Background and purpose: Fatigue is a common symptom in amyotrophic lateral
sclerosis (ALS). Although sleep disturbances are a candidate factor that may interfere
with fatigue in patients with ALS, the role of sleep-related abnormalities in determining
fatigue in ALS is unknown.
Objective: To evaluate the frequency and determinants of fatigue in a group of 91
consecutive patients with ALS, with special attention to the relationship between
fatigue and sleep problems.
Methods: Measures included the Fatigue Severity Scale (FSS), Pittsburgh Sleep
Quality Index (PSQI), Epworth Sleepiness Scale (ESS), ALS Functional Rating Scale-
Revised (ALSFRS-R), and Beck Depression Inventory (BDI).
Results: The mean FSS score was 4.35 ± 1.1, and 48 patients with ALS (52.75%)
reported clinical significant fatigue. FSS score correlated with ALSFRS-R score,
forced vital capacity, ESS, BDI, and global PSQI score. Patients with fatigue were
significantly more disabled and more frequently reported difficulties staying asleep and
nocturnal complaints, such as nocturia and disturbing muscle cramps. After multivariate
analysis, patients  disability and nocturnal complaints were significantly
associated with fatigue.
Conclusion: In this study, we demonstrated that fatigue, a troublesome and disabling
symptom in ALS, is associated with physical impairment and night-time complaints
(such as nocturia and muscle cramps), suggesting that treating sleep problems might
be useful in alleviating fatigue in these patients

LA BELLA, Vincenzo

LO COCO, Daniele

D. Lo Coco

V. La Bella

Crossref

European Journal of Neurology

Fatigue, sleep, and nocturnal complaints in patients with amyotrophic lateral sclerosis

