Impact And Nature Of Fatigue In Pd

Fatigue in PD was first mentioned in 1967 by Hoehn and Yahr,55 which is notable because fatigue, rather than motor dysfunction, was the presenting complaint in a handful of patients. The study of fatigue was begun in earnest in 1993, with studies by Van Hilten et al.51 and Friedman and Friedman.6

Van Hilten et al.51 published the first report focused on fatigue in PD. They compared nondemented patients with PD to age-matched controls to test the hypothesis that fatigue in PD worsened over the course of the day.

Activity monitors were used to assess movement of the nondominant hand, and fatigue was assessed by frequency rather than severity and found to be "often," "very often," or "continuously present" in 31 of 65 patients. Of the fatigued patients, there was no discernible diurnal distribution of activity, nor any correlation between fatigue, motor activity, and bedtime.

Following shortly after the paper by Van Hilten et al., a survey of fatigue in PD patients conducted by Friedman and Friedman6 was published. PD patients were compared to a same sex friend or relative without PD who was within five years of the subject's age. PD patients reported significantly greater levels of depression and fatigue than the control subjects, and one-third of patients reported fatigue as the single worst symptom of PD. More than half (58%) of the PD patients "agreed" or "strongly agreed" with question, "Fatigue is one of the three most disabling symptoms of PD." Most described fatigue as having a different quality than the fatigue experienced prior to the onset of PD. Although fatigue correlated with depression, not all patients with fatigue were depressed. Fatigue was not associated with motor dysfunction as hypothesized by other authors.51,56

Other studies have followed these seminal papers, but fatigue in PD remains an uncommon topic in the scientific literature. Most studies have described the nature and correlates of fatigue; none has evaluated treatments of fatigue in PD. What is clear from the literature is that there is strong, consistent evidence of a higher prevalence of fatigue in PD patients compared to healthy subjects. Several studies, using a variety of instruments and performed in different countries, have documented a higher frequency of fatigue in PD patients as compared to healthy age- and gender-matched control subjects.61751-54 These studies have shown consistently that about one-half of PD patients suffer from fatigue, but it is notable that fatigue is not a symptom common to all patients with PD. There is also some evidence54 that the prevalence of fatigue in PD patients is higher that other patients suffering with some other chronic disease, although these findings need confirmation by others. A study by Herlofson and Larson54 found that a higher proportion of patients with PD reported fatigue as compared to patients with diabetes and pre-hip surgery patients.

Friedman and Friedman,57 following patients over nine years, found fatigue not only to be a consistent finding over time, but, in addition, the fatigue did not substantially change in severity in most patients, even with treatment and changes in disease severity. PD patients score higher on all dimensions of fatigue as compared with health controls.17 Lou et al.17 reported this, including physical fatigue, general fatigue, reduced motivation, reduced activity, mental fatigue, although mental fatigue was not significantly different between PD patients and control subjects. These results suggest that physical and mental fatigue are independent symptoms that should be evaluated separately.

PD patients often complain of weakness, which probably is a reflection of the fatigue of the skeletal muscles in performing repeated exercises.17,22-24 Ziv et al.23 observed that PD patients fatigued twice as quickly as healthy control subjects, and fatigue improved following a dose of carbidopa-levodopa, although the magnitude of this improvement was associated with disease severity. These results were confirmed by recent work by Lou et al.25

Recently, Hwang and Lin22 used stimulated single fiber electromyography to evaluate the neuromuscular junction, hypothesizing that fatigue was due to cholinergic defect at the level of the muscle. Results showed that none of the patients had an abnormal individual mean consecutive difference in single fiber potentials, suggesting that the peripheral cholinergic system is intact in PD patients with fatigue. These results all suggest that peripheral muscle fatigue results from a central origin and perhaps is just one more manifestation of central fatigue. Interestingly, myasthenia, a paradigmatic example of peripheral fatigue, is also plagued by central fatigue. Supporting this possibility are several examples in other patient populations. Paul et al.,5859 studying patients with myasthenia gravis, found high levels of "cognitive fatigue," demonstrated by diminished cognitive performance correlated with self-perception of fatigue. This is somewhat surprising, because the weakness and neuropathology are limited to skeletal muscles, despite the known inflammatory process. Similarly, a study of fatigue in patients who had recovered from Guil-lain Barre syndrome found fatigue was not only a common sequellae but also inversely correlated with the degree of recovery.60

