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ABSTRACTBackgroundChronic fatigue syndrome [CFS] may occur alone or with fibromyalgia. This has led some to believe the two occur along a common illness spectrum. Evaluating whether this is the case is important as differences in burden or severity of CFS with fibromyalgia (FM) would suggest different underlying pathophysiological processes.ObjectiveTo determine if Insomnia Severity Index [ISI] scores differ between patients with CFS and those with CFS plus FM. In addition, we aim to determine if insomnia severity is impacted by other comorbid medically unexplained diagnoses.Methods247 patients with CFS completed the ISI and the Centers for Epidemiological Study – Depression. Patient groups were stratified on CFS severity and the presence of FM. A secondary analysis was conducted to evaluate insomnia severity related to the number of comorbid medically unexplained diagnoses including, FM, multiple chemical sensitivity and/or irritable bowel syndrome.ResultsWhen controlling for depressed mood, ISI did not differ significantly across patient groups defined by CFS severity and FM status. However, independent of mood, ISI was sensitive to multiple diagnoses showing a significant increasing trend from CFS alone to CFS plus one, two or three comorbid diagnoses.ConclusionAlthough CFS severity and FM status do not impact insomnia severity, increased illness burden as manifested by multiple medically unexplained diagnoses does appear to influence insomnia. In contrast to our earlier studies, this study did not find that a comorbid diagnosis of FM in patients with CFS is related to a worse outcome in the variable of interest.

ABSTRACTIntroductionThe diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is generally reached based on meeting the criteria of a case definition and eliminating other conditions that could be causing the patient’s symptoms. Investigators in the ME/CFS field are currently confronted with 139 medical exclusionary conditions listed among the various ME/CFS case definitions. There is a need to standardize the illnesses/diagnoses that should be excluded.MethodsExclusionary conditions were listed for several prominent ME/CFS case definitions. From this list, symptoms were also identified as exclusionary by several physicians with experience in diagnosing ME/CFS. Input was also solicited from representatives from the patient community for a consensus list of exclusionary comorbid conditions.ResultsOnce overlapping illnesses were eliminated, a consensus was reached on a briefer set of exclusionary conditions. The final set of exclusionary conditions is divided into 14 categories with 53 specific examples.ConclusionsIt is important for ME/CFS researchers to select uniform medical conditions to exclude from their studies so that samples across different studies are consistent and generate generalizable ME/CFS findings. This list can be applied to ME/CFS case definitions in order to enhance the reproducibility of identifying patients with ME/CFS for research studies.

The authors used cardiopulmonary exercise testing (CPET) to define unexplained dyspnea in patients with post-acute sequelae of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (PASC). We assessed participants for criteria to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.

Fatigue, one of the most common complaints in primary care practice, may be due to a broad spectrum of organic and emotional disorders. Here's how to sort out the possibilities [...]

PURPOSE: To evaluate the aerobic power (as maximum volume of oxygen consumed [VO [sub 2] max!) of women with chronic fatigue syndrome (CFS). PATIENTS AND METHODS: Twenty-one women with CFS and 22 sedentary healthy controls (CON) were studied at the CFS Cooperative Research Center Exercise Laboratory at the VA Medical Center, East Orange, New Jersey. Performance was measured on an incremental treadmill protocol walking to exhaustion. Expired gases were analyzed by a metabolic system, heart rate was recorded continuously, and ratings of perceived exertion (RPE) were taken at each workload. The groups were divided into those who achieved VO [sub 2] max (CFS-MAX and CON-MAX) and those who stopped at a submaximal level (CFS-NOMAX and CON-NOMAX) by using standard criteria. RESULTS: Seventeen CON and 10 CFS subjects achieved VO [sub 2] max. The VO [sub 2] max (mL/kg/min) of the CFS-MAX (28.1 [+ or -] 5.1) was lower than that of the CON-MAX (32.1 [+ or -] 4.3, P = 0.05). The CFS-MAX achieved 98 [+ or -] 11% of predicted VO [sub 2] max. The CFS group had a higher RPE at the same absolute workloads as controls (P < 0.01) but not the same relative workloads. CONCLUSION: Compared with normal controls, women with CFS have an aerobic power indicating a low normal fitness level with no indication of cardiopulmonary abnormality. Our CFS group could withstand a maximal treadmill exercise test without a major exacerbation in either fatigue or other symptoms of their illness. Am J Med. 1996;100:634--640.

