MEETING REPORT: Nevada Chronic Fatigue Syndrome Consensus Conference Journal: J of Chronic Fatigue Syndrome, Vol. 9 (1/2) 2001, pp. 53-62 Authors: Paul H. Levine, MD; Nancy Klimas, MD; Roseanne Armitage, PhD; Robert Fredericks, MD; Julian Stewart, MD, PhD; William Torch, MD; Stanley Schwartz, MD; Robert Suhadolnik, PhD; Nancy L. Reichenbach; Lea Rhodes Affiliation: The authors are the members of the Nevada Consensus Panel. Address correspondence to: Paul H. Levine, MD, Department of Epidemiology and Biostatistics, The George Washington University School of Public Health and Health Services, Ross Hall 120, 2300 Eye Street NW, Washington, DC 20037. The Nevada Consensus Panel was sponsored by the Nevada CFS Association and the Pioneer Foundation, non-profit organizations committed to advancing the methodologies used by clinicians to better diagnose, manage, treat, and rehabilitate patients with CFS. Chronic fatigue syndrome (CFS), a debilitating disorder of unknown etiology, has been the subject of a growing body of literature as information accumulates on the epidemiology, pathogenesis, and disease markers. For the practicing physician and patient, however, there are major obstacles to distinguishing well-documented management techniques that are reliable and applicable to most patients. The challenge for the physician is whether to rely upon reportedly successful techniques that have not been confirmed in the literature or which may only be useful in a subset of patients that have not been well characterized. In order to begin the process of developing a manual based on peer-reviewed literature, a consensus panel was conducted March 16-18, 2000 to address the question: "Which of the research tools and techniques currently under evaluation are now clinically useful in the management of patients with CFS?" The consensus panel consisted of the following members: Nancy Klimas, MD, and Paul H. Levine, MD, co-chairs; Roseanne Armitage, PhD, Robert Fredericks, MD, Lea Rhodes, Julian Stewart, MD, PhD, William Torch, MD, Stanley Schwartz, MD, and Robert Suhadolnik, PhD, and Nancy L. Reichenbach was executive secretary. It was not feasible over the two-day session to discuss every CFS-related symptom in the same detail. Consequently, particular attention was devoted to those symptoms which appeared to have the most concordant information leading to conclusions that can be based on the most consistent data in the peer-reviewed literature. Neuropsychiatric problems and pain management were not discussed since they were to he the subject of conferences planned by The CFIDS Association of America and future meetings of the Nevada group. Rehabilitation was discussed by a separate concurrent panel, and a number of recommendations immediately applicable to clinical practice were reviewed. These will be published in a separate document. At the outset, the panel noted that one of the major problems in providing generalized guidelines for clinician management of CFS is the heterogeneity of the disorder. A number of studies suggest that the 1994 CDC-sponsored revision of the original 1988 case definition, while broadening the criteria for inclusion of patients into the CFS umbrella, increased the heterogeneity. It was strongly suggested by the panel that subtypes be defined using factor analysis, as has been used in the subgrouping of Gulf War Syndrome (1). In spite of the problems created by the current case definition, recommendations were made when appropriate according to criteria adapted from earlier consensus panels that have undertaken the evaluation of data in the literature (Table I ). The emphasis of this particular consensus panel was on laboratory evaluation and the management of sleep disorders, orthostatic hypotension and endocrine abnormalities. LABORATORY EVALUATION Until recently, the role of the laboratory has been considered to be restricted solely to excluding other disorders that could cause chronic fatigue. A ruling by the Social Security Administration in June 1999 allowed immune system abnormalities, abnormal Epstein-Barr virus antibody, and other laboratory tests to support the presence of a medically determinable condition in patients seeking disability. It should be emphasized that CFS may be severe and disabling without any significant physical findings or laboratory abnormalities. A number of virologic and immunologic abnormalities may be found in CFS patients, but none are consistent and, therefore, no single test at the present time can be considered diagnostic for CFS. Part of the problem results from the heterogeneity of CFS and, as noted above, it has become readily apparent that subgroups need to be identified. The identification of useful subgroups remains in question, although reports suggest that classification by the nature of onset (acute vs. gradual) and symptom complex (such as infectious, i.e., sore