Search

Chronic fatigue syndrome (CFS) is a multi-faceted disorder for which no etiology has been determined. This paper discusses the implications of the new clinical case definition of CFS on previous and future studies of this illness. The authors' own management approach is also discussed.

Chronic fatigue syndrome is characterized by persistent or relapsing debilitating fatigue for at least 6 months in the absence of a medical diagnosis that would explain the clinical presentation. Because primary glucocorticoid deficiency states and affective disorders putatively associated with a deficiency of the arousal-producing neuropeptide CRH can be associated with similar symptoms, we report here a study of the functional integrity of the various components of the hypothalamic-pituitary-adrenal axis in patients meeting research case criteria for chronic fatigue syndrome. Thirty patients and 72 normal volunteers were studied. Basal activity of the hypothalamic-pituitary-adrenal axis was estimated by determinations of 24-h urinary free cortisol-excretion, evening basal plasma total and free cortisol concentrations, and the cortisol binding globulin-binding capacity. The adrenal cortex was evaluated indirectly by cortisol responses during ovine CRH (oCRH) stimulation testing and directly by cortisol responses to graded submaximal doses of ACTH. Plasma ACTH and cortisol responses to oCRH were employed as a direct measure of the functional integrity of the pituitary corticotroph cell. Central CRH secretion was assessed by measuring its level in cerebrospinal fluid. Compared to normal subjects, patients demonstrated significantly reduced basal evening glucocorticoid levels (89.0 +/- 8.7 vs. 148.4 +/- 20.3 nmol/L; P less than 0.01) and low 24-h urinary free cortisol excretion (122.7 +/- 8.9 vs. 203.1 +/- 10.7 nmol/24 h; P less than 0.0002), but elevated basal evening ACTH concentrations. There was increased adrenocortical sensitivity to ACTH, but a reduced maximal response [F(3.26, 65.16) = 5.50; P = 0.0015). Patients showed attenuated net integrated ACTH responses to oCRH (128.0 +/- 26.4 vs. 225.4 +/- 34.5 pmol/L.min, P less than 0.04). Cerebrospinal fluid CRH levels in patients were no different from control values (8.4 +/- 0.6 vs. 7.7 +/- 0.5 pmol/L; P = NS). Although we cannot definitively account for the etiology of the mild glucocorticoid deficiency seen in chronic fatigue syndrome patients, the enhanced adrenocortical sensitivity to exogenous ACTH and blunted ACTH responses to oCRH are incompatible with a primary adrenal insufficiency. A pituitary source is also unlikely, since basal evening plasma ACTH concentrations were elevated. Hence, the data are most compatible with a mild central adrenal insufficiency secondary to either a deficiency of CRH or some other central stimulus to the pituitary-adrenal axis. Whether a mild glucocorticoid deficiency or a putative deficiency of an arousal-producing neuropeptide such as CRH is related to the clinical symptomatology of the chronic fatigue syndrome remains to be determined.

Abnormal physical exhaustion and fatigue are often simply regarded as a natural consequence of pulmonary diseases. Apart from factors not specifically related to pulmonary diseases (e.g. consequences of infections or malignant diseases of the lungs), increased work of breathing due to impaired lung/thoracic cage mechanics, the effects of chronic hypoxia and hypercapnia, the consequences of disturbed sleep and psychosocial factors are mainly responsible for the impaired physical fitness and the fatigue in association with lung diseases. A careful case history including psychosocial aspects and a thorough physical examination are essential for an efficient diagnostic evaluation. Tests of pulmonary function not only in the awake patient at rest, but also during sleep or adequate physical exercise can reveal the causes of impaired physical performance and fatigue related to lung diseases.

Quadriceps isometric strength, activation and fatiguability were measured in 11 patients with symptoms of fatigue three months after glandular fever or a glandular fever-like illness. Predicted normal and lower limits of normal muscle strength were calculated from height and age. These measures and the fatigue index were compared with a group of healthy students of similar age. Two of the patients were unable to activate fully their muscles. After allowing for this inhibition the group mean (SD) strength was 104 (22%) of predicted. Although there was no significant difference in the fatigue index between the patients and the control group, there was a trend for the patients to show less fatigue than controls. There was no difference in the muscle results for those patients who were found to have Epstein-Barr virus infections and those who did not. The feelings of weakness and fatigue experienced by the patients could not be explained by either physiological muscle fatigue or lack of effort.

