Fatigue is a disabling symptom common to many neurologic conditions, including Parkinson disease, post-stroke syndromes, and traumatic brain injury. Fatigue in the neurologic population is defined differently from that in the general population, and this has implications for assessment, research, and treatment. A considerable amount of research has been done in recent years aiming to describe, quantify, and ultimately treat this problem. There are relatively few proven treatments for fatigue in these populations, but the mainstays of therapy can be divided into pharmacologic and nonpharmacologic approaches.
Fatigue is a commonly reported symptom after traumatic brain injury (TBI), after stroke, and in persons living with Parkinson disease (PD). Fatigue compounds the underlying impairments of all these neurologic disabilities, leading to greater handicap and lower life satisfaction. Fatigue in neurologic illnesses has serious social and public health implications. One study looking at social security disability insurance (SSDI) in PD found that 82% of patients in their sample felt they were too disabled to work full-time at a mean of 3.4 years after PD diagnosis. The primary debilitating symptom that contributed to applying for SSDI in this study was fatigue.
Merriam-Webster’s Collegiate Dictionary defines fatigue as “weariness or exhaustion from labor, exertion or stress; the temporary loss of power to respond that is induced in a sensory receptor or motor end organ by continued stimulation,” and tiredness is defined as, “the state of being drained of strength and energy; fatigued often to the point of exhaustion.” In laypersons’ terms, they are synonyms. Medical literature generally employs yet another similar definition, describing fatigue as a subjectively overwhelming sense of tiredness, lack of energy, and feeling of exhaustion. These similar definitions are all irrespective of sleep status.
It is important to note that people with neurologic disorders describe fatigue differently from the way that the general population does. One paramount distinction is that fatigue experienced by individuals with neurologic disorders does not respond to sleep or rest nor is it accompanied by the desire to sleep, whereas people in the general population report an amelioration of fatigue symptoms with a nap or a full night’s sleep. This important difference in definitions has implications for research, because scales used to quantify fatigue in the general population may not accurately measure fatigue in those with neurologic conditions.
Although there is no universally accepted definition for fatigue, there is a general distinction between peripheral and central fatigue. Peripheral fatigue, or physical fatigue, is most commonly expressed as musculoskeletal symptoms that impair mobility and the ability to perform activities of daily living (ADLs).
Central fatigue, also known as mental or cognitive fatigue, results from dysfunction of the supratentorial structure involved in performing cognitive tasks. Central fatigue is a difficulty initiating and sustaining mental and physical tasks in the absence of motor or physical impairments. The inability to maintain focused attention is a key component of central fatigue, since focused attention is necessary to incorporate the mental, physical, and sensory inputs involved in completing a task. Once focused attention is impaired, integrating the various types of information needed to complete a task becomes more difficult and requires greater effort to complete.
In persons with TBI and stroke, central fatigue predominates, whereas in PD, fatigue complaints are often mixed. In evaluating patients with complaints of fatigue, differentiating between central and peripheral fatigue is an important initial step, as inciting agents and treatments differ between the 2. The goal of this article is to provide the reader with an overview of the etiology, assessment, quality of life (QoL) implications, and treatment of this common symptom in adults with neurologic disabilities.
Epidemiology
Fatigue is reported to be almost ubiquitous in individuals with neurologic disorders. Estimates of prevalence depend somewhat on the specific neurologic disorder in question, the scale used, and the study cited. Additionally, as discussed, the definition of fatigue tends to vary from study to study, so statistics cannot always be directly compared. Regardless, it is accepted that fatigue is an extremely common problem associated with neurologic disorders, which is reported with significantly higher frequency than that in the general population and may significantly affect an individual’s return to independent living.
Fatigue can be a debilitating symptom of PD, affecting all aspects of life. Although the literature studying fatigue in PD lags behind that of other neurologic entities, it has recently begun to flourish. The prevalence of fatigue in PD varies in the literature from 33% to 81%. Two important studies done in 1993 were among the first to highlight the relationship between fatigue and PD. These studies reported for the first time that the rate of fatigue in PD was high. In the study by Friedman and colleagues, more than 50% of their PD patients reported that fatigue was among the 3 most disabling symptoms of their disease. This is important to keep in mind, because physicians on the whole are not doing an adequate job of recognizing fatigue in their PD patients. In 1 study, 42% of patients with PD complained of fatigue, whereas only 25% of the physicians uncovered the symptom.