Archivio istituzionale della ricerca - Università di Palermo

Fatigue, sleep, and nocturnal complaints in patients withamyotrophic lateral sclerosisD. Lo Cocoa,b and V. La BellaaaALS Research Center, Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Universita` di Palermo, Palermo; bSleepDisorders Clinic, U.O. Neurologia e Neuroﬁsiopatologia, Dipartimento di Neuroscienze, Ospedale Civico – ARNAS, Palermo, ItalyKeywords:ALS Functional RatingScale-Revised, amyo-trophic lateral sclerosis,cramps, fatigue, nocturia,sleepReceived 17 October 2011Accepted 17 November 2011Background and purpose: Fatigue is a common symptom in amyotrophic lateralsclerosis (ALS). Although sleep disturbances are a candidate factor that may interferewith fatigue in patients with ALS, the role of sleep-related abnormalities in deter-mining fatigue in ALS is unknown.Objective: To evaluate the frequency and determinants of fatigue in a group of 91consecutive patients with ALS, with special attention to the relationship betweenfatigue and sleep problems.Methods: Measures included the Fatigue Severity Scale (FSS), Pittsburgh SleepQuality Index (PSQI), Epworth Sleepiness Scale (ESS), ALS Functional Rating Scale-Revised (ALSFRS-R), and Beck Depression Inventory (BDI).Results: The mean FSS score was 4.35 ± 1.1, and 48 patients with ALS (52.75%)reported clinical signiﬁcant fatigue. FSS score correlated with ALSFRS-R score,forced vital capacity, ESS, BDI, and global PSQI score. Patients with fatigue weresigniﬁcantly more disabled and more frequently reported diﬃculties staying asleep andnocturnal complaints, such as nocturia and disturbing muscle cramps. After multi-variate analysis, patients disability and nocturnal complaints were signiﬁcantlyassociated with fatigue.Conclusion: In this study, we demonstrated that fatigue, a troublesome and disablingsymptom in ALS, is associated with physical impairment and night-time complaints(such as nocturia and muscle cramps), suggesting that treating sleep problems mightbe useful in alleviating fatigue in these patients.IntroductionFatigue is a common symptom in amyotrophic lateralsclerosis (ALS), aﬀecting 44–86% of patients with ALS[1–3]. Fatigue has been deﬁned as an overwhelmingsense of tiredness, lack of energy, and feeling ofexhaustion [4]. It has an important impact on quality oflife in patients with ALS [1], and it has been indicated asone of the reasons for shortening life in a Dutch study[5]. Fatigue in ALS has been associated with diseaseprogression, age, site of ALS onset, ALS severity, anddepression [1–3].The causes and mechanisms of fatigue in ALS aremultifactorial, including both central and peripheralfatigue [4]. Psychological factors linked to disease evo-lution and the physical obligates of daily life, respira-tory impairment, and medications (including riluzole,antispasticity, and antidepressants) could also play arole [4].Poor quality of sleep and excessive daytime somno-lence could also contribute to fatigue in ALS. In pre-vious studies, patients with ALS showed reduced totalsleep time, reduced sleep eﬃciency, and increased ap-neas and hypopneas [6,7]. Moreover, patients with ALSfrequently reported night-time complaints such asnocturia, muscle cramps, and restless legs syndrome [7–9]. However, whether speciﬁc aspects of sleep aﬀectfatigue in patients with ALS remains unknown [4].Therefore, we decided to investigate the frequencyand determinants of fatigue in a large group of patientswith ALS, with special attention to the relationshipbetween fatigue and sleep problems.Patients and methodsWe collected detailed clinical data of 91 consecutivepatients with ALS during their routine visit to our ALSCorrespondence: Daniele Lo Coco, ALS Research Center,Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche(BioNeC), Universita` di Palermo, Via G. La Loggia, 1 – 90129Palermo, Italy (tel.: +39 091 655 5158; fax: +39 091 655 5198;e-mail: danielelococo@yahoo.com).760 2012 The Author(s)European Journal of Neurology  2012 EFNSEuropean Journal of Neurology 2012, 19: 760–763 doi:10.1111/j.1468-1331.2011.03637.xCenter between February 2009 and June 2011. Patientswere diagnosed as deﬁnite or probable ALS according tothe El-Escorial WFN revised criteria [10].All subjects underwent a standardized face-to-faceinterview with a neurologist and expert in sleep medi-cine (DLC), board certiﬁed by the Italian Associationof Sleep Medicine. The structured interview collecteddata on sleep problems (yes or no type of answer).Subjects had to specify whether they had: (i) persistentinitial insomnia (diﬃculty falling asleep within 30 minor more); (ii) diﬃculties staying asleep (more than two‡30-min nocturnal awakenings independently of theneed to use the bathroom, or undesirable early morningawakening with inability to fall asleep again); (iii) un-refreshing sleep (feeling tired and sleepy after waking inthe morning). Symptoms should have lasted at least for1 month and had an impact on the subjects daily life.Information was also sought on whether patientssnored, had nocturia, postural discomfort, pain, ormuscle cramps. Nocturnal complaints were deﬁned bythe presence of two or more of the above-mentionedsymptoms for at least three nights at week, and theyhad to cause subjective discomfort.In addition, the Pittsburgh Sleep Quality Index(PSQI) was administered to all the study participants[11]. A PSQI score > 5 was taken to indicate poorsleep. Daytime somnolence was evaluated using theEpworth Sleepiness Scale (ESS) [12]. Excessive daytimesleepiness (EDS) was deﬁned by an ESS score ‡ 10.Fatigue was evaluated by the Fatigue Severity Scale(FSS) in which a score ‡ 4 indicates clinically signiﬁ-cant fatigue [13]. The scale has been recently validatedin a large sample size of healthy subjects, who showed amean score of 3.0 ± 1.08 [14].We also collected the following parameters for eachpatient with ALS included in the study: date and area ofALS onset, medical and drug history, forced vitalcapacity (FVC), and use of nocturnal ventilation.Severity of physical impairment was assessed by theALS Functional Rating Scale-Revised (ALSFRS-R)[15]. Depression was evaluated using Beck DepressionInventory (BDI) [16]. A score of >14 indicatesdepression.This study was approved by the institutional reviewboard of the University of Palermo. Written informedconsent was obtained from all participants.Statistical analyses were carried out using SPSS 10.0software (SPSS, Chicago, IL, USA). Continuous vari-ables were compared with the Mann–Whitney U test,and categorical variables were analyzed using the chi-square test. Binary correlation was evaluated withSpearmans correlation (q). Clinical and demographiccharacteristics, and sleep-related complaints were alsocompared in patients with and without fatigue (FSS ‡or < 4) using a univariate statistical analysis. Resultswere controlled using a stepwise multiple logisticregression model. Odds ratios (ORs) and 95% conﬁ-dence intervals (CIs) were calculated. Because of mul-tiple comparisons, a P value of < 0.01 (two-tailed) wasconsidered signiﬁcant.ResultsA total of 91 patients with ALS (36 women, 55 men;mean age: 61.26 ± 10.1 years) were included in thestudy. The site of ALS onset was bulbar in 24 patients(26.4%). Patients had a mean duration of ALS symp-toms of 24.9 ± 15.4 months, a mean ALSFRS-R scoreof 33.85 ± 8.75, and a mean FVC of 75.1% ± 23.45.Twelve patients used non-invasive ventilation. All butsix patients were taking riluzole. Mean BDI score was10.5 ± 5.12, and 25 patients (27.5%) were depressed.Sixteen patients (17.6%) were taking antispasticity orantidepressants. No patients had overt dementia.The mean global PSQI score of patients with ALSwas 7.0 ± 3.74. Fifty-two patients (57.14%) wereclassiﬁed as poor sleepers (global PSQI score > 5). Themean value of all components of PSQI is reported inTable 1. The most common sleep problems reported bypatients with ALS were nocturia (62.6%), nocturnalcramps (45%), diﬃculties turning in bed (38.5%), andsnoring (36.3%). Mean ESS score was 7.48 ± 2.54, and22 patients (24.2%) had EDS.The mean FSS score was 4.35 ± 1.1. Using the ac-cepted cut-oﬀ of ‡4, 48 of 91 patients (52.75%) reportedclinical signiﬁcant fatigue. FSS score was signiﬁcantlycorrelated with ALSFRS-R score (q = )0.51,P < 0.001), FVC (q = )0.34, P = 0.001), ESS score(q = 0.28, P = 0.007), BDI score (q = 0.31,P = 0.003), and global PSQI score (q = 0.25,P = 0.01).Table 2 shows the clinical and demographic charac-teristics of ALS patients with and without signiﬁcantfatigue (FSS ‡4). Patients with fatigue were signiﬁcantlymore disabled (P < 0.001) and more frequently re-ported diﬃculties staying asleep (P = 0.009) and noc-turnal complaints (P = 0.002) than those withoutfatigue. In the multivariate analysis – including ALS-FRS-R, FVC, ESS, BDI, global PSQI, insomnia, andnight-time complaints as confounding factors – patientsdisability (OR 0.91, 95% CI 0.86–0.97, P = 0.003) andnocturnal complaints (OR 3.19, 95% CI 1.24–8.24,P = 0.01) were signiﬁcant predictors of fatigue.DiscussionIn this cross-sectional study, we demonstrated thatfatigue, a troublesome and disabling symptom in ALS,Sleep and fatigue in ALS 761 2012 The Author(s)European Journal of Neurology  2012 EFNS European Journal of Neurologyis associated with sleep disturbances, in particular sleepmaintenance insomnia and night-time complaints.Moreover, in common with previous ﬁndings [1–3], weconﬁrmed that fatigue is a frequent problem in patientswith ALS, and in our study, more than half of patientsreported clinical signiﬁcant fatigue.Both peripheral fatigue (muscle fatigability owing todisorders of muscle and neuromuscular junction) andcentral