Fatigue in early Parkinson s disease: the Norwegian ParkWest study

ORIGINAL ARTICLE Fatigue in early Parkinson s disease: the Norwegian ParkWest study S. O. Ongre a, J. P. Larsen b, O. B. Tysnes c and K. Herlofson a a Department of Neurology, Sorlandet Hospital, Arendal; b Network for Medical Sciences, University of Stavanger, Stavanger; and c Department of Neurology, Haukeland University Hospital, Bergen, Norway See editorial by Friedman on page 5. Keywords: fatigue, Fatigue Severity Scale, longitudinal, non-motor symptoms, Parkinson s disease Received 8 April 2016 Accepted 9 August 2016 European Journal of Neurology 2017, 24: 105 111 doi:10.1111/ene.13161 Introduction The non-motor symptoms of Parkinson s disease (PD) are increasingly recognized but far from fully understood [1]. They are common, diverse and reported to reduce quality of life even more than the motor symptoms [2]. According to several studies, and in agreement with Braak s hypothesis, the non-motor symptoms may precede the motor symptoms by several years [3,4]. Fatigue in PD is a common, early and debilitating non-motor symptom that has been shown to affect as many as 55% of incident, drug-na ıve patients in recent Correspondence: K. Herlofson, Department of Neurology, Sorlandet Hospital Arendal, P.b. 783, Stoa, N-4809 Arendal, Norway (tel.: +47 91570201; fax: +47 37014010; e-mail: karen.herlofson@ sshf.no). Background and purpose: Fatigue is a common and disabling non-motor symptom in Parkinson s disease (PD). The pathogenesis is unknown, and the treatment options are limited. The aim of the present study was to investigate the development of fatigue during the first year after diagnosis. Methods: The study design was a prospective, controlled population-based longitudinal cohort study, comprising 181 de novo, drug-na ıve patients with PD and 162 control participants. PD was diagnosed according to the Gelb criteria. Fatigue was assessed by the Fatigue Severity Scale (FSS). Both groups were assessed for fatigue at baseline and after 1 year. Results: Patients reported more fatigue than the control subjects at baseline and at the 1-year follow-up evaluation. The FSS scores in the patient group improved from a mean score of 4.4 (SD 1.6) to 4.0 (SD 1.6). Patients with fatigue at baseline received higher doses of dopaminergic medication during follow-up. Patients who received dopamine agonists improved slightly more than patients who received levodopa. A regression analysis did not show a correlation between an improvement in fatigue and a change in disease severity, depressive symptoms, sleep problems, apathy or cognitive impairment. Conclusion: Fatigue is a common symptom in PD, also in early, untreated patients. During the first year of observation, an improvement in the fatigue scores was found. The improvement could not be attributed to a change in disease severity or depressive symptoms. The results indicate a better effect of dopamine agonists than of levodopa. This may have implications for treatment in patients with PD-associated fatigue. community-based studies [5 7]. There is no generally accepted definition of fatigue, but the sensation is often described as an overwhelming sense of tiredness, lack of energy, and feeling of exhaustion [8], not lack of motivation or sleepiness, and involves difficulty in initiating or sustaining voluntary activity [9]. Thus far, the longitudinal development [6,10,11] of fatigue has been studied mostly in selected patient groups, and the possible effect of medical treatment is unclear. Medications, including levodopa, dopamine agonists, monoamine oxidase B inhibitors, selective serotonin/serotonin-norepinephrine reuptake inhibitors, amantadine and modafinil have all been hypothesized to influence the degree of fatigue experienced, but the evidence is scarce [12]. The present study is part of the Norwegian Park- West study, a prospective, longitudinal cohort study EUROPEAN JOURNAL OF NEUROLOGY 105

