Fatigue is complex and can occur as a primary or secondary symptom as well as a comorbidity of neurological disease; multiple types can coexist in the same patient
Disentangling the origin and nature of fatigue in patients with neurological diseases is challenging and often fails to achieve an unambiguous assignment of fatigue
Fatigue can be characterized by standardized self-report questionnaires and fatigability testing, which can help to determine the impact of fatigue on patients' daily life
Assessments of fatigue can help to guide pharmacological treatment decision-making even in the absence of convincing evidence-based strategies
Nonpharmacological strategies, such as mindfulness-based stress reduction, cooling, yoga, exercise and cognitive rehabilitation, can help to manage fatigue in patients with neurological diseases
Fatigue, best described as an overwhelming feeling of tiredness and exhaustion, occurs in the context of various neurological diseases. The high prevalence of fatigue as either a symptom or a comorbidity of neurological disease must be taken seriously, as fatigue interferes with patients' activities of daily living, has a remarkable negative impact on quality of life, and is a major reason for early retirement. The tremendous consequences of fatigue are consistent across neurological diseases, as is the uncertainty concerning its underlying pathophysiological mechanisms. Inconsistencies in defining fatigue contribute to the present situation, in which fatigue represents one of the least-studied and least- understood conditions. Tools for assessing fatigue abound, but few can be recommended for clinical or research use. To make matters worse, evidence-based pharmacological treatment options are scarce. However, non-pharmacological approaches are currently promising and likely to become of increasing importance. In sum, fatigue is challenging for both health-care professionals and patients. The present article aims to provide a comprehensive review of the literature on fatigue in neurological disease, and to reveal its complexity, as well as weaknesses in the concept of fatigue itself.
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Lagrange, F. Physiologie des Exercices du Corps (Félix Alcan, 1888).
Beard, G. M. American Nervousness, its Causes and Consequences; A Supplement to Nervous Exhaustion (Neurasthenia) (W. Wood & Company, 1881).
Beard, G. M. A Practical Treatise on Nervous Exhaustion, (Neurasthenia); Its Symptoms, Nature, Sequences, Treatment. (W. Wood & Company,1880).
Dubois, P. Die Psychoneurosen und ihre Psychische Behandlung (Francke, 1905).
Dittner, A. J., Wessely, S. C. & Brown, R. G. The assessment of fatigue: a practical guide for clinicians and researchers. J. Psychosom. Res. 56, 157–170 (2004).
Chaudhuri, A. & Behan, P. O. Fatigue in neurological disorders. Lancet 363, 978–988 (2004).
Kluger, B. M., Krupp, L. B. & Enoka, R. M. Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy. Neurology 80, 409–416 (2013).
Lou, J.-S. et al. Levodopa improves physical fatigue in Parkinson's disease: a double-blind, placebo-controlled, crossover study. Mov. Disord. 18, 1108–1114 (2003).
Bailey, A., Channon, S. & Beaumont, J. G. The relationship between subjective fatigue and cognitive fatigue in advanced multiple sclerosis. Mult. Scler. 13, 73–80 (2007).
Krupp, L. B. & Elkins, L. E. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology 55, 934–939 (2000).
Roelcke, U. et al. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology 48, 1566–1571 (1997).
Filippi, M. et al. Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis. Neuroimage 15, 559–567 (2002).
Heesen, C. et al. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J. Neurol. Neurosurg. Psychiatry 77, 34–39 (2006).
Gottschalk, M. et al. Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis. Arch. Neurol. 62, 277–280 (2005).
Téllez, N. et al. Fatigue in progressive multiple sclerosis is associated with low levels of dehydroepiandrosterone. Mult. Scler. 12, 487–494 (2006).
Veauthier, C. et al. Treatment of sleep disorders may improve fatigue in multiple sclerosis. Clin. Neurol. Neurosurg. 115, 1826–1830 (2013).
Veauthier, C. et al. Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study. Mult. Scler. 17, 613–622 (2011).
Stanton, B. R., Barnes, F. & Silber, E. Sleep and fatigue in multiple sclerosis. Mult. Scler. 12, 481–486 (2006).
Kroenke, K., Wood, D. R., Mangelsdorff, A. D., Meier, N. J. & Powell, J. B. Chronic fatigue in primary care. prevalence, patient characteristics, and outcome. JAMA 260, 929–934 (1988).
