The epidemiology of chronic fatigue in San Francisco

Chronic fatigue syndrome (CFS) is a recently defined condition characterized by severe disabling fatigue that persists for a minimum of six months, and a host of somatic and neurocognitive symptoms. Although conditions similar to CFS have been described in the medical literature for over 100 years, little is known about the epidemiology of CFS or of chronic fatigue generally. The San Francisco Fatigue Study was undertaken to describe the prevalence and characteristics of self-reported chronic fatigue and associated conditions in a diverse urban community. The study utilized a cross-sectional telephone survey of a random sample of households in San Francisco, followed by case/control interviews of fatigued and nonfatigued subjects. Respondents were classified as chronically fatigued (CF) if they reported severe fatigue lasting six months or longer, then further classified as having CFS-like illness if, based on self-reported information, their condition appeared to meet CFS case definition criteria. Subjects who reported idiopathic chronic fatigue that did not meet CFS criteria were classified as having ICF-like illness.^ 8004 households were screened, yielding fatigue and demographic information on 16970 residents. CF was reported by 635 persons, 3.7% of the study population. CFS-like illness was identified in 34 subjects (0.2%), and ICF-like illness in 259 subjects (1.6%). Logistic regression analysis indicated that prevalence odds ratios for CFS-like illness were significantly elevated for females compared to males (OR = 2.9), and in Blacks (OR = 2.9) and Native Americans (OR = 13.2) relative to Whites, but significantly lower in Asians (OR = 0.12). Above-average household income was protective for all categories of CF. CFS-like subjects reported more symptoms and were more severely disabled than ICF-like subjects, but the pattern of symptoms experienced by both groups was similar. In conclusion, unexplained chronic fatigue, including CFS-like illness, occurs in all sociodemographic groups, but may be most prevalent among persons with lower incomes and in some racial minorities. Future studies that include clinical evaluation of incident cases of CFS and ICF are required to further clarify the epidemiology of unexplained chronic fatigue in the population. ^

Expression of neuromuscular junction messenger RNAs and protein in aged rats

The loss of skeletal muscle mass is believed to be the dominant reason for reduced strength in aging humans. The purpose of this investigation was to gain some information as to why skeletal muscles lose mass as we age. Since nervous system innervation is essential for skeletal muscle fiber viability, incomplete regional reinnervation during normal synaptic junction turnover has been hypothesized to result in selective muscle fiber loss. Examined here was the age-related association in skeletal muscle between atrophy and the expression of mRNAs encoding the γ- and ϵ-subunits of the nicotinic acetylcholine receptor, myogenin, and muscle specific receptor kinase (MuSK). Gastrocnemius and biceps brachii muscles were collected from young (2 month), adult (18 month), and old (31 month) Fischer 344 cross brown Norway F 1 male rats. In the gastrocnemius, muscles of old vs. young and adult rats, lower muscle mass was accompanied by significantly elevated acetylcholine receptor γ-subunit, myogenin, and MuSK mRNA levels. In contrast, the biceps brachii muscle in the same animals exhibited neither atrophy nor a change in acetylcholine receptor γ-subunit, myogenin, or MuSK mRNA levels. Expression of the acetylcholine receptor ϵ-subunit mRNA did not change with age in either gastrocnemius or biceps brachii muscles. Since acetylcholine receptor γ-subunit, myogenin, and MuSK mRNA levels are upregulated in surgically denervated skeletal muscles of young rats while expression of the acetylcholine receptor ϵ-subunit does not change, the findings of the current investigation suggest that a select fiber population within atrophied skeletal muscles of old rats may be in a denervated-like state. I speculate that increases in γ-subunit, myogenin, and MuSK mRNA levels in atrophied muscles of old rats are compensatory responses to nerve terminal retraction. Indeed, a prolongation of denervation in these muscle fibers would subsequently result in their atrophy and death, ultimately leading to a decline in the number of force generating elements present in the muscle. ^

The potential of a mindfulness-enhanced, integrative neuropsychotherapy program for treating fatigue following stroke: A preliminary Study

Fatigue is a frequently reported symptom after a stroke. Although the phenomenology of poststroke fatigue is well known, clear definitions as well as diagnostic and therapeutic guidelines are missing. Poststroke fatigue can be regarded as a multidimensional phenomenon that might be influenced by neurological, physical, psychological, and cognitive factors. It can range from mild to severe and can affect every area of the activities of daily life. The objective of our preliminary study was to outline aspects of a specific treatment program for the management of poststroke fatigue. Eight patients were recruited for a mindfulness-enhanced, integrative neuropsychotherapy program. The treatment was a combination of neuropsychological interventions, psychoeducation, cognitive-behavioral therapy, and mindfulness techniques. The main treatment foci were (a) to facilitate an increased awareness of fatigue symptoms, (b) to help the patient detect and manage triggers of fatigue, and (c) to equip the patient with multiple self-help tools. Measures were assessed at the beginning, during, and at the end of treatment using self-assessment questionnaire for mental fatigue and related symptoms after neurological disorders and injuries. Significant pre- to post-assessment differences were observed. These findings suggest that patients may benefit from a specific treatment program in order to better adapt to poststroke fatigue. These findings encourage further investigation of this integrative treatment in larger samples that include adequate control treatments.

Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data.

Background:Erythropoiesis-stimulating agents (ESAs) reduce the need for red blood cell transfusions; however, they increase the risk of thromboembolic events and mortality. The impact of ESAs on quality of life (QoL) is controversial and led to different recommendations of medical societies and authorities in the USA and Europe. We aimed to critically evaluate and quantify the effects of ESAs on QoL in cancer patients.Methods:We included data from randomised controlled trials (RCTs) on the effects of ESAs on QoL in cancer patients. Randomised controlled trials were identified by searching electronic data bases and other sources up to January 2011. To reduce publication and outcome reporting biases, we included unreported results from clinical study reports. We conducted meta-analyses on fatigue- and anaemia-related symptoms measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) and FACT-Anaemia (FACT-An) subscales (primary outcomes) or other validated instruments.Results:We identified 58 eligible RCTs. Clinical study reports were available for 27% (4 out of 15) of the investigator-initiated trials and 95% (41 out of 43) of the industry-initiated trials. We excluded 21 RTCs as we could not use their QoL data for meta-analyses, either because of incomplete reporting (17 RCTs) or because of premature closure of the trial (4 RCTs). We included 37 RCTs with 10 581 patients; 21 RCTs were placebo controlled. Chemotherapy was given in 27 of the 37 RCTs. The median baseline haemoglobin (Hb) level was 10.1 g dl(-1); in 8 studies ESAs were stopped at Hb levels below 13 g dl(-1) and in 27 above 13 g dl(-1). For FACT-F, the mean difference (MD) was 2.41 (95% confidence interval (95% CI) 1.39-3.43; P<0.0001; 23 studies, n=6108) in all cancer patients and 2.81 (95% CI 1.73-3.90; P<0.0001; 19 RCTs, n=4697) in patients receiving chemotherapy, which was below the threshold (⩾3) for a clinically important difference (CID). Erythropoiesis-stimulating agents had a positive effect on anaemia-related symptoms (MD 4.09; 95% CI 2.37-5.80; P=0.001; 14 studies, n=2765) in all cancer patients and 4.50 (95% CI 2.55-6.45; P<0.0001; 11 RCTs, n=2436) in patients receiving chemotherapy, which was above the threshold (⩾4) for a CID. Of note, this effect persisted when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy. There was some evidence that the MDs for FACT-F were above the threshold for a CID in RCTs including cancer patients receiving chemotherapy with Hb levels below 12 g dl(-1) at baseline and in RCTs stopping ESAs at Hb levels above 13 g dl(-1). However, these findings for FACT-F were not confirmed when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy.Conclusions:In cancer patients, particularly those receiving chemotherapy, we found that ESAs provide a small but clinically important improvement in anaemia-related symptoms (FACT-An). For fatigue-related symptoms (FACT-F), the overall effect did not reach the threshold for a CID.British Journal of Cancer advance online publication, 17 April 2014; doi:10.1038/bjc.2014.171 www.bjcancer.com.

The craniosacral progression of muscle development influences the emergence of neuromuscular junction alterations in a severe murine model for spinal muscular atrophy.

AIMS As 4-day-old mice of the severe spinal muscular atrophy (SMA) model (dying at 5-8 days) display pronounced neuromuscular changes in the diaphragm but not the soleus muscle, we wanted to gain more insight into the relationship between muscle development and the emergence of pathological changes and additionally to analyse intercostal muscles which are affected in human SMA. METHODS Structures of muscle fibres and neuromuscular junctions (NMJs) of the diaphragm, intercostal and calf muscles of prenatal (E21) and postnatal (P0 and P4) healthy and SMA mice were analysed by light and transmission electron microscopy. NMJ innervation was studied by whole mount immunofluorescence in diaphragms of P4 mice. RESULTS During this period, the investigated muscles still show a significant neck-to-tail developmental gradient. The diaphragm and calf muscles are most and least advanced, respectively, with respect to muscle fibre fusion and differentiation. The number and depth of subsynaptic folds increases, and perisynaptic Schwann cells (PSCs) acquire a basal lamina on their outer surface. Subsynaptic folds are connected to an extensive network of tubules and beaded caveolae, reminiscent of the T system in adult muscle. Interestingly, intercostal muscles from P4 SMA mice show weaker pathological involvement (that is, vacuolization of PSCs and perineurial cells) than those previously described by us for the diaphragm, whereas calf muscles show no pathological changes. CONCLUSION SMA-related alterations appear to occur only when the muscles have reached a certain developmental maturity. Moreover, glial cells, in particular PSCs, play an important role in SMA pathogenesis.