106 S. O. ONGRE ET AL. of patients with incident PD and controls [13]. The aim was to investigate the development of central fatigue, both mental and physical, as measured by the Fatigue Severity Scale (FSS), in a community-based population of de novo, initially drug-na ıve PD patients during the first year after diagnosis. The evolution of fatigue in these PD patients was compared to the corresponding development in the control group and the possible influence of dopaminergic treatment on fatigue was explored in the patient group. Study population Patients and methods This study is part of the Norwegian ParkWest project, a prospective controlled population-based longitudinal cohort study of patients with incident PD in western and southern Norway. The diagnosis of PD was made according to the Gelb and UK Brain Bank diagnostic criteria [14,15]. The ParkWest study originally included 212 patients, and the diagnostic procedures and methods of case ascertainment have been described in detail previously [13]. In this study, 31 patients were excluded for one or more of the following reasons: not drug na ıve at baseline, dementia at baseline that was diagnosed post hoc, re-diagnosed as not having PD during the study period or had incomplete data evaluating fatigue. The included subjects comprised 181 drug-na ıve, newly diagnosed PD patients and 162 control subjects matched for age and gender. All persons included were Caucasians. The study protocol for ParkWest was approved by the Regional Committee for Medical Research Ethics in western Norway. Signed informed consent was obtained from all participants. Evaluation programme All patients underwent extensive semi-structured interviews by both neurologists and study nurses and completed self-assessment forms that were validated for the Norwegian language. In addition, a physical examination was performed by a neurologist both at inclusion and at the 1-year follow-up evaluation. All patients were examined and interviewed in the on period. Disease severity was assessed by the Unified Parkinson Disease Rating Scale (UPDRS) [16], the modified Hoehn and Yahr staging scale [17] and the Schwab and England scale [18]. All patients were evaluated by all four subscales of the UPDRS (I: Mentation, behaviour and mood; II: Activities of daily living; III: Motor; IV: Complications), whereas the control subjects were evaluated only by subscale II. Levodopa equivalent dose (LED) was calculated for the different dopaminergic medications [19]. Fatigue was measured by the FSS, a nine-item selfadministered scale that is validated for PD and recommended for both screening and severity rating [8,20]. The psychometric properties have also been validated in Norwegian [21]. Each question is rated on a sevenpoint Likert scale in which 1 signifies I strongly disagree and 7 signifies I strongly agree. The total score is given as the mean score of all items. A total FSS mean score 4 is used by the developers and most other groups as a cut-off for clinically significant fatigue and has been adopted in the present study [8]. Depressive symptoms were assessed by the Montgomery and Aasberg Depression Rating Scale (MADRS), a 10-item interview in which the questions are rated from 0 to 6 with an increasing severity [22]. This yields a range of 0 60, where a score of 15 indicates clinically significant depressive symptoms [23]. Apathy was evaluated using the Starkstein Apathy Scale [24]. A higher score indicates a higher degree of apathy. Sleep quality was evaluated by the Parkinson s disease sleep scale (PDSS) [25] and the Epworth Sleepiness Scale (ESS) [26]. Cognition was evaluated by the Mini Mental State Examination (MMSE) [27], an interview-based questionnaire with a score ranging from 0 to 30. Scores <24 indicate cognitive impairment [28]. Statistical analyses All data were analysed using the software program SPSS version 16.0 and 21.0 (SPSS Inc., Chicago, IL, USA). Comparisons of means between patients and controls for continuous variables were analysed using Student s t test for independent samples or paired samples where appropriate. A chi-squared test was used for gender. All P values are two-tailed, and P values <0.05 were considered statistically significant. The relationship between the change in FSS mean sum scores and the demographic and clinical properties for the patient group was analysed with multiple linear regression analysis. Results The demographic and clinical data at baseline and after 1 year of follow-up for the 181 patients and the 162 control subjects are presented in Table 1. The patient population displayed more fatigue, depressive