Taylor, R. R., Jason, L. A. & Jahn, S. C. Chronic fatigue and sociodemographic characteristics as predictors of psychiatric disorders in a community-based sample. Psychosom. Med. 65, 896–901 (2003).
Harvey, S. B., Wadsworth, M., Wessely, S. & Hotopf, M. The relationship between prior psychiatric disorder and chronic fatigue: evidence from a national birth cohort study. Psychol. Med. 38, 933–940 (2008).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Publishing, 2013).
Corfield, E. C., Martin, N. G. & Nyholt, D. R. Co-occurrence and symptomatology of fatigue and depression. Compr. Psychiatry 71, 1–10 (2016).
Addington, A. M., Gallo, J. J., Ford, D. E. & Eaton, W. W. Epidemiology of unexplained fatigue and major depression in the community: the Baltimore ECA follow-up, 1981–1994. Psychol. Med. 31, 1037–1044 (2001).
Hanley, N. S. & Van de Kar, L. D. Serotonin and the neuroendocrine regulation of the hypothalamic–pituitary–adrenal axis in health and disease. Vitam. Horm. 66, 189–255 (2003).
Qamhawi, Z. et al. Clinical correlates of raphe serotonergic dysfunction in early Parkinson's disease. Brain 138, 2964–2973 (2015).
Kos, D., Kerckhofs, E., Nagels, G., D'hooghe, M. B. & Ilsbroukx, S. Origin of fatigue in multiple sclerosis: review of the literature. Neurorehabil. Neural Repair 22, 91–100 (2007).
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008).
Harrison, N. A. et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol. Psychiatry 66, 407–414 (2009).
Hanken, K., Eling, P. & Hildebrandt, H. The representation of inflammatory signals in the brain — a model for subjective fatigue in multiple sclerosis. Front. Neurol. 5, 264 (2014).
Veauthier, C. The Berlin treatment algorithm. Recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue. EPMA J. 7, 25 (2016).
Gold, S. M. et al. Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. J. Neurol. Neurosurg. Psychiatry 82, 814–818 (2011).
Powell, D. J. H., Moss-Morris, R., Liossi, C. & Schlotz, W. Circadian cortisol and fatigue severity in relapsing-remitting multiple sclerosis. Psychoneuroendocrinology 56, 120–131 (2015).
Pellicano, C. et al. Relationship of cortical atrophy to fatigue in patients with multiple sclerosis. Arch. Neurol. 67, 447–453 (2010).
Yaldizli, Ö. et al. Fatigue and progression of corpus callosum atrophy in multiple sclerosis. J. Neurol. 258, 2199–2205 (2011).
Yaldizli, Ö. et al. The relationship between total and regional corpus callosum atrophy, cognitive impairment and fatigue in multiple sclerosis patients. Mult. Scler. 20, 356–364 (2014).
Sander, C. et al. The impact of MS-related cognitive fatigue on future brain parenchymal loss and relapse: a 17-month follow-up study. Front. Neurol. 7, 155 (2016).
Sepulcre, J. et al. Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways. Mult. Scler. 15, 337–344 (2008).
Pardini, M., Bonzano, L., Mancardi, G. L. & Roccatagliata, L. Frontal networks play a role in fatigue perception in multiple sclerosis. Behav. Neurosci. 124, 329 (2010).
Zhang, J.-J. et al. Abnormal resting-state neural activity and connectivity of fatigue in Parkinson's disease. CNS Neurosci. Ther. 23, 241–247 (2017).
Pravatà, E. et al. Hyperconnectivity of the dorsolateral prefrontal cortex following mental effort in multiple sclerosis patients with cognitive fatigue. Mult. Scler. 13, 1665–1675 (2016).
Finke, C. et al. Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue. Mult. Scler. 21, 925–934 (2015).
Ponchel, A., Bombois, S., Bordet, R. & Hénon, H. Factors associated with poststroke fatigue: a systematic review. Stroke Res. Treat. 2015, 347920 (2015).
Wu, S., Mead, G., Macleod, M. & Chalder, T. Model of understanding fatigue after stroke. Stroke 46, 893–898 (2015).
