and anxiety on a visual analogue scale.

During the provocation of fatigue, CFS patients reported feelings of both fatigue and anxiety and, compared to controls, they showed increased activation in the occipitoparietal cortex, posterior cingulate gyrus and parahippocampal gyrus, and decreased activation in dorsolateral and dorsomedial prefrontal cortices. The reverse pattern of findings was observed during the anxiety-provoking scenarios.

The finding “is consistent with the cognitive-behavioural model of CFS, which proposes that fear and avoidance are key maintaining factors for the disorder (Chalder et al. 2000). It could be argued that patients remember feeling severely fatigued in the past and that they are anxious about feeling so fatigued again. It is the fear of feeling fatigue that can lead them to avoid activity.”

The results may suggest that, in CFS patients, the provocation of fatigue is associated with exaggerated emotional responses that patients may have difficulty suppressing. These findings are discussed in relation to the cognitive-behavioural model of CFS.

[Ed. Note: As there was no medically ill control group, e.g. patients with MS who also report high levels of fatigue, it is difficult to link the findings to CFS, as opposed to aspects of disability. Nijs et al did not find a fear of activity in people with CFS, though in some patients, particularly those who have not learnt to pace themselves and stabilise their condition, the perceived lack of control may result in a degree of apprehension and hypervigilence. The sample size means that it is difficult to draw firm conclusions.]

Chen, R., Moriya, J., Yamakawa, JI., Takahashi, T., Li, Q., Morimoto, S., Iwai, K., Sumino, H., Yamaguchi, N and Kanda, T. Brain atrophy in a murine model of chronic fatigue syndrome and beneficial effect of Hochu-ekki-to (TJ-41). Neurochemical Research, 2008 Mar 4 [Epub ahead of print]. DOI: 10.1007/s11064-008-9620-1.

Brain-derived neurotrophic factor (BDNF) is associated with the main symptoms of CFS and neuron apoptosis. Nevertheless, no study has been performed directly to explore the relationship between CFS, BDNF and neuron apoptosis. We induced a CFS model by six injections of killed Brucella abortus antigen in BALB/c mice and treated them with Hochu-ekki-to (TJ-41). Daily running activity, body weight (BW), ratio of cerebral weight to BW (CW/BW) and expression levels of BDNF and Bcl-2 mRNA in the hippocampus were determined.

The daily activity and CW/BW decreased significantly in the CFS model. BDNF and Bcl-2 mRNA expression levels in the hippocampus were suppressed in the CFS model and TJ-41 treated mice, while no significant difference was found between them. We improved a murine model to investigate the relationship between CFS and brain dysfunction. In this model, reduced daily activity might have been associated with decreased hippocampal BDNF mRNA expression, hippocampal apoptosis and brain atrophy. TJ-41 increased the daily running activity of the model, which was independent of brain recovery.

Dietert, RR and Dietert, JM. Possible role for early-life immune insult including developmental immunotoxicity in chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME). Toxicology, 2008, 247, 1, 61-72.

CFS, also known as myalgic encephalomyelitis (ME) in some countries, is a debilitating disease with a constellation of multi-system dysfunctions primarily involving the neurological, endocrine and immune systems. While substantial information is available con-cerning the complex dysfunction-associated symptoms of CFS, environmental origins of the disease have yet to be determined. Part of the dilemma in identifying the cause(s) has been the focus on biomarkers (hormones, neurotransmitters, cytokines, infectious agents) that are contemporary with later-life CFS episodes. Yet, recent investigations on the origins of environmental diseases of the neurological, endocrine, reproductive, respiratory and immune systems suggest that early life toxicologic and other insults are pivotal in producing later-life onset of symptoms. As with autism and childhood asthma, CFS can also occur in children where the causes are certainly early-life events. Immune dysfunction is recognized as part of the CFS phenotype but has received comparatively less attention than aberrant neurological or endocrine function. However, recent research results suggest that early life immune insults (ELII) including developmental immunotoxicity (DIT), which is induced by xenobiotics, may offer an important clue to the origin(s) of CFS. The developing immune system is a sensitive and novel target for environmental insult (xenobiotic, infectious agents, stress) with major ramifications for postnatal health risks. Additionally, many prenatal and early postnatal neurological lesions associated with postnatal neurobehavioral diseases are now recognized as linked to prenatal immune insult and inflammatory dysregulation. This review considers the potential role of ELII including DIT as an early-life component of later-life CFS.

Friedberg, F., Sohl, SJ and Halperin, PJ. Teaching medical students about medically unexplained illnesses: A preliminary study. Medical Teacher, 2008 May 20:1-4. [Epub ahead of print]. DOI:10.1080/01421590801946970.

This study examined how an interactive seminar focusing on two medically unexplained illnesses, CFS and FM, influenced medical student attitudes toward CFS, a more strongly stigmatized illness.

Forty-five fourth year medical students attended a 90 minute interactive seminar on the management of medically unexplained illnesses that was exemplified with CFS and FM. A modified version of the CFS attitudes test was administered immediately before and after the seminar.

Pre-seminar assessment revealed neutral to slightly favorable attitudes toward CFS. At the end of the seminar, significantly more favorable attitudes were found toward CFS in general (p<0.01) and for specific items that focused on (1) supporting more CFS research funding (p<0.001; (2) employers providing flexible hours for people with CFS (p<0.01); and (3) viewing CFS as not primarily a psychological disorder (p<0.01).

This type of instruction may lead to potentially more receptive professional attitudes toward providing care to these underserved patients.

Gilje, AM., Söderlund, A and Malterud, K. Obstructions for quality care experienced by patients with chronic fatigue syndrome (CFS) - A case study. Patient Education and Counseling, 2008 May 15. [Epub ahead of print]. DOI: 10.1016/j.pec.2008.04.001.

To explore obstructions for quality care from experiences by patients suffering from CFS, we conducted a qualitative case study with data drawn from a group meeting, written answers to a questionnaire and a follow-up meeting. Subjects were 10 women and 2 men with physician-diagnosed CFS, of various ages, recruited from a local patient organization, assumed to have a special awareness for quality care.

CFS patients said that lack of acknowledgement could be even worse than the symptoms. They wanted their doctors to ask questions, listen to them and take them seriously, instead of behaving degradingly. Many participants felt that the doctors psychologized too much, or trivialized the symptoms. Participants described how doctors' lack of knowledge about the condition would lead to long-term uncertainty or maltreatment. Even with doctors who were supportive, it would usually take months and sometimes years until a medical conclusion would be reached, or other disorders were ruled out. Increased physical activity had been recommended, but most of the informants experienced that this made them worse.

Current medical scepticism and ignorance regarding CFS shapes the context of medical care and the illness experiences of CFS patients, who may feel they neither get a proper assessment nor management. CFS patients' reports about patronizing attitudes and ignorance among doctors call for development of evidence based strategies and empowerment of patients, acknowledging the patients' understanding of symptoms and the complex nature of the disease.

Goudsmit, EM. CFS – challenging assumptions. The Psychologist, 2008, 21, 6, 549.

Letter commenting on the theory that avoidance is a maladaptive universal response and that pacing is self-defeating. It also challenges the promotion of mindfulness and the acceptance of symptoms and distress.

Griffith, JP and Zarrouf, FA. A systematic review of chronic fatigue syndrome: Don’t assume it’s depression. Primary Care Companion to the Journal of Clinical Psychiatry, 2008, 10, 2, 120-128.

CFS is characterized by profound, debilitating fatigue and a combination of several other symptoms resulting in substantial reduction in occupational, personal, social, and educational status. CFS is often misdiagnosed as depression. The objective of this study was to evaluate and discuss different etiologies, approaches, and management strategies of CFS and to present ways to differentiate it from the fatigue symptom of depression.

A MEDLINE search was conducted to identify existing information about CFS and depression using the headings chronic fatigue syndrome AND depression. The alternative terms major depressive disorder and mood disorder were also searched in conjunction with the term chronic fatigue syndrome. Additionally, MEDLINE was searched using the term chronic fatigue. All searches were limited to articles published within the last 10 years, in English. A total of 302 articles were identified by these searches. Also, the term chronic fatigue syndrome was searched by itself. This search was limited to articles published within the last 5 years, in English, and resulted in an additional 460 articles. Additional publications were identified by manually searching the reference lists of the articles from both searches. CFS definitions, etiologies, differential diagnoses (especially depression) and management strategies were extracted, reviewed, and summarized to meet the objectives of this article.

CFS is underdiagnosed in more than 80% of cases, and is often misdiagnosed as depression. Genetic, immunologic, infectious, metabolic, and neurologic etiologies were suggested to explain CFS. A biopsychosocial model was suggested for evaluating, managing, and differentiating CFS from depression.

Evaluating and managing chronic fatigue is a challenging situation for physicians, as it is a challenging and difficult condition for patients. A biopsychosocial approach in the evaluation and management is recommended. More studies about CFS manifestations, evaluation, and management are needed.

Grinde, B. Is chronic fatigue syndrome caused by a rare brain infection of a common, normally benign virus? Medical Hypotheses, 2008, 71, 2, 270-274.

CFS is a disabling disease of unknown aetiology. A variety of factors have been suggested as possible causes. Although the symptoms and clinical findings are heterogeneous, the syndrome is sufficiently distinct, at least in relation to the more obvious cases, that a common explanation seems likely. In this paper, it is proposed that the disease is caused by a ubiquitous, but normally benign virus, e.g., one of the circoviruses. Circoviruses are chronically present in a majority of people, but are rarely tested for diagnostically. Normally these viruses do not penetrate the blood-brain barrier, but exceptions have been reported, and related viruses cause disease in the central nervous system of animals. The flu-like illness that often precedes the onset of CFS may either suppress immune function, causing an increased viremia, and/or lower the blood-brain barrier. In both cases the result may be that a virus already present in the blood enters the brain. It is well known that zoonotic viruses typically are more malignant than viruses with a long history of host-virus evolution. Similarly, a virus reaching an unfamiliar organ may cause particular problems.

Gur, A and Oktayoglu, P. Central nervous system abnormalities in fibromyalgia and chronic fatigue syndrome. Current Pharmaceutical Design, 2008, 14, 13, 1274-1294.

FM and CFS are poorly understood disorders that share similar demographic and clinical characteristics. The etiology and pathophysiology of these diseases remain unclear. Because of the similarities between both disorders it was suggested that they share a common pathophysiological mechanisms, namely, central nervous system (CNS) dysfunction. Current hypotheses center on atypical sensory processing in the CNS and dysfunction of skeletal muscle nociception and the hypothalamic- pituitary-adrenal (HPA) axis. Researches suggest that the (CNS) is primarily involved in both disorders in regard to the pain, fatigue and sleep disturbances. Many patients experience difficulty with concentration and memory and many others have mood disturbance, including depression and anxiety... CFS is a descriptive term used to define a recognisable pattern of symptoms that cannot be attributed to any alternative condition. The symptoms are currently believed to be the result of disturbed brain function. To date, no pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore primarily directed at relief of symptoms and minimising impediments to recovery. This chapter presents data demonstrating CFS, abnormal pain processing and autonomic nervous system (ANS) dysfunction in FM and CFS and concludes by reviewing the new concepts in treatments in CFS and FM.

Hou, R., Moss-Morris, R., Bradley, BP., Peveler, R and Mogg, K. Attentional bias towards health-threat information in chronic fatigue syndrome. Journal of Psychosomatic Research, 2008, 65, 1, 47-50.

The aim was to investigate whether individuals with CFS show an attentional bias towards health-threat information. Attentional bias (AB) was assessed in 11 individuals with CFS (CDC criteria ’94) recruited from a self-help group and 17 healthy controls using a visual probe task which presented health-threat and neutral words and pictures for 500 ms. Self-report questionnaires were used to assess CFS symptoms (PFRS), depression, anxiety, and social desirability.

Compared to a healthy control group, the CFS group showed an enhanced AB towards heath-threat stimuli relative to neutral stimuli. The AB was not influenced by the type of stimulus (pictures vs. words).

The finding of an AB towards health-threat information in individuals with CFS is supportive of models of CFS which underlie CBT.

[Ed. Note: There was no difference between the groups in terms of employment status, suggesting most patients were mildly affected. The failure to include a medically ill control group makes it difficult to relate the findings to CFS per se. Also of note is the small sample size.]

Kishi, A., Struzik, ZR., Natelson, BH., Togo, F and Yamamoto, Y. Dynamics of sleep stage transitions in healthy humans and patients with chronic fatigue syndrome. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology, 2008, 294, 6, R1980-1987.

Physiological and/or pathological implications of the dynamics of sleep stage transitions have not, to date, been investigated. We report detailed duration and transition statistics between sleep stages in healthy subjects and in others with CFS; in addition, we also compare our data with previously published results for rats.

Twenty-two healthy females and 22 female patients with CFS, characterized by complaints of unrefreshing sleep, underwent one night of polysomnographic recording.

We found that duration of deep sleep (Stages III and IV) follows a power-law probability distribution function; in contrast, Stage II sleep durations follow a stretched exponential and Stage I and REM sleep durations follow an exponential function. These stage duration distributions show a gradually increasing departure from the exponential form with increasing depth of sleep towards a power-law type distribution for deep sleep, suggesting increasing complexity of regulation of deeper sleep stages. We also found a substantial number of REM to non-REM sleep transitions in humans, while this transition is reported to be virtually non-existent in rats. The relative frequency of this REM to non-REM sleep transition is significantly lower in CFS than in controls, resulting in a significantly greater relative transition frequency of from both REM and Stage I sleep to awake. Such an alteration in the transition pattern suggests that the normal continuation of sleep in light or REM sleep is disrupted in CFS. We conclude that dynamic transition analysis of sleep stages is useful for elucidating yet-to-be-determined human sleep regulation mechanisms with pathophysiological implications.

Maes, M., Mihaylova, I., Kubera, M and Leunis, JC. An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: Evidence that nitrosative stress is another factor underpinning the comorbidity between [them]. NeuroEndocrinology Letters, 2008, 29, 313-319.

The aim of the present study was to examine whether CFS and MDD are accompanied by an IgM-mediated immune response directed against nitro-serum bovine albumin (BSA), which is a neoepitope of BSA formed by damage caused by nitrosative stress. Toward this end, we examined serum IgM antibodies to nitro-BSA in 13 patients with CFS, 14 subjects with partial CFS, 16 patients with MDD and 11 normal controls.

We found that the prevalence and mean values for the serum IgM levels directed against nitro-BSA were significantly greater in patients with partial CFS, CFS and MDD than in normal controls, and significantly greater in CFS than in those with partial CFS and MDD. We found significant and positive correlations between serum IgM levels directed against nitro-BSA and symptoms of the FibroFatigue scale, i.e. aches and pain and muscular tension. There was also a strong positive correlation between serum IgM titers directed against nitroBSA and an index of increased gut permeability ("leaky gut"), i.e. serum IgM and IgA directed against LPS of different gram-negative enterobacteria.

The above-mentioned results indicate that both CFS and MDD are accompanied by a) an increased gut permeability which has allowed an exaggerated passage of BSA through a compromised epithelial barrier; b) increased nitrosative stress which has induced damage to BSA; and c) an IgM-mediated immune response which is directed against the nitro-BSA neoepitopes. Nitrosative stress is one of the factors underpinning the co-morbidity and clinical overlap between CFS and MDD.

Meeus, M., Nijs, J., Van de Wauwer, N., Toeback, L and Truijen, S. Diffuse noxious inhibitory control is delayed in chronic fatigue syndrome: An experimental study. Pain, 2008 Jul 8. [Epub ahead of print]. DOI:10.1016/j.pain.2008.05.018.

Deficient endogenous pain inhibition, e.g. diffuse noxious inhibitory controls (DNIC), or hormonal abnormalities like hypocortisolism, could be responsible for chronic widespread pain in CFS. Thirty-one CFS-patients (CDC criteria ’94) with chronic pain and 31 healthy controls were subjected to spatial summation of thermal noxious stimuli by gradual immersion (ascending or descending) of the arm in warm water (46 degrees C). They rated pain intensity every 15s. Every immersion took 2min, alternated with 5min rest. Before and after immersion, salivary cortisol was assessed.

Overall pain ratings were higher in CFS-patients, but the evolution was not different between patients and controls, during both ascending and descending immersion. Pain intensity and immersed surface were only correlated during the descending session in both patients (r=.334) and controls (r=.346). When comparing the first and the last 15s of every emersion, it was found that pain inhibition starts slower for CFS-patients in comparison to healthy sub-jects. Both pre- or post-values and cortisol response did not differ between controls and pa-tients. The drop in cortisol was significantly correlated to pain intensity in CFS (r between .357 and .402). In addition to the hyperalgesia in CFS, DNIC react slower to spatial sum-mation of thermal noxious stimuli. We found no evidence for hypocortisolism in CFS, and the cortisol response to nociception was not different in CFS compared to healthy subjects. In conclusion, delayed pain inhibition may play a role in chronic widespread pain in CFS but further research is required.

Togo, F., Natelson, BH., Cherniack, NS., FitzGibbons, J., Garcon, C and Rapoport, DM. Sleep structure and sleepiness in chronic fatigue syndrome with or without co-existing fibromyalgia. Arthritis Research & Therapy, 2008, 10:R56 [Epub ahead of print].

DOI:10.1186/ar2425

We evaluated polysomnograms of CFS patients with or without FM to determine if patients in either group had elevated rates of sleep disturbed breathing (obstructive sleep apnea or upper airway resistance syndrome) or periodic leg movement disorder. We also determined whether feelings of unrefreshing sleep were associated with differences in sleep architecture from normal.

We compared sleep structures and subjective scores on visual analog scales for sleepiness and fatigue in 26 CFS patients (CDC criteria ’94), 12 of whom also had FM, to 26 healthy subjects; none had current major depressive disorder, and all were studied during the same menstrual phase.

CFS patients had significant differences in polysomnograpic findings from healthy controls and felt sleepier and more fatigued than controls after a night's sleep. CFS patients as a group had less total sleep time, lower sleep efficiency and less REM sleep than controls. A possible explanation for the unrefreshing quality of sleep in CFS patients was revealed by stratification of patients into those who reported more or less sleepiness after a night's sleep (AM sleepier or less sleepy respectively). Those in the sleepier group reported that sleep did not improve their symptoms and had poorer sleep efficiencies and shorter runs of sleep than both controls and patients in the less sleepy group; patients in the less sleepy group reported reduced fatigue and pain after sleep and had relatively normal sleep structures. This dif-ference in sleep effects was primarily due to a decrease in the length of periods of uninterrupted sleep in the AM sleepier group.

CFS patients had significant differences in polysomnograpic findings from healthy controls and felt sleepier and more fatigued than controls after a night's sleep. This difference was due to neither diagnosable sleep disorders nor co-existing FM, but primarily due to a decrease in the length of periods of uninterrupted sleep in the patients with more sleepiness in the morning than on the night before. This sleep disruption may explain the overwhelming fatigue, report of unrefreshing sleep, and pain in this subgroup of patients.

http://arthritis-research.com/content/pdf/ar2425.pdf

Scheeres, K., Wensing, M., Severens, H., Adang, E and Bleijenberg, G. Determinants of health care use in chronic fatigue syndrome patients: A cross-sectional study. Journal of Psychosomatic Research, 2008, 65, 1, 39-46.

CFS is associated with a high use of health care services. To reduce the related costs for patients and society, it will be useful to know which factors determine CFS patients' amount of health care use. Little is known, however, about these factors.

The present study retrospectively performed a cross-sectional analysis to investigate the possible factors determining CFS patients' health care use. A total of 263 patients with CFS (CDC criteria ’94), derived from two subgroups (149 from tertiary care and 114 from primary/secondary care), participated. Health care use was measured with a questionnaire asking details on consumption over the past 6 months. Fatigue severity and physical functioning were measured with the subscale Experienced Fatigue of the Checklist Individual Strength (CIS-20) and the Physical Functioning subscale of the SF-36, respectively.

The regression analysis revealed that, after controlling for patient characteristics (explaining 13%), fatigue factors added 4% predictive value and certain perpetuating factors of fatigue, including focus on bodily symptoms and attributions of fatigue, added another 5%. The analysis of subgroups revealed that, compared to the tertiary care population, fewer patients from primary/secondary care had visited a medical specialist (50% vs. 71%), used anti-depressants (16% vs. 25%) and tranquilizers (3% vs. 18%), and had spent a night in hospital (7% vs. 10%). However, overall costs of health care between these subgroups did not differ.

This study showed that illness duration, physical impairment due to fatigue, and psychological perpetuating factors of fatigue (including self-efficacy and somatic attributions) determine the variance in CFS patients' health care use. Psychological attributions and physical activity showed a negative relation with health care use. Fatigue severity showed no relationship with health care use. These results give clear directions for treating CFS patients and managing health care for CFS.

[Ed. Note: This study did not include a comparison control group and the assessment of health care use relied on memory.]

Valdizán Usón, JR and Idiazábal Alecha, MA. Diagnostic and treatment challenges of chronic fatigue syndrome: Role of immediate-release methylphenidate. Expert Reviews of Neurotherapeutics, 2008, 8, 6, 917-927.

CFS is a distinct entity belonging to the group of persistent fatigue that can be challenging to diagnose and to treat. It is characterized by a combination of prolonged fatigue, other nonspecific somatic manifestations and neuropsychological symptoms, including difficulties with concentration, short-term memory and thinking, as well as impaired attention and slowed processing speed. Neurostimulants increasing dopamine and norepinephrine activity, such as bupropion, dextroamphetamine and recently immediate-release methylphenidate have been advocated to improve neurocognitive deficits. The use of immediate-release methyl-phenidate in CFS has been shown in one small study. Using the positive results of this study and the well-known beneficial effects of the drug on a range of similar cognitive symptoms in attention-deficit/hyperactivity disorder, this perspective addresses CFS and other related disorders and provides a discussion on the potential promising role of methylphenidate in the therapeutic armamentarium of CFS.

[Ed. Note: The research does not support the claim that CFS is a ‘distinct entity’, let alone one which responds to a single treatment.]

RESEARCH ON FATIGUE

RESEARCH ON RELATED DISORDERS

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