What is not in doubt is that fatigue in all of its manifestations occurs in PD, and it has a strong negative influence on quality of life and physical function in PD patients.61-63 Fatigue has been reported to cause emotional distress and problems "in the areas of physical functioning, role limitation (physical), and social functioning and vitality" in nondepressed PD patients in multiple studies.61-62 An inverse association between fatigue, habitual physical activity levels, physical function, and functional capacity in PD patients has been reported by Garber and Friedman.63 Fatigued patients tend to be less active and have poorer functional capacity compared with those with lower levels of fatigue.63 Van Hilten et al.51 hypothesized that motor activity would have a diurnal pattern in PD patients, but their results documented only a lower activity level in the morning. After this "slow start," PD patients' activity increased and did not decline as expected as the day progressed. The pattern of activity also did not correlate with fatigue levels.


There are multiple factors that probably contribute to the sense of fatigue in PD. One of the most obvious factors is disease severity. While studies show an association between more severe disease and fatigue,51,52,54 none has found an independent association between disease severity and fatigue,6,51-54,63 suggesting that disease severity in itself cannot explain fatigue. Furthermore, Friedman and Friedman57 found that, even with progression of disease, fatigue declined but did not change substantially in PD patients followed clinically.

Other explanations for fatigue in PD include sleep dysfunction causing excessive daytime sleepiness, depression and other mood disorders, medication effects, and the motor dysfunction itself. Fatigue has, in fact, been associated with other comorbid conditions, including mood and sleep disorders in some, but not all, studies.

Drugs have been implicated both in exacerbating and reducing fatigue. For example, Pramiprexole has been associated with increased fatigue in several studies.64,65 It should be considered, however, that most of the reports of increased fatigue related to drug therapy has come from randomized clinical trials of the efficacy of drugs in the treatment of motor symptoms of PD, and the data on fatigue has been collected as an adverse effect. Interpretation of the cause and effect relationships between a drug and adverse side effects is notoriously difficult,66 so these results should be interpreted with caution, particularly because fatigue is a frequent complaint and a commonly reported adverse effect of many drugs.

Studies evaluating the effect of pharmacologic agents on fatigue in PD are rare. Carbidopa-Levodopa has been shown to reduce central and peripheral fatigue23,25,67 but has also been found to be a predictor of fatigue in cross-sectional studies (e.g., Ref. 63). Recently, Abe et al.68 compared fatigue in patients taking pergolide mesilate to bromocriptine and found that patients with pergolide had reduced levels of fatigue after taking the drug, but there was no change in patients taking bromocriptine. These results suggest the possibility that the D-1 receptor is involved in the sensation of fatigue in PD patients, but more work confirming these findings is needed.

There have been more studies evaluating drug therapy on fatigue in MS; however, none has been shown to have clear benefit.69-71 Amantadine has been evaluated in several studies in the treatment of fatigue of MS (but not in PD); however, a Cochrane review70 of its efficacy reports, "...[amantadine's] efficacy in reducing fatigue in people with MS is poorly documented and there is insufficient evidence to make recommendations to guide prescribing." More recently, trials of Prokarin,71 Pemoline,72 and 4-aminopyridine73 have reported preliminary, although slightly promising, results in reducing fatigue in MS.

Whether these results will be verified by other studies, or the drugs might be used to treat fatigue in PD, remains to be seen.

Depression is often associated with the general feelings of tiredness and malaise that are often associated with fatigue,74,75 but the link between depression and fatigue is complex. Lou et al.,17 reporting on a sample of PD patients and healthy controls, found that PD patients on average had higher scores on the Profile of Mood States (POMS) and depression. Further depression correlated with all dimension of fatigue except physical fatigue. Karlsen et al.52 also found an association between fatigue and depression as well as between fatigue and the use of sleeping pills. However, they also found fatigue to be equally prevalent in patients with and without depression and depression was not predictive of fatigue. Herlof-son and Larsen,54 using a multivariable analysis, also found that sleep disorders and pain were not independent predictors of fatigue. These results suggest that fatigue is an independent symptom of PD, overlapping with but not causally related to depression.

The same may be said about sleep disorders and fatigue. Sleep disorders are undeniably common in PD.7,51,76-79 Although associated with fatigue, sleep disorders do not predict fatigue in PD patients.54 Van Hilten and colleagues51 reported that the prevalence of daytime sleepiness was similar in both PD patients and controls, with both having a diurnal pattern of sleepiness peaking in the early afternoon. On the other hand, in these subjects, fatigue was fairly constant throughout the day and more common in PD compared with controls.

Hogl et al.80 evaluated daytime sleepiness in control subjects and in patients with PD. They found that, while daytime sleepiness was more common in PD patients compared with control subjects, in both groups, sleepiness was associated with heavy snoring, suggesting that daytime sleepiness reflects the presence of a sleep disorders. Other studies81 have supported these findings, but not all. Fabbrini et al.82 found no differences in daytime sleepiness in PD patients as compared with healthy control subjects, but they did find that sleepiness was associated with PD drug treatments, suggesting that sleepiness is a side effect of treatment rather than caused by the disease itself.

PD patients have higher resting energy utilization than age-matched controls.83-85 The resting metabolic rate decreases with treatment in those patients who were stiff and, in general, there is a loose correlation between the improvement in rigidity and the decline in energy require-ments.83 L-dopa induced dyskinesias produce yet higher energy requirements.83 Even early, untreated patients have an increased energy requirement.87 Several authors have proposed that the increased energy expenditure may be a contributing factor to the weight loss that so commonly affects PD patients.83,84 Data from Tzelepis et al.88 have demonstrated that energy use for respiration is also increased in PD, which partly explains the increased resting energy requirements.

Given the increased energy requirements of PD patients at rest, it is a natural question to then ask, "Do PD patients who exercise less efficiently; that is, require more calories to perform a given exercise, suffer more from fatigue than those who are more efficient?" Preliminary data from our laboratory87 suggest that PD patients use a higher proportion of their ventilation capacity as compared to health control subjects at a similar exercise workload. Thus, exercise may be more fatiguing in PD subjects due to a great ventilatory effort.

None of these factors discussed explain the phenomenon of fatigue in PD; they only assist researchers in identifying "clues" that may help to determine the underlying etiology of fatigue, which is not known. Several hypotheses have been proposed to explain fatigue in PD and other chronic diseases, but these remain largely untested.1118 Hypothesized mechanisms of fatigue range from altered activation of the hypothalamic-pituitary-adrenal axis due to prolonged stress, inflammatory processes, and alterations in neurotransmitters and neurotransmission within the CNS, including disruption of the nonmotor functions in the basal ganglia and dysfunction of the striato-thalamo-cortical loop.1118

It remains a problem that fatigue, depression, sleep disorders, drug side effects, and other comorbid conditions are common in PD patients and, importantly, these symptoms and conditions are often not recognized by clinicians in their patients with PD patients.8 To illustrate this problem, Shulman et al.,8 studying patients with PD, found that 44% reported depression, 39% were anxious, 42% were fatigued, and 43% had sleep problems. On the other hand, these problems were often not diagnosed by the patient's neurologist. Of these same patients, 35% had been diagnosed with depression, 42% with anxiety disorder, 25% with fatigue, and 60% with sleep disturbance. The later is interesting, showing how patients often do not recognize sleep problems in themselves.

Although some authorities argue that better definitions and rating instruments are needed,88 it is likely only that different rating instruments will be developed that are disease specific. It is unlikely, for example, that the fatigue of myasthenia gravis will be measured sensitively by an instrument aimed at multiple sclerosis or lupus, where effects of medications or polysystem diseases are important.

In summary, fatigue is one of most common disabling symptoms in patients with PD. The impact of fatigue on the quality of life of patients is substantial, although health care providers often underestimate it. Fatigue has two components that may be related but are likely independent: peripheral (local muscle) fatigue and mental fatigue. Fatigue is associated with sleepiness and depres sion, but patients with fatigue may not be depressed or have sleep disorders. Drugs may exacerbate or improve fatigue. Research of the causes of and treatments for fatigue are sorely needed.89

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