Derache, N. et al. Fatigue is associated with metabolic and density alterations of cortical and deep gray matter in relapsing–remitting-multiple sclerosis patients at the earlier stage of the disease: a PET/MR study. Mult. Scler. Relat. Disord. 2, 362–369 (2013).
Dobryakova, E., Genova, H. M., DeLuca, J. & Wylie, G. R. The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. Front. Neurol. 6, 52 (2015).
Krupp, L. B., LaRocca, N. G., Muir-Nash, J. & Steinberg, A. D. The fatigue severity scale: application to patients with multiple sclerosis and systemic lupus erythematosus. Arch. Neurol. 46, 1121–1123 (1989).
Bakshi, R. et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult. Scler. 6, 181–185 (2000).
Flachenecker, P. et al. Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Mult. Scler. 8, 523–526 (2002).
Elbers, R. G. et al. Self-report fatigue questionnaires in multiple sclerosis, Parkinson's disease and stroke: a systematic review of measurement properties. Qual. Life Res. 21, 925–944 (2012).
Fisk, J. D., Pontefract, A., Ritvo, P. G., Archibald, C. J. & Murray, T. J. The impact of fatigue on patients with multiple sclerosis. Can. J. Neurol. Sci. 21, 9–14 (1994).
Téllez, N. et al. Does the modified fatigue impact scale offer a more comprehensive assessment of fatigue in MS? Mult. Scler. 11, 198–202 (2005).
Penner, I. K. et al. The fatigue scale for motor and cognitive functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult. Scler. 15, 1509–1517 (2009).
Hubacher, M. et al. Assessment of post-stroke fatigue: the fatigue scale for motor and cognitive functions. Eur. Neurol. 67, 377–384 (2012).
Liu, X. et al. Increased TH17/TReg ratio in poststroke fatigue. Mediators Inflamm. 2015, 931398 (2015).
McNair, D. M., Droppleman, L. F. & Lorr, M. EdITS Manual for the Profile of Mood States: POMS (EdITS, 1992).
Krupp, L. B., Alvarez, L. A., LaRocca, N. G. & Scheinberg, L. C. Fatigue in multiple sclerosis. Arch. Neurol. 45, 435–437 (1988).
Colosimo, C. et al. Fatigue in MS is associated with specific clinical features. Acta Neurol. Scand. 92, 353–355 (1995).
Comi, G., Leocani, L., Rossi, P. & Colombo, B. Physiopathology and treatment of fatigue in multiple sclerosis. J. Neurol. 248, 174–179 (2001).
Amato, M. P. et al. Quality of life in multiple sclerosis: the impact of depression, fatigue and disability. Mult. Scler. 7, 340–344 (2001).
Flensner, G., Landtblom, A.-M., Söderhamn, O. & Ek, A.-C. Work capacity and health-related quality of life among individuals with multiple sclerosis reduced by fatigue: a cross-sectional study. BMC Public Health 13, 224 (2013).
Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis: Evidence-Based Management Strategies For Fatigue in Multiple Sclerosis (Paralyzed Veterans of America, 1998).
Mills, R. J. & Young, C. A. The relationship between fatigue and other clinical features of multiple sclerosis. Mult. Scler. 17, 604–612 (2011).
Veauthier, C. & Paul, F. Fatigue in multiple sclerosis: which patient should be referred to a sleep specialist? Mult. Scler. 18, 248–249 (2012).
Veauthier, C. & Paul, F. Sleep disorders in multiple sclerosis and their relationship to fatigue. Sleep Med. 15, 5–14 (2014).
Veauthier, C. & Paul, F. Therapy of fatigue in multiple sclerosis: a treatment algorithm [German]. Nervenarzt 87, 1310–1321 (2016).
Mücke, M. et al. Pharmacological treatments for fatigue associated with palliative care. Cochrane Database Syst. Rev. 5, CD006788 (2015).
Asano, M. & Finlayson, M. L. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Mult. Scler. Int. 2014, 798285 (2014).
Peuckmann, V., Elsner, F., Krumm, N., Trottenberg, P. & Radbruch, L. Pharmacological treatments for fatigue associated with palliative care. Cochrane Database Syst. Rev. 11, CD006788 (2010).
Tur, C. Fatigue management in multiple sclerosis. Curr. Treat. Options Neurol. 18, 26 (2016).
