Chronic Fatigue Syndrome: US Mid-Atlantic

Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G. · Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 6N252, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620, USA. · Ann Intern Med. · Pubmed #12416949 links to  free full text

Abstract: The term dysautonomia refers to a change in autonomic nervous system function that adversely affects health. The changes range from transient, occasional episodes of neurally mediated hypotension to progressive neurodegenerative diseases; from disorders in which altered autonomic function plays a primary pathophysiologic role to disorders in which it worsens an independent pathologic state; and from mechanistically straightforward to mysterious and controversial entities. In chronic autonomic failure (pure autonomic failure, multiple system atrophy, or autonomic failure in Parkinson disease), orthostatic hypotension reflects sympathetic neurocirculatory failure from sympathetic denervation or deranged reflexive regulation of sympathetic outflows. Chronic orthostatic intolerance associated with postural tachycardia can arise from cardiac sympathetic activation after "patchy" autonomic impairment or blood volume depletion or, as highlighted in this discussion, from a primary abnormality that augments delivery of the sympathetic neurotransmitter norepinephrine to its receptors in the heart. Increased sympathetic nerve traffic to the heart and kidneys seems to occur as essential hypertension develops. Acute panic can evoke coronary spasm that is associated with sympathoneural and adrenomedullary excitation. In congestive heart failure, compensatory cardiac sympathetic activation may chronically worsen myocardial function, which rationalizes treatment with beta-adrenoceptor blockers. A high frequency of positive results on tilt-table testing has confirmed an association between the chronic fatigue syndrome and orthostatic intolerance; however, treatment with the salt-retaining steroid fludrocortisone, which is usually beneficial in primary chronic autonomic failure, does not seem to be beneficial in the chronic fatigue syndrome. Dysautonomias are an important subject in clinical neurocardiology.

Natelson BH, Lange G. · Department of Neurosciences, Chronic Fatigue Syndrome Cooperative Research Center, UMDNJ, Newark, USA. · Environ Health Perspect. · Pubmed #12194905 links to  free full text

Abstract: 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.

Engel CC, Adkins JA, Cowan DN. · Deployment Health Clinical Center, Walter Reed Army Medical Center, Washington, DC, USA. · Environ Health Perspect. · Pubmed #12194900 links to  free full text

Abstract: Medically unexplained physical symptoms (MUPS) are persistent idiopathic symptoms that drive patients to seek medical care. MUPS syndromes include chronic fatigue syndrome, fibromyalgia syndrome, and multiple chemical sensitivities. When MUPS occur after an environmental exposure or injury, an adversarial social context that we call "contested causation" may ensue. Contested causation may occur publicly and involve media controversy, scientific disagreement, political debate, and legal struggles. This adversarial social context may diminish the effectiveness of the provider-patient relationship. Contested causation also may occur privately, when disagreement over the causes of MUPS takes place in the patient-provider context. These patient-provider disagreements over causation often occur because of the enigmatic nature of MUPS. We suggest that a context of contested causation may have serious negative effects on healthcare for individuals with MUPS. Context plays a larger role in MUPS care than it does for most medical care because of the uncertain nature of MUPS, the reliance of standard MUPS therapies on a potentially tenuous patient-provider partnership, and the clinical need to rely routinely on subjective MUPS assessments that often yield discordant patient and provider conclusions. Contested causation may erode patient-provider trust, test the provider's self-assurance and capacity to share power with the patient, and raise problematic issues of compensation, reparation, and blame. These issues may distract patients and providers from therapeutic goals. In occupational and military settings, the adverse impact of contested causation on the patient-provider partnership may diminish therapeutic effectiveness to a greater degree than it does in other medical settings. Contested causation therefore raises questions regarding generalizability of standard therapies for MUPS and related syndromes to these settings. Future research is needed to learn whether intuitively sensible and evidence-based MUPS therapies benefit occupational and military medical patients who are afforded care in the context of contested causation.

Sigal LH, Hassett AL. · Division of Rheumatology and Connective Tissue Research, Department of Medicine, Lyme Disease Center, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903-0019, USA. · Environ Health Perspect. · Pubmed #12194894 links to  free full text

Abstract: Lyme disease is a relatively well-described infectious disease with multisystem manifestations. Because of confusion over conflicting reports, anxiety related to vulnerability to disease, and sensationalized and inaccurate lay media coverage, a new syndrome, "chronic Lyme disease," has become established. Chronic Lyme disease is the most recent in a continuing series of "medically unexplained symptoms" syndromes. These syndromes, such as fibromyalgia, chronic fatigue syndrome, and multiple chemical sensitivity, meet the need for a societally and morally acceptable explanation for ill-defined symptoms in the absence of objective physical and laboratory findings. We describe factors involved in the psychopathogenesis of chronic Lyme disease and focus on the confusion and insecurity these patients feel, which gives rise to an inability to adequately formulate and articulate their health concerns and to deal adequately with their medical needs, a state of disorganization termed aporia.