throat, fever, Iymphadenopathy, vs. non-infectious) would be useful. One laboratory test that the panel believed had the most promise was the RNase L test. The overactive response of the antiviral defense pathway in people with CFS has been well documented (2,3). These laboratory markers have been utilized in clinical trials (4,5) and include increased activity of RNase L and the presence of a low molecular weight (LMW) form of RNase L that is more active than the naturally occurring form. Several thousand CFS patients have been tested (using PBMC) for the LMW RNase L, and the results are among those pointing to the important decrease in specificity with the 1994 case definition: Eighty percent of patients meeting the 1988 case definition were positive in one study vs. 60 percent of those meeting the 1994 case definition (K. DeMeirlier, personal communication). The presence of the LMW RNase L is a quantitative measure; it correlates well with severity of CFS symptoms and with low NK cell function. It is consistent with a state of chronic immune activation, but has not been found in rheumatoid arthritis, lupus erythematosus, HIV infection, fibromyalgia, or depression (K. DeMeirlier, personal communication). In some cases of multiple sclerosis, the LMW RNase L is evident (D. Peterson, personal communications). Regarding virologic and immunologic markers, the literature has been confusing and extensive discussion led to the following recommendations: I. Epstein-Barr virus serology does not provide valuable information for the physician and is not recommended (although as noted above, elevated antibody titers do support the presence of a medically determinable illness in the Social Security evaluation). 2. No evidence currently exists that anti-viral therapy has a beneficial effect. Treatment for mycoplasma, an unproven etiologic agent, should not be given until the results of a large study of mycoplasma treatment in Gulf War Syndrome is completed. 3. While HHV-6 may play a role in exacerbating CFS and chronic Epstein-Barr virus infection may occur, although rarely, an infectious disease expert should be consulted before treatment is initiated on the basis of viral assays. 4. In addition to RNase L, other measures of immune activation, such as natural killer cell function and T-cell activation (CD2CD26, CD8DR cell markers) may play a role in supporting the diagnosis of CFS. As with all use of biological testing, however, it is critical that the laboratories used for the above tests should have proven records and stringent quality standards. SLEEP DISORDERS Sleep abnormalities in CFS are widely recognized, but often are not well characterized. Fragmented sleep (periods of wakefulness throughout the sleep period) and lack of deep stage sleep are very common in CFS patients. True insomnia (inability to fall asleep) is uncommon, although patients may have delayed sleep onset because of a disrupted circadian rhythm. Non-restorative sleep with multiple awakenings and no deep slow wave sleep is characteristic of CFS. The absence of these essential components of sleep is important for immune function, serotonin, and hormonal balance. The sleep pattern characteristic of CFS is very different from that experienced by individuals with depression or fibromyalgia. Assessment of sleep abnormalities in CFS is essential because treatment implications are different for CFS without a concurrent sleep disorder. The panel recommended that educational programs be developed for physicians to explain the biological necessity for sleep in CFS. A detailed history and structured sleep interviews are most valuable for physicians to use in assessing the sleep abnormalities in CFS. Standardized and validated test instruments (such as the Pittsburgh Sleep Quality Index) are useful in identifying primary sleep disturbances without the need for expensive sleep lab studies. A sleep laboratory study at an accredited sleep disorder center is indicated only if a primary sleep disorder is evident on the sleep interview. Body motion sensors, such as Actigraphs, can also be very useful. Behavioral management can be very effective in dealing with sleep disorders in CFS, including a regular daily sleep/wake cycle, hot baths before sleep, and short naps. A hot bath 90 minutes before sleep (not at bedtime) is a useful tool; declining body temperature is a strong sleep inducer. Standard neurological assessment of CFS is very expensive. It utilizes two insensitive tools in this population (MRI and standard EEG), which can miss even severe cases of encephalitis-although both tools can be useful in ruling out other illnesses. More sensitive research tools are available, such as quantitative EEG that demonstrate abnormalities not present in MRI scans. Regarding the pharmacologic treatment of sleep disorders, some medications commonly used in CFS