Brenner, P. & Piehl, F. Fatigue and depression in multiple sclerosis: pharmacological and non-pharmacological interventions. Acta Neurol. Scand. 134, 47–54 (2016).
Hader, W. et al. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can. J. Neurol. Sci. 14, 273–278 (1987).
Cohen, R. A. & Fisher, M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch. Neurol. 46, 676–680 (1989).
Ledinek, A. H., Sajko, M. C. & Rot, U. Evaluating the effects of amantadin, modafinil and acetyl-l-carnitine on fatigue in multiple sclerosis — result of a pilot randomized, blind study. Clin. Neurol. Neurosurg. 115 (Suppl. 1), S86–S89 (2013).
Geisler, M. W. et al. The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis. Arch. Neurol. 53, 185–188 (1996).
Krupp, L. B. et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 45, 1956–1961 (1995).
Murray, T. J. Amantadine therapy for fatigue in multiple sclerosis. Can. J. Neurol. Sci. 12, 251–254 (1985).
Rosenberg, G. A. & Appenzeller, O. Amantadine, fatigue, and multiple sclerosis. Arch. Neurol. 45, 1104–1106 (1988).
Ashtari, F., Fatehi, F., Shaygannejad, V. & Chitsaz, A. Does amantadine have favourable effects on fatigue in Persian patients suffering from multiple sclerosis? Neurol. Neurochir. Pol. 43, 428–432 (2009).
Shaygannejad, V., Janghorbani, M., Ashtari, F. & Zakeri, H. Comparison of the effect of aspirin and amantadine for the treatment of fatigue in multiple sclerosis: a randomized, blinded, crossover study. Neurol. Res. 34, 854–858 (2012).
Pucci, E. et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst. Rev. 1, CD002818 (2007).
Taus, C., Giuliani, G., Pucci, E., D'Amico, R. & Solari, A. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst. Rev. 2, CD002818 (2003).
Ziemssen, T., Hoffman, J., Apfel, R. & Kern, S. Effects of glatiramer acetate on fatigue and days of absence from work in first-time treated relapsing–remitting multiple sclerosis. Health Qual. Life Outcomes 6, 67 (2008).
Putzki, N., Yaldizli, Ö., Tettenborn, B. & Diener, H. C. Multiple sclerosis associated fatigue during natalizumab treatment. J. Neurol. Sci. 285, 109–113 (2009).
Yildiz, M., Tettenborn, B. & Putzki, N. Multiple sclerosis-associated fatigue during disease-modifying treatment with natalizumab, interferon-β and glatiramer acetate. Eur. Neurol. 65, 231–232 (2011).
Iaffaldano, P. et al. Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study. PLoS ONE 7, e35843 (2012).
Svenningsson, A. et al. Natalizumab treatment reduces fatigue in multiple sclerosis. Results from the TYNERGY trial; a study in the real life setting. PLoS ONE 8, e58643 (2013).
Confavreux, C. et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 13, 247–256 (2014).
Vermersch, P. et al. Teriflunomide versus subcutaneous interferon-β1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult. Scler. 20, 705–716 (2014).
Flensner, G., Ek, A.-C., Söderhamn, O. & Landtblom, A.-M. Sensitivity to heat in MS patients: a factor strongly influencing symptomology — an explorative survey. BMC Neurol. 11, 27 (2011).
Schwid, S. R. et al. A randomized controlled study of the acute and chronic effects of cooling therapy for MS. Neurology 60, 1955–1960 (2003).
Miller, E., Kostka, J., Włodarczyk, T. & Dugué, B. Whole-body cryostimulation (cryotherapy) provides benefits for fatigue and functional status in multiple sclerosis patients. A case–control study. Acta Neurol. Scand. 134, 420–426 (2016).
Sutherland, G., Andersen, M. B. & Morris, T. Relaxation and health-related quality of life in multiple sclerosis: the example of autogenic training. J. Behav. Med. 28, 249–256 (2005).
Dayapoğlu, N. & Tan, M. Evaluation of the effect of progressive relaxation exercises on fatigue and sleep quality in patients with multiple sclerosis. J. Altern. Complement. Med. 18, 983–987 (2012).
Mills, P. J. et al. The self-directed biological transformation initiative and well-being. J. Altern. Complement. Med. 22, 627–634 (2016).