Kipen HM, Fiedler N. · Environmental and Occupational Health Sciences Institute--Occupational Health Division, University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA. · Environ Health Perspect. · Pubmed #12194892 links to  free full text

Abstract: Symptoms, and especially those without clear underlying medical explanations, account for a large percentage of clinical encounters. Many unexplained symptoms have been organized by patients and practitioners into syndromes such as chronic fatigue syndrome, multiple chemical sensitivity, sick building syndrome, Gulf War syndrome, and the like. All these syndromes are defined solely on the basis of symptoms rather than by medical signs. Some of the above-described conditions overlap strongly with explained conditions such as asthma. The relationship of such symptoms and syndromes to environmental exposure is often sharply debated, as is the distinction between the various syndromes. This leads to problems of what type of research should be conducted and who should conduct it. It is time to develop a comprehensive research agenda to sort out nomenclature, epidemiology, and environmental causation for these conditions, moving toward comprehensive and effective public health and clinical approaches.

Weinstein A, Britchkov M. · Section of Rheumatology, Washington Hospital Center, Washington, DC 20010, USA. · Curr Opin Rheumatol. · Pubmed #12118171 No free full text.

Abstract: In the United States, intermittent or chronic mono- or oligoarthritis, particularly affecting the knee, is the most common manifestation of late Lyme disease (LD). Lyme arthritis (LA) can usually be prevented by early treatment of acute LD. However, the erythema migrans rash may go undetected in children and in the dark skin of African Americans, leading to delayed treatment and a relatively increased incidence in LA. Virtually all untreated patients with LA have high levels of serum immunoglobulin G antibodies, and sometimes low levels of immunoglobulin M antibodies, to Borrelia burgdorferi (Bb) by ELISA and Western blot. These responses may persist for many years after antibiotic treatment, and therefore, serologic results do not accurately distinguish between active or past infection. Most patients with LA respond well to standard courses of antibiotic treatment, but a small percentage have persistent knee synovitis, in some cases possibly related to the triggering of intrasynovial autoimmunity. Other patients develop a syndrome of diffuse arthralgia, myalgia, fatigue, and subjective cognitive difficulty during or soon after LD, which persists despite antibiotic treatment. Patients with this post-treatment, post-LD syndrome were recently studied in a placebo-controlled double-blind antibiotic trial. There was no evidence of Borrelial infection in these patients by culture or detection of Bb DNA in blood or spinal fluid. Furthermore, there was no difference in responsiveness of these patients to a 3-month course of antibiotic compared with placebo treatment. Thus, LA caused by active Bb infection, post-treatment LA with persistent knee synovitis and post-LD syndrome are distinct and distinguishable clinical entities.

Natelson BH, Haghighi MH, Ponzio NM. · Departments of Neurosciences, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey 07018 USA. · Clin Diagn Lab Immunol. · Pubmed #12093668 links to  free full text

This publication has no abstract.

Fiedler N, Kipen HM. · UMDNJ-Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854, USA. · Ann N Y Acad Sci. · Pubmed #12000025 No free full text.

Abstract: Sensitivities to chemicals are characterized by symptoms in multiple organ systems in response to low-level chemical exposures. This paper reviews studies of controlled exposures to odorants and to mixtures of volatile organic compounds. Sensitive subgroups include subjects who met Cullen's 1987 criteria for multiple chemical sensitivity (MCS), Gulf War veterans with chronic fatigue syndrome and chemical sensitivity (CFS/CS), and subjects with specific self-reported sensitivities to methyl terbutyl ether (MTBE) in gasoline (MTBE-sensitive). All studies include comparison of age- and sex-matched healthy controls. Studies of olfaction did not support unusual sensitivity, defined as lower odor thresholds, among MCS subjects; however, a dose-response pattern of symptoms was observed in response to suprathreshold concentrations of phenyl ethyl alcohol. In blinded, controlled exposures to clean air, gasoline, gasoline/11% MTBE, and gasoline/15% MTBE, a threshold effect was observed with MTBE-sensitive subjects reporting significantly increased symptoms to gasoline/15% MTBE exposure. Autonomic arousal (heart and respiration rate; end-tidal CO2) in response to odor of chemical mixtures may mediate symptoms for subjects with generalized chemical sensitivities, but not for those whose sensitivities are confined to specific chemicals. For example, Gulf War veterans with CFS/CS experienced reduced end-tidal CO2 when exposed to diesel fumes, while exposure to MTBE did not produce any psychophysiologic changes in MTBE-sensitive subjects. Controlled olfactory and exposure studies reveal that significant responses can be observed in chemically sensitive subjects even when de-adaptation has not occurred. However, these studies suggest that symptoms are not necessarily accompanied by changes in physiologic arousal. Subject characteristics play a critical role in outcomes.