This experiment was designed to study the effect of stressor intensity on habituation/sensitization of the adrenocortical stress response in rats. Rats were given 18 shocks in 3-hr daily sessions for 8 days, and a single shock probe before the sessions was used to determine how adrenocortical responsiveness changed with repeated exposure to the stress sessions. When lower intensity shock was given, the changes in plasma corticosterone response to shock probes followed a U-shaped curve--with a response that first habituated to no-shock control levels but later returned to the same magnitude as seen on the 1st probe day. Plasma corticosterone responses in rats given higher intensity shock never habituated and instead demonstrated an increased response indicative of sensitization; a temporal delay of 1 week occurred before sensitization developed. Responsiveness to exogenous adrenocorticotropin 24 hr after the last stress session was monotonically related to the intensity of the stressor presented during the experimental sessions. These data are consistent with the rule from the habituation literature that stimulus intensity is inversely related to the magnitude of habituation. Thus the data extend the dual process theory of Groves and Thompson (1970) to an endocrine respondent. The data also suggest that an explanation as to discrepancies in the literature concerning adrenocortical response to repeated presentation of stressors may relate to differences in the stressor parameters used.

Four decades of research in the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have yielded lessons that may be instructive for those devising criteria to better comprehend Post-Acute Sequelae of SARS CoV-2 Infection (PASC) and Long COVID. For instance, substantial effort has been devoted to defining classification systems, operationalizing methods, and developing instruments with adequate reliability and validity in the ME/CFS field. The current article provides guidelines for developing a case definition for Long COVID and discusses the significance of psychometric issues and criterion variance, including how to specify symptoms, develop thresholds, subtypes, and exclusionary conditions. ME/CFS research could enhance our knowledge of Long COVID pathophysiology, early diagnosis, prognosis, and the identification of effective treatments.

The effect of submaximal steady-state exercise on cognitive performance in patients with chronic fatigue syndrome (CFS) alone, CFS with comorbid fibromyalgia (FM), and sedentary healthy controls are determined. CFS patients without comorbid FM exhibit subtle cognitive deficits in terms of speed, consistency, and efficiency that are not improved or exacerbated by light exercise.

Results demonstrate that ratings of perceived exerion are higher in Gulf veterans with chronic fatigue syndrome both by absolute or relative exercise intensity, indicating that Gulf veterans differ from their civilian counterparts.

Results indicae that in terms of absolute exercise intensity, ratings of perceived exertion are higher in civilians with chronic faigue syndrome. However, there are no differences when ratings of perceived exertion is compared to oxygen consumpion rates.

Background: Airway function, as assessed by standard spirometry, and the intensity of dyspnea reported by asthmatic patients correlate poorly. Objective: This study tests the following two hypotheses: (1) that measures [...]

More than 68 000 of the 700 000 veterans of the Gulf War have become members of the Veteran Affairs' Gulf War Registry. In 1995, we undertook a questionnaire study of the symptoms and medical histories reported by a randomly selected subsample of 1 935 of these veterans to characterize their complaints. All results reported were based on questionnaire responses without face-to-face evaluation or physical examinations. Inasmuch as initial registry symptoms overlapped those of Chronic Fatigue Syndrome and Multiple Chemical Sensitivities, we also included standard questions for these syndromes in the questionnaire. A total of 1 161 (60%) individuals responded, and there were no major demographic biases; therefore, 15.7% of registry veterans qualified for Chronic Fatigue Syndrome in accordance with the 1994 Centers for Disease Control definition. In addition, 13.1% qualified for multiple chemical sensitivities in accordance with a widely used definition, and 3.3% of the respondents had both conditions. There were no effects of gender, race, branch, duty status (active or reserve), or rank, although Multiple Chemical Sensitivities was somewhat more prevalent in women and African Americans. The data gleaned in this study suggested that the unexplained symptom syndromes of Chronic Fatigue and Multiple Chemical Sensitivities may characterize an appreciable portion of the complaints of those who volunteered for the Veterans Affairs' Gulf War Registry, and further investigation is warranted., OPERATION DESERT SHIELD commenced in August 1990. Hostilities associated with its successor, Operation Desert Storm, ceased in March 1991. During this brief period, approximately 697 000 American soldiers served in [...]