FATIGUE IN EARLY PARKINSON S DISEASE 107 Table 1 Demographic and clinical data for the patient and control groups at baseline and at the 1-year follow-up Baseline 1 year Characteristic Patients (n = 181) Controls (n = 162) Patients (n = 181) Controls (n = 162) Male, n (%) 110 (60.8) 98 (60.5) Age at inclusion, years 67.3 (9.3) 67.2 (8.9) Education, years 11.2 (3.3) 11.7 (3.3) MADRS, mean score 4.5 (4.9) a 1.2 (2.6) 3.2 (4.2) ab 1.5 (3.6) MMSE, mean score 27.9 (2.3) a 28.6 (1.4) 28.1 (2.3) a 28.8 (1.2) ESS, mean score 6.0 (3.7) a 5.1 (2.9) 6.4 (4.0) a 5.2 (2.9) PDSS, mean score 118.3 (19.9) a 125.4 (15.0) 120.2 (17.6) a 127.1 (13.8) b SAS, mean score 15.4 (4.7) a 13.7 (3.9) 15.9 (4.5) a 14.0 (4.2) UPDRS I, mean score 2.0 (1.8) 1.9 (1.7) UPDRS II, mean score 8.6 (4.7) a 0.60 (1.3) 7.5 (4.2) ab 0.62 (1.6) UPDRS III, mean score 22.8 (10.8) 18.5 (9.9) b UPDRS IV, mean score 0.56 (1.1) 0.82 (1.2) b Hoehn and Yahr, mean score 1.9 (0.62) 1.9 (0.71) Schwab and England, mean score 88.6 (8.9) 89.7 (9.2) FSS, total mean average score 4.4 (1.6) a 3.1 (1.3) 4.0 (1.6) ab 3.0 (1.4) MADRS, Montgomery and Aasberg Depression Rating Scale; MMSE, Mini-Mental State Examination; ESS, Epworth Sleepiness Scale; PDSS, Parkinson s Disease Sleep Scale; SAS, Starkstein Apathy Scale; UPDRS, Unified Parkinson s Disease Rating Scale (I: Mentation, behaviour and mood; II: Activities of daily living; III: Motor; IV: Complications); FSS, Fatigue Severity Scale. Values presented as mean (SD). a Represents significant difference between patients and controls at the corresponding visit, two-sided P < 0.05, independent sample t test; b Represents significant difference within the patient or control group between the two visits, two-sided P < 0.05, paired sample t test. symptoms, cognitive impairment, sleep problems and apathy than the control subjects, both at baseline and at the 1-year follow-up examination. The patient group showed small improvements in depressive symptoms, UPDRS II, UPDRS III and fatigue scores. The improvements in the FSS scores were equal for both genders. The control subjects had a slight but statistically significant improvement in sleep quality, but they were stable considering the other variables assessed. The changes in the FSS scores are shown in Table 2. There were significant differences between patients and controls regarding all nine items of the FSS, both at baseline and at the 1-year follow-up. The FSS mean sum scores and scores on four of the individual items were lower in the patient group at the 1-year visit compared to baseline. The improvements were 9.1% for the total mean sum score, 12.5% for FSS item 1 ( My motivation is lower when I am fatigued ), 11.1% for FSS item 7 ( Fatigue interferes with carrying out certain duties ), 12.8% for FSS item 8 ( Fatigue is amongst my three most disabling symptoms ) and 12.8% for FSS item 9 ( Fatigue interferes with my work, family or social life ). Persistence of fatigue Clinically significant fatigue was present in 63 of 181 patients at both assessments. Between baseline and the 1-year follow-up evaluation 25 patients had developed fatigue, and 35 patients no longer had a score indicating clinically significant symptoms (Fig. 1). There was no correlation between improvement in the FSS mean sum score and changes in depressive symptoms, as measured by the MADRS. Effect of medication During the first year after the diagnosis, 157 patients were started on antiparkinson medication. Amongst these 157 patients, 117 received monotherapy, 37 were treated with two medications and three were treated with levodopa, dopamine agonist and monoamine oxidase B inhibitor. None of the patients was medicated with other antiparkinson drugs. The mean daily LED at the 1-year follow-up was 292 mg (confidence interval 268; 316); 111 patients used less than 400 mg and 46 patients used 400 mg or above. For the treated patients who did not have fatigue at baseline, the mean LED was 262 mg (229; 295) (N = 74) and 319 mg (285; 353) amongst the fatigued patients (N = 83). Student s t test for independent samples yielded a two-sided P value of 0.017 with a mean difference in LED of 57 mg. Table 3 shows that only dopamine agonists showed a statistically significant effect on fatigue with a mean decrease in the FSS total mean sum of 1.4. The same analyses were performed for the patients who were non-fatigued at baseline (N = 83), but there were no significant differences for any of the variables.