Clauw DJ. · Georgetown Chronic Pain and Fatigue Research Center, Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia 20007, USA. · Ann N Y Acad Sci. · Pubmed #12000024 No free full text.

Abstract: The symptom of chemical intolerance may occur in isolation, but often occurs in conjunction with other chronic symptoms such as pain, fatigue, memory disturbances, etc. This frequent clustering of symptoms in individuals has led to the definition of several chronic multisymptom syndromes, such as multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, and Gulf War illnesses. The aggregate research into these syndromes has suggested some unifying mechanisms that contribute to symptomatology. Multiple lines of evidence suggest that there is aberrant function of numerous efferent neural pathways, such as the autonomic nervous system and hypothalamic-pituitary axes, in subsets of individuals with these conditions. There is perhaps the greatest evidence for abnormal sensory processing in these syndromes, with a low "unpleasantness threshold" for multiple types of sensory stimuli. Psychological and behavioral factors are known to play a significant role in initiating or perpetuating symptoms in some persons with these illnesses. In the field of pain research, the interrelationship between physiologic and psychologic factors in symptom expression has been well studied. Using both established and novel methodologies, studies have suggested that psychologic factors such as hypervigilance and expectancy are playing a relatively minor role in most individuals with fibromyalgia and that clear evidence exists of physiologic amplification of sensory stimuli. These studies need to be extended to more sensory tasks and to larger numbers of subjects with related conditions. It is of note, though, that existing data on this spectrum of illnesses would suggest that there may be greater psychologic contributions to symptomatology if an illness is defined in part by behavior (e.g., avoidance of chemical exposures) rather than on the basis of symptoms alone.

Craig T, Kakumanu S. · Department of Medicine, Pennsylvania State University College of Medicine, Hershey 17033, USA. · Am Fam Physician. · Pubmed #11925084 links to  free full text

Abstract: Severe fatigue is a common complaint among patients. Often, the fatigue is transient or can be attributed to a definable organic illness. Some patients present with persistent and disabling fatigue, but show no abnormalities on physical examination or screening laboratory tests. In these cases, the diagnosis of chronic fatigue syndrome (CFS) should be considered. CFS is characterized by debilitating fatigue with associated myalgias, tender lymph nodes, arthralgias, chills, feverish feelings, and postexertional malaise. Diagnosis of CFS is primarily by exclusion with no definitive laboratory test or physical findings. Medical research continues to examine the many possible etiologic agents for CFS (infectious, immunologic, neurologic, and psychiatric), but the answer remains elusive. It is known that CFS is a heterogeneous disorder possibly involving an interaction of biologic systems. Similarities with fibromyalgia exist and concomitant illnesses include irritable bowel syndrome, depression, and headaches. Therefore, treatment of CFS may be variable and should be tailored to each patient. Therapy should include exercise, diet, good sleep hygiene, antidepressants, and other medications, depending on the patient's presentation.

Petzke F, Clauw DJ. · Division of Rheumatology, Immunology, and Allergy, Georgetown University Medical Center, LL Gorman Building, 3800 Reservoir Road NW, Washington, DC 20007. · Curr Rheumatol Rep. · Pubmed #11123048 No free full text.

Abstract: This review focuses on studies of the sympathetic nervous system in fibromyalgia (FM). First, a brief review of the sympathetic system, and its relationship to the human stress response, is outlined. Then various studies of functional assessment of sympathetic function in FM are highlighted. Certain methods of assessment (eg, heart rate variability, biochemical, and psychophysical responses to various stressors) that we believe to be of specific importance for future research are discussed in greater detail. Finally, findings on autonomic function in related disorders--specifically, chronic fatigue syndrome, irritable bowel syndrome, and migraine--will be briefly presented.

Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. · Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. · Pharmacol Rev. · Pubmed #11121511 links to  free full text

Abstract: The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

O'Malley PG, Jackson JL, Santoro J, Tomkins G, Balden E, Kroenke K. · Department of Medicine, Walter Reed Army Medical Center, Washington, DC, USA. · J Fam Pract. · Pubmed #10628579 No free full text.

Abstract: OBJECTIVE: To determine the efficacy of antidepressant therapy for unexplained symptoms or symptom syndromes. SEARCH STRATEGIES: We identified original studies through searching MEDLINE, EMBASE, PsycLIT, the Federal Research in Progress database, and The Cochrane Library. We also searched the bibliographies of primary and review articles for additional studies. SELECTION CRITERIA: We excluded trials of patients with neuropathic, oncologic, or degenerative joint pain. Independent duplicate review of 392 articles identified 94 relevant reports of randomized trials involving 6595 patients across 6 symptom syndromes. Independent duplicate assessment was made for inclusion and data abstraction. Meta-analysis was performed on extractable placebo-controlled data. MAIN RESULTS: Of 94 included trials, most studied either tricyclic antidepressants, antiserotonin antidepressants, selective serotonin reuptake inhibitors (SSRIs), or multiple agents for the treatment of the following syndromes: headache (50), fibromyalgia (18), functional gastrointestinal syndromes (13), idiopathic pain (11), tinnitus (2), and chronic fatigue (2). The quality of the studies was fair (mean score = 4.8 on a scale of 0 to 8). A majority of the studies (69%) demonstrated benefit for at least one outcome measure. Symptom improvement typically did not correlate with depression response in the few studies where it was assessed. Meta-analysis of all extractable data showed a substantial benefit from antidepressants: For the dichotomous outcome of improvement, the odds ratio was 3.4 (95% confidence interval [CI], 2.6 - 4.5), and for continuous outcomes, the standardized mean difference was 0.87 (95% CI, 0.59-1.14). The absolute percentage difference in improvement between the antidepressant and placebo arms was 32%, yielding a number needed to treat of 3 to improve one person's symptoms. Meta-regression indicated no differential effect across the classes of antidepressants; however, onbivariate tally tricyclic studies were associated with a greater likelihood of efficacy than SSRI studies (P = .02). CONCLUSIONS: Antidepressants can be effective for various physical symptoms and symptom syndromes. The relation of outcome to depression and the efficacy of SSRIs needs further study.

Kakumanu S, Yeager M, Craig TJ. · Pennsylvania State University, College of Medicine, Hershey, USA. · J Am Osteopath Assoc. · Pubmed #10624375 No free full text.

Abstract: The chronic fatigue syndrome is an illness of unknown etiology characterized by severe fatigue, myalgias, lymphadenopathy, arthralgias, chills, fevers, and postexertional malaise. Recognizing chronic fatigue syndrome is primarily a method of exclusion with no definitive diagnostic test or physical findings. As research continues to delve into the many possible etiologic agents for chronic fatigue syndrome--infectious, immunologic, neurologic, or psychiatric alone or in combination--the answer remains elusive. What is known is that chronic fatigue syndrome is a heterogeneous disorder very possibly involving an interaction of biological systems. Therefore, chronic fatigue syndrome may describe a large subset of patients, each exhibiting unique symptoms and serologic profiles dependent on the nature of the onset of illness and the genetic profile of individual patients.

Sorenson WG. · Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA. · Environ Health Perspect. · Pubmed #10423389 links to  free full text

Abstract: Fungi have long been known to affect human well being in various ways, including disease of essential crop plants, decay of stored foods with possible concomitant production of mycotoxins, superficial and systemic infection of human tissues, and disease associated with immune stimulation such as hypersensitivity pneumonitis and toxic pneumonitis. The spores of a large number of important fungi are less than 5 microm aerodynamic diameter, and therefore are able to enter the lungs. They also may contain significant amounts of mycotoxins. Diseases associated with inhalation of fungal spores include toxic pneumonitis, hypersensitivity pneumonitis, tremors, chronic fatigue syndrome, kidney failure, and cancer.

Amsterdam JD, Shults J, Rutherford N. · Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, United States. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #17804135 No free full text.