ABSTRACTBackground:Chronic fatigue syndrome (CFS) and fibromyalgia (FM) frequently have overlapping symptoms, leading to the suggestion that the same disease processes may underpin the two disorders – the unitary hypothesis. However, studies investigating the two disorders have reported substantial clinical and/or biological differences between them, suggesting distinct pathophysiological underpinnings.Purpose:The purpose of this study was to further add to the body of evidence favoring different disease processes in CFS and FM by comparing ventricular cerebrospinal fluid lactate levels among patients with CFS alone, FM alone, overlapping CFS and FM symptoms, and healthy control subjects.Methods:Ventricular lactate was assessed in vivowith proton magnetic resonance spectroscopic imaging (1H MRSI) with the results normed across the two studies in which the data were collected.Results:Mean CSF lactate levels in CFS, FM and CFS + FM did not differ among the three groups, but were all significantly higher than the mean values for control subjects.Conclusion:While patients with CFS, FM and comorbid CFS and FM can be differentiated from healthy subjects based on measures of CFS lactate, this neuroimaging outcome measure is not a viable biomarker for differentiating CFS from FM or from patients in whom symptoms of the two disorders overlap.

ABSTRACTA major hypothesis regarding the cause of chronic fatigue syndrome (CFS) is immune dysregulation, thought to be reflected in upregulated proinflammatory cytokines leading to the symptoms that are characteristic of this illness. Because the symptoms worsen with physical exertion or sleep loss, we hypothesized that we could use these stressors to magnify the underlying potential pathogenic abnormalities in the cytokine systems of people with CFS. We conducted repeat blood sampling for cytokine levels from healthy subjects and CFS patients during both postexercise and total sleep deprivation nights and assayed for protein levels in the blood samples, mRNA activity in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs. We found that these environmental manipulations did not produce clinically significant upregulation of proinflammatory cytokines. These data do not support an important role of immune dysregulation in the genesis of stress-induced worsening of CFS.

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained conditions that often have overlapping symptoms, including sleep-related complaints. However, differences between the 2 conditions have been reported, and we hypothesized that dynamic aspects of sleep would be different in the 2 groups of patients.

The natural progression of chronic fatigue syndrome (CFS) in adults is not well established. The aims of this longitudinal study were to (a) compare CFS Improvers and Non-Improvers; (b) determine whether an initial diagnosis of fibromyalgia (FM) was associated with CFS nonimprovement; and (c) determine whether this effect could be explained by the presence of nonspecific physical symptoms. Consecutive referrals to a tertiary clinic that satisfied case criteria for CFS were invited to enroll in a longitudinal study. After an initial on-site physical examination and psychiatric interview, a total of 94 female care-seekers completed biannual telephone surveys, including the Short Form-36 physical functioning (PF) scale, over a period of 2½ years. There were very few differences between Improvers and Non-Improvers at baseline but at final assessment Improvers had less disability, less fatigue, lower levels of pain, fewer symptoms of depressed mood, and fewer nonspecific physical complaints. Participants with FM at baseline were 3.23 times (p< 0.05) more likely to become Non-Improvers than those without FM. Participants identified initially as Somatizers were 3.33 times (p< 0.05) more likely to become Non-Improvers. Patients with CFS who bear the added burden of FM are at greater risk of a negative outcome than patients with CFS alone. This effect could not be explained by the presence of multiple, nonspecific symptoms.

ABSTRACTThe symptoms of chronic fatigue syndrome (CFS) are consistent with cytokine dysregulation. This has led to the hypothesis of immune dysregulation as the cause of this illness. To further test this hypothesis, we did repeated blood sampling for cytokines while patients and matched healthy controls slept in the sleep lab. Because no one method for assaying cytokines is acknowledged to be better than another, we assayed for protein in serum, message in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs. We found no evidence of proinflammatory cytokine upregulation. Instead, in line with some of our earlier studies, we did find some evidence to support a role for an increase in interleukin-10, an anti-inflammatory cytokine. Although the changes were small, they may contribute to the common complaint in CFS patients of disrupted sleep.

Fibromyalgia (FM), which primarily affects women, is one of several medically unexplained illnesses. In many instances, FM is accompanied by one or more of these illnesses, which often confounds the approach to diagnosis and treatment. Although the pain and tenderness of FM are very real, many patients seen in the primary care setting are not taken seriously and do not receive appropriate treatment. However, the equation has changed with the recent approval of 3 drugs for FM. This article describes FM, reviews the evidence supporting FM as a chronic central pain state (as opposed to a rheumatologic disorder), and explains how FM relates to other medically unexplained illnesses. The article also presents an algorithm for the treatment of FM in clinical practice. [ABSTRACT FROM AUTHOR]