Fatigue as an independent symptom in PD is a relatively new concept. Karlsen and colleagues were the first to present evidence backing the claim that the high prevalence of fatigue seen in PD cannot be explained by comorbid depression, dementia, or sleep disorders alone. Alves and colleagues studied PD patients for 8 years, measuring the prevalence of fatigue at the inception of the study and 4 and 8 years later. They found that the prevalence of fatigue in patients without depression and excessive daytime sleepiness remained high and increased from 32.1% to 38.9% during the 8-year study period.
The prevalence of fatigue after stroke ranges from 30% to 68%. Fatigue is reported both in the acute phase and the late phase after stroke. Ingles and colleagues found that fatigue problems, measured by the Fatigue Impact Scale (FIS), were reported in 68% of subjects between 3 and 13 months after stroke, compared to 36% of age-matched control subjects. Two years after stroke, 51% of survivors have elevated scores on the fatigue subscale of the Checklist Individual Strength compared to 12% of control subjects, and 50% report that fatigue is their main complaint. Controlling for depression, 39.2% of stroke survivors experience significant fatigue independent of reports of depression. In addition, the frequency of fatigue associated with clinically relevant depression was found to be 67% in individuals who had strokes at least 7 years earlier.
A 2006 study tracked the natural history of post-stroke fatigue for 1 year. The authors used the Fatigue Severity Scale (FSS) to measure fatigue at admission, 6 months, and then 1 year after stroke. They found that the incidence of fatigue increased with each subsequent evaluation and that fatigue impact was greater among women, older subjects, and those who exhibited more depressive symptoms.
There is no clear primary etiology of fatigue after TBI. Depression, pain, sleep disturbance, and neuroendocrine abnormalities all have been associated with fatigue after TBI. It has also been hypothesized that the injured brain requires more effort to compensate for impairments in attention and processing speed. Many individuals with TBI describe mental tasks as being effortful and fatiguing.
Fatigue is a commonly experienced symptom after TBI and occurs at a greater frequency than that in the general population. Fatigue is among the most pervasive symptoms after TBI. Estimates of the incidence of fatigue in individuals living in the community range from 50% to 80%. Fatigue after TBI appears to be independent of severity and age at time of injury and is associated with duration after TBI in some studies and not others. In a 2-year prospective longitudinal study by Bushnik and colleagues of individuals with moderate to severe TBI, improvements in fatigue were seen in the first year. Further changes were not seen up to 2 years after TBI. The subset of individuals who reported significant increases in fatigue during the first 2 years demonstrated poorer outcomes in multiple domains than did those with stable or decreased fatigue.
Effects on quality of life
Parkinson Disease
Patients with PD have worse QoL scores compared with those of the general population, and PD patients with fatigue have even lower scores. A shifting focus from defining the symptoms of this disease to describing their QoL implications is reflected in current literature. It is well known that fatigue is rated among the most disabling symptoms of PD, but it was not until recently that we knew how this symptom compared with other common symptoms. A 2008 British study looked at the relative importance of symptoms with respect to QoL in PD patients and found that fatigue was as important as some of the classic motor symptoms, such as shuffling and falls.
A well-done Slovakian study used several scales to measure the effects that fatigue has on QoL in PD patients. The authors found that the existence of fatigue in PD patients was associated with lower scores on all QoL domains, the most affected being bodily discomfort, mobility, and emotional well-being. In addition, a 2003 Norwegian study described the influence of fatigue on health-related QoL in patients with PD. The authors’ sample included patients without known depression or dementia, and they used the FSS as a measuring tool. They found that 50% of the patients had significant fatigue and that those with fatigue had a more advanced disease than those without. They also uncovered a strong correlation between fatigue and high distress scores on health-related QoL scales.
Stroke
Fatigue in a post-stroke patient can have significant QoL-lowering effects. Van de Port and colleagues were the first to show that fatigue is an independent variable in post-stroke patients. They also found that post-stroke fatigue is more closely related to instrumental activities of daily living (IADLs), such as shopping and cleaning, than to simple ADLs. Another study found that health-related QoL in patients who survived an ischemic stroke was lowest in the domain of physical mobility. It is not surprising that fatigue is predictive of mobility decline 1 year after stroke, yet the relationship between ambulatory activity and post-stroke fatigue is complex. Several other studies have shown no relationship between mobility and fatigue or daily step activity and fatigue, yet it is clear to all that the 2 have a relationship. It is likely that more salient variables such as hemiparesis or social isolation become the primary obstacles to mobility after stroke.
