Repetitive transcranial magnetic stimulation ameliorates symptoms in patients with myalgic encephalomyelitis (chronic fatigue syndrome).

Background: Central nervous system dysfunction has been postulated to cause debilitating symptoms in patients with myalgic encephalomyelitis (ME) (originally called "chronic fatigue syndrome"). Repetitive transcranial magnetic stimulation (rTMS) is a newly developed neuromodulatory procedure and has been suggested to facilitate the cortical neural activity. Methods: This study enrolled 30 patients with ME (7 men and 23 women) with a mean age of 39 ± 12 years, who received rTMS treatment of both the left dorsolateral prefrontal cortex and the left primary motor area in the brain. The performance status score (0-9) for restricting activities of daily living, orthostatic intolerance (OI) during a 10-min standing test, neurologic disequilibrium diagnosed as unstable standing with their feet together and eyes closed, neuropathic pain or fibromyalgia, and muscle weakness were compared before and after treatment. Results: After therapy, favorable effects were observed with a decrease in performance status score or index for restriction of activities of daily living of ≥ 2 points in 20 patients (67%). OI with the inability to complete the 10-min standing test was resolved in 10 (83%) out of 12 patients, and disequilibrium was resolved in 15 (88%) out of 17 patients. Neuropathic pain or fibromyalgia was attenuated in seven (70%) out of 10 patients. Muscle weakness with grip power of < 10 kg was resolved in two (50%) out of four patients. No untoward effects were encountered in all the study patients. Conclusion: The treatment with rTMS is effective in alleviating various symptoms, especially OI and disequilibrium, and in improving the activities of daily living in patients with ME.

Orthostatic Intolerance and Chronotropic Incompetence in Patients With Myalgic Encephalomyelitis or Chronic Fatigue Syndrome.

Background: Orthostatic intolerance markedly affects the day-to-day activities of patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. Chronotropic incompetence (CI), defined as an impaired chronotropic response or reduced increases in heart rate during exercise and resulting in lower exercise capacity, may also be observed during orthostasis in patients with ME. Methods and Results: In this study, the recordings of 101 adult patients with ME (36 men, 65 women; mean [±SD] age 37±12 years) who underwent conventional active 10-min standing tests at least 3 times to determine the presence of CI were analyzed. Recordings were selected for 13 patients who experienced tests both with and without exhibiting postural orthostatic tachycardia syndrome (POTS; an increase in heart rate of ≥30 beats/min or an actual heart rate of ≥120 beats/min) while also both successfully completing and failing to complete 10-min standing on different occasions. Subjects in whom failure without POTS was observed in any test(s) while success was associated with POTS on other occasions were considered positive for CI during orthostasis. Of the 13 patients, 12 (92%) were CI positive, 5 (38%) of whom exclusively failed the tests without experiencing POTS. Conclusions: Some patients with ME were CI positive during standing tests, suggesting impaired sympathetic activation. The presence of POTS appears to be essential for maintaining orthostasis in these patients.

Oral Minocycline Therapy Improves Symptoms of Myalgic Encephalomyelitis, Especially in the Initial Disease Stage.

Objective Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been suggested to be the main cause of chronic fatigue syndrome. In animal models of chronic fatigue, minocycline was reported to act as a suppressor of neural inflammation. Minocycline may thus exert favorable therapeutic effects in patients with ME. Methods Oral minocycline (100 mg×2 on the first day, followed by 100 mg/day for 41 days) was administered to 100 patients with ME. The performance status score (0-9), orthostatic intolerance during the 10-min standing test, neurologic disequilibrium, and neuropathic pain were compared before and after treatment. Results After therapy completion, favorable effects were observed with a decrease in the performance status score of ≥2 points in 27 patients (27%). Before treatment, 6 of the 27 patients had orthostatic intolerance with an inability to complete the 10-min standing test; after treatment, this symptom resolved in 4 and improved in 2 patients. In addition, after treatment, postural orthostatic tachycardia resolved in five of eight patients, disequilibrium resolved in five of eight patients, and fibromyalgia or neuropathic pain was attenuated in four of five patients. The favorable effects appeared dependent on a shorter disease duration, primarily for a duration of less than three years and most frequently within six months of the disease onset. However, acute adverse effects with nausea and/or dizziness caused 38 patients (38%) to discontinue treatment in the first few days. Conclusion Oral minocycline therapy may be an effective treatment option for patients with ME, especially in the initial stage of the disease.