Abstract: OBJECTIVE: Chronic fatigue syndrome (CFS) is a debilitating disorder with prominent symptoms of malaise, fatigue, myalgia, arthralgia, and impaired concentration. The symptoms of CFS may often overlap those of Major Depressive Disorder (MDD). Treatment of CFS has generally been disappointing. We hypothesized that s-citalopram therapy may improve the symptoms of both disorders in CFS patients with co-morbid depression. METHODS: 16 patients received s-citalopram 10 mg to 20 mg daily for up to 12 weeks. Outcome measures of CFS included the Chalder Fatigue Questionnaire (CFQ), the multi-dimensional Fatigue Impact Scale (FIS), the CFS symptom rating (CFS-SR) 100 mm visual analogue scale, and the clinical global impressions severity (CGI/S) and change (CGI/C) ratings. Secondary outcomes of MDD included the Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and the CGI/S and CGI/C ratings of MDD. RESULTS: We observed reductions in the mean CFQ score (p<0.0005), FIS score (p<0.0005), and CGI/S (p<0.0005) and CGI/C (p<0.0005) ratings over time. There was a significant improvement in 5 of the 8 CFS-SR symptoms: post-exertion malaise (p=0.001), headaches (p<0.0005), un-refreshing sleep (p<0.0005), and impaired memory and concentration (p<0.0005). There was also a reduction in mean HAM-D (p<0.0005), BDI (p<0.0005), CGI/S (p=0.001) and CGI/C (p<0.0005) ratings of MDD. LIMITATIONS: The sample size was limited and the study design was not double-blind or placebo controlled. CONCLUSION: We observed a significant reduction in both CFS and co-morbid MDD symptom severity ratings, and improvement in 5 of 8 core somatic symptoms of CFS during s-citalopram therapy.

Chen KW, Hassett AL, Hou F, Staller J, Lichtbroun AS. · Department of Psychiatry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, USA. · J Altern Complement Med. · Pubmed #17109575 No free full text.

Abstract: OBJECTIVES: Although qigong is an important part of Traditional Chinese medicine (TCM) based on a philosophy similar to acupuncture, few studies of qigong exist in the Western medicine literature. To evaluate qigong therapy as a modality in treating chronic pain conditions such as fibromyalgia syndrome (FMS), we report a pilot trial of 10 women with severe FMS who experienced significant improvement after external qigong therapy (EQT). DESIGN: Ten patients with FMS completed five to seven sessions of EQT over 3 weeks with pre- and posttreatment assessment and a 3-month follow-up. Each treatment lasted approximately 40 minutes. OUTCOME MEASURES: Tender point count (TPC) and Fibromyalgia Impact Questionnaire (FIQ) were the primary measures. McGill Pain Questionnaire (MPQ), Beck Depression Inventory (BDI), anxiety, and self-efficacy were the secondary outcomes. RESULTS: Subjects demonstrated improvement in functioning, pain, and other symptoms. The mean TPC was reduced from 136.6 to 59.5 after EQT treatment; mean MPQ decreased from 27.0 to 7.2; mean FIQ from 70.1 to 37.3; and mean BDI from 24.3 to 8.3 (all p < 0.01). Many subjects reported reductions in other FMS symptoms, and two reported they were completely symptom-free. Results from the 3-month follow-up indicated some slight rebound from the post-treatment measures, but still much better than those observed at baseline. CONCLUSIONS: Treatment with EQT resulting in complete recovery for some FMS patients suggests that TCM may be very effective for treating pain and the multiplicity of symptoms associated with FMS. Larger controlled trials of this promising intervention are urgently needed.

Shoemaker RC, House DE. · Chronic Fatigue Center, 500 Market Street, Suite 103, Pocomoke City, MD 21851, USA. <> · Neurotoxicol Teratol. · Pubmed #17010568 No free full text.