Fatigue and sleep-disordered breathing in multiple sclerosis: a clinically relevant association?

Background. Fatigue in patients with multiple sclerosis (MS) is highly prevalent and severely impacts quality of life. Recent studies suggested that sleep-disordered breathing (SDB) significantly contributes to fatigue in MS. Study Objective. To evaluate the importance of routine respirography in MS patients with severe fatigue and to explore the effects of treatment with continuous positive airway pressure (CPAP). Patients and Methods. We prospectively assessed the presence of severe fatigue, as defined by a score of ≥5.0 on the Fatigue Severity Scale (FSS), in 258 consecutive MS patients. Ninety-seven patients (38%) suffered from severe fatigue, whereof 69 underwent overnight respirography. Results. We diagnosed SDB in 28 patients (41%). Male sex was the only independent associate of SDB severity (P = 0.003). CPAP therapy in 6 patients was associated with a significant reduction of FSS scores (5.8 ± 0.5 versus 4.8 ± 0.6, P = 0.04), but the scores remained pathological (≥4.0) in all patients. Conclusion. Respirography in MS patients with severe fatigue should be considered in daily medical practice, because SDB frequency is high and CPAP therapy reduces fatigue severity. However, future work is needed to understand the real impact of CPAP therapy on quality of life in this patient group.

Eye movements discriminate fatigue due to chronotypical factors and time spent on task--a double dissociation

Systematic differences in circadian rhythmicity are thought to be a substantial factor determining inter-individual differences in fatigue and cognitive performance. The synchronicity effect (when time of testing coincides with the respective circadian peak period) seems to play an important role. Eye movements have been shown to be a reliable indicator of fatigue due to sleep deprivation or time spent on cognitive tasks. However, eye movements have not been used so far to investigate the circadian synchronicity effect and the resulting differences in fatigue. The aim of the present study was to assess how different oculomotor parameters in a free visual exploration task are influenced by: a) fatigue due to chronotypical factors (being a 'morning type' or an 'evening type'); b) fatigue due to the time spent on task. Eighteen healthy participants performed a free visual exploration task of naturalistic pictures while their eye movements were recorded. The task was performed twice, once at their optimal and once at their non-optimal time of the day. Moreover, participants rated their subjective fatigue. The non-optimal time of the day triggered a significant and stable increase in the mean visual fixation duration during the free visual exploration task for both chronotypes. The increase in the mean visual fixation duration correlated with the difference in subjectively perceived fatigue at optimal and non-optimal times of the day. Conversely, the mean saccadic speed significantly and progressively decreased throughout the duration of the task, but was not influenced by the optimal or non-optimal time of the day for both chronotypes. The results suggest that different oculomotor parameters are discriminative for fatigue due to different sources. A decrease in saccadic speed seems to reflect fatigue due to time spent on task, whereas an increase in mean fixation duration a lack of synchronicity between chronotype and time of the day.

Prevalence and predictors of fatigue in glioblastoma: a prospective study.

BACKGROUND The main goal of this study was to assess frequency, clinical correlates, and independent predictors of fatigue in a homogeneous cohort of well-defined glioblastoma patients at baseline prior to combined radio-chemotherapy. METHODS We prospectively included 65 glioblastoma patients at postsurgical baseline and assessed fatigue, sleepiness, mean bedtimes, mood disturbances, and clinical characteristics such as clinical performance status, presenting symptomatology, details on neurosurgical procedure, and tumor location and diameter as well as pharmacological treatment including antiepileptic drugs, antidepressants, and use of corticosteroids. Data on fatigue and sleepiness were measured with the Fatigue Severity Scale and the Epworth Sleepiness Scale, respectively, and compared with 130 age- and sex-matched healthy controls. RESULTS We observed a significant correlation between fatigue and sleepiness scores in both patients (r = 0.26; P = .04) and controls (r = 0.36; P < .001). Only fatigue appeared to be more common in glioblastoma patients than in healthy controls (48% vs 11%; P < .001) but not the frequency of sleepiness (22% vs 19%; P = .43). Female sex was associated with increased fatigue frequency among glioblastoma patients but not among control participants. Multiple linear regression analyses identified depression, left-sided tumor location, and female sex as strongest associates of baseline fatigue severity. CONCLUSIONS Our findings indicate that glioblastoma patients are frequently affected by fatigue at baseline, suggesting that factors other than those related to radio- or chemotherapy have significant impact, particularly depression and tumor localization.