fatigue (the subjective sense of fatigue essentiallyperceived at the level of the central nervous system)could contribute to physical fatigue in ALS [4]. More-over, incapacitating fatigue could be the result of apotentially correctable sleep-related abnormality [4]. Inour study, sleep maintenance insomnia was signiﬁcantlycorrelated with the presence of fatigue, and night-timecomplaints strongly predicted clinical signiﬁcant fatigueafter physical disability had been controlled for. Ourresults, then, strengthen the hypothesis that sleep dis-turbances could be an important cause of fatigue inpatients with ALS. As nocturia and muscle cramps werethe most frequently reported night-time complaints, it ispossible that addressing these symptoms may improvenot only sleep but also fatigue in many patients. On thecontrary, initial insomnia and unrefreshing sleep werenot signiﬁcantly associated with the presence of fatigue.These ﬁndings have implications for clinical man-agement. As data on pharmacological agents relievingfatigue in ALS are sparse, the clinician must use amultimodality approach. It has been shown that psy-chostimulant treatment (modaﬁnil) could be helpful, ifno treatable cause is identiﬁed [17]. Treatment ofassociated depression or poor nutrition could also beeﬀective. On the other hand, because there is someevidence that ventilatory support could reduce fatiguein other populations, non-invasive ventilation should beconsidered in those patients with respiratory impair-ment. In addition, muscle cramps should be aggres-sively treated, and although at present there areinsuﬃcient data to support or refute any speciﬁcintervention, gabapentin, vitamin E, and quinine couldbe of use [18]. Nocturia can be treated with a number ofpossible therapy options, depending on the etiology ofthe condition, including anticholinergics (e.g. toltero-dine, darifenacin, solifenacin), a-blockers/a-adrenergicblockers (e.g. tamsulosin), or with desmopressin [19].Finally, a variety of medications are available for use inpatients with insomnia, including benzodiazepines, thenon-benzodiazepine hypnotics (zolpidem, eszopiclone,and zaleplon), antihistamines, and the sedating antide-pressants (trazodone, amitriptyline, and mirtazapine).Another interesting ﬁnding of the study was that wedocumented a fair-to-moderate association betweenfatigue and depression, daytime somnolence, andrespiratory function. These associations however wereno longer signiﬁcant when other contributing factors,such as physical impairment, were accounted for,showing that ALS severity was the most importantclinical predictor of fatigue in the patients studied.Similarly, McElhiney et al. [3] also found an associationTable 2 Characteristics of patients with ALS with and without clinical signiﬁcant fatiguePatients with fatigue (n = 48) Patients without fatigue (n = 43) PAge, years 62.6 ± 8.66 59.77 ± 11.47 n.s.Gender, M/F 29/19 26/17 n.s.Duration of ALS symptoms, months 23.46 ± 14.78 26.51 ± 16.02 n.s.Bulbar ALS onset 10 (20.8%) 14 (32.6%) n.s.FVC, % of predicted 71.02 ± 21.87 79.65 ± 24.55 n.s.ALSFRS-R score 30.65 ± 8.59 37. 24 ± 7.54 <0.001ESS score 7.81 ± 2.74 7.12 ± 2.26 n.s.BDI score 10.69 ± 4.83 10.28 ± 5.47 n.s.Global PSQI score 7.36 ± 3.72 6.67 ± 3.75 n.s.Difﬁculties falling asleep 17 (35.4%) 17 (39.5%) n.s.Difﬁculties staying asleep 31 (64.6%) 16 (37.2%) 0.009Unrefreshing sleep 18 (37.5%) 10 (23.3%) n.s.Nocturnal complaints 28 (58.3%) 11 (25.6%) 0.002ALS, amyotrophic lateral sclerosis; FVC, forced vital capacity; ALSFRS-R, ALS Functional Rating Scale-Revised; ESS, Epworth SleepinessScale; BDI, Beck Depression Inventory; PSQI, Pittsburgh Sleep Quality Index.Table 1 Components PSQI scores in patients with ALSComponents of PSQI ALS group, mean ± SDSubjective sleep quality 0.93 ± 0.74Sleep latency 1.32 ± 1.11Sleep duration 1.14 ± 0.9Habitual sleep efﬁciency 1.07 ± 0.92Sleep disturbances 1.33 ± 0.61Use of sleeping medication 0.32 ± 0.84Daytime dysfunction 1.0 ± 0.86Global PSQI score 7.0 ± 3.74ALS, amyotrophic lateral sclerosis; PSQI, Pittsburgh Sleep QualityIndex.762 D. Lo Coco and V. La Bella 2012 The Author(s)European Journal of Neurology  2012 EFNS European Journal of Neurologybetween clinical signiﬁcant fatigue and ALS severity.They reported that the later stage of illness was asso-ciated with higher rates of fatigue, and there was somedegree of overlap between symptoms of fatigue anddepression. In partial contrast, Ramirez et al. [2] re-ported that fatigue was greater in the youngest patientsand worsened during follow-up, even if there was nocorrelation between fatigue and ALSFRS-R score. Louet al. [1] also studied a small population of 25 patientsand found that fatigue had a signiﬁcant impact onquality of life, but the severity of fatigue did not cor-relate with physical impairment, measured using