The impact of mood disorders on the evaluation and management of fatigue in Parkinson’s
Drs. Roy G. Elbers, universitair docent, klinisch epidemioloog, fysiotherapeut
Approximately 32% to 50% of people with Parkinson’s disease (PD) complain about fatigue(1,2). Previous studies suggested that fatigue has a negative impact on health-related quality of life (HRQOL)3and physical activity(4,5). However, the real impact of fatigue on daily lifeis unknown. Depression and sleep disturbances commonly overlap with, or exacerbate feelings of fatigue(6). Given that mechanisms contributing to fatigue are still not well known(7) and the impact of fatigue on daily life is likely influenced by other factors, theevaluation and effective management of fatigue in people with PD is difficult.
The impact of fatigue and mood disorders on daily activity in PD
Recent studiesshowed that fatiguewas longitudinally associated with poorer overall HRQOL(8) and reduced physical activity(9). The association between fatigue and HRQOL was confounded by anxiety and depression(8), whereas the impact of fatigue on actual performed physical activity was distorted by depression(9). In contrast, motor impairment did not significantly distort the longitudinal association between fatigue and physical activity in people with PD(9). Above findings may support the hypothesis that decreased physical activity in people with chronic fatigue should primarily be understood in terms of reduced effort tolerance, caused by impaired neurobiological stress system functioning, rather than reduced effort capacity(10). Although fatigue has been reported as a primary symptom(1), recent evidenceunderlines that depression and other mood disorders are related to fatiguein people with PD(11-14). This implies that the evaluation and management of fatigue should include the assessment and treatment of underlying mood disorders.
Evaluation of fatigue in PD
Fatigue can be assessed through self-report or by direct observation of behavior. Recently the Multidimensional Fatigue Inventory (MFI)(15,16), the Functional Assessment of Chronic Illness Therapy Fatigue subscale (FACIT-F)(17) and the Fatigue Severity Scale (FSS)(15,16) have been recommended to evaluate fatigue in people with PD. However, it remains unclear if measurement error of these instruments is acceptable for detecting clinically meaningful change(15,17). Furthermore, structural validity has been questioned as the original dimensions of the MFI were not replicated in a principal component analysis(15), and item response theory methods found inadequate structural validity of the FACIT-F and FSS in people with PD(18). The latter suggests that items within the FACIT-F and the FSS measure different aspects of fatigue and that IRT adapted versions of these questionnaires may more specifically measure the impact of fatigue on activities in daily life when compared to the original versions.
Given the methodological limitations of available self-report questionnaires, one may argue that observation of performance may be a more precise assessment of fatigue. However, perceived fatigue and fatigability have been reported as distinct symptoms in people with PD(19), suggesting that self-report questionnaires and performance tests measure different aspects of fatigue.
Management of fatigue in PD
Treatment of fatigue usually involves pharmacological and non-pharmacological interventions. A recent Cochrane Review(20) suggests that doxepin may reduce fatigue and that rasagiline may reduce physical aspects of fatigue in people with PD. Based on the current evidence however, no clear recommendations can be provided for the use of pharmacological interventions to treat fatigue in people with Parkinson’s disease(20).
Although there has been increasing support for non-pharmacological interventions as an adjuvant to pharmacological treatment in people with PD(21), there is no consistent evidence that exercise reduces fatigue in people with PD. A meta-analysis showed that exercise did not significantly affect the impact of fatigue on activities in daily life or fatigue severity(20). This may be disappointing, as accumulating evidence suggests that exercise improves depression in the general population(22), and intensive goal-based exercise therapy combined with aerobic training may to some degree restore neuroplasticity within the basal ganglia in people with PD(23,24), and with that, may alleviate fatigue.
No studies that investigated the effect of cognitive-behavioral therapy on fatigue in people in PD were identified(20).
As fatigue may be secondary to mood disorders, and depression may exacerbate feelings of fatigue in people with PD(6), it has been suggested that depressive disorders may modify the effect of interventions on fatigue in people with PD(20). Therefore, treatment of fatigue should always be accompanied by evaluation and treatment of underlying depression(20).
Implications for practice
It is believed that fatigue has a negative impact on HRQOL and people with PD often complain that fatigue limits their physical activity. However, the impact of fatigue on HRQOL and physical activity is small and likely distorted by depression and anxiety. This suggests the involvement of a neurobiological stress system dysfunction in the adaptation and recovery from physical activity.Therefore, the management of fatigue in people with PD should always encompass a comprehensive assessment of mood disorders.
The MFI, FACIT-F and the FSS show promise for the assessment of fatigue; however, the structural validity of these self-report questionnaires seems inadequate. Robust IRT-adapted versions of these instruments allow a more valid and accurate measurement of fatigue in people with PD.
Based on the current evidence, it is difficult to provide recommendations for the treatment of fatigue in people with PD. Patient characteristics, such as underlying mood disorders, should be considered when treating fatigue. Effective pharmacological treatment of underlying depression, anxiety and sleep disorders may improve effort tolerance and should precede participation in an exercise program that aims to improve effort capacity. A combination of dopaminergic treatment, antidepressants and exercise therapy may provide synergistic benefits not seen with either intervention alone.
Implications for research
Fatigue and physical activity in people with PD may be understood in terms of reduced effort tolerance linked to abnormalities of the neurobiological stress system. However, the exact underlying neurobiological pathways that contribute to perceived fatigue, HRQOL and physicalactivity remain unclear. Future translational research should focus on the underlying neurohormonal mechanisms and clinical aspects reflecting effort capacity, effort tolerance and physical activity in people with PD.