Oken, B. S. et al. Randomized controlled trial of yoga and exercise in multiple sclerosis. Neurology 62, 2058–2064 (2004).
Velikonja, O., Čurić, K., Ožura, A. & Jazbec, S. Š. Influence of sports climbing and yoga on spasticity, cognitive function, mood and fatigue in patients with multiple sclerosis. Clin. Neurol. Neurosurg. 112, 597–601 (2010).
Razazian, N. et al. Exercising impacts on fatigue, depression, and paresthesia in female patients with multiple sclerosis. Med. Sci. Sports Exerc. 48, 796–803 (2016).
Andreasen, A. K., Stenager, E. & Dalgas, U. The effect of exercise therapy on fatigue in multiple sclerosis. Mult. Scler. 17, 1041–1054 (2011).
Mostert, S. & Kesselring, J. Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis. Mult. Scler. 8, 161–168 (2002).
Plow, M. A., Mathiowetz, V. & Lowe, D. A. Comparing individualized rehabilitation to a group wellness intervention for persons with multiple sclerosis. Am. J. Health Promot. 24, 23–26 (2009).
McCullagh, R., Fitzgerald, A. P., Murphy, R. P. & Cooke, G. Long-term benefits of exercising on quality of life and fatigue in multiple sclerosis patients with mild disability: a pilot study. Clin. Rehabil. 22, 206–214 (2008).
Dalgas, U. et al. Fatigue, mood and quality of life improve in MS patients after progressive resistance training. Mult. Scler. 16, 480–490 (2010).
Kargarfard, M., Etemadifar, M., Baker, P., Mehrabi, M. & Hayatbakhsh, R. Effect of aquatic exercise training on fatigue and health-related quality of life in patients with multiple sclerosis. Arch. Phys. Med. Rehabil. 93, 1701–1708 (2012).
Bansi, J., Bloch, W., Gamper, U. & Kesselring, J. Training in MS: influence of two different endurance training protocols (aquatic versus overland) on cytokine and neurotrophin concentrations during three week randomized controlled trial. Mult. Scler. 19, 613–621 (2012).
Heine, M., van de Port, I., Rietberg, M. B., van Wegen, E. E. & Kwakkel, G. Exercise therapy for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 9, CD009956 (2015).
van Kessel, K. et al. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom. Med. 70, 205–213 (2008).
Poettgen, J. et al. Online fatigue management program for patients with multiple sclerosis — a randomized controlled trial. Mult. Scler. 21, 41–42 (2015).
Catalan, M. et al. Treatment of fatigue in multiple sclerosis patients: a neurocognitive approach. Rehabil. Res. Pract. 2011, 670537 (2011).
Grossman, P. et al. MS quality of life, depression, and fatigue improve after mindfulness training: a randomized trial. Neurology 75, 1141–1149 (2010).
Rosti-Otajärvi, E. M. & Hämäläinen, P. I. Neuropsychological rehabilitation for multiple sclerosis. Cochrane Database Syst Rev. 2, CD009131 (2014).
Vogt, A. et al. Working memory training in patients with multiple sclerosis — comparison of two different training schedules. Restor. Neurol. Neurosci. 27, 225–235 (2009).
Becker, K. J. Inflammation and the silent sequelae of stroke. Neurotherapeutics 13, 801–810 (2016).
Hackett, M. L., Köhler, S., O'Brien, J. T. & Mead, G. E. Neuropsychiatric outcomes of stroke. Lancet Neurol. 13, 525–534 (2014).
van der Werf, S. P., van den Broek, H. L., Anten, H. W. & Bleijenberg, G. Experience of severe fatigue long after stroke and its relation to depressive symptoms and disease characteristics. Eur. Neurol. 45, 28–33 (2001).
Choi-Kwon, S., Choi, J., Kwon, S. U., Kang, D.-W. & Kim, J. S. Fluoxetine is not effective in the treatment of post-stroke fatigue: a double-blind, placebo-controlled study. Cerebrovasc. Dis. 23, 103–108 (2007).
Lynch, J. et al. Fatigue after stroke: the development and evaluation of a case definition. J. Psychosom. Res. 63, 539–544 (2007).
Duncan, F., Wu, S. & Mead, G. E. Frequency and natural history of fatigue after stroke: a systematic review of longitudinal studies. J. Psychosom. Res. 73, 18–27 (2012).