Traumatic Brain Injury
Cantor and colleagues studied community dwelling individuals who had suffered a range of severity of TBI to examine the relationships between post-TBI fatigue and comorbid conditions, participation in activities, QoL, and demographic and injury variables. A noninjured control group was also examined. Fatigue was more severe and prevalent in individuals with TBI and more severe among women. It was not correlated with other demographic and injury variables. Fatigue was correlated with health-related QoL and overall QoL but was not generally related to participation in major life activities.
Effects on quality of life
Parkinson Disease
Patients with PD have worse QoL scores compared with those of the general population, and PD patients with fatigue have even lower scores. A shifting focus from defining the symptoms of this disease to describing their QoL implications is reflected in current literature. It is well known that fatigue is rated among the most disabling symptoms of PD, but it was not until recently that we knew how this symptom compared with other common symptoms. A 2008 British study looked at the relative importance of symptoms with respect to QoL in PD patients and found that fatigue was as important as some of the classic motor symptoms, such as shuffling and falls.
A well-done Slovakian study used several scales to measure the effects that fatigue has on QoL in PD patients. The authors found that the existence of fatigue in PD patients was associated with lower scores on all QoL domains, the most affected being bodily discomfort, mobility, and emotional well-being. In addition, a 2003 Norwegian study described the influence of fatigue on health-related QoL in patients with PD. The authors’ sample included patients without known depression or dementia, and they used the FSS as a measuring tool. They found that 50% of the patients had significant fatigue and that those with fatigue had a more advanced disease than those without. They also uncovered a strong correlation between fatigue and high distress scores on health-related QoL scales.
Stroke
Fatigue in a post-stroke patient can have significant QoL-lowering effects. Van de Port and colleagues were the first to show that fatigue is an independent variable in post-stroke patients. They also found that post-stroke fatigue is more closely related to instrumental activities of daily living (IADLs), such as shopping and cleaning, than to simple ADLs. Another study found that health-related QoL in patients who survived an ischemic stroke was lowest in the domain of physical mobility. It is not surprising that fatigue is predictive of mobility decline 1 year after stroke, yet the relationship between ambulatory activity and post-stroke fatigue is complex. Several other studies have shown no relationship between mobility and fatigue or daily step activity and fatigue, yet it is clear to all that the 2 have a relationship. It is likely that more salient variables such as hemiparesis or social isolation become the primary obstacles to mobility after stroke.
Traumatic Brain Injury
Cantor and colleagues studied community dwelling individuals who had suffered a range of severity of TBI to examine the relationships between post-TBI fatigue and comorbid conditions, participation in activities, QoL, and demographic and injury variables. A noninjured control group was also examined. Fatigue was more severe and prevalent in individuals with TBI and more severe among women. It was not correlated with other demographic and injury variables. Fatigue was correlated with health-related QoL and overall QoL but was not generally related to participation in major life activities.
Differential diagnosis
Fatigue should always be suspected and inquired about when encountering a patient with a neurologic condition, yet it is critical to keep in mind that the patient’s fatigue may not be due to that neurologic condition. It is important to determine whether the fatigue is primary or in fact secondary to another condition. The differential diagnosis for fatigue is vast, but Table 1 provides a summary of the most common non-neurologic causes of fatigue.