treatment, including Klonopin, Flexeril and selective serotonin reuptake inhibitors or SSRIs (most notably fluoxetine Prozac) may actually worsen sleep fragmentation. Tricyclic antidepressants and behavioral management as noted above are helpful sleep treatments in CFS patients. ORTHOSTATIC INTOLERANCE Orthostatic intolerance, or the inability to maintain adequate cerebral blood flow while standing upright, is another well-described abnormality in CFS although it is not seen with the same frequency as sleep disorders. Circulatory abnormalities have been well described in patients with CFS (6-9), and important information has also been obtained from studies of patients with other disorders sharing the same type of orthostatic disability seen in CFS patients (10). The term neurally-mediated hypotension, which can be readily applied to vasovagal faint, cannot be consistently applied to chronic orthostatic intolerance (COI) in which hypotension does not always occur. Several forms of orthostatic intolerance are seen in patients with CFS and include: 1. Chronic orthostatic intolerance, which includes the defining symptoms of lightheadness in all patients with a high incidence of altered vision (blurring, 'white outs,' 'black-outs' ), fatigue, nausea, palpitations, headache, tremulousness, difficulty breathing or swallowing, sweating, pallor, and other vasomotor symptoms; 2. Vasovagal faint, which is associated with loss of conciousness, nausea, dizziness, heat, heavy breathing and sweatiness associated with an abrupt decrease in both blood pressure and heart rate. Thus COI, the form seen in CFS patients is most important to treat. COI is characterized by tachycardia, whereas vasovagal faint and neurally mediated hypotension are associated with bradycardia. COI-POTS (postural orthostatic tachycardia syndrome) is often associated with an unusual amount of pooling in the dependent extremities and is associated with cyanosis. This pooling can be documented by measuring leg circumference before and after standing 30 minutes. Evaluation of COI should begin with a careful history and physical examination should include resting heart rate and orthostatic heart rate. A tilt table test is generally not required but is indicated if the patient has a strong history for orthostatic intolerance (lightheadedness, fainting, pallor when upright) or has evidence for upright tachycardia (> 30 beats/min). Referral should also be made if the patient has upright orthostatic symptoms using a 5-10 minute period of standing after being supine with blood pressure and heart rate taken once per minute. It is also important to note that tilt table patterns in children are not the same as in adults. Regarding treatment for COI, fludrocortisone has been shown to have no significantly greater effect than placebo (11) but it may be useful in some patients. Current approaches to treatment include conservative management such as the use of support hose and avoiding standing for long periods of time. ENDOCRINE DYSFUNCTION The literature on HPA axis dysfunction in CFS reveals low plasma and urinary cortisol, elevated basal evening corticotropin, enhanced adrenal sensitivity to corticotropin with a reduced maximal response, and normal CSF corticotropin releasing hormone (CRH) levels (12). Rather than suggest a specific work-up to document a CFS-related endocrine abnormality, the panel suggested that the appropriate endocrine work-up in CFS patients is to exclude other illnesses, i.e., hypothyroidism (by CBC and TSH) and Addison's disease (fasting cortisol). Among the reasons for not considering a CFS-specific endocrine work-up is the failure of therapeutic intervention with cortisol to show improvement that reached statistical significance (13). Therefore, particularly with the inherent danger of prolonged treatment, steroid treatment (14) cannot be recommended. Similarly, a trial with fludrocortisone (11) in neurally mediated hypotension and a Phase I trial of growth hormone ( 15) did not show significant improvement. COMMENT A number of important issues emerged during the panel discussion that deserve mention as possibilities for application in the near future. Definitive statements could not be made, however, since the field currently lacks one of the important characteristics that have yielded such significant advances in the field of cancer treatment - multicenter longitudinal trials. For multicenter longitudinal trial in CFS, unlike cancer, it is appropriate to monitor natural history and clinical markers in addition to intervention trials with medications currently in use. An emphasis on identifying subgroups in these studies is important since preliminary studies suggest, for example, that CFS patients with the LMW RNase L are more likely to respond to Ampligen (4, K. DeMeirlier, personal communication). 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