Abstract: Occupants of water-damaged buildings (WDBs) with evidence of microbial amplification often describe a syndrome involving multiple organ systems, commonly referred to as "sick building syndrome" (SBS), following chronic exposure to the indoor air. Studies have demonstrated that the indoor air of WDBs often contains a complex mixture of fungi, mycotoxins, bacteria, endotoxins, antigens, lipopolysaccharides, and biologically produced volatile compounds. A case-series study with medical assessments at five time points was conducted to characterize the syndrome after a double-blinded, placebo-controlled clinical trial conducted among a group of study participants investigated the efficacy of cholestyramine (CSM) therapy. The general hypothesis of the time series study was that chronic exposure to the indoor air of WDBs is associated with SBS. Consecutive clinical patients were screened for diagnosis of SBS using criteria of exposure potential, symptoms involving at least five organ systems, and the absence of confounding factors. Twenty-eight cases signed voluntary consent forms for participation in the time-series study and provided samples of microbial contaminants from water-damaged areas in the buildings they occupied. Twenty-six participants with a group-mean duration of illness of 11 months completed examinations at all five study time points. Thirteen of those participants also agreed to complete a double-blinded, placebo-controlled clinical trial. Data from Time Point 1 indicated a group-mean of 23 out of 37 symptoms evaluated; and visual contrast sensitivity (VCS), an indicator of neurological function, was abnormally low in all participants. Measurements of matrix metalloproteinase 9 (MMP9), leptin, alpha melanocyte stimulating hormone (MSH), vascular endothelial growth factor (VEGF), immunoglobulin E (IgE), and pulmonary function were abnormal in 22, 13, 25, 14, 1, and 7 participants, respectively. Following 2 weeks of CSM therapy to enhance toxin elimination rates, measurements at Time Point 2 indicated group-means of 4 symptoms with 65% improvement in VCS at mid-spatial frequency-both statistically significant improvements relative to Time Point 1. Moderate improvements were seen in MMP9, leptin, and VEGF serum levels. The improvements in health status were maintained at Time Point 3 following a 2-week period during which CSM therapy was suspended and the participants avoid re-exposure to the WDBs. Participants reoccupied the respective WDBs for 3 days without CSM therapy, and all participants reported relapse at Time Point 4. The group-mean number of symptoms increased from 4 at Time Point 2 to 15 and VCS at mid-spatial frequency declined by 42%, both statistically significant differences relative to Time Point 2. Statistically significant differences in the group-mean levels of MMP9 and leptin relative to Time Point 2 were also observed. CSM therapy was reinstated for 2 weeks prior to assessments at Time Point 5. Measurements at Time Point 5 indicated group-means of 3 symptoms and a 69% increase in VCS, both results statistically different from those at Time Points 1 and 4. Optically corrected Snellen Distance Equivalent visual acuity scores did not vary significantly over the course of the study. Group-mean levels of MMP9 and leptin showed statistically significant improvement at Time Point 5 relative to Time Points 1 and 4, and the proportion of participants with abnormal VEGF levels was significantly lower at Time Point 5 than at Time Point 1. The number of participants at Time Point 5 with abnormal levels of MMP9, leptin, VEGF, and pulmonary function were 10, 10, 9, and 7, respectively. The level of IgE was not re-measured because of the low incidence of abnormality at Time Point 1, and MSH was not re-measured because previously published data indicated a long time course for MSH improvement. The results from the time series study supported the general study hypothesis that exposure to the indoor air of WDBs is associated with SBS. High levels of MMP9 indicated that exposure to the complex mixture of substances in the indoor air of the WDBs triggered a pro-inflammatory cytokine response. A model describing modes of action along a pathway leading to biotoxin-associated illness is presented to organize current knowledge into testable hypotheses. The model links an inflammatory response with tissue hypoxia, as indicated by abnormal levels of VEGF, and disruption of the proopiomelanocortin pathway in the hypothalamus, as evidenced by abnormalities in leptin and MSH levels. Results from the clinical trial on CSM efficacy indicated highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline in the 7 participants randomly assigned to receive 2 weeks of CSM therapy, but no improvement in the 6 participants assigned placebo therapy during that time interval. However, those 6 participants also showed a highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline following a subsequent 2-week period of CSM therapy. Because the only known benefit of CSM therapy is to enhance the elimination rates of substances that accumulate in bile by preventing re-absorption during enterohepatic re-circulation, results from the clinical trial also supported the general study hypothesis that SBS is associated with exposure to WDBs because the only relevant function of CSM is to bind and remove toxigenic compounds. Only research that focuses on the signs, symptoms, and biochemical markers of patients with persistent illness following acute and/or chronic exposure to WDBs can further the development of the model describing modes of action in the biotoxin-associated pathway and guide the development of innovative and efficacious therapeutic interventions.

Kreitman RJ, Squires DR, Stetler-Stevenson M, Noel P, FitzGerald DJ, Wilson WH, Pastan I. · Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bldg 5124b, 9000 Rockville Pike, Bethesda, MD 20892, USA. · J Clin Oncol. · Pubmed #16061911 No free full text.

Abstract: PURPOSE: To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 microg/Kg every other day x 3 doses. RESULTS: BL22 was active in HCL, with 19 complete remissions (CRs; 61%) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at > or = 40 microg/Kg every other day x 3, and 41% at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 microg/Kg IV. QOD x 3. The most common toxicities at 30 to 50 microg/Kg every other day x 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema. CONCLUSION: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response.

Lange G, Steffener J, Cook DB, Bly BM, Christodoulou C, Liu WC, Deluca J, Natelson BH. · Department of Radiology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, 07103, USA. · Neuroimage. · Pubmed #15907308 No free full text.