Paradigm shift to disequilibrium in the genesis of orthostatic intolerance in patients with myalgic encephalomyelitis and chronic fatigue syndrome.

BACKGROUND: Orthostatic intolerance (OI) markedly impairs activities of daily living in patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. OI is surmised to be a cardiovascular symptom correlated with cerebral hypo-perfusion and exaggerated sympathetic activation. Postural instability or disequilibrium may be part of the etiology of OI. METHODS: The study comprised 72 patients with ME (18 men, 54 women; mean age, 37 ± 10 years) who underwent neurological examinations and the 10 min standing test. We quantified disequilibrium (instability upon standing with feet together and eyes shut), ability to complete the 10 min standing test, and postural orthostatic tachycardia (POT) during the test. RESULTS: Disequilibrium was detected in 23/72 (32%) patients and POT in 16 (22%). Nineteen (26%) patients failed to complete the 10 min standing test; disequilibrium was significantly more common in the 19- patient subgroup than in the 53-patient test-completing subgroup (89% vs. 11%, p < 0.01). However, the rate of POT was not different between the groups (21% vs. 23%, p = 1.00). Compared with the 49 (68%) patients without disequilibrium, the 23 (32%) patients with disequilibrium were significantly more likely to have failed to complete the test (74% vs. 4%, p < 0.01). The rate of POT was comparable between the groups (23% vs. 22%, p = 1.00). Among patients with disequilibrium who failed to complete the 10 min standing test and had a previous record, 6/8 had completed the test 6-24 months earlier when all six had reported no disequilibrium. CONCLUSION: Disequilibrium should be recognized as an important cause of OI in patients with ME.

The etiologic relation between disequilibrium and orthostatic intolerance in patients with myalgic encephalomyelitis (chronic fatigue syndrome).

BACKGROUND: Orthostatic intolerance (OI) causes a marked reduction in the activities of daily living in patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. Most symptoms of OI are thought to be related to cerebral hypo-perfusion and sympathetic activation. Because postural stability is an essential element of orthostatic tolerance, disequilibrium may be involved in the etiology of OI. METHODS AND RESULTS: The study comprised 44 patients with ME (men, 11 and women, 33; mean age, 37±9 years), who underwent neurological examinations and 10-min standing and sitting tests. Symptoms of OI were detected in 40 (91%) patients and those of sitting intolerance were detected in 30 (68%). Among the 40 patients with OI, disequilibrium with instability on standing with their feet together and eyes shut, was detected in 13 (32.5%) patients and hemodynamic dysfunction during the standing test was detected in 19 (47.5%); both of these were detected in 7 (17.5%) patients. Compared with 31 patients without disequilibrium, 13 (30%) patients with disequilibrium more prevalently reported symptoms during both standing (100% vs. 87%, p=0.43) and sitting (92% vs. 58%, p=0.06) tests. Several (46% vs. 3%, p<0.01) patients failed to complete the 10-min standing test, and some (15% vs. 0%, p=0.15) failed to complete the 10-min sitting test. Among the seven patients with both hemodynamic dysfunction during the standing test and disequilibrium, three (43%) failed to complete the standing test. Among the 6 patients with disequilibrium only, 3 (50%) failed while among the 12 patients with hemodynamic dysfunction only, including 8 patients with postural orthostatic tachycardia, none (0%, p=0.02) failed. CONCLUSIONS: Patients with ME and disequilibrium reported not only OI but also sitting intolerance. Disequilibrium should be recognized as an important cause of OI and appears to be a more influential cause for OI than postural orthostatic tachycardia in patients with ME.

Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been postulated as the cause of chronic fatigue syndrome (CFS). A small heart or reduced left ventricular volume with reduced cardiac output has been reported to be common in patients with ME. The main circulatory blood volume regulators may be down-regulated. METHODS: Plasma levels of the neurohumoral factors that regulate circulatory blood volume were determined in 18 patients with ME and 15 healthy subjects (Controls). RESULTS: The echocardiographic examination revealed that the mean values for the left ventricular end-diastolic diameters, stroke volume index, and cardiac index as well as the mean blood pressure were all significantly smaller in the ME group than in the Controls. The mean plasma renin activity (1.6±1.0ng/ml/h vs. 2.5±1.5ng/ml/h, p=0.06) was considerably lower in the ME group than in the Controls. Both the mean plasma aldosterone (104±37pg/ml vs. 157±67pg/ml, p=0.004) and antidiuretic hormone (ADH) (2.2±1.0pg/ml vs. 3.3±1.5pg/ml, p=0.02) concentrations were significantly lower in the ME group than in the Controls. Desmopressin (120µg), a synthetic version of arginine vasopressin, was orally administered for five successive days to 10 patients with ME. In five patients (50%), the symptoms of orthostatic intolerance during a 10min active standing test were ameliorated in association with a significant increase in urinary osmotic pressure and decrease in heart rate. Furthermore, in five patients (50%), the performance status scores for the activities of daily living were improved. CONCLUSIONS: Both the renin-aldosterone and ADH systems were down-regulated despite the existence of reduction in cardiac preload and output in patients with ME. Desmopressin improved symptoms in half of the patients.

Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance.

Central nervous system dysfunction with myalgic encephalomyelitis (ME) has been suggested as the main cause of chronic fatigue syndrome. Fluctuation of the symptom severity and hierarchy is a characteristic feature in ME patients. The characteristics of the sympathetic activation may differ between the "good days" and "bad days" in them. Twenty-four ME patients with orthostatic intolerance underwent a conventional 10-min active standing test and echocardiography both on a "good day" and a "bad day", defined according to the severity of their symptoms. The mean heart rate at rest was significantly higher on the "bad days" than on the "good days". During the standing test on a "bad day", 5 patients (21 %) failed to maintain an upright posture for 10 min, whereas on a "good day" all the 24 patients maintained it. Postural orthostatic tachycardia (POT) (increase in heart rate ≥30 beats/min) or severe POT (heart rate ≥120 beats/min) was observed on the "bad days" in 10 patients (43 %) who did not suffer from the severe tachycardia on the "good days", suggesting the exaggerated sympathetic nervous activation. In contrast, POT did not occur or severe POT was attenuated on the "bad days" in 5 patients (21 %) who developed POT or severe POT on the "good days", suggesting the impaired sympathetic activation. Echocardiography revealed significantly lower mean values of both the left ventricular end-diastolic diameter and stroke volume index on the "bad days" compared with the "good days". In conclusion, in ME patients with orthostatic intolerance, the exaggerated activation of the sympathetic nervous system while standing appears to switch to the impaired sympathetic activation after the system is loaded with the additional accentuated stimuli associated with the preload reduction.

Cardiac dysfunction and orthostatic intolerance in patients with myalgic encephalomyelitis and a small left ventricle.

