Athough only given the name "chronic fatigue syndrome" (CFS) with specific criteria by the Centers for Disease Control (CDC),1 the complex of symptoms of CFS in the modern era was reported from 1934 in Los Angeles.2 This outbreak of "mild poliomyelitis" had atypical symptoms of sensory, vasomotor, and arthritic changes without atrophy or loss of tendon reflexes. Further, there were only slight temperature elevations, pain aggravated by exercise, and miscellaneous other symptoms, including muscle tenderness, easy fatigability, and crying spells. This was followed by reports from Akureyi, Iceland; Denmark; the United Kingdom; and the United States. Labels given to this illness have included benign myalgic encephalitis, chronic mononucleosislike syndrome, chronic Epstein-Barr-Virus (EBV) syndrome, and fibrositis. Unfortunately, the most popular label, EBV syndrome, was later disproven.3
This initial draft criteria1 included a required history of a minimum of 6 months of increased fatigue with either eight of 11 minor criteria or six of 11 criteria plus two of three physical signs. Minor criteria included fever, sore throat, painful lymph nodes, muscle weakness, prolonged fatigue after exercise previously tolerated, headaches, migratory arthralgia, neuropsychological complaints, sleep disturbance, and development of symptoms over a few hours to a few days. Physical signs included low-grade fever, nonexudative pharyngitis, and palpable or tender lymph nodes. As a consequence of research results, these criteria were revised in 1994.4 At present, they are (1) persistent or relapsing chronic fatigue that is of new or definite onset with (2) concurrent occurrence of four or more symptoms that have followed onset of the fatigue and persisted or recurred for at least 6 months. Those four are from a list of the following: (1) impairment in short-term memory or concentration, (2) sore throat, (3) tender lymph nodes, (4) muscle pain, (5) multi-joint pain without swelling or redness, (6) headaches, (7) unrefreshing sleep, and (8) post-exertional malaise lasting more than 24 hours. Thie definition was further reevaluated this past year by Komaroff who suggested eliminating three symptoms (muscle weakness, arthralgias, and sleep difficulty) but substituting two others with discriminatory power - 'anorexia and nausea.5 The deletion of the physical examination criteria was suggested because of infrequent contribution to successful diagnosis. Another recent report showed that CDC definition may only identify CFS patients with chronic fatigue and poorer prognosis. Results from a sample of 495 patients suggested that coexistence of dysthymia was associated with poorer outcome.8
Fibromyalgia (FM) overlaps with CFS in terms of rates of fatigue, myalgia, sleep disturbance, and mood problems, among other criteria.7 FM focuses more, by definition, on a 3» month history of generalized aches and stiffness with a minimum of at least six typical and reproducible tender points8; there is no requirement for fatigue. Other criteria for FM are headaches, neuropsychiatrie symptoms, subjective joint swelling, numbness, irritable bowel syndrome, and modulation of symptoms by activity, weather, and stress. As a consequence, in the discussion below, results for both FM and CFS will be presented.
This article clearly differentiates chronic fatigue syndrome and fibromyalgia, discussed as "chronic fatigue and related immune deficiency syndromes" (CFIDS) [from depression! in terms of physical signs and symptoms, sleep, fatigue, memory, biological parameters, brain imaging, immunology, and treatment. The focus will be on practical applications of research findings with a focus on future ability to show clear biologic separation and specific treatment.
PHYSICAL SIGNS AND SYMPTOMS
Typically, patients with major depressive disorder (MDD) have no specific signs or symptoms. In contrast, CFIDS patients have been reported9,10 to have multiple findings. Some, as expected, relate to criteria of the diagnosis, eg, myalgia (20% to 95%), pharyngitis (50% to 75%), and painful lymph nodes (30% to 40%). However, many others are independent, including visual blurring (50% to 60%), nausea (50% to 60%), nocturia (30% to 40%), night sweats (30% to 40%), abnormal Romberg balanced test results (10% to 20%), and hepatomegaly (5% to 20%). Of particular interest have been abnormal ophthalmic reports.11·12 These have included findings of disturbed near and distant vision (50% to 60%), photophobia (70%), black spots (35%), and halos (25%). Evaluations have discovered a 76% rate of preocular tear film abnormalities, a 72% rate of reduced accommodation for age, and a 32% rate of visual field defects.
