Increased upper body sweating, an early sign of diabetic sympathetic
It is often said that impaired parasympathetic function is an early sign of diabetic autonomic neuropathy, whereas sympathetic function is relatively spared. However, the lack of sensitive measurements of sympathetic function may explain why its impairment is underestimated. In this study, forearm sweat production in response to acetylcholine was ~60% higher in 37 patients with recently diagnosed type I diabetes compared to 41 controls. Likewise, the ratio of upper/lower body sweating was ~40% higher in the diabetic patients. This redistribution of sudomotor responses likely represent sympathetic nerve injury in lower body with compensatory sweating in the upper body. This defect can be detected very early in type I diabetes and could be used as a biomarker for disease progression.
(Hoeldtke RD, et al. Diabetes 2001;50:436-443)
Are b-blockers effective in the prevention of
Isoproterenol is often used to induce syncope during tilt, and sympathetic cardiac stimulation is thought to trigger neurogenic syncope. Therefore, b-blockers are often used to treat patients suspected of having neurogenic syncope. There are, however, very few controlled studies about the treatment of this condition. Patients with "recurrent" neurogenic syncope were randomized to atenolol (n=26) vs placebo (n=24). The time to first recurrence of syncope, the main endpoint, was no different between groups. So, are $-blockers useless in the treatment of neurogenic syncope? Before reaching this conclusion we need to consider that only 40% of patients entered into this study had a positive tilt test and they had a median number of syncopal episodes of only 3 per year. This probably explains the approximate 50% success rate with placebo, which makes it difficult to assess the efficacy of active treatment.
(Madrid AH, et al. J Am Coll Cardiol 2001; 37:554-9)
Fludrocortisone fails to improve Chronic Fatigue Syndrome (CFS)
Patients with CFS are more likely than healthy persons to develop neurally mediated hypotension (NMH) in response to prolonged orthostatic stress. It is proposed that this hypotension contributes to CFS symptoms. The long-awaited results are in, on this randomized, double-blind, placebo-controlled trial started in 1996 to examine the efficacy of fludrocortisone acetate as monotherapy for adults with both CFS and NMH. Out of 750 patients screened, 83 (18 to 50 years old) with CFS and a positive tilt-table test received either 0.1 mg/d fludrocortisone or placebo for 9 weeks. No differences between groups were observed in symptom scores or in the proportion of patients with negative tilt test at the end of treatment. Thus, fludrocortisone is not effective in the long-term prevention of neurally-mediated hypotension or in the symptomatic treatment of chronic fatigue. Given that fludorcortisone has not been proven in controlled studies to be effective in neurogenic syncope, these results do not necessarily disprove the hypothesis that NMH contributes to CFS.
(Rowe PC, et al. JAMA 2001; 1:52-9)
Differences in the Auditory Startle Response (ASR) in patients with dementia
with Lewy bodies (DLB) and multiple system atrophy (MSA)
ASR induces a transient sympathetic activation with a discrete pattern (i.e., it increases skin, but not muscle, sympathetic nerve traffic). The reflex originates in the nucleus reticularis pontis caudalis of the brainstem and is distributed up the brainstem and down the spinal cord. Its presence, therefore, can reveal the level of neural lesion in certain disorders. Patients with parkinsonism and DLB had impaired ASR, whereas this sympathetic reflex was exaggerated in MSA patients. These results suggest that neurons in the rostro ventral lateral medulla, where sympathetic pacemaker neurons are located, and distal pathways, are preserved in MSA.
(Kofler M, et al. Mov Disord 2001; 16:62-71)
Opiod addiction depresses sympathetic activity
Resting sympathetic tone was decreased in 15 young patients on chronic methadone for mono-opioid addiction. Peroneal muscle sympathetic nerve activity (MSNA) was 4 vs. 22 bursts/min in normals and plasma norepinephrine plasma was 100 vs. 256 pg/mL, despite similar arterial blood pressure and heart rate. Acute opioid withdrawal with naloxone (during general anesthesia with propofol), resulted in marked sympathetic activation, with increased MSNA (from 5 to 24 bursts/min), arterial norepinephrine levels (from 49 to 305 pg/mL) epinephrine (from 13 to 482 pg/mL), mean arterial pressure (from 82 to 108 mm Hg) and heart rate (from 70 to 86 bpm). These results suggest that chronic opiod addiction is associated with a low sympathetic tone, which can be reversed with acute opiod withdrawal. It is of interest to note the exceedingly low plasma norepinephrine (comparable to those found in patients with severe pure autonomic failure) found in these patients during general anesthesia.