108 S. O. ONGRE ET AL. Table 2 FSS scores including sub-items for the patient and control groups at baseline and at the 1-year follow-up Baseline 1 year Patients (n = 181) Controls (n = 162) Patients (n = 181) Controls (n = 162) FSS total Total score 4.4 (1.6) a 3.1 (1.3) 4.0 (1.6) ab 3.0 (1.4) FSS item 1 My motivation is lower when I am fatigued 5.6 (1.8) a 4.8 (1.8) 4.9 (1.9) ab 4.4 (2.0) b FSS item 2 Exercise brings on my fatigue 4.7 (1.9) a 3.3 (1.8) 4.4 (1.8) a 3.2 (1.8) FSS item 3 I am easily fatigued 4.2 (2.1) a 2.6 (1.6) 4.1 (1.9) a 2.8 (1.8) FSS item 4 Fatigue interferes with my physical functioning 4.8 (1.9) a 4.0 (2.0) 4.7 (1.9) a 3.6 (2.0) b FSS item 5 Fatigue causes frequent problems for me 3.6 (2.1) a 2.3 (1.6) 3.5 (2.0) a 2.3 (1.7) FSS item 6 My fatigue prevents sustained physical functioning 4.2 (2.1) a 2.9 (1.9) 4.0 (2.0) a 2.8 (1.8) FSS item 7 Fatigue interferes with carrying out certain duties and responsibilities 4.5 (2.0) a 3.0 (1.9) 4.0 (1.9) ab 2.8 (1.8) FSS item 8 Fatigue is amongst my three most disabling symptoms 3.9 (2.2) a 2.1 (1.7) 3.4 (2.2) ab 2.2 (1.7) FSS item 9 Fatigue interferes with my work, family or social life 3.9 (2.2) a 2.3 (1.8) 3.4 (2.0) ab 2.4 (1.8) FSS, Fatigue Severity Scale. Values presented as mean (SD). a Represents significant difference between patients and controls at the corresponding visit, two-sided P < 0.05, independent sample t test; b Represents significant difference within the patient or control group between the two visits, two-sided P < 0.05, paired sample t test. Fatigued at baseline N = 98 Non-fatigued at baseline N = 83 N = 35 N = 25 N = 63 N = 58 Fatigued at the one-year follow-up N = 88 Non-fatigued at the one-year follow-up N = 93 Figure 1 Diagram of fatigue change over time. Regression analysis A multiple linear regression model was performed for all patients with the FSS mean difference as the dependent variable. The demographic and clinical data at baseline, as listed in Table 1, comprised the independent variables. The adjusted explained variance was 28.5%. In the final model, only the FSS mean sum at baseline (b = 0.546) and age (b = 0.026) had significant P values (cut-off P < 0.05). Sleep, as measured by the PDSS and ESS, and depression as measured by the MADRS did not yield statistically significant contributions. Many of the variables showed a difference of more than 25% between the crude and adjusted b indicating confounding factors. A multiple regression model was then performed for the 98 patients with FSS score 4 at baseline. As independent variables age, gender, UPDRS motor score, MMSE, FSS sum score at baseline, medication with levodopa and medication with agonist were included. The adjusted explained variance was 15.0% and only the FSS sum score at baseline (b = 0.532) and medication with agonist (b = 0.875) contributed to the model (P < 0.05). Discussion This study shows that fatigue was improved in patients with PD between the drug-na ıve baseline evaluation and 1 year later when medical treatment had been initiated. The improvement was moderate, but it was considered clinically relevant for the patient. There was no change in the total fatigue score during follow-up in the control group. Patients with fatigue at baseline received higher doses of dopaminergic medication at the 1-year follow-up, and our results indicate a better effect of dopamine agonists than levodopa on the severity of fatigue symptoms. This may have implications for the choice of treatment in patients with PD-associated fatigue.