Insomnia and hypersomnia are well-known symptoms for MDD.13 The insomniac patient has been defined as reduced total sleep time, reduced sleep efficiency, reduced stage 3 and 4 sleep, increased REM density, and redistribution of REM sleep toward sleep onset. One of the most replicated findings is early-onset REM sleep (prior to 90 minutes). CFIDS patients, as a criteria of diagnosis, report a 90% rate of sleep difficulties.10 However, some studies have shown presence of a non-REM sleep anomaly at a greater rate in these patients than in controls (2.4 vs 0.914; 2.2 vs 1.215). Another report found this abnormality in 36% of CFS patients,16 although it has not always been replicated.17
Fatigue in CFIDS is a key criteria related to the complaint of being "tired," with an incidence of post-exertional malaise of 50% to 80%. 10 Before CFIDS, these patients had been physically active. At this time, although initially feeling well and energized after exercise, within 6 to 24 hours most patients notice the onset of extreme fatigue, loss of cognition, fever, and sore throats requiring retirement to bed. Muscle fiber has been found anatomically to be normal but with reduced exercise tolerance (8.1 vs 11.3 minutes).18 CNS exhaustion has been defined from results that indicated that after exhaustion of peripheral nervous stimulation, there still remained added force in the muscles of CFS patients as contrasted with controls (80% vs 15%).19 Increased CNS fatigue led to". . . a progressive failure to fully activate the muscle during this strenuous exercise." Other correlated findings include deficiencies in carnitine, an essential regulator of mitochondrial metabolism.20 Another report recently found that in terms of aerobic power, CFS patients had low fitness levels and a low range of maximal oxidative capacity.21
Memory impairment has been commonly reported both in MDD and CFIDS. Regarding short-term memory, consensus of research focuses on the fact that deficits are more of a problem with attention than memory storage. A review22 showed that CFIDS patients have had particular problems, in contrast to controls, with the Stroop Color/Word test, Digit Symbol testing, and Trail Making B test. One study that contrasted CFS and MDD indicated that paired associate learning was much worse in CFS than MDD. Results were interpreted to indicate that MDD deficits are because of reduced confidence and reaction time, whereas CFS deficits were true deficits in memory consolidation.23 The most recent report showed CFS patients to have slow decision-making speed, and to have more trouble than controls sustaining attention to figurai and verbal stimuli.24 In contrast with depressed patients, who have more trouble with figures than verbal stimuli, CFS patients are equally impaired in both areas.
In terms of neurochemistry, although urinary methylhydroxyphenolglycol (MHPG) levels (mg/24 hours) have been frequently found to be lower in MDD, plasma studies of MHPG in melancholia have generally found higher levels than in controls.25,26 However, in CFS, mean plasma MHPG has been reported as lower than in controls (8.3 vs 10.8; P<0.002).27 With regard to serotonin, there appear to be a number of contrasts between MDD and CFIDS. Patients with MDD have been reported to have, in contrast to controls, lower plasma 5HIAA,28 lower cerebrospinal fluid 5HIAA,25 and lower platelet Imipramine binding.29 In contrast, CFS patients have been reported to have greater plasma 5HIAA than controls (67.3 vs 37.3; P=0.002),28 higher cerebrospinal fluid 5HIAA (111.1 vs 95. 1),28 and higher platelet IB in some30 but not all studies.31 More recently, a study contrasting response in age, weight, sex, and menstrual cycle-matched samples of 10 CFS, 15 MDD, and 25 control subjects indicated that prolactin responses to the 5HT-releasing agent fenfluramine were highest in CFS patients, followed by controls, and then by MDD patients (P=0.01).32 Finally, in contrast to only 6% of blood donors, 74% of FM patients have been reported to have anti-serotonin antibodies in their sera.33 This finding was recently replicated with a 77% rate of anti-5HT antibodies in FM, in contrast to only 19% in patients with acute eosinophilia-myalgia syndrome (EMS) and 18% in controls.34
Among the most replicated findings in MDD are those of abnormalities in the hypothalamicpituitary-adrenal (HPA) axis. These include nypercortisolémia, elevated urinary-free cortisol, and exaggerated Cortisol response to corticotropin.25 In contrast, CFS patients have been found to have lower plasma Cortisol (89 vs 148 mmol/L; P<.01) and lower 24-hour urinary free Cortisol (2.9 vs 8.9 mmol/L; P<.04) than controls, and a reduction in responsiveness to corticotropin.35 In the only direct comparison study,32 levels of circulating Cortisol levels were highest in depressed patients, followed by normal controls, and finally, in CFS patients (P=.01). Thus, it may be possible in the future to easily differentiate CFS patients from MDD patients biologically, with a simple combination of a plasma Cortisol and a serotonin test.