Fatigue is a frequent but ill defined symptomatology in many disorders of the central and the peripheral nervous system. It is characterized as a fluctuating incapacity or weakness, often in the absence of overt paresis. Experimental or diagnostic evidence of fatigue is available only in disorders of the peripheral motor neuron, the neuromuscular junction and the muscle fibers, but not in CNS disorders. Fatigue, as a fluctuating symptomatology may be misdiagnosed as simulation or malingering not only by lay persons, but also by doctors.

The exact pathophysiology of excessive fatigue in patients with postviral fatigue syndrome (PVFS) remains uncertain in spite of increasing investigation. One objective abnormality of neuromuscular function is the increased jitter on single fibre EMG studies. While this is a sensitive technique which indicates a disturbance in the peripheral part of the motor unit, it is non-specific and its role in the pathophysiology remains unclear. Impaired muscular activation with added force in response to superimposed electrical stimulation suggests an extra-muscular and/or central component of fatigue. Conventional neurophysiological studies and those of strength and endurance have shown no objective abnormality in patients compared with controls. The previous reports of disturbed muscle metabolism on NMR spectroscopy have not been confirmed in more recent studies and no consistent abnormality of excitation-contraction coupling has so far emerged. Finally, unlike patients with depression, cognitive evoked potential studies suggest impaired attention, memory and stimulus evaluation in postviral fatigue syndrome. In future studies, the importance of utilising approved clinical criteria for patient inclusion cannot be overemphasized. Control groups should include sedentary or deconditioned as well as depressed subjects to help standardise these important variables.

Many different neurological and psychiatric syndromes follow viral infections, but their clinical pictures and pathogeneses are poorly understood. The syndromes include acute disseminated encephalomyelitis (post-infectious encephalomyelitis), the Guillain-Barre syndrome (post-infectious neuritis) and Reye's syndrome. Recently, attention has been focused on another common postviral neurological syndrome, i.e. the postviral fatigue syndrome (PVFS)--termed myalgic encephalomyelitis (ME) and a host of other designations. PVFS occurs both sporadically and in epidemics, with cases being reported from all over Europe, the United States, Australasia and South Africa. It is difficult to make the diagnosis and this has meant, in the past, that it is not until an epidemic has occurred that random cases which presented in the preceding years are realised to represent the same condition. With renewed interest in the syndrome and greater attention from physicians, however, diagnosis of sporadic cases is now becoming more common.

Patients with postviral fatigue syndrome (PVFS) usually complain of the skeletal muscle-related symptoms of fatigue and myalgia. It is not surprising therefore that the muscles have recently been the object of intensive studies which have used a variety of biochemical and physiological techniques. The aim of this chapter is to review these findings, and to discuss their significance or otherwise to the presenting symptoms and course of the condition.

The postviral fatigue syndrome overlaps with psychiatry at a number of points. First, there is the influence that some psychological states have on physiological processes, such as immunity. Second, psychological symptoms, particularly depression but also anxiety, are a major feature of the syndrome. Third, difficulties in the doctor-patient relationship are common. Each of these three areas are discussed in detail. Special attention is given to the possible mechanisms underlying the occurrence of psychological symptoms, which are sufficient to make a psychiatric diagnosis in at least two thirds of cases. It is concluded that the bulk of the scientific evidence points to psychiatric disturbances being primary but that this does not account for the syndrome in its entirety and other mechanisms probably operate as well. Much of the conflict between doctor and patient arises from misconceptions about the nature and cause of psychological disturbances.

Thirty-five patients with chronic fatigue syndrome according to the criteria of Holmes were followed for periods of up to eight years. The most frequent symptoms were severe fatigue, arthralgias and myalgias, recurrent oropharyngitis and various psychiatric disorders. More than half of the patients suffered from neuropathy, lymphadenopathy, gastrointestinal complaints and recurrent low-grade fever. Recurrent or persistent activity of human herpesvirus -6 infection was seen in 73% of the patients and of Epstein-Barr virus in 34.4%. In addition, various other infections were diagnosed at lower frequency. Initial routine immunologic screening revealed various types of deficiencies, these were yet inconsistent and variable when different patients were compared with each other. Tentative treatments included in immunoglobulins, nonspecific immunostimulation and virostatic drugs. No consistently positive results were obtained with any treatment schedule although immunoglobulins appeared the most efficient measure. In addition, psychologic care of the patients is indicated, since disturbances in the psycho-neuroimmunologic regulation may play a significant role in the pathogenesis of the disease.

There continues to be an emerging body of literature related to fibromyalgia and the related conditions chronic fatigue syndrome and myofascial pain. During the past year, the most notable contributions included a large multicenter study providing new diagnostic criteria for the classification of fibromyalgia and clinical studies describing the overlap of fibromyalgia, chronic fatigue syndrome, and myofascial pain. Pathophysiologic studies were often preliminary and uncontrolled but the focus of these studies on abnormal nociception, neurohormones, and muscle metabolism provides an exciting hypothesis to unify pain, fatigue, and sleep disturbances, the primary symptoms of fibromyalgia. Unfortunately, new therapeutic trials were neither innovative nor especially encouraging.