FATIGUE IN EARLY PARKINSON S DISEASE 109 Table 3 Overview of antiparkinson medication and comparison of change in FSS mean sum score between baseline and the 1-year evaluation in patients with fatigue (FSS mean sum score 4) at baseline (N = 98) Yes No Medication Number of patients Change in FSS mean sum Number of patients Change in FSS mean sum P value Any PD medication (LD, DA, MAO-Bi) 83 0.98 15 0.72 0.52 Levodopa 51 0.75 47 1.2 0.17 Dopamine agonist 37 1.4 61 0.65 0.010 a MAO-Bi 17 1.38 81 0.85 0.18 LED above 400 28 0.94 70 0.94 0.996 FSS, Fatigue Severity Scale; PD, Parkinson s disease; LD, levodopa; DA, dopamine agonist; MAO-Bi, monoamine oxidase B inhibitor; LED, levodopa equivalent dose. FSS mean sum score at the 1-year follow-up minus FSS mean sum score at baseline. a Represents statistically significant difference in the change in FSS mean sum score between the fatigued and non-fatigued groups. Two-sided P < 0.05 Student t test for independent samples. Fatigue is a frequent complaint in patients with PD, and it may be severe in some patients. Nevertheless, little progress has been made in the understanding of important issues related to its causes and treatment. In addition, the development of fatigue over time has been insufficiently explored. Three studies [6,10,11] evaluating fatigue at different time points have all concluded that fatigue is a persistent symptom and may increase over time. None of these studies evaluated fatigue from the time of diagnosis. In this study of early PD, a significant improvement in the mean FFS score was observed, from 4.4 without medication to 4.0 after 1 year of treatment with dopaminergic drugs. In addition, our study showed a positive small effect of dopamine agonists but not of levodopa treatment. Studies with dopaminergic or other treatments in more advanced PD have been disappointing. In a recent review [12], it was concluded that so far there is insufficient evidence to support the treatment of fatigue in PD with any drug or non-drug treatment. Our positive findings must be interpreted with caution, as patients who received agonists tended to be younger with less advanced disease. The pathogenesis of fatigue is unknown. The proposed mechanisms include dysfunction of dopaminergic pathways in the striatum and extrastriatal pathways, non-dopaminergic pathways, inflammatory mechanisms, frontal/prefrontal dysfunction and involvement of the autonomic nerve system. Studies of fatigue in PD have not shown a strong association with the severity of the motor symptoms of the disease, the degree of reduced dopamine metabolism in DaT scans or the duration of disease [7]. This indicates that factors other than reduced levels of dopamine are mainly responsible for the presence and severity of fatigue. A multiple regression analysis was performed to uncover any clinical or demographic factors that could predict the development of fatigue during the first year after diagnosis. It was found that a higher FSS score at the time of diagnosis and age were the only remaining significant factors in the model. This implicates that older patients with early symptoms of fatigue in particular should be informed about this complaint as part of the disease process, and later on during management and follow-up they should be especially observed for this symptom. There are several possible confounding factors that need to be considered as to why fatigue improved during the study period. Many patients may have had symptoms for some time before receiving a diagnosis, and the uncertainty caused by experiencing a wide range of symptoms may contribute to both disease burden and fatigue. After receiving a diagnosis, all patients are followed regularly, and they receive information and advice in addition to medical treatment. During this first year, not only are the fatigue scores improved, but also the motor symptoms and depressive symptoms showed a positive development. In the patient group with improvement in FSS there was no correlation with a change in depressive symptoms, as measured by the MADRS. The main strength of this study is the well-defined patient population. Great care was taken to include all newly identified patients in a certain geographical area. Established diagnostic criteria for PD were used at inclusion, and the attrition rate during follow-up was very low. One of the challenges of exploring fatigue in patients with PD is the lack of case definition. The main feature is usually described as a lack of energy, not a lack of motivation or sleepiness. Fatigue therefore needs to be distinguished from other symptoms, such as sleep disturbances, depressive symptoms or apathy, but comorbidity is common. As the different symptoms may have a different biological basis and a different response to treatment, it is important to discriminate between them. Our study indicates a

110 S. O. ONGRE ET AL. possible positive effect of dopamine agonists on fatigue. However, dopamine agonists are known to cause increased sleepiness [29], thus underpinning the need to differentiate between these two common symptoms of the disease. In this study, it was found that during the first year of observation there was a small improvement in the fatigue scores. There was no association with levodopa, but there was an indication that dopamine agonists might have a positive effect. The further development of fatigue over time needs to be studied over a longer timeframe to establish the development of fatigue in patients with PD. Acknowledgements The authors are grateful to all patients and control subjects for their willingness to participate in this study and thank all personnel involved in planning and conducting the Norwegian ParkWest study. The study was supported by a grant from the South-eastern Norway Health Authority. 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