Brain imaging studies have proliferated in recent years including both positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Frontal hypoperfusion in PET scans have been reported in both MDD and CFS.36'37 Other studies in MDD have found left anterior prefrontal cortex hypoperfusion and temporal hypoperfusion36; CFS patients may also have mid-brain hypoperfusion.37 SPECT comparison studies have found, by degree, more severe findings in CFS than MDD.38 The mideerebral uptake index, an objective measurement reflecting radionuclide uptake in the brain, was found to be reduced in CFS (0.667) and in AIDS (0.650) in contrast to depression (0.731) and controls (0.716). White matter abnormalities on magnetic resonance images have not been found with any regularity in CFS patients.39
Although it might seem that CFIDS could easily be separated from MDD on the basis of laboratory indices of immune function, this is not the case. Differences are those of degree rather than absolute. Tests of mitogen-induced lymphocyte stimulation with PHA (phytohemagglutinin) were reduced in six of 14 tests in MDD.40 A comparison study reported PHA responsiveness to be 25% lower in CFS than in either MDD or control subjects.41 Natural killer cell function of lymphocytes was reduced in five of seven studies in severe MDD.40 CFS studies have found 70% reductions in lytic units of natural killer cells, ie, 39 for CFS versus 120 for controls.42
Thus, diagnostic differentiation of CFS from MDD should be focused on physical signs and symptoms. Possibilities for a future composite include memory test differences, sleep EEG, serotonin function indices, and plasma Cortisol testing.
First, the obvious difference between treatment MDD and treatment of CFS is that non-psychotropic drugs have been used with some success in CFS. These include antivirals, immune modifiers, and ion flow treatments.43 Antiviral agents have included acyclovir, immunoglobulins, essential fatty acids, and adenosine. Acyclovir, based on the theory of causation of CFS because of EBV, failed clinically.44 Two of three studies using IgG were successful45·46; a minimum dose of 2 g/kg/mo appear to be important. At that dose, improvements were noted in Quality of Life visual analogue scale (41%), Hamilton Depression Rating Scale (42%), and in CD4 count (37%). Essential fatty acids at a dose of two capsules four times per day for 3 months led to improvement in fatigue and myalgia rather than in depression and concentration.47 Adenosine was beneficial in uncontrolled reports.48
The list of immune modifiers includes polyribonucleotide (Ampligen), LEFAC (liver extract, folic acid, and B12), Kutapressin (liver derivative complex), interferon, interleukin-2, and transfer factor. Ampligen is mismatched double-stranded RNA, which appears to regulate expression of interferon, interleukin, and transfer necrosis factor while activating intracellular pathways that are antiviral and enhance immune resistance. Two studies49,50 have been completed that administered up to 400 mg twice per week for 24 weeks; a placebo-controlled study showed improvements in overall functioning, perceived cognitive deficit, and exercise duration. LEFAC did not lead to significant improvement in a 1-week doubleblind trial; however, because CFS symptoms may require months to improve, it is likely that this was too short a trial.51 The follow-up open trial showed much more success. Kutapressin, a mixture of polypeptides that may be a bradykinin potentiator, has been reported to be successful in 75% of CFS patients given a mean of 33 injections at an initial rate of one per week, followed by three per week.52 A single study of oral interferon at a dose greater than 1500 IU/day produced rapid relief of pain over 5 days with a much slower change in muscle tone.53 Other case and open studies involving interleukin-2, transfer factor, and magnesium showed initial success but have failed in attempts at replication.
An unusual treatment for CFS was based on the hypothesis that this disorder might be related to neurally mediated hypotension.54 Abnormal responses to upright tilt testing were found in 22 of 23 patients and four of 14 control subjects (P<.001). Treatment was a general instruction to increase dietary salt intake taken by over 90% in combination with 0.1 mg of fludrocortisone. Of 19 patients treated for at least 2 weeks, nine reported subjective improvement or remission. Although interesting and different, the measures used are too general to establish a new therapy, and this approach needs replication.