Andersen, G., Christensen, D., Kirkevold, M. & Johnsen, S. P. Post-stroke fatigue and return to work: a 2-year follow-up. Acta Neurol. Scand. 125, 248–253 (2012).
Tang, W. K. et al. Acute basal ganglia infarcts in poststroke fatigue: an MRI study. J. Neurol. 257, 178–182 (2010).
Tang, W. K. et al. Poststroke fatigue is associated with caudate infarcts. J. Neurol. Sci. 324, 131–135 (2013).
Choi-Kwon, S., Han, S. W., Kwon, S. U. & Kim, J. S. Poststroke fatigue: characteristics and related factors. Cerebrovasc. Dis. 19, 84–90 (2005).
Christensen, D. et al. Dimensions of post-stroke fatigue: a two-year follow-up study. Cerebrovasc. Dis. 26, 134–141 (2008).
Elf, M., Eriksson, G., Johansson, S., von Koch, L. & Ytterberg, C. Self-reported fatigue and associated factors six years after stroke. PLoS ONE 11, e0161942 (2016).
Brioschi, A. et al. Effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients. Eur. Neurol. 62, 243–249 (2009).
Poulsen, M. B., Damgaard, B., Zerahn, B., Overgaard, K. & Rasmussen, R. S. Modafinil may alleviate poststroke fatigue: a randomized, placebo-controlled, double-blinded trial. Stroke 46, 3470–3477 (2015).
Lillicrap, T. et al. Modafinil In Debilitating fatigue After Stroke (MIDAS): study protocol for a randomised, double-blinded, placebo-controlled, crossover trial. Trials 17, 410 (2016).
Bivard, A. et al. MIDAS (Modafinil in Debilitating Fatigue After Stroke): a randomized, double-blind, placebo-controlled, cross-over trial. Stroke 48, 1293–1298 (2017).
Karaiskos, D., Tzavellas, E., Spengos, K., Vassilopoulou, S. & Paparrigopoulos, T. Duloxetine versus citalopram and sertraline in the treatment of poststroke depression, anxiety, and fatigue. J. Neuropsychiatry Clin. Neurosci. 24, 349–353 (2012).
Kim, J. S. Post-stroke mood and emotional disturbances: pharmacological therapy based on mechanisms. J. Stroke 18, 244–255 (2016).
Clarke, A., Barker-Collo, S. L. & Feigin, V. L. Poststroke fatigue: does group education make a difference? A randomized pilot trial. Top. Stroke Rehabil. 19, 32–39 (2012).
Zedlitz, A. M., Rietveld, T. C., Geurts, A. C. & Fasotti, L. Cognitive and graded activity training can alleviate persistent fatigue after stroke: a randomized, controlled trial. Stroke J. 43, 1046–1051 (2012).
Johansson, B., Bjuhr, H. & Rönnbäck, L. Mindfulness-based stress reduction (MBSR) improves long-term mental fatigue after stroke or traumatic brain injury. Brain Inj. 26, 1621–1628 (2012).
Alves, G., Wentzel-Larsen, T. & Larsen, J. P. Is fatigue an independent and persistent symptom in patients with Parkinson disease? Neurology 63, 1908–1911 (2004).
Herlofson, K. & Larsen, J. P. Measuring fatigue in patients with Parkinson's disease — the fatigue severity scale. Eur. J. Neurol. 9, 595–600 (2002).
Havlikova, E. et al. Impact of fatigue on quality of life in patients with Parkinson's disease. Eur. J. Neurol. 15, 475–480 (2008).
Friedman, J. H. et al. Fatigue rating scales critique and recommendations by the Movement Disorders Society task force on rating scales for Parkinson's disease. Mov. Disord. 25, 805–822 (2010).
Elbers, R. G., Verhoef, J., van Wegen, E. E., Berendse, H. W. & Kwakkel, G. Interventions for fatigue in Parkinson's disease. Cochrane Database Syst Rev. 10, CD010925 (2015).
Elbers, R. G., Berendse, H. W. & Kwakkel, G. Treatment of fatigue in Parkinson disease. JAMA 315, 2340–2341 (2016).