The etiology of chronic fatigue syndrome (CFS) is unknown. Myalgic encephalomyelitis (ME) has been recently postulated to be the cause of CFS. Orthostatic intolerance (OI) has been known as an important symptom in predicting quality of life in CFS patients. Cardiac function may be impaired in patients with ME. The presence or absence of OI was determined both symptomatically and by using a 10-min stand-up test in 40 ME patients. Left ventricular (LV) dimensions and function were determined echocardiographically in the ME patients compared to 40 control subjects. OI was noted in 35 (97%) of the 36 ME patients who could stand up quickly. The mean values for the cardiothoracic ratio, systemic systolic and diastolic pressures, LV end-diastolic diameter (EDD), LV end-systolic diameter, stroke volume index, cardiac index and LV mass index were all significantly smaller in the ME group than in the controls. Both a small LVEDD (<40 mm, 45 vs. 3%) and a low cardiac index (<2 l/ min/mm2, 53 vs. 8%) were significantly more common in the ME group than in the controls. Both heart rate and LV ejection fraction were similar between the groups. In conclusion, a small LV size with a low cardiac output was common in ME patients, in whom OI was extremely common. Cardiac dysfunction with a small heart appears to be related to the symptoms of ME.

Small heart with low cardiac output for orthostatic intolerance in patients with chronic fatigue syndrome.

BACKGROUND: The etiology of chronic fatigue syndrome (CFS) is unknown. Orthostatic intolerance (OI) is common in CFS patients. Recently, small heart with low cardiac output has been postulated to be related to the genesis of both CFS and OI. HYPOTHESIS: Small heart is associated with OI in patients with CFS. METHODS: Study CFS patients were divided into groups of 26 (57%) CFSOI(+) and 20 (43%) CFSOI(-) according to the presence or absence of OI. In addition, 11 OI patients and 27 age- and sex-matched control subjects were studied. Left ventricular (LV) dimensions and function were determined echocardiographically. RESULTS: The mean values of cardiothoracic ratio, systemic systolic and diastolic pressures, LV end-diastolic dimension, LV end-systolic dimension, stroke volume index, cardiac index, and LV mass index were all significantly smaller in CFSOI(+) patients than in CFSOI(-) patients and healthy controls, and also in OI patients than in controls. A smaller LV end-diastolic dimension (<40 mm) was significantly (P<0.05) more prevalently noted in CFSOI(+) (54%) and OI (45%) than in CFSOI(-) (5%) and controls (4%). A lower cardiac index (<2 L/min/mm(2)) was more prevalent in CFSOI(+) (65%) than in CFSOI(-) (5%, P<0.01), OI (27%), and controls (11%, P<0.01). CONCLUSIONS: A small size of LV with low cardiac output was noted in OI, and its degree was more pronounced in CFSOI(+). A small heart appears to be related to the genesis of OI and CFS via both cerebral and systemic hypoperfusion. CFSOI(+) seems to constitute a well-defined and predominant subgroup of CFS.

Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome.

The etiology of chronic fatigue syndrome remains unknown. Oxidative stress may be involved in its pathogenesis. Vitamin E is a major endogenous lipid-soluble antioxidative substance, and is consumed during the lipid peroxidation process. We studied a population comprising 27 patients with chronic fatigue syndrome (10 men and 17 women, 29 +/- 6 years of age) and 27 age- and sex-matched control subjects. Serum vitamin E (alpha-tocopherol) concentrations were determined and expressed as mg/g total lipids (total cholesterol and triglyceride) to evaluate oxidative stress. Serum alpha-tocopherol concentrations (mg/g lipids) were significantly (P < 0.001) lower in the patients with chronic fatigue syndrome (2.81 +/- 0.73) than in the control subjects (3.88 +/- 0.65). The patients with chronic fatigue syndrome were re-examined during a follow-up interval. After 8 +/- 2 months, 16 patients exhibited a status that warranted re-examination during remission of the symptoms at a regular visit to our hospital (Group 1), while the remaining 11 did not (Group 2). The serum alpha-tocopherol levels were significantly elevated during remission as compared with those at baseline in Group 1 (2.71 +/- 0.62 --> 3.24 +/- 0.83, P < 0.001). The levels did not significantly change after the interval in Group 2 (2.97 +/- 0.86 --> 2.85 +/- 0.73, not significant). In conclusion, serum alpha-tocopherol concentrations were significantly lower in the patients with chronic fatigue syndrome as compared with the control subjects, suggesting increased oxidative stress in the former. The low level of serum alpha-tocopherol was ameliorated during the remission phase as compared with the exacerbation phase in the patients with chronic fatigue syndrome, suggesting that increased oxidative stress may be involved in the pathogenesis of chronic fatigue syndrome and might also be directly related to the severity of the symptoms of chronic fatigue syndrome.