Structural validity of self-report fatigue questionnaires should be confirmed in studies that use robust IRT methods.
Well-designed and adequately powered randomized controlled trials are needed to investigate the effect of intensive goal-based exercise in combination with aerobic training on exercise capacity, exercise tolerance, fatigue in people with PD. Future studies should focus on programs that target the behavioral or cognitive aspects of maladaptive behavior or coping related to fatigue. The role of patient characteristics, such as underlying mood disorders, should be considered when studying the effect of pharmacological and non-pharmacological interventions for fatigue.
Roy G. Elbers, MSc, assistant professor, clinical epidemiologist, physical therapist
Erwin E.H. van Wegen, PhD, senior researcher, human movement scientist
John Verhoef, PhD, professor, human movement scientist, physical therapist
Gert Kwakkel, PhD, professor in neurorehabilitation, human movement scientist, physical therapist
1. Alves G, Wentzel-Larsen T, Larsen J: Is fatigue an independent and persistent symptom in patients with Parkinson disease? Neurology 2004; 63: 1908-1911.
2. Herlofson K, Larsen J: Measuring fatigue in patients with Parkinson’s disease - the fatigue severity scale. Eur J Neurol 2002; 9: 595-600.
3. Havlikova E, Rosenberger J, Nagyova I, et al.: Impact of fatigue on quality of life in patients with Parkinson’s disease. Eur J Neurol 2008; 15: 475-480.
4. Herlofson K, Larsen J: The influence of fatigue on health-related quality of life in patients with Parkinson’s disease. Acta Neurol Scand 2003; 107: 1-6.
5. Garber C, Friedman J: Effects of fatigue on physical activity and function in patients with Parkinson’s disease. Neurology 2003; 60: 1119-1124.
6. Herlofson K, Ongre S, Enger L, et al.: Fatigue in early Parkinson’s disease. Minor inconvenience or major distress? Eur J Neurol 2012; 19: 963-968.
7. Friedman J, Brown R, Comella C, et al.: Fatigue in Parkinson’s disease: a review. Mov Disord 2007; 22: 297-308.
8. Elbers R, van Wegen E, Verhoef J, etal.:Impact of fatigue on health-related quality of life in patients with Parkinson’s disease:a prospective study. Clin Rehabil 2014; 28: 300-311.
9. Elbers R, van Wegen E, Rochester L, et al.: Is impact of fatigue an independent factor associated with physical activity in patients with idiopathic Parkinson’s disease? Mov Disord 2009; 24: 1512-1518.
10. Van Houdenhove B, Verheyen L, Pardaens K, et al.: Rehabilitation of decreased motor performance in patients with chronic fatigue syndrome: should we treat low effort capacity or reduced effort tolerance? Clin Rehabil 2007; 21: 1121-1142.
11. Metta V, Logishetty K, Martínez-Martín P, et al.: The possible clinical predictors of fatigue in Parkinson’s disease: a study of 135 patients as part of international nonmotor scale validation project. Parkinsons Dis 2011; 2011: 125271.
12. Van Dijk J, Havlikova E, Rosenberger J, et al.: Influence of disease severity on fatigue in patients with Parkinson’s disease is mainly mediated by symptoms of depression. European neurology 2013; 70: 201-209.
13. Skorvanek M, Nagyova I, Rosenberger J, et al.: Clinical determinants of primary and secondary fatigue in patients with Parkinson’s disease. J Neurol 2013; 260: 1554-1561.
14. Stocchi F, Abbruzzese G, Ceravolo R, et al.: Prevalence of fatigue in Parkinson disease and its clinical correlates. Neurology 2014; 83: 215-220.
15. Elbers R, van Wegen E, Verhoef J, et al.: Reliability and structural validity of the multidimensional fatigue inventory (MFI) in patients with idiopathic Parkinson’s disease. Parkinsonism Relat Disord 2012; 18: 532-536.
16. Friedman J, Alves G, Hagell P, et al.: Fatigue rating scales critique and recommendations by the Movement Disorders Society task force on rating scales for Parkinson’s disease. Mov Disord 2010; 25: 805-822.
17. Elbers R, Rietberg M, van Wegen E, et al.: Self-report fatigue quationnaires in multiple sclerosis, Parkinson’s disease and stroke: a systematic review of measurement properties. Qual Life Res 2012; 21: 925-944.
18. Hagell, Höglund A, Reimer J, et al.: Measuring fatigue in Parkinson’s disease: a psychometric study of two brief generic fatigue questionnaires. J Pain Symptom Manage 2006; 32: 420-432.
19. Lou J, Kearns G, Benice T, et al.: Levodopa improves physical fatigue in Parkinson’s disease: a double-blind, placebo-controlled, crossover study. Mov Disord 2003; 18: 1108-1114.
20. Elbers R, Verhoef J, van Wegen E, et al.: Interventions for fatigue in Parkinson’s disease. Cochrane Database Syst Rev 2015: CD010925.
21. Tomlinson C, Patel S, Meek C, et al.: Physiotherapy intervention in Parkinson’s disease: systematic review and meta-analysis. BMJ 2012; 345: e5004.
22. Cooney G, Dwan K, Greig C, et al.: Exercise for depression. Cochrane Database Syst Rev 2013: CD004366.
23. Petzinger G, Fisher B, McEwen S, et al.: Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet Neurol 2013; 12: 716-726.
24. Van Wegen E, Hirsch M, Huiskamp M, et al.: Harnessing cueing training for neuroplasticity in Parkinson disease. Top GeriatrRehabil 2014; 30: 46-57.