Cantor, F. Central and peripheral fatigue: exemplified by multiple sclerosis and myasthenia gravis. PM R. 2, 399–405 (2010).
Vinge, L. & Andersen, H. Muscle strength and fatigue in newly diagnosed patients with myasthenia gravis. Muscle Nerve 54, 709–714 (2016).
Hoffmann, S. et al. Quantitative motor assessment of muscular weakness in myasthenia gravis: a pilot study. BMC Neurol. 15, 265 (2015).
Sanders, D. B. et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology 87, 419–425 (2016).
Paul, R. H., Cohen, R. A., Goldstein, J. M. & Gilchrist, J. M. Fatigue and its impact on patients with myasthenia gravis. Muscle Nerve 23, 1402–1406 (2000).
Symonette, C. J., Watson, B. V., Koopman, W. J., Nicolle, M. W. & Doherty, T. J. Muscle strength and fatigue in patients with generalized myasthenia gravis. Muscle Nerve 41, 362–369 (2010).
Elsais, A., Wyller, V. B., Loge, J. H. & Kerty, E. Fatigue in myasthenia gravis: is it more than muscular weakness? BMC Neurol. 13, 132 (2013).
Suarez, G. A. et al. The autonomic symptom profile: a new instrument to assess autonomic symptoms. Neurology 52, 523–528 (1999).
Askmark, H., Haggård, L., Nygren, I. & Punga, A. R. Vitamin D deficiency in patients with myasthenia gravis and improvement of fatigue after supplementation of vitamin D3: a pilot study. Eur. J. Neurol. 19, 1554–1560 (2012).
Abraham, A. & Drory, V. E. Fatigue in motor neuron diseases. Neuromuscul. Disord. 22 (Suppl. 3), S198–S202 (2012).
Ramirez, C., Piemonte, M. E., Callegaro, D. & Da Silva, H. C. Fatigue in amyotrophic lateral sclerosis: frequency and associated factors. Amyotroph. Lateral Scler. 9, 75–80 (2008).
Lou, J.-S., Reeves, A., Benice, T. & Sexton, G. Fatigue and depression are associated with poor quality of life in ALS. Neurology 60, 122–123 (2003).
McElhiney, M. C., Rabkin, J. G., Gordon, P. H., Goetz, R. & Mitsumoto, H. Prevalence of fatigue and depression in ALS patients and change over time. J. Neurol. Neurosurg. Psychiatry 80, 1146–1149 (2009).
Jenkins, T. M., Hollinger, H. & McDermott, C. J. The evidence for symptomatic treatments in amyotrophic lateral sclerosis. Curr. Opin. Neurol. 27, 524–531 (2014).
Carter, G. T. et al. Modafinil to treat fatigue in amyotrophic lateral sclerosis: an open label pilot study. Am. J. Hosp. Palliat. Care 22, 55–59 (2005).
Rabkin, J. G. et al. Modafinil treatment of fatigue in patients with ALS: a placebo-controlled study. Muscle Nerve 39, 297–303 (2009).
Payne, C., Wiffen, P. J. & Martin, S. Interventions for fatigue and weight loss in adults with advanced progressive illness. Cochrane Database Syst. Rev. 1, CD008427 (2012).
Jarius, S., Wildemann, B. & Paul, F. Neuromyelitis optica: clinical features, immunopathogenesis and treatment. Clin. Exp. Immunol. 176, 149–164 (2014).
Metz, I. et al. Serum peptide reactivities may distinguish neuromyelitis optica subgroups and multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 3, e204 (2016).
Zekeridou, A. & Lennon, V. A. Aquaporin-4 autoimmunity. Neurol. Neuroimmunol. Neuroinflamm. 2, e110 (2015).
Trebst, C. et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J. Neurol. 261, 1–16 (2014).
Chanson, J.-B. et al. Evaluation of health-related quality of life, fatigue and depression in neuromyelitis optica. Eur. J. Neurol. 18, 836–841 (2011).
Muto, M. et al. Current symptomatology in multiple sclerosis and neuromyelitis optica. Eur. J. Neurol. 22, 299–304 (2015).
Chavarro, V. S. et al. Insufficient treatment of severe depression in neuromyelitis optica spectrum disorder. Neurol. Neuroimmunol. Neuroinflamm. 3, e286 (2016).