Among 200 adults with a chief complaint of chronic fatigue evaluated in an internal medicine practice, currently active panic disorder was diagnosed in 26 patients (13%), a frequency tenfold greater than that in the general population. Panic disorder preceded or was coincidental with the onset of chronic fatigue in 21 of these patients. In comparison with the rest of the study cohort, significantly more patients with panic disorder had a history of severe depression, including persistent thoughts of death or suicide. Moreover, more patients with panic disorder showed a lifetime tendency to have physical symptoms that remained unexplained after medical evaluation. Our findings suggest that treatable panic disorder is an important contributor not only to major depression and somatization, but also to the etiology and clinical presentation of chronic fatigue in patients in an outpatient practice.

The decrease in maximal force-generating capacity, the degree of central activation of the muscle, and the subjective perception of effort were measured during prolonged submaximal isometric exercise in 12 male patients suffering from the 'chronic fatigue syndrome' and 13 naive, healthy male subjects. Maximal voluntary isometric torque generated by the elbow flexors was measured before, and at 5 min intervals during an endurance sequence of 45 min of repetitive isometric contractions (6 s duration, 4 s rest interval) producing 30% of the initial maximal voluntary torque. Electrical stimuli were also delivered to the elbow flexors to measure the contractile force in the intervals between voluntary contractions. The degree of central motor activation during maximal voluntary contractions was assessed using a sensitive method of twitch interpolation. In addition, the perceived effort required to achieve the target submaximal contractions was recorded using a standardized self-report scale. A high degree of central activation was achieved in maximal contractions during the endurance sequence both in the patients (mean of maximal force 93.6%; SD 7.8%), and in the control subjects (mean 90.9%; SD 9.5%). The relative torque produced by either voluntary or electrically stimulated contractions was not significantly different between patients and control subjects throughout the test. There was no significant difference in the perceived exertion between the patients and control subjects. These findings support the concept that neither poor motivation, nor muscle contractile failure is important in the pathogenesis of 'fatigue' in patients with the chronic fatigue syndrome.

Oxidative metabolism is the major source of energy for muscle activity, and maximal oxygen uptake (VO2max), the product of maximal cardiac output and maximal arteriovenous oxygen difference, indicates individual capacity for oxidative metabolism and performance of exercise by the large muscles. Strength, a function of muscle cross-sectional area, motor-unit recruitment, and neuromuscular coordination, is the ability to develop force in a single, brief, maximal-effort voluntary contraction of rested muscle. Weakness is a diminished ability of rested muscle to exert maximal force. Fatigue is a loss of maximal force-generating capacity that develops during muscular activity, likely originates within muscle itself, and persists until muscle is fully recovered. Individual perception of motor effort can be determined with standardized rating scales. These concepts are discussed in detail, their relevance to the pathophysiology of exercise in chronic fatigue syndrome is analyzed, and a general strategy of exercise evaluation pertinent to chronic fatigue syndrome is presented.

The clinical and laboratory findings from studies of patients with chronic fatigue syndrome (CFS) from northern Nevada are summarized. Physicians caring for these patients have estimated that greater than 400 patients with CFS from northern Nevada and nearby communities in California were identified between 1984 and 1988. As a result of these studies, a cluster of clinical and laboratory features associated with the illness in moderately to severely affected patients has been identified: profound fatigue of prolonged duration; cervical lymphadenopathy; recurrent sore throat and/or symptoms of influenza; loss of cognitive function manifested by loss of memory and loss of ability to concentrate; myalgia; impairment of fine motor skills; abnormal findings on magnetic resonance imaging brain scan; depressed level of antibody to Epstein-Barr virus (EBV) nuclear antigen; elevated level of antibody to EBV early antigen restricted component; elevated ratio of CD4 helper to CD8 suppressor cells; and strong evidence of association of this syndrome with infection with human herpesvirus 6. More-serious and longer-lasting neurologic impairments, including seizures, psychosis, and dementia, have also been observed in some of these patients.

Patients with chronic fatigue syndrome (CFS) often complain of dysequilibrium that is nonspecific. The basis of this complaint is unknown but may be related to vestibular system abnormalities, in that an association between inner-ear deficits and infectious mononucleosis has been established in the medical literature. An overview of quantitative vestibular function testing is given, including vestibulo-ocular and vestibulospinal tests. The basic principles of caloric and rotational testing are provided, including the interaction between vision and the vestibular system. Moving-platform posturography is described. Preliminary results from quantitative vestibular function testing of a small group of individuals with CFS are provided.