In 1990, The American College of Rheumatology laid out several sets of criteria for the diagnosis of fibromyalgia syndrome (FM). The first criterion required patients to report at least 3 months of widespread pain. Pain was considered widespread if it was present in four quadrants of the body—the right and left side as well as above and below the waist. Axial skeleton pain is also very commonly present in FM and is often considered a fifth “quadrant.” The second diagnostic criterion was widespread pain in response to a tender point examination. In this assessment the clinician presses on 18 specific areas with enough pressure to blanche his fingertip (~4 kg). The patient's report of pain and not pressure on such testing in at least 11 of the tender points completes the requirements for the diagnosis of FM (Slide 1). Although these criteria were established to standardize patients for research studies, many physicians follow them for diagnostic purposes as well. However, these criteria must be viewed in the same context as the definition of hypertension (ie, blood pressures =140/90). Patients who do not quite attain these criteria should still be considered to have probable hypertension; and the same applies to FM. A patient who has three-quadrant pain and 9 tender points does not meet the criteria for FM, but the therapeutic approach to this patient is the same as it is for the patient with definitive FM.

Among systemic abnormalities caused by the novel coronavirus, little is known about the critical attack on the central nervous system (CNS). Few studies have shown cerebrovascular pathologies that indicate CNS involvement in acute patients. However, replication studies are necessary to verify if these effects persist in COVID-19 survivors more conclusively. Furthermore, recent studies indicate fatigue is highly prevalent among ‘long-COVID’ patients. How morphometry in each group relate to work-related fatigue need to be investigated.

Combat veterans often return from deployment having experienced a wide range of exposures, symptoms, and medical conditions. The Department of Veterans Affairs established war-related illness and injury study centers to serve combat veterans with unexplained illnesses. We report the exposures, clinical status, and utilization of 53 combat veterans who participated in the National Referral Program (NRP) from January 2002 until March 2004. Participants were primarily male (81%) and served in the Persian Gulf War (79%). Common diagnoses were chronic fatigue syndrome (n = 23, 43%), neurotic depression (n = 21, 40%), and post-traumatic stress disorder (n = 20, 38%). Self-reported exposures related to weaponry, disease prophylaxis, environmental hazards, stress, and poor hygiene. A small increase in mean SF-36V mental component scores (2.8 points, p = 0.009) and use of rehabilitation therapies (1.6 additional visits, p = 0.018) followed the NRP referral. The small gain in mental function suggests that the NRP may benefit combat veterans with long and complex medical histories.

ABSTRACTArguments exist as to the cause of chronic fatigue syndrome (CFS). Some think that it is an example of symptom amplification indicative of functional or psychogenic illness, while our group thinks that some CFS patients may have brain dysfunction. To further pursue our encephalopathy hypothesis, we did spinal taps on 31 women and 13 men fulfilling the 1994 case definition for CFS and on 8 women and 5 men serving as healthy controls. Our outcome measures were white blood cell count, protein concentration in spinal fluid, and cytokines detectable in spinal fluid. We found that significantly more CFS patients had elevations in either protein levels or number of cells than healthy controls (30 versus 0%), and 13 CFS patients had protein levels and cell numbers that were higher than laboratory norms; patients with abnormal fluid had a lower rate of having comorbid depression than those with normal fluid. In addition, of the 11 cytokines detectable in spinal fluid, (i) levels of granulocyte-macrophage colony-stimulating factor were lower in patients than controls, (ii) levels of interleukin-8 (IL-8) were higher in patients with sudden, influenza-like onset than in patients with gradual onset or in controls, and (iii) IL-10 levels were higher in the patients with abnormal spinal fluids than in those with normal fluid or controls. The results support two hypotheses: that some CFS patients have a neurological abnormality that may contribute to the clinical picture of the illness and that immune dysregulation within the central nervous system may be involved in this process.

The degree of neuropsychological dysfunction across multiple domains was examined in individuals suffering from chronic fatigue syndrome (CFS). In this descriptive study, a similar series of neuropsychological tests was administered to a group of CFS patients and healthy participants. More specifically, CFS patients (n = 141) who met the 1994 Case Definition criteria were compared to 76 healthy control participants on tests of memory, attention (concentration), speed of information processing, motor speed, and executive functioning. On the 18 measures administered, CFS patients scored 1 standard deviation below the healthy mean on nine measures and scored 2 standard deviations below the healthy mean on four of the measures. Moreover, results indicated that CFS patients were more likely than healthy controls to fail (1.6 SD below the healthy mean) at least one test in each of the following domains: attention, speed of information processing, and motor speed, but not on measures of memory and executive functioning. Finally, CFS patients demonstrated a greater total number of tests failed across domains. (JINS, 2004, 10, 278–285.)