Pitavastatin reduces lectin-like oxidized low-density lipoprotein receptor-1 ligands in hypercholesterolemic humans.

The aim of this study was to determine the impact of pitavastatin on low-density lipoprotein cholesterol (LDL-C) and lectin-like oxidized LDL receptor-1 (LOX-1) in patients with hypercholesterolemia. Twenty-five hypercholesterolemic patients (8 male, 17 female; age 66 +/- 13, 21-80 years) who had not received anti-dyslipidemic agents and had LDL-C levels of more than 160 mg/dL were examined. Biochemical factors were measured at baseline and after treatment with pitavastatin (2 mg/day) for 6 months. Serum levels of LOX-1 with apolipoprotein B-100 particle ligand and a soluble form of LOX-1 (sLOX-1) were measured by ELISA. All subjects completed the study with no adverse side effects. Total-C (268 +/- 26 vs. 176 +/- 17 mg/dL), LDL-C (182 +/- 21 vs. 96 +/- 14 mg/dL), and LOX-1 ligand (867 +/- 452 vs. 435 +/- 262 ng/mL) were reduced with pitavastatin treatment (P < 0.0001 for each). Significant decreases in triacylglycerols were noted (P < 0.0001), but there were no changes in high-density lipoprotein cholesterol. After 6 months, there were no significant changes in high-sensitivity CRP or soluble LOX-1. At baseline, there were no significant correlations between LOX-1 ligand and either LDL-C or sLOX-1. The decrease in LOX-1 ligand was not correlated with the decrease in LDL-C, but was correlated with the decrease in sLOX-1 (r = 0.47, P < 0.05). In conclusion, pitavastatin therapy had beneficial effects on markers of oxidative stress in hypercholesterolemic subjects. Serum levels of LOX-1 ligand may be a useful biomarker of the pleiotropic effects of statins.

Cardiovascular dysfunction with low cardiac output due to a small heart in patients with chronic fatigue syndrome.

OBJECTIVE: Little attention has been paid to possible cardiovascular involvement in patients with chronic fatigue syndrome (CFS), although many of their symptoms and signs suggest cardiovascular dysfunction. Possible cardiovascular symptoms and cardiac function were investigated in CFS patients. METHODS: Cardiovascular symptoms were intensively investigated and cardiac function was evaluated echocardiographically. PATIENTS: Fifty-three patients (23 men and 30 women, mean age: 31+/-7 years) with CFS under 50 years were studied. RESULTS: Slender build (body mass index <20 kg/m(2)) was common (47%). Possible cardiovascular symptoms including shortness of breath (32%), dyspnea on effort (28%), rapid heartbeat (38%), chest pain (43%), fainting (43%), orthostatic dizziness (45%) and coldness of feet (42%), were all frequent complaints. Hypotension (28%) was occasionally noted. Electrocardiograms frequently revealed right axis deviation (21%) and severe sinus arrhythmia (34%) suggesting accentuated parasympathetic nervous activity. Small heart shadow (cardiothoracic ratio

Appearance of electrocardiographic initial U-wave inversion dependent on pressure-induced early diastolic impairment in patients with hypertension.