Abstract: Individuals with Chronic Fatigue Syndrome (CFS) often have difficulties with complex auditory information processing. In a series of two Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) studies, we compared BOLD signal changes between Controls and individuals with CFS who had documented difficulties in complex auditory information processing (Study 1) and those who did not (Study 2) in response to performance on a simple auditory monitoring and a complex auditory information processing task (mPASAT). We hypothesized that under conditions of cognitive challenge: (1) individuals with CFS who have auditory information processing difficulties will utilize frontal and parietal brain regions to a greater extent than Controls and (2) these differences will be maintained even when objective difficulties in this domain are controlled for. Using blocked design fMRI paradigms in both studies, we first presented the auditory monitoring task followed by the mPASAT. Within and between regions of interest (ROI), group analyses were performed for both studies with statistical parametric mapping (SPM99). Findings showed that individuals with CFS are able to process challenging auditory information as accurately as Controls but utilize more extensive regions of the network associated with the verbal WM system. Individuals with CFS appear to have to exert greater effort to process auditory information as effectively as demographically similar healthy adults. Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.

Baraniuk JN, Whalen G, Cunningham J, Clauw DJ. · Chronic Pain and Fatigue Research Center, Division of Rheumatology, Immunology and Allergy, Room B107, Lower Level Kober-Cogan Building, Georgetown University, 3800 Reservoir Road, N,W, Washington, DC 20007-2197, USA. · BMC Musculoskelet Disord. · Pubmed #15588296 links to  free full text

Abstract: BACKGROUND: The mechanism(s) of nociceptive dysfunction and potential roles of opioid neurotransmitters are unresolved in the chronic pain syndromes of fibromyalgia and chronic low back pain. METHODS: History and physical examinations, tender point examinations, and questionnaires were used to identify 14 fibromyalgia, 10 chronic low back pain and 6 normal control subjects. Lumbar punctures were performed. Met-enkephalin-Arg6-Phe7 (MEAP) and nociceptin immunoreactive materials were measured in the cerebrospinal fluid by radioimmunoassays. RESULTS: Fibromyalgia (117.6 pg/ml; 85.9 to 149.4; mean, 95% C.I.; p = 0.009) and low back pain (92.3 pg/ml; 56.9 to 127.7; p = 0.049) groups had significantly higher MEAP than the normal control group (35.7 pg/ml; 15.0 to 56.5). MEAP was inversely correlated to systemic pain thresholds. Nociceptin was not different between groups. Systemic Complaints questionnaire responses were significantly ranked as fibromyalgia > back pain > normal. SF-36 domains demonstrated severe disability for the low back pain group, intermediate results in fibromyalgia, and high function in the normal group. CONCLUSIONS: Fibromyalgia was distinguished by higher cerebrospinal fluid MEAP, systemic complaints, and manual tender points; intermediate SF-36 scores; and lower pain thresholds compared to the low back pain and normal groups. MEAP and systemic pain thresholds were inversely correlated in low back pain subjects. Central nervous system opioid dysfunction may contribute to pain in fibromyalgia.

Dang CV. · Ross Research Bldg, Room 1025, Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205, USA. · JAMA. · Pubmed #11495622 No free full text.

Abstract: Macrocytic anemia occurring in patients with fatigue suggests numerous diagnoses, ranging from nutritional deficiencies to a myelodysplastic syndrome. A careful history-taking is critically important for recognition of runner's anemia, which is due to plasma volume expansion, with hemolysis from the pounding of feet on pavement, and hemoglobinuria. Gastrointestinal blood loss may also contribute to anemia in long-distance runners. Early recognition of runner's anemia in patients with a complex presentation of anemia is important in circumventing many diagnostic tests. Runner's anemia should be considered when, amidst a constellation of signs and symptoms, mild anemia is well tolerated by an avid runner.

Rowe PC, Calkins H, DeBusk K, McKenzie R, Anand R, Sharma G, Cuccherini BA, Soto N, Hohman P, Snader S, Lucas KE, Wolff M, Straus SE. · Departments of Pediatrics and Medicine, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287, USA. · JAMA. · Pubmed #11150109 links to  free full text