Temporal variations of dyspnea, fatigue, and lung function in chronic lung disease

Background. Research investigating symptom management in patients with chronic obstructive pulmonary disease (COPD) largely has been undertaken assuming the homeostatic construct, without regard to potential roles of circadian rhythms. Temporal relations among dyspnea, fatigue, peak expiratory flow rate (PEFR) and objective measures of activity/rest have not been reported in COPD. ^ Objectives. The specific aims of this study were to (1) explore the 24-hour patterns of dyspnea, fatigue, and PEFR in subjects with COPD; (2) examine the relations among dyspnea, fatigue, and PEFR in COPD; and (3) examine the relations among objective measures of activity/rest and dyspnea, fatigue, and PEFR in COPD. ^ Methods. The repeated-measures design involved 10 subjects with COPD who self-assessed dyspnea and fatigue by 100 mm visual analog scales, and PEFR by peak flow meter in their home 5 times a day for 8 days. Activity/rest was measured by wrist actigraphy. Single and population mean cosinor analyses and correlations were computed for dyspnea, fatigue, and PEFR; correlations were done among these variables and activity/rest. ^ Results. Circadian rhythms were documented by single cosinor analysis in 40% of the subjects for dyspnea, 60% for fatigue, and 60% for PEFR. The population cosinor analysis of PEFR yielded a significant rhythm (p < .05). The 8-day 24-hour means of dyspnea and fatigue was moderately correlated (r = .48, p < .01). Dyspnea and PEFR, and fatigue and PEFR, were weakly correlated in a negative way (r = −.11, p < .05 and r = −.15, p < .01 respectively). Weak to moderate correlations (r = .12–.34, p < .05) were demonstrated between PEFR and mean activity level measured up to 4 hours before PEFR measurement. ^ Conclusions. The findings suggest that (1) the dyspnea and fatigue experienced by COPD patients are moderately related, (2) there is a weak to modest positive relation between PEFR and activity levels, and (3) temporal variation in lung function may not affect the dyspnea and fatigue experienced by patients with COPD. Further research, examining the relations among dyspnea, fatigue, PEFR, and activity/rest is needed. Replication of this study is suggested with a larger sample size. ^

The effect of thyroxine and triiodothyronine on fatigue, depression, and memory in a hypothyroid population

Background. This study was planned at a time when important questions were being raised about the adequacy of using one hormone to treat hypothyroidism instead of two. Specifically, this trial aimed to replicate prior findings which suggested that substituting 12.5 μg of liothyronine for 50 μg of levothyroxine might improve mood, cognition, and physical symptoms. Additionally, this trial aimed to extend findings to fatigue. ^ Methods. A randomized, double-blind, two-period, crossover design was used. Hypothyroid patients stabilized on levothyroxine were invited to participate. Thirty subjects were recruited and randomized. Sequence one received their standard levothyroxine dose in one capsule and placebo in another during the first six weeks. Sequence two received their usual levothyroxine dose minus 50 μg in one capsule and 10 μg of liothyronine in another. At the end of the first six week period, subjects were crossed over. T tests were used to assess carry-over and treatment effects. ^ Results. Twenty-seven subjects completed the trial. The majority of completers had an autoimmune etiology. Mean baseline levothyroxine dose was 121 μg/d (±26.0). Subjects reported small increases in fatigue as measured by the Piper Fatigue Scale (0.9, p = 0.09) and in symptoms of depression measured by the Beck Depression Inventory-II (2.3, p = 0.16) as well as the General Health Questionnaire-30 (4.7, p = 0.14) while treated with substitution treatment. However, none of these differences was statistically significant. Measures of working memory were essentially unchanged between treatments. Thyroid stimulating hormone was about twice as high during substitution treatment (p = 0.16). Free thyroxine index was reduced by 0.7 (p < 0.001), and total serum thyroxine was reduced by 3.0 (p < 0.001) while serum triiodothyronine was increased by 20.5 (p < 0.001) on substitution treatment. ^ Conclusions. Substituting an equivalent amount of liothyronine for a portion of levothyroxine in patients with hypothyroidism does not decrease fatigue, symptoms of depression, or improve working memory. However, due to changes in serum hormone levels and small increments in fatigue and depression symptoms on substitution treatment, a question was raised about the role of T3 in the serum. ^