BACKGROUND: ECG U-wave inversion can be classified as initial and terminal U inversion according to the phasic relationship to positive U-wave deflection. Initial U inversion is occasionally observed in hypertensive patients while terminal U inversion frequently appears during severe myocardial ischemia. HYPOTHESIS: The genesis of initial U inversion may be related to pressure-induced diastolic dysfunction. METHODS: In order to clarify the genesis of initial U-wave inversion we studied 11 consecutive hypertensive patients with both initial U inversion and impaired left ventricular early relaxation who were evaluated using Doppler echocardiography. RESULTS: The U inversion disappeared during acute pressure lowering by sublingual administration of nitroglycerin. The U inversion also disappeared and relaxation improved significantly after chronic blood pressure lowering. Initial U inversion reappeared during a cold pressor test. CONCLUSION: The appearance of initial U inversion was dependent on the pressure-induced impaired left ventricular early relaxation in hypertensive patients.

Cardiac function fluctuates during exacerbation and remission in young adults with chronic fatigue syndrome and "small heart".

BACKGROUND: "Small heart syndrome", previously referred to as so-called "neurocirculatory asthenia" associated with a small heart shadow on the chest roentgenogram, is characterized by weakness or fatigue even after mild exertion, palpitation, dyspnea, and fainting, many of which resemble symptoms in patients with chronic fatigue syndrome (CFS). METHODS AND RESULTS: The study population comprised 42 patients with CFS younger than 40 years of age. Cardiothoracic ratio was determined on the chest roentgenogram and echocardiographic examination was performed to evaluate both the cardiac chamber size and function. "Small heart" (cardiothoracic ratio < or = 42%) on the chest X-ray photograph was noted in 26 (62%) of the study CFS patients. Echocardiographic examination demonstrated significantly smaller mean values of both the left ventricular (LV) end-diastolic and end-systolic dimensions, stroke volume indexes and cardiac indexes in CFS patients with "small heart" than in those without it and also in 20 control subjects. Thus, CFS patients with "small heart" had an actually small LV chamber and poor cardiac performance. During a long follow-up period of 10 CFS patients with "small heart", all echocardiographic parameters mentioned above improved and cardiothoracic ratios increased significantly during the remission phase as compared with exacerbation phase. CONCLUSIONS: "Small heart" on the chest X-ray photograph was prevalently noted in CFS patients. Echocardiographic examination revealed that CFS patients with "small heart" had an actually small LV chamber and poor cardiac performance. Cardiac functional changes evaluated by repeated examinations appeared to be directly associated with the severity of their symptoms. Small heart syndrome with impaired cardiac function may contribute to the development of CFS through low cardiac output as a constitutional factor.

Increased oxidative stress suggested by low serum vitamin E concentrations in patients with chronic fatigue syndrome.

Serum alpha-tocopherol concentrations were determined in 50 patients with chronic fatigue syndrome (CFS) and 40 control subjects (Control). Prevalence of each or any coronary risk factor was not significantly different between CFS and Control. CFS had significantly lower alpha-tocopherol concentrations than Control. The concentrations were significantly lower in the subjects with any coronary risk factors than those without in CFS as well as Control. Even among the subjects with any coronary risk factors and also among those without, CFS had significantly lower alpha-tocopherol concentrations than Control. In conclusion, CFS had significantly lower alpha-tocopherol concentrations irrespective of coronary risk factors than Control, suggesting the presence of increased oxidative stress in CFS.

Small heart syndrome in patients with chronic fatigue syndrome.

BACKGROUND: Small heart syndrome has previously been reported as neurocirculatory asthenia, associated with a small heart shadow on a chest roentgenogram. This is characterized as weakness or fatigue even after ordinary exertion, palpitation, dyspnea, and fainting, resembling patients with chronic fatigue syndrome (CFS). HYPOTHESIS: Small heart syndrome may be prevalent in patients with CFS. METHODS: The study population consisted of 56 patients (<50 y of age) with CFS, and 38 control subjects. Chest roentgenographic, echocardiographic, and physical examinations were performed. RESULTS: Small heart syndrome (cardiothoracic ratio