Chronic fatigue is one of the most common complaints. However, it can be a vexing problem in clinical practice. In contrast to serum cholesterol or blood pressure, fatigue may seem immeasurable. The management of fatigue is often complicated by the uncertainty surrounding of its cause and the frequent lack of specific therapy. Recently, criteria were established for the diagnosis of chronic fatigue syndrome. This working case definition does provide some guidance for the practicing physician.

Eosinophilia-myalgia syndrome has been linked to ingestion of tryptophan, but the exact cause of this recently recognized syndrome is unclear. As in other reported cases, the disease in the patient described here developed while she was taking tryptophan. Although eosinophilia resolved following glucocorticoid therapy, the disease in this patient continues to progress.

Purpose: Currently, there is no established therapy for chronic fatigue syndrome (CFS), a recently defined illness that has been associated with a variety of immunologic abnormalities. Based on the hypothesis that a chronic viral infection or an immunoregulatory defect is involved in the pathogenesis of CFS, the therapeutic benefit of intravenous immunoglobulin G (IV IgG) was evaluated in a group of patients with CFS. Additionally, serum immunoglobulin concentrations and peripheral blood lymphocyte subset numbers were measured at the outset of the study, and the effect of IV IgG therapy on IgG subclass levels was determined., Patients and Methods: Thirty patients with CFS were enrolled in a double-blind, placebo-controlled trial of IV IgG. The treatment regimen consisted of IV IgG (1 g/kg) or intravenous placebo (1% albumin solution) administered every 30 days for 6 months. Participants completed a self-assessment form prior to each of the six treatments, which was used to measure severity of symptoms, functional status, and health perceptions. Patients were also asked to report adverse experiences defined as worsening of symptoms occurring within 48 hours of each treatment., Results: Twenty-eight patients completed the trial. At baseline, all 28 patients complained of moderate to severe fatigue, and measures of social functioning and health perceptions showed marked impairment. Low levels of IgG1 were found in 12 (42.9%), and 18 (64.3%) had low levels of IgG3. At the end of the study, no significant therapeutic benefit could be detected in terms of symptom amelioration or improvement in functional status, despite restoration of IgG1 levels to a normal range. Major adverse experiences were observed in 20% of both the IV IgG and placebo groups., Conclusion: The results of this study indicate that IV IgG is unlikely to be of clinical benefit in CFS. In addition to the ongoing need for placebo-controlled trials of candidate therapies for CFS, an expanded research effort is needed to define the etiology and pathogenesis of this disorder.

Purpose: The chronic fatigue syndrome (CFS) is characterized by profound fatigue, neuropsychiatric dysfunction, and frequent abnormalities in cell-mediated immunity. No effective therapy is known., Patients and Methods: Forty-nine patients (40 with abnormal cell-mediated immunity) participated in a randomized, double-blind, placebo-controlled trial to determine the effectiveness of high-dose intravenously administered immunoglobulin G. The patients received three intravenous infusions of a placebo solution or immunoglobulin at a dose of 2 g/kg/month. Assessment of the severity of symptoms and associated disability, both before and after treatment, was completed at detailed interviews by a physician and psychiatrist, who were unaware of the treatment status. In addition, any change in physical symptoms and functional capacity was recorded using visual analogue scales, while changes in psychologic morbidity were assessed using patient-rated indices of depression. Cell-mediated immunity was evaluated by T-cell subset analysis, delayed-type hypersensitivity skin testing, and lymphocyte transformation with phytohemagglutinin., Results: At the interview conducted by the physician 3 months after the final infusion, 10 of 23 (43%) immunoglobulin recipients and three of the 26 (12%) placebo recipients were assessed as having responded with a substantial reduction in their symptoms and recommencement of work, leisure, and social activities. The patients designated as having responded had improvement in physical, psychologic, and immunologic measures (p less than 0.01 for each)., Conclusion: Immunomodulatory treatment with immunoglobulin is effective in a significant number of patients with CFS, a finding that supports the concept that an immunologic disturbance may be important in the pathogenesis of this disorder.