| Neuropsychiatric |
| Depression |
| Sleep disorders |
| Dementia |
| Infectious |
| Endocrine |
| Hypothyroidism |
| Anterior pituitary dysfunction |
| Hypogonadism |
| Growth hormone deficiency |
| Adrenal insufficiency |
| Chronic disease |
| Diabetes |
| Cardiac disease |
| Pulmonary disease |
| Anemia |
| Cancer |
| Hepatorenal disease |
| Rheumatologic disease |
| Medications |
| Antispasticity agents & muscle relaxants |
| Analgesics |
| Anticonvulsants |
| Antihistamines |
| Anti-inflammatories |
| Antipsychotics |
| Antidepressants |
| Gastrointestinal drugs |
The issues of fatigue and disordered sleep are closely intertwined, and differentiating the 2 is often a problem for physicians. Although sleep disorders are common in many neurologic conditions, it is believed that fatigue itself is an independent symptom, often unexplained by a comorbid sleep disorder. Though they share common symptomatology, the treatments are quite different. It is a challenge to the physician to disentangle this perplexing constellation of symptoms and determine the root of the problem so that proper therapy can then be administered. Depression is another entity common in both the general population and among those with neurologic diseases. As with sleep disorders, it is possible that a patient’s fatigue is not primary but secondary to comorbid depression. Another important thing to remember is that dementia occurs in 10% to 15% of PD patients, so it is important not to neglect this possibility in your differential diagnosis of fatigue.
Assessment
When evaluating any patient with symptoms of fatigue, it is crucial to conduct a thorough diagnostic workup looking for underlying causes that may be unrelated to any known neurologic diagnoses. Initially, the clinician should attempt to differentiate between central and peripheral origins as well as primary versus secondary causes. Central fatigue questioning and examination typically focus on the presence of fatigue when attempting to perform cognitive tasks that require 1 or more steps. Peripheral fatigue questions focus on fatigue with physical activities such as walking, lifting, or completing ADLs.
It is also important to think in terms of primary and secondary causes for fatigue. Primary fatigue is caused by the neurologic disorder itself, whereas secondary fatigue can be due to multiple factors such as anemia, lack of conditioning, depression, side effects of medications, infection, endocrine dysfunction, or sleep disturbance ( Table 2 ). Many medications can cause fatigue as a side effect, and examples are listed in Table 1 . Checking serum levels of some medications and review of medications for interactions should be a part of the compulsory evaluation of fatigue. In assessing for secondary causes of fatigue, inquiring about current medications, difficulties sleeping, and depression can also yield useful information.
| Ascertain type of fatigue |
| • Mental fatigue: Fatigue with cognitive tasks |
| • Physical fatigue: Fatigue with walking, lifting, and other activities of daily living |
| Evaluate for secondary causes of fatigue (See Table 1 ) |
| • Assess for depression |
| • Sleep dysfunction |
| Sleep onset |
| Staying asleep |
| Nightmares |
| • Infection |
| Fever |
| Chills |
| Sweats |
| Urinary symptoms |
| • Underlying malignancy |
| Weight loss |
| Loss of appetite |
| Anemia |
| Careful review of medications |
| • Side effects |
| • Drug–drug interactions |
| Laboratory and imaging studies when appropriate |
Evaluation for sleep disturbance is a core component in evaluating the etiology of the fatigue. High rates of sleep disturbance have been shown to be associated with all neurologic disabilities, although for varying reasons. Management of sleep impairment through sleep hygiene, treatment of comorbid illness, or through pharmacology can decrease fatigue. Depression is often associated with disturbances in sleep, appetite, concentration, as well as fatigue.
Hematologic, infectious, endocrine, cardiac, rheumatologic, and metabolic causes of fatigue should be considered. History and physical will help guide the workup, but laboratory testing for metabolic and endocrine function should be standard.
Anterior pituitary dysfunction has been documented after TBI, stroke, and diagnosis of PD. Endocrine dysfunction has been shown to be as high as 59% after TBI. Growth hormone deficiency and hypogonadism are associated with decreased bone mineral densities, aerobic capacity, muscle strength, lower QoL, cognitive impairments, as well as fatigue. Basic screening for endocrine dysfunction should include a thyroid panel, AM cortisol, testosterone, facioscapulohumeral dystrophy, and luteinizing hormone as appropriate, and insulin-like growth factor-1 as a marker of growth hormone. The relationship between fatigue and neuroendocrine dysfunction is still evolving.
A driving assessment should be a routine part of any patient encounter when fatigue is an issue. Driving safety is a controversial issue without clear guidelines in this population, and specific recommendations are often left to the careful discretion of physicians. There is a small but important body of literature looking at the effects that fatigue in PD has on driving. One study assessed the effects of auditory-verbal distraction on driving performance in PD, showing that drivers with PD made more errors during baseline and with distraction than did their counterparts without the disease. In this study, daytime sleepiness predicted worsening of driving due to distraction. Another study questioned PD patients about occurrences of sudden onset of