To examine the relative influence of speed of information processing versus working memory ability, CFS participants with psychiatric comorbidity (CFS–Psych) and CFS without a psychiatric history (CFS–noPsych) were examined on tests of visual and auditory processing speed and visual and auditory working memory. Compared to healthy controls (HC) and a group of participants with rheumatoid arthritis (RA), the CFS–noPsych group displayed significantly reduced performance on tests of information processing speed, but not on tests of working memory. No significant differences were observed between the CFS–Psych group and any other group in the study. The implications of group heterogeneity on the understanding of cognitive impairment in CFS are discussed. (JINS, 2004, 10, 101–109.)

A large overlap exists between the diagnosis of chronic fatigue syndrome (CFS) and the unexplained symptoms reported by many Gulf War veterans (GV). Previous investigations have reported reduced aerobic capacity in civilians with CFS. The present investigation examined metabolic responses to maximal exercise in GVs with CFS compared with healthy GVs. Cardiorespiratory and metabolic responses were recorded during a maximal exercise test on a cycle ergometer. The groups were not different in any demographic category (p > 0.05) or self-reported physical activity (p > 0.05). No differences were observed between groups for maximal oxygen uptake (28.9 +/- 6.7 mL/kg/min for CFS vs. 30.8 +/- 7.1 mL/kg/min for controls; p = 0.39), heart rate (155.8 +/- 16.1 bpm for CFS vs. 163.3 +/- 14.9 bpm for controls; p = 0.17), exercise time (9.6 +/- 1.5 minutes for CFS vs. 10.2 +/- 1.4 minutes for controls; p = 0.26), or workload achieved (208 +/- 36.7 W for CFS vs. 224 +/- 42.9 W for controls; p = 0.25). Likewise, no differences were observed at submaximal intensities (p > 0.05). Compared with healthy controls, GVs who report multiple medically unexplained symptoms and meet criteria for CFS do not show a decreased exercise capacity. Thus, it does not appear that the pathology of the GVs with CFS includes a deficiency with mobilizing the cardiopulmonary system for strenuous physical effort.

The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced blood flow and oxidative delivery to skeletal muscle. Patients with CFS according to CDC (Center for Disease Control) criteria (n=19) were compared with normal sedentary subjects (n=11). Muscle blood flow was measured with Doppler ultrasound after cuff ischaemia and exercise. Muscle oxygen delivery was measured as the rate of post-exercise and post-ischaemic oxygen-haem resaturation. Oxygen-haem resaturation was measured in the medial gastrocnemius muscle using continuous wavelength near-IR spectroscopy. Muscle metabolism was measured using 31P magnetic resonance spectroscopy. CFS patients and controls were not different in the peak blood flow after cuff ischaemia, the rate of recovery of phosphocreatine after submaximal exercise, and the rate of recovery of oxygen saturation after cuff ischaemia. In conclusion, CFS patients showed no deficit in blood flow or oxidative metabolism. This suggests that CFS symptoms do not require abnormal peripheral function.

The use of symptoms generated by head up tilt (HUT) is not a useful tool in identifying chronic fatigue syndrome (CFS). We investigated whether heart rate variability (HRV) assessed early during HUT might be useful. A sample of 46 female subjects (24 with CFS and 22 sedentary, age-matched healthy controls; CON) who had exhibited no difference in time to syncope during tilt was examined for HRV responses to 10 min of 70° HUT after 5 min of baseline in the supine position. HRV data were analyzed by the method of coarse graining spectral analysis. Variables compared between groups included mean and standard deviation (SDRRI) of RR intervals (RRI), amplitudes of low- (ALF; 0.04–0.15 Hz) and high-frequency (AHF; >0.15 Hz) harmonic as well as aperiodic, fractal (AFR; 1/fβ) spectral components, the spectral exponent β, and the difference in these values between baseline and HUT for each subject. In the supine baseline, only mean RRI was significantly (P< 0.01) lower in CFS than in CON. During HUT, however, mean RRI (P < 0.01), SDRRI, (P < 0.01), AHF(P < 0.05), and AFR(P < 0.01) were significantly lower in CFS than in CON. When the difference in values between baseline and HUT for each subject was examined, only the difference for AFR(ΔAFR) was significantly (P < 0.01) lower in CFS than in CON, suggesting that AFRis a disease-specific response of HRV to HUT. When a cut-off level was set to ΔAFR= –2.7 msec, the sensitivity and the specificity in differentiating CFS from controls were 90% and 72%, respectively. The data suggest that a decrease in aperiodic fractal component of HRV in response to HUT can be used to differentiate patients with CFS from CON.