theALSFRS. Taken together, these studies show that fa-tigue can have a great impact on patients with ALS,although diﬀerences in the populations studied and inthe methodologies used might account for the dispari-ties reported.The main limitation of the present study is the lack ofobjective measures of sleep quality, such as actigraphyor polysomnography, to verify the accuracy of self-report data, but we think it is extremely diﬃcult toobtain these measures when examining large popula-tions of patients. Moreover, the tools used in this studyare brief and easily administered, allowing a simple andstraightforward implementation in everyday clinicalpractice.Another limitation of the study is that we used aunidimensional instrument to assess fatigue, so wecould not measure physical and mental fatigue inde-pendently.In conclusion, the results of our study furtherstrengthen the need for routine enquiries about fatiguein ALS and suggest that questions about sleep andnocturnal complaints should be included in the regularreview of patients with ALS, in particular thosereporting fatigue.Disclosure of conflict of interestThe authors report no ﬁnancial support and noconﬂicts of interest.References1. Lou JS, Reeves A, Benice T, Sexton G. Fatigue anddepression are associated with poor quality of life in ALS.Neurology 2003; 60: 122–123.2. Ramirez C, Piemonte ME, Callegaro D, Da Silva HC.Fatigue in amyotrophic lateral sclerosis: frequency andassociated factors. Amyotroph Lateral Scler 2008; 9: 75–80.3. McElhiney MC, Rabkin JG, Gordon PH, Goetz R, Mit-sumoto H. Prevalence of fatigue and depression in ALSpatients and change over time. J Neurol Neurosurg Psy-chiatry 2009; 80: 1146–1149.4. Lou JS. Fatigue in amyotrophic lateral sclerosis. PhysMed Rehabil Clin N Am 2008; 19: 533–543.5. Maessen M, Veldink JH, Onwuteaka-Philipsen BD, et al.Trends and determinants of end-of-life practices in ALS inthe Netherlands. Neurology 2009; 73: 954–961.6. Ferguson KA, Strong MJ, Ahmad D, George CF. Sleep-disordered breathing in amyotrophic lateral sclerosis.Chest 1996; 110: 664–669.7. Lo Coco D, Mattaliano P, Spataro R, Mattaliano A, LaBella V. Sleep-wake disturbances in patients with amyo-trophic lateral sclerosis. J Neurol Neurosurg Psychiatry2011; 82: 839–842.8. Lo Coco D, Piccoli F, La Bella V. Restless legs syndromein patients with amyotrophic lateral sclerosis. Mov Disord2010; 25: 2658–2661.9. Limousin N, Blasco H, Corcia P, Arnulf I, Praline J. Thehigh frequency of restless legs syndrome in patients withamyotrophic lateral sclerosis. Amyotroph Lateral Scler2011; 12: 303–306.10. Brooks BR, Miller RG, Swash M, et al. El Escorialrevisited: revised criteria for the diagnosis of amyotrophiclateral sclerosis. Amyotroph Lateral Scler Other MotorNeuron Disord 2000; 1: 293–299.11. Busse DJ, Reynolds CF III, Monk TH, et al. ThePittsburgh Sleep Quality Index: a new instrument forpsychiatric practice and research. Psychiat Res 1989; 28:193–213.12. Johns MW. A new method for measuring daytime sleep-iness: the Epworth sleepiness scale. Sleep 1991; 14: 540–545.13. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD.The fatigue severity scale. Application to patients withmultiple sclerosis and systemic lupus erythematosus. ArchNeurol 1989; 46: 1121–1123.14. Valko PO, Bassetti CL, Bloch KE, Held U, Baumann CR.Validation of the fatigue severity scale in a Swiss cohort.Sleep 2008; 31: 1601–1607.15. Jesse M, Cedarbaum JM, Stambler N, et al. The ALS-FRS-R: a revised ALS functional rating scale that incor-porates assessments of respiratory function. J Neurol Sci1999; 169: 13–21.16. Beck A, Ward CH, Mendelson M, et al. An inventory formeasuring depression. Arch Gen Psychiatry 1961; 4: 561–571.17. Rabkin JG, Gordon P, McElhiney M, et al. Modaﬁniltreatment of fatigue in patients with ALS: a placebo-controlled study. Muscle Nerve 2009; 39: 297–303.18. Miller RG, Jackson CE, Kasarskis EJ, et al. Practiceparameter update: the care of the patient with amyo-trophic lateral sclerosis: multidisciplinary care, symptommanagement, and cognitive/behavioral impairment (anevidence-based review): report of the Quality StandardsSubcommittee of the American Academy of Neurology.Neurology 2009; 73: 1227–1233.19. Ancoli-Israel S, Bliwise DL, Nørgaard JP. The effect ofnocturia on sleep. Sleep Med Rev 2011; 15: 91–97.Sleep and fatigue in ALS 763 2012 The Author(s)European Journal of Neurology  2012 EFNS European Journal of Neurology

FATIGUE, SLEEP, AND NOCTURNAL COMPLAINTS IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS.

https://iris.unipa.it/retrieve/handle/10447/64565/45595/EJoN%20-%202012.pdf

FATIGUE, SLEEP, AND NOCTURNAL COMPLAINTS IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS.

Abstract

Similar works

Full text

Available Versions

Crossref

Archivio istituzionale della ricerca - Università di Palermo