Psychotropics In Chronic Fatigue Syndrome
Regarding the use of psychotropics, it is well known that tertiary tricyclic antidepressants, eg, amitriptyline, produce relief of major depression generally at doses between 150 and 300 mg/day.25 As previously reviewed, patients with CFIDS often improve at doses as low as 75 mg/day.55 In contrast to MDD, there may be a differentiation in symptom response in CFS. Serotonin-based treatments may be more effective for immune, pain, and global responses; norepinephrine-based treatments may be better for the depressive symptoms associated with CFIDS. In terms of tricyclic antidepressants, Imipramine failed at a dose of 75 mg/day for 12 weeks.56 Amitriptyline has been reported successful in most studies, even at 50 mg/day, although the most recent result at 25 mg/day was not very successful.16·5759 Improvement was found in morning stiffness, myalgia, fatigue, tender points, and pain tolerance. Nortriptyline, in a single A-B-A-B controlled case study, produced significant improvement in depression and overall CFIDS ratings.60 Maprotiline was contrasted to clomipramine in a controlled study in FM; maprotiline was better at improving depression, whereas clomipramine was better at reducing pain.61 Bupropion, similarly, with specific effects to block reuptake of norepinephrine and dopamine, has been found to be excellent for improvement of depression but not for immune indices.62,63
Regarding the selective serotonin reuptake inhibitors, results are available concerning fluoxetine, sertraline, and Citalopram. After initially promising case reports at a dose of 20 to 40 mg/day, fluoxetine appears, in controlled open studies for up to 12 weeks, to produce benefit for both global functioning and natural killer cell values.64"67 More recently, two double-blind studies, one in FM68 and one in CFS69 of only 6 weeks, did not show the same success. There are three reports available concerning sertraline; all are open studies that agree on significant improvement in multiple areas.55,70·71 Improvement has been found in fatigue, myalgia, sleep disturbances, depression, pain, and global ratings. One of these studies clearly documented that improvement in MF symptoms was independent of the drug's efficacy as an antidepressant; thus, the biological activity of sertraline was directly responsible for its efficacy in the immune disorder.70 Citalopram has failed in one double-blind, placebo-controlled study.72 Finally, venlafaxine, perhaps because of its balanced effect to block reuptake of both norepinephrine and serotonin, was reported effective in ease reports and one open trial in improving both depression and pain/immune parameters.73,74 We have preliminary evidence in a small series of three patients that the serotonin receptor modulator, nefazodone, in select patients, may reduce pain and improve sleep, and memory. See the Table for more details on study results.
Other reports have been presented on monoamine oxidase inhibitors, alprazolam, and basic molecules.55 One report indicated that phenelzine at 15 to 30 mg/day produced good responses in 60% of patients, with 52% having prolonged improvement.76 Alprazolam at 3.0 mg/day maximum dose had no significant effect on any clinical measures.76 Basic molecules have included s-adenosylmethionine (SAM), 5hydroxytryptophan (5HTP), and lithium. SAM, a methyl group donor that has been used successfully in the treatment of depression, was administered at a dose of 200 mg/day intramuscularly for 21 days and led to significant reductions in both trigger points and Hamilton Depression Rating Scale.77 5HTP, a precursor of serotonin, given for 1 month in two controlled studies at a dose of 100 mg three times per day, reduced numbers of tender points by over 40% and improved measures of fatigue and sleep.78 Lithium augmentation of tricyclic antidepressants at serum levels of 0.5 to 1.1 meq/L led to improvement in stiffness and pain in three cases.79
Thus, in terms of treatment of CFIDS, in contrast to MDD, nonpsychotropics, eg, IgG, may be effective, particularly if the patient's serum levels are low. Also, when available, Ampligen may be of universal benefit, and in some patients, Kutapressin may be of value. Regarding psychotropics, if the patient's focus is on fatigue or depressive symptoms, bupropion and/or low-dose tricyclic antidepressants may be successful. In contrast, if the CFIDS symptom picture is more of global dysfunction and immune difficulties, a serotonergic approach with sertraline may be particularly beneficial. An additional bonus to use of sertraline may be its benefits on cognitive functioning.80 Venlafaxine may be of value in the combination of symptoms as another alternative.
When depressive symptoms co-occur with those of chronic fatigue syndrome, an accurate differentiation can usually be accomplished by focusing on diagnostic criteria. The presence of multiple physical signs and symptoms in CFIDS may of great value. In terms of laboratory testing, a single helpful test may be measuring plasma Cortisol, which is usually high in depression and low in CFIDS. Other future work may focus also on the combination of plasma Cortisol with an index of serotonin function, which is high in CFIDS and low in depression. Future research may be helpful in developing other immune or brain imaging areas of differentiation. In terms of treatment, for the patient with significant depression or MDD with CFIDS, one should think of the noradrenergic approach of bupropion or low-dose tricyclic antidepressants in combination with a selective serotonin reuptake inhibitor, eg, sertraline, to aid improvement of global, pain, and immunologic parameters. Future research may point to benefits with these and other antidepressants, eg, venlafaxine, nefazodone.
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Psychotropics In Chronic Fatigue Syndrome