Medical history has shown that clinical disease entities or syndromes are composed of many subgroups — each with its own cause and pathogenesis. Although we cannot be sure, we expect the same outcome for chronic fatigue syndrome (CFS), a medically unexplained condition characterized by disabling fatigue accompanied by infectious, rheumatological, and neuropsychiatric symptoms. Although the ailment clearly can occur after severe infection, no convincing data exist to support an infectious (or immunologic) process in disease maintenance. Instead, data point to several possible pathophysiological processes: a covert encephalopathy, impaired physiological capability to respond to physical and mental Stressors, and psychological factors related to concerns about effort exacerbating symptoms. Each of these is under intense investigation. In addition, some data do exist to indicate that environmental agents also can elicit a state of chronic fatigue. We expect data to accumulate to support the belief that CFS has multiple causes. Key words: brain, cardiovascular, chronic fatigue syndrome, cognition, immunologic, psychiatric, viral. Environ Health Perspect 110(suppl 4):673-677 (2002). http://ehpnet1.niehs.nih.gov/docs/2002/suppl-4/673-677natelson /abstract.html [ABSTRACT FROM AUTHOR]

In this investigation, the effects of unexplained fatiguing illness and psychiatric disturbance on functional status and quality of life in Gulf War veterans (GWVs) was examined. Twenty-nine GWVs with unexplained fatigue (Fukuda et al., 1994) and an Axis I psychiatric diagnosis, 19 GWVs with fatigue and no Axis I psychiatric disorder, and 45 healthy GWVs were evaluated. GWVs with unexplained fatigue suffered from significant functional decline and decreased well-being in all spheres, relative to healthy GWVs. Veterans with comorbid psychiatric illnesses demonstrated the most impaired functioning on measures of life quality that emphasized psychological well-being, but they did not demonstrate reduced physical functioning relative to other fatigued veterans. Thus, reduced physical functioning and well-being in GWVs cannot be attributed to psychiatric disturbance but seems to result from unexplained fatiguing illness.

This article reviews the current state of research in chronic fatigue syndrome (CFS). The evolving definition, prevalence, and prognosis of this controversial illness are presented. We review studies examining psychiatric, personality, and psychosocial etiology for CFS. The evidence for pathophysiology in CFS is also presented, and studies investigating viral, immune, neuroimaging, neuroendocrine, and central and autonomic nervous system abnormalities in CFS are assessed. Current evidence indicates that CFS is multidetermined and heterogeneous and that subgrouping patients according to factors such as psychiatric state and symptom onset may be fruitful. The current state of treatment for CFS is reviewed, and the challenges for research aimed at resolving this prototypical mind/body problem are discussed.

The study assessed peripheral sensory function and its relation to self-reported wartime exposures to potentially neurotoxic substances in Gulf War veterans with chronic fatigue syndrome (CFS). Male Gulf veterans fulfilling the 1994 CDC diagnostic criteria for CFS were compared with matched controls. Quantitative sensory testing was performed to establish thresholds of perception for the sense of light touch and radiant heat. The Devens survey was used to collect data on self-reported exposures to by-products of combustion and organophosphate compounds. Gulf veterans with CFS had elevated tactile but normal thermal thresholds compared with their controls. Sick veterans had greater rates of self-reported exposures and/or noxious side effects for all assessed toxicants. Interestingly, both Gulf veteran groups, including those reporting no symptoms, had impaired perception of light touch when compared with age-matched samples of non-Gulf war veteran men. The results of this study are consistent with a hypothesis that Gulf veterans with CFS have a subtle neurological deficit that might reflect underlying peripheral neuropathy. The association between this deficit and self-report of multiple potentially neurotoxic exposures suggests that war zone pollutants may be possible contributing factors. Copyright &copy; 1999 John Wiley & Sons, Ltd.