Abstract: CONTEXT: Patients with chronic fatigue syndrome (CFS) are more likely than healthy persons to develop neurally mediated hypotension (NMH) in response to prolonged orthostatic stress. OBJECTIVE: To examine the efficacy of fludrocortisone acetate as monotherapy for adults with both CFS and NMH. DESIGN: Randomized, double-blind, placebo-controlled trial conducted between March 1996 and February 1999. SETTING: Two tertiary referral centers in the United States. PATIENTS: One hundred individuals aged 18 to 50 years who satisfied Centers for Disease Control and Prevention criteria for CFS and had NMH provoked during a 2-stage tilt-table test. Eighty-three subjects had adequate outcome data to assess efficacy. INTERVENTION: Subjects were randomly assigned to receive fludrocortisone acetate, titrated to 0.1 mg/d (n = 50) or matching placebo (n = 50) for 9 weeks, followed by 2 weeks of observation after discontinuation of therapy. MAIN OUTCOME MEASURE: Proportion of subjects in each group with at least a 15-point improvement on a 100-point global wellness scale. RESULTS: Baseline demographic and illness characteristics between the groups were similar; CFS had been present for at least 3 years in 71%. Using an intention-to-treat analysis, 7 subjects (14%) treated with fludrocortisone experienced at least a 15-point improvement in their wellness scores compared with 5 (10%) among placebo recipients (P =.76). No differences were observed in several other symptom scores or in the proportion with normal follow-up tilt test results at the end of the treatment period. CONCLUSIONS: In our study of adults with CFS, fludrocortisone as monotherapy for NMH was no more efficacious than placebo for amelioration of symptoms. Failure to identify symptomatic improvement with fludrocortisone does not disprove the hypothesis that NMH could be contributing to some of the symptoms of CFS. Further studies are needed to determine whether other medications or combination therapy are more effective in treating orthostatic intolerance in patients with CFS.

McKenzie R, Reynolds JC, O'Fallon A, Dale J, Deloria M, Blackwelder W, Straus SE. · Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, Maryland , USA. · J Rheumatol. · Pubmed #10990237 No free full text.

Abstract: OBJECTIVE: While osteoporosis and bone fractures are clearly recognized side effects of high dose glucocorticoids, the effect of low dose glucocorticoids remains controversial. We investigated the effect of 3 months of low dose hydrocortisone on bone mineral density (BMD). METHODS: Subjects, 18 to 55 years old with chronic fatigue syndrome and no medical or psychiatric illness requiring medication, were randomized in a double blind, placebo controlled trial to receive oral hydrocortisone, 13 mg/m2 body surface area every morning and 3 mg/m2 every afternoon (25 to 35 mg/day, equivalent to about 7.5 mg prednisone/day) or placebo for 12 weeks. Before and after treatment BMD of the lumbar spine was measured by dual energy x-ray absorptiometry. RESULTS: We studied 23 subjects (19 women, 4 men). For the 11 hydrocortisone recipients there was a mean decrease in BMD: mean change from baseline of the lateral spine was -2.0% (95% CI -3.5 to -0.6. p = 0.03) and mean change of the anteroposterior spine was -0.8% (95% CI -1.5 to -0.1, p = 0.06). Corresponding changes for the 12 placebo recipients were +1.0% (95% CI -1.0 to 3.0, p = 0.34) and +0.2% (95% CI -1.4 to 1.5, p = 0.76). CONCLUSION: A 12 week course of low dose glucocorticoids given to ambulatory subjects with chronic fatigue syndrome was associated with a decrease in BMD of the lumbar spine. This decrease was statistically significant in lateral spine measurements and nearly so in anteroposterior spine measurements.

Caccappolo E, Kipen H, Kelly-McNeil K, Knasko S, Hamer RM, Natelson B, Fiedler N. · University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Piscataway 08854, USA. · J Occup Environ Med. · Pubmed #10874656 No free full text.

Abstract: Patients with multiple chemical sensitivities (MCS) often report heightened sensitivity to odors. Odor detection thresholds to phenyl ethyl alcohol (PEA) and pyridine (PYR) were evaluated as a measure of odor sensitivity for 33 MCS subjects, 13 chronic fatigue syndrome subjects, 16 asthmatic subjects, and 27 healthy controls. Odor identification ability (based on University of Pennsylvania Smell Identification Test results) and ratings in response to four suprathreshold levels of PEA and PYR were also assessed. Odor detection thresholds for PEA and PYR and odor identification ability were equivalent for all groups; however, when exposed to suprathreshold concentrations of PEA, MCS subjects reported significantly more trigeminal symptoms and lower esthetic ratings of PEA. No group differences were found in response to suprathreshold concentrations of PYR. In summary, MCS subjects did not demonstrate lower olfactory threshold sensitivity or enhanced ability to identify odors accurately. Furthermore, they were differentiated from the other groups in their symptomatic and esthetic ratings of PEA, but not PYR.