(Klenbaum P, et al. Circulation 2001; 103:850-5)
Etiology of syncope in a large cohort
The authors review the diagnosis of 641 cases of syncope in a tertiary care facility: vasovagal syncope (35%), carotid sinus hypersensitivity and other neurally-mediated syncopes (8%), autonomic failure not previously recognized (5%), other medical causes (8%), non-autonomic neurological causes (e.g., vestibular disorders, seizures, 7%) and psychogenic (9%). Of note, no cause was found in 28% of cases despite autonomic evaluation and tilt test.
(Mathias CJ, et al. Lancet 2001; 357:348-53)
Neuropathological studies reveal involvement of the cortical motor area in
patients with multiple system atrophy (MSA)
Extrapiramidal involvement is prominent in MSA patients, but motor tracts may also be involved. The following were found in MSA brains: glial cytoplasmic inclusions (GCIs) in the cortex and subcortical white matter of the motor and supplementary motor areas, loss of small to medium-sized pyramidal neurons, and astrocytosis in the motor cortex. The severity of neuronal loss in the motor cortex was highly correlated with the incidence of GCIs and the involvement of the nigrostriatal pathway. These results suggest that the motor area is compromised in MSA.
(Su M, et al. Acta Neuropathol 2001; 101:57-64)
Differences in asynuclein inclusions in Lewy body
diseases and multiple system atrophy
Intracellular inclusions containing "-synuclein ("SN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). There may be, however, differences in the characteristics of "SN deposited in these diseases processes. Both detergent-soluble and detergent-insoluble "SN were detected in grey matter homogenates from DLB and PD, in greater amounts compared to controls. MSA cases also had higher levels of "SN in brain samples from pons and white matter but this was limited to detergent-soluble forms of "SN. Detergent-insoluble "SN was not detected in MSA. It is unclear how these differences translates to the pathophysiology of these disease processes.
(Campbell, et al. J Neurochem 2001; 76:87-96)
Relative contribution of nitric oxide to flow-mediated dilatation (FMD)
There is little doubt that endothelium-derived nitric oxide (NO) is an important mediator of vascular tone. Impaired NO function is often seen in conditions characterized by endothelial damage (e.g., hypercholesterolemia). Endothelial cells are known to release NO in response to shear stress (flow mediated dilatation, FMD). FMD is often used as an indicator of adequate NO function, by measuring the increase in brachial artery diameter (by ultrasound) in response to reactive hyperemia induced distally to the measurement site. This technique is operator dependent and relies on the accurate measurement of very small changes in arterial diameter. In this study, the FMD induced by short periods of reactive hyperemia was blocked by L-NMMA, indicating that it was mediated by NO. On the other hand, FMD induced by prolonged episodes of ischemia was not attenuated by inhibition of NO synthesis. The results obtained with L-NMMA mimicked those seen in patients with hypercholesterolemia; impaired FMD responses to short periods of reactive hyperemia, but normal responses to prolonged hyperemia. These results highlight the necessity to use FMD carefully, and confirm the selective NO-deficiency in hypercholesterolemia.
(Mullen MJ, et al. Circ Res 2001; 88:145-51)
Progression of dysarthria and dysphagia: clinical signs of multiple system
Parkinson syndromes are commonly associated with dysarthria and dysphagia. The progression of these symptoms was evaluated in patients with autopsy-proven cases of Parkinson disease (PD, n=17), or "atypical parkinson disorders" such as dementia with Lewy bodies (DLB, 14), corticobasal degeneration (CBD, 13), multiple system atrophy (MSA, 15), and progressive supranuclear palsy (PSP, 24). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (specificity, 100%) but failed to distinguish between them. Once present, it was a poor prognostic sign, regardless of the diagnosis. Survival time after onset of dysphagia was similar in PD, MSA, and PSP (15-24 months).