Shi, Z. et al. Factors that impact health-related quality of life in neuromyelitis optica spectrum disorder: anxiety, disability, fatigue and depression. J. Neuroimmunol. 293, 54–58 (2016).
Akaishi, T., Nakashima, I., Misu, T., Fujihara, K. & Aoki, M. Depressive state and chronic fatigue in multiple sclerosis and neuromyelitis optica. J. Neuroimmunol. 283, 70–73 (2015).
Song, Y. et al. Sleep abnormality in neuromyelitis optica spectrum disorder. Neurol. Neuroimmunol. Neuroinflamm. 2, e94 (2015).
Rammohan, K. W. et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J. Neurol. Neurosurg. Psychiatry 72, 179–183 (2002).
Stankoff, B. et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology 64, 1139–1143 (2005).
Möller, F. et al. HAGIL (Hamburg Vigil Study): a randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis. Mult. Scler. 17, 1002–1009 (2011).
Lange, R., Volkmer, M., Heesen, C. & Liepert, J. Modafinil effects in multiple sclerosis patients with fatigue. J. Neurol. 256, 645–650 (2009).
Zifko, U. A., Rupp, M., Schwarz, S., Zipko, H. T. & Maida, E. M. Modafinil in treatment of fatigue in multiple sclerosis. J. Neurol. 249, 983–987 (2002).
Nagels, G. et al. P300 and treatment effect of modafinil on fatigue in multiple sclerosis. J. Clin. Neurosci. 14, 33–40 (2007).
Ford-Johnson, L. et al. Cognitive effects of modafinil in patients with multiple sclerosis: a clinical trial. Rehabil. Psychol. 61, 82–91 (2016).
Tomassini, V. et al. Comparison of the effects of acetyl l-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. J. Neurol. Sci. 218, 103–108 (2004).
Wingerchuk, D. M. et al. A randomized controlled crossover trial of aspirin for fatigue in multiple sclerosis. Neurology 64, 1267–1269 (2005).
Pavsic, K., Pelicon, K., Ledinek, A. H. & Sega, S. Short-term impact of fampridine on motor and cognitive functions, mood and quality of life among multiple sclerosis patients. Clin. Neurol.Neurosurg. 139, 35–40 (2015).
Allart, E. et al. Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life. J. Neurol. 262, 1936–1945 (2015).
Lou, J.-S. et al. Using modafinil to treat fatigue in Parkinson disease: a double-blind, placebo-controlled pilot study. Clin. Neuropharmacol. 32, 305–310 (2009).
Tyne, H. L., Taylor, J., Baker, G. A. & Steiger, M. J. Modafinil for Parkinson's disease fatigue. J. Neurol. 257, 452–456 (2010).
The authors' work is supported by Deutsche Forschungs-gemeinschaft (grant DFG Exc 257 to F.P.) The authors thank Hanna Zimmermann for her valuable editorial support in preparing the manuscript.
The authors declare that I.-K.P. has received honoraria for speaking at scientific meetings, serving on scientific advisory boards and consulting activities from Adamas Pharma, Bayer Pharma, Biogen, Genzyme, Merck Serono, Novartis, Roche, Teva Pharmaceuticals; and that she has received research support from Novartis, the German Multiple Sclerosis Society, and Teva Pharmaceuticals. F.P. declares that he has served on scientific advisory boards for MedImmune and Novartis; received speaker honoraria and travel funding from Alexion, Bayer, Biogen Idec, Chugai, MedImmune, Merck Serono, Novartis, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, and Shire; is an academic editor of PLoS ONE and an associate editor of Neurology Neuroimmunology & Neuroinflammation; has consulted for Alexion, Biogen Idec, MedImmune, Sanofi-Aventis/Genzyme and Shire; and received research support from Alexion, Arthur Arnstein Stiftung Berlin, Bayer, Biogen Idec, EU FP7 Framework Program, German Ministry of Education and Research, German Research Council, Guthy-Jackson Charitable Foundation, Merck Serono, National Multiple Sclerosis Society of the USA, Novartis, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, and Werth Stiftung of the City of Cologne.
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Penner, IK., Paul, F. Fatigue as a symptom or comorbidity of neurological diseases. Nat Rev Neurol 13, 662–675 (2017). https://doi.org/10.1038/nrneurol.2017.117
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