Objective: To determine the aerobic work capacity of patients with the chronic fatigue syndrome and compare it with that of two control groups, and to assess the patients' perception of their level of activity before and during illness., Design: A symptom limited exercise treadmill test with on line gas analysis and blood sampling was used. Subjects were assessed by one investigator, who was blind to the group which they were in., Setting: Department of medicine, Royal Victoria Hospital, Belfast., Subjects: 13 Patients (10 women, three men) who fulfilled the diagnostic criteria for chronic fatigue syndrome. Two control groups of similar age, sex, and body weight: 13 normal subjects (10 women, three men) and seven patients (five women, two men) with the irritable bowel syndrome., Main Outcome Measures: Aerobic work capacity as assessed by several variables such as length of time on treadmill, heart rate, and biochemical measurements; Borg score; and visual analogue scores of perceived level of physical activity., Results: The patients with the chronic fatigue syndrome had a reduced exercise capacity compared with that of the other subjects, spending a significantly shorter time on the treadmill. They had a significantly higher heart rate at submaximal levels of exertion and at stage III exertion had significantly higher blood lactate concentrations. Using a Borg score, they showed a significantly altered perception of their degree of physical exertion with a mean score of 8.2 compared with 6.6 and 5.3 for the normal subjects and patients with the irritable bowel syndrome respectively. Using a visual analogue scale they indicated that they had a greater capacity for activity before illness than had the patients with the irritable bowel syndrome, but the scores were not significantly different between the two groups. Both groups of patients indicated reduced activity at the time of testing. Normal controls and patients with the irritable bowel syndrome aspired to a greater level of activity than their current level, but the patients with the chronic fatigue syndrome aspired to a level similar to that which they had had before their illness., Conclusions: Patients with the chronic fatigue syndrome have reduced aerobic work capacity compared with normal subjects and patients with the irritable bowel syndrome. They also have an altered perception of their degree of exertion and their premorbid level of physical activity.

The number of patients who are identified as having chronic fatigue syndrome (CFS) has increased, and as a result, chronic fatigue syndrome has received widespread attention. Research has demonstrated that cognitive, affective and behavioural symptoms are prominent in CFS. Psychiatrists are therefore being asked to participate in the assessment and management of patients with this syndrome. This paper will provide an overview of the clinical characteristics of CFS and the current empirical findings related to its pathology, and will conclude with a discussion of the management of these patients.

A double-blind, placebo-controlled study of the efficacy and tolerability of 5-hydroxytryptophan (5-HTP) was conducted in 50 patients with primary fibromyalgia syndrome. All the clinical parameters studied were significantly improved by treatment with 5-HTP and only mild and transient side-effects were reported. Further controlled studies are required to define properly the value of 5-HTP in patients with primary fibromyalgia syndrome.

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

Fibromyalgia and chronic fatigue syndrome have similar clinical and demographic features. We found that most patients with chronic fatigue syndrome have a tender point examination similar to patients with fibromyalgia. Similar pathophysiologic mechanisms are also being explored in each syndrome, including a potential role for viral induced immune dysfunction.

Chronic fatigue syndrome (CFS) is characterized by chronic, debilitating fatigue lasting greater than 6 months. Frequent chronic and recurrent findings include fever, pharyngitis, myalgias, adenopathy, arthralgias, difficulties in cognition and disorders of mood. In the majority of patients, the illness starts suddenly with an acute, "flu-like" illness. The following laboratory abnormalities are seen with some frequency, although none are seen in all patients: lymphocytosis, atypical lymphocytosis, monocytosis, elevation of hepatocellular enzymes, low levels of antinuclear antibodies, varying levels of antithyroid antibodies, partial hypergammaglobulinemia, elevated CD4:CD8 ratio, decreased cytolytic activity of natural killer cells, and low levels of immune complexes. Clinical and serologic studies suggest an association of CFS with all of the human herpesviruses, particularly Epstein-Barr virus (EBV) and the recently discovered human B lymphotropic virus (HBLV) or human herpesvirus 6; neither EBV nor HBLV has yet been shown to play a causal role in the illness. Preliminary evidence suggests that many of these features of CFS also are seen in patients with fibromyalgia.

Ten patients with post-viral fatigue syndrome and abnormal serological, virological, immunological and histological studies were examined by the single-fibre electromyographic (EMG) technique after excluding concurrent problems in the neuromuscular system. No abnormality of fibre density was noted but all patients had abnormal jitter values. Very high jitter values were not associated with impulse or concomitant blocking. The findings confirm the organic nature of the disease. A muscle membrane disorder probably arising from defective myogenic enzymes is the likely mechanism for the fatigue and the single-fibre EMG abnormalities. This muscle membrane defect may be due to the effects of a persistent viral infection.

This review summarizes the physiologic and clinical evidence that shows nonrestorative sleep to be associated with chronic fatigue and diffuse myalgia after a flulike illness. Such a febrile illness may trigger alteration in sleep-wake brain and immune functions in patients with fibrositis or chronic fatigue syndromes.