(Muller J, et al. Arch Neurol 2001; 58:259-64)
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Campbell BC, McLean CA, Culvenor
JG et al. The solubility of alpha-synuclein in multiple system atrophy
differs from that of dementia with Lewy bodies and Parkinson's disease. J.Neurochem.
2001; 76: 87-96.
Abstract: Intracellular inclusions containing alpha-synuclein (alphaSN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of alphaSN, this study compared the levels, solubility and molecular weight species of alphaSN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble alphaSN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had significantly higher levels of alphaSN in the detergent-soluble fraction of brain samples from pons and white matter but detergent-insoluble alphaSN was not detected. There was an inverse correlation between buffered saline-soluble and detergent-soluble levels of alphaSN in individual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of alphaSN between grey and white matter in disease may result from different processing of alphaSN in neurons compared with oligodendrocytes. Highly insoluble alphaSN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of alphaSN are involved in the pathogenesis of other alphaSN-related diseases
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Hoeldtke RD, Bryner KD, Horvath GG,
Phares RW, Broy LF, Hobbs GR. Redistribution of sudomotor responses is an
early sign of sympathetic dysfunction in type 1 diabetes. Diabetes 2001;
Abstract: Patients with diabetic neuropathy typically have decreased sweating in the feet but excessive sweating in the upper body. Previous studies of sudomotor function in diabetes ha ce included patients with longstanding disease. The present study was designed to test for the early presence of sudomotor dysfunction and to characterize its relation to glycemic control and other aspects of peripheral nerve function. A total of 37 patients (10 males, 27 females) enrolled in a longitudinal study in which autonomic function was evaluated annually for 3 years. Patients enrolled 2-22 months after the diagnosis of type 1 diabetes. Forty-one age- and sex-matched healthy control subjects were also studied. Sweat production in response to acetylcholine stimulation was dramatically increased in the forearm at the time of the first evaluation (1.67 +/- 0.24 mul/cm(2) in the diabetic patients vs. 1.04 +/- 0.14 mul/cm(2) in the control subjects, P < 0.05). Likewise, the ratio of sweating in the forearm to sweating below the waist was higher in the diabetic patients (0.553 +/- 0.07 <mu>l/cm(2)) than in the control subjects (0.385 +/- 0.04 mul/cm(2), P < 0.05). Forearm sweat was negatively associated with the renin-to-prorenin ratio and vanillylmandelic acid (VMA) excretion (P < 0.025), tests of sympathetic nerve function. The ratio of sweating in the forearm to sweating in the foot was likewise increased in diabetic patients with poor glycemic control. We interpret this redistribution of sudomotor responses to be indicative of sympathetic nerve injury and conclude 1) that the sympathetic nervous system is especially vulnerable to the adverse effects of chronic hyperglycemia and 2) that sympathetic dysfunction can be detected very early in type 1 diabetes
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Kienbaum P, Heuter T, Michel MC,
Scherbaum N, Gastpar M, Peters J. Chronic ?-Opioid Receptor Stimulation in
Humans Decreases Muscle Sympathetic Nerve Activity. Circulation 2001;
Abstract: BACKGROUND:-Opioid-addicted patients undergoing detoxification provide a unique opportunity to assess the effects of chronic opioid receptor stimulation on the sympathetic nervous system. We tested the hypothesis that chronic oral methadone intake decreases resting efferent sympathetic nerve activity to muscle (MSA). Furthermore, we assessed whether this effect is reversed by ?-opioid receptor blockade during antagonist-supported detoxification under general anesthesia. Methods and Results-Fifteen young patients (30+/-1 years old, mean+/-SEM) with a long history of mono-opioid addiction and under oral methadone substitution therapy (65+/-10 mg/d for 21+/-6 months) were selected. Peroneal MSA (microneurography) and catecholamine plasma concentrations (high-performance liquid chromatography) were assessed in the awake state and compared with those of age-matched healthy control subjects. The effects of ?-opioid receptor blockade by naloxone (12.4 mg IV) were determined during propofol anesthesia. Compared with healthy volunteers, resting MSA (4+/-2 versus 22+/-2 bursts/min, P:<0.0001) and antecubital venous norepinephrine plasma concentration (100+/-64 versus 256+/-48 pg/mL, P:=0.01) were markedly decreased in addicted patients despite similar arterial blood pressure and heart rate. Opioid receptor blockade markedly increased MSA (5+/-2 to 24+/-3 bursts/min) and norepinephrine (49+/-12 to 305+/-48 pg/mL) and epinephrine (13+/-2 to 482+/-67 pg/mL) arterial plasma concentrations as well as mean arterial pressure (82+/-4 to 108+/-3 mm Hg) and heart rate (70+/-3 to 86+/-4 beats/min). CONCLUSIONS:-Chronic ?-opioid receptor stimulation by methadone decreases resting MSA in humans
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Kofler M, Muller J, Wenning GK et
al. The auditory startle reaction in parkinsonian disorders. Mov Disord.