The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced oxygen delivery to muscles. Patients with CFS according to CDC (Center for Disease Control) criteria (n = 20) were compared with normal sedentary subjects (n = 12). Muscle oxygen delivery was measured as the rate of post-exercise and post-ischaemia oxygen-haem resaturation. Oxygen-haem resaturation was measured in the medial gastrocnemius muscle using continuous-wavelength near-IR spectroscopy. Phosphocreatine resynthesis was measured simultaneously using 31P magnetic resonance spectroscopy. The time constant of oxygen delivery was significantly reduced in CFS patients after exercise (46.5±16 s; mean±S.D.) compared with that in controls (29.4±6.9 s). The time constant of oxygen delivery was also reduced (20.0±12 s) compared with controls (12.0±2.8 s) after cuff ischaemia. Oxidative metabolism was also reduced by 20% in CFS patients, and a significant correlation was found between oxidative metabolism and recovery of oxygen delivery. In conclusion, oxygen delivery was reduced in CFS patients compared with that in sedentary controls. This result is consistent with previous studies showing abnormal autonomic control of blood flow. Reduced oxidative delivery in CFS patients could be specifically related to CFS, or could be a non-specific effect of reduced activity levels in these patients. While these results suggest that reduced oxygen delivery could result in reduced oxidative metabolism and muscle fatigue, further studies will be needed to address this issue.

• 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. RESULTS. —The mean number of correctly identified responses collapsed across the four PASAT trials was significantly different across groups (F[2,31 ]=4.03; P&lt;.05). While the CFS and MS groups did not differ from each other, subjects with CFS (SEM, 124.2±6.4) and subjects with MS (SEM, 112.9±10.9) scored significantly below controls (SEM, 146.4±6.4) (Fisher's Protected Least Significant Difference test; P&lt;.05). There were significant differences among the three groups on mean Digit Span Test performance (F[2,31]=5.5; P&lt;.01). While the CFS and MS group did not differ significantly from each other, only the CFS group was significantly lower than control (Fisher's Protected Least Significant Difference test; P&lt;.05). Mean performance on the Similarities test did not differ among the three groups (F=0.58). In addition, there were significant differences among the three groups in mean BDI scores (F[2,31 ]=7.6; P&lt;.01). The CFS and MS groups did not differ significantly from each other, and both groups showed a statistically significantly elevated mean BDI score relative to the control group (Fisher's Protected Least Significant Difference test; P&lt;.05). No significant correlations were found between BDI scores and PASAT total scores (CFS, r=−.21; MS, r=.13; control, r=.27), or between BDI and Digit Span Test (CFS, r=−.32; MS, r=−.40; control, r=−.19). Results of the PASAT and Digit Span Test were significantly correlated in the CFS group (r=.71; P&lt;.01), but not in the MS (r=.06) or control groups (r=.49). 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. Selective impairment in information processing efficiency may lie at the root of other cognitive complaints made by patients with CFS.

In Experiment 1 the number and size of ulcers resulting from exposure to an activity-stress procedure were inversely related to the length of the pre-stress experience with either 1 hr or 2 hr daily feeding schedules. In Experiment 2, rats housed in group cages during the pre-stress period were more vulnerable to the ulcerogenic effects of the activity-stress procedure. A pellet food or powdered food treatment condition failed to provide significant group differences. Vulnerability to stress-ulcer is discussed in terms of the disparity of the environmental conditions between the acclimation period and the activity-stress period.

Guinea pigs were subjected to Pavlovian fear conditioning signaled shock and then infused with a fast acting digitalis preparation on a day when all experimental stimuli except shock were delivered. A significant shortening in latency to the onset of lifethreatening digitalis toxicity was found when comparisons were made to control pigs that had never been shocked. This effect was not found in other guinea pigs infused with ouabain after exposure to sessions of unsignaled shock. These experiments indicate that psychological factors, when divorced form physical factors, may produce lethal digitalis toxicity in an organism that would otherwise by asymptomatic. The data from these experiments suggest that the intense arousal associated with a signal that had previously been paired with shock is sufficient to precipitate cardiac arrhythmias in an animal with a predisposition to cardiac automaticity such as is produced by digitalis. Conversely, the less intense arousal associated with unsignaled shock is inadequate to produce this effect. This interpretation indicates that the state of an animal's health will affect its psychosomatic response to signaled or unsignaled shock.

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.

Our previous work has shown that constant light can prolong the life of hamsters with heart disease. Although we have seen this result several times, constant light was not protective in our most recent experiment. We undertook this study because we had changed some conditions. As in previous experiments, we found that life in constant light extended life for cardiomyopathic hamsters as compared with others living in a 12:12-hr light:dark environment. A second factor affecting survival was the number of hamsters in a group. Hamsters housed in groups of five lived longer than those housed in groups of two under the same lighting conditions. Data from one experiment suggested that a short photoperiod (6:18 light:dark) was also protective. Although these experiments indicate that the protective effects of different light:dark schedules are not simple ones, they are important because their use may prove to be a helpful adjunct in the treatment of congestive heart failure.

Our earlier work showed that stress had progressively more serious consequences in a hamster model of congestive heart failure as the magnitude of heart failure worsened. Based on that study, we hypothesized that the intensity of the stressor used might play an important part in determining this outcome as well as in influencing coronary reactivity to arginine vasopressin (AVP). Cardiomyopathic (2.5, 6.5, and 10 months) hamsters (CMHs) were stressed with a 2-hr period of supine immobilization for five consecutive days. Stressor intensity was increased by exposing the hamsters to progressively longer periods at 4°C: the low stress group was never put in the cold; the moderate stress group was exposed to cold for 1 hr, and the high stress group for 2 hr. CMHs were anesthetized and sacrificed 5 days after stress, and their hearts were perfused using a modified Langendorff system. Maximum ±dP/dt, developed pressure, ventricular relaxation time, (T), and coronary vascular resistance (CVR) were recorded, and CVR was also measured following coronary infusion of AVP. Stressor intensity had no effect on cardiac mechanics in 2.5-month CMHs. In 6.5-month CMHs, only the high-intensity stressor impaired ventricular mechanics (decreased maximum ±dP/dtand developed pressure, increased T; P<0.05), while low and moderate stress produced no effects. In 10-month CMHs, stress at all intensities exacerbated ventricular dysfunction (decreased maximum ±dP/dtand developed pressure; P< 0.05). These results support our first hypothesis that stressor intensity interacts multiplicatively with severity of the underlying disease to influence the course of heart failure. However, our second hypothesis was not supported, because stress—regardless of intensity—affected reactivity of the coronary vasculature to AVP only in 2.5-month CMHs. A further test of the relation of stressor intensity and coronary vascular reactivity requires study of additional groups of CMHs during the period of their disease characterized by coronary vasospasm.

By arranging a series of psychological contingencies (unpredictability, uncontrollability, conflict), coupled with delivery of a physical stimulus (electric shock), we produced gastroduodenal mucosal lesions in 7 of 8 rhesus monkeys. The most severe conflict paradigm most consistently produced lesions across subjects. Of the 30 lesions observed by endoscopy, 80% occurred near the anatomic junction of gastric body and antrum, in the antrum, or in the duodenum. Lesions varied in severity from discolorations of the mucosa to disruptions of mucosal integrity. Lesions in the stomach generally disappeared in several days despite the continuation of stress; some duodenal lesions were equally evanescent, but in 2 monkeys, lesions lasted over a week. Hydrogen ion kinetics were measured in 2 monkeys that developed gastric lesions and 2 that developed duodenal lesions. The rate at which hydrogen ion entered the duodenum was uniformly suppressed for all 4 monkeys during their first session of shock avoidance; during their last session, the gastric subgroup continued to show suppression while the duodenal subgroup returned towards control levels. Serum gastrin levels were unchanged by the multiple-stress procedures. Our finding of consistently producible, stress-induced gastroduodenal pathology in anatomic areas similar to those involved in man suggests that the subhuman primate is suitable for further efforts to produce an animal model of psychosomatic ulcer disease.

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.

Chronic fatigue syndrome (CFS) is an illness that results in debilitating fatigue as well as rheumatological, infectious, and neuropsychiatric symptoms. The present paper is a brief overview of the neuropsychological and psychiatric research on CFS. Studies from our laboratory contrasting CFS with patients with multiple sclerosis, depression, and healthy controls are detailed. Our hypothesis of the neuropsychological impairments in CFS is discussed.

• We studied the neuropathologic effects of chronic alcohol ingestion on the brains of healthy, well-nourished, male mongrel dogs. Five experimental dogs were provided 36% of their calories as ethyl alcohol for 1 year. Following killing, their brains were weighed, photographed, sectioned, and processed for computerized morphometric determinations of ventricular size, cortical thickness, and neocortical neuron and glial cell populations. Compared with a similarly handled control group, the alcoholic dog brains showed lateral ventricular enlargement, cortical thinning in the temporal lobe only, and fewer glial cells in the temporal and frontal cortices. There were no statistically significant differences between the alcoholic and control groups in brain weight, frontal or parietal cortical thickness, or neocortical neuron populations. These results imply a disproportionate vulnerability of white matter to the damaging effects of alcohol with consequent lateral ventricular enlargement, and some regional variation in neocortical susceptibility to alcohol-induced cortical thinning and glial cell loss. In general, such changes are consistent with those described in neuroradiologic imaging studies of human alcoholics.