2001; 16: 62-71.
Abstract: The auditory startle reaction to an unexpected loud stimulus is regarded as a brainstem reflex originating in the nucleus reticularis pontis caudalis and being distributed up the brainstem and down the spinal cord along slowly conducting pathways. Auditory startle responses (ASR) have been reported absent or reduced in progressive supranuclear palsy (PSP), and delayed in Parkinson's disease (PD), but normal in multiple-system atrophy (MSA). For the first time we studied ASR in patients fulfilling the clinical criteria of dementia with Lewy bodies (DLB) (n = 8), a neurodegenerative disorder characterized by cortical and subcortical depositions of Lewy bodies resulting in parkinsonism and progressive cognitive decline. For comparison, we also investigated patients with PD (n = 10), MSA (n = 7), PSP (n = 10), and age-matched healthy controls (n = 10). ASR were elicited by binaural high-intensity auditory stimuli. Surface electromyographic activity was simultaneously recorded from facial, upper, and lower extremity muscles. For each muscle, we assessed response probability and measured latency, amplitude, duration, and habituation rate. Patients with DLB had fewer and abnormally delayed ASR of low amplitude and short duration in extremity muscles compared to healthy controls. Furthermore, we confirm and extend previous findings of abnormal ASR in PSP and PD, and also demonstrate exaggerated ASR in extremity muscles of MSA patients. The different patterns of ASR abnormalities may reflect distinct types of brainstem dysfunction in DLB
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Madrid AH, Ortega J, Rebollo JG et
al. Lack of efficacy of atenolol for the prevention of neurally mediated
syncope in a highly symptomatic population: A prospective, double-blind,
randomized and placebo-controlled study. Journal of the American College of
Cardiology 2001; 37: 554-9.
Abstract: OBJECTIVES This study was designed to evaluate the efficacy of atenolol for the long-term management of patients with vasovagal syncope. The primary hypothesis was that atenolol is not superior to placebo for the treatment of vasovagal syncope. BACKGROUND There is no definitive well-controlled analysis of the efficacy of beta-adrenergic blocking agents in patients with recurrent vasovagal syncope. METHODS This is a prospective, randomized, double-blind, placebo-controlled study. Fifty patients with recurrent vasovagal syncope were included (at least two episodes in the last year). A baseline tilt test was performed. Twenty patients (40%) had a positive tilt test. Intravenous atenolol prevented a second positive tilt in five patients. The patients were randomized to receive either atenolol or a placebo (26 patients atenolol 50 mg/day, 24 patients placebo). The follow-up procedure lasted one year. The primary end point of the study was the time to first recurrence of syncope. RESULTS In the intention-to-treat analysis, the group treated with atenolol had a similar number of patients with recurrent syncopal episodes as the placebo group. The Kaplan-Meier actuarial estimates of time to first syncopal recurrence showed that the probability of remaining between both curves (patients treated with atenolol vs. the placebo) with a log-rank test p value of 0.4517. CONCLUSIONS The recurrence of neurocardiogenic syncope in highly symptomatic patients treated with atenolol is similar to that of patients treated with placebo. (C) 2001 by the American College of Cardiology
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Mathias CJ, Deguchi K, Schatz I.
Observations on recurrent syncope and presyncope in 641 patients. Lancet
2001; 357: 348-53.
Abstract: BACKGROUND: Syncope is a common disorder that is potentially disabling and affects both young and old. Once neurological, cardiological, and metabolic causes have been excluded, there remains a group in which diagnosis is unclear; some may have an autonomic basis. We therefore did a retrospective study on consecutive patients referred to our tertiary referral autonomic centres between 1992 and 1998 with recurrent syncope and presyncope, in whom non-autonomic causes, before referral, had been sought and excluded. The object was to find out whether autonomic investigation helped diagnosis. METHODS: Data from case notes and from the autonomic database on 641 patients were analysed. Syncopal patients with a known or provisional diagnosis of autonomic failure were excluded from analysis. The role of screening tests in establishing or excluding an autonomic cause was assessed. Response to additional autonomic tests (such as head-up tilt with or without venepuncture, and food challenge and exercise) was documented. Some patients underwent further testing if non-autonomic neurological, psychiatric, and other disorders were considered. FINDINGS: Screening autonomic function tests indicated orthostatic hypotension and confirmed chronic autonomic failure in 31 (4.8%) patients. Neurally mediated syncope was diagnosed in 279 (43.5%) on the basis of clinical features and autonomic testing. Most had vasovagal syncope (227 [35%]); other causes included carotid sinus hypersensitivity (37 [5.8%]), and a group of 15 (2.3%) were associated with rarer causes such as micturition and swallowing. Miscellaneous cardiovascular causes (systemic hypotension, arrhythmias), or drugs, contributed to syncope in 53 (8.3%). Non-autonomic neurological causes included vestibular dysfunction (32 [5%]) and epilepsy (11 [1.7%]). In 56 (8.7%) a psychiatric cause was thought to be contributory. In 179 (27.9%), syncope was of unknown cause. INTERPRETATION: In recurrent syncope and presyncope, when cardiac, neurological, and metabolic causes have been excluded, autonomic investigation can aid management by making, confirming, or excluding various factors or diagnoses
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Mullen MJ, Kharbanda RK, Cross J et
al. Heterogenous Nature of Flow-Mediated Dilatation in Human Conduit
Arteries In Vivo : Relevance to Endothelial Dysfunction in Hypercholesterolemia.
Circ.Res. 2001; 88: 145-51.
Abstract: -Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli
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Muller J, Wenning GK, Verny M et
al. Progression of Dysarthria and Dysphagia in Postmortem-Confirmed
Parkinsonian Disorders. Arch.Neurol. 2001; 58: 259-64.
Abstract: BACKGROUND: Dysarthria and dysphagia are known to occur in parkinsonian syndromes such as Parkinson disease (PD), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Differences in the evolution of these symptoms have not been studied systematically in postmortem-confirmed cases. OBJECTIVE: To study differences in the evolution of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders. PATIENTS AND METHODS: Eighty-three pathologically confirmed cases (PD, n = 17; MSA, n = 15; DLB, n = 14; PSP, n = 24; and CBD, n = 13) formed the basis for a multicenter clinicopathological study organized by the National Institute of Neurological Disorders and Stroke, Bethesda, Md. Cases with enough clinicopathological documentation for the purpose of the study were selected from research and neuropathological files of 7 medical centers in 4 countries (Austria, France, England, and the United States). RESULTS: Median dysarthria latencies were short in PSP and MSA (24 months each), intermediate in CBD and DLB (40 and 42 months), and long in PD (84 months). Median dysphagia latencies were intermediate in PSP (42 months), DLB (43 months), CBD (64 months), and MSA (67 months), and long in PD (130 months). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (APDs) (specificity, 100%) but failed to further distinguish among the APDs. Survival time after onset of a complaint of dysphagia was similar in PD, MSA, and PSP (15 to 24 months, P =.7) and latency to a complaint of dysphagia was highly correlated with total survival time (rho = 0.88; P<.001) in all disorders. CONCLUSIONS: Latency to onset of dysarthria and dysphagia clearly differentiated PD from the APDs, but did not help distinguish different APDs. Survival after onset of dysphagia was similarly poor among all parkinsonian disorders. Evaluation and adequate treatment of patients with PD who complain of dysphagia might prevent or delay complications such as aspiration pneumonia, which in turn may improve quality of life and increase survival time
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Rowe PC, Calkins H, DeBusk K et al.
Fludrocortisone acetate to treat neurally mediated hypotension in chronic
fatigue syndrome: A randomized controlled trial. JAMA 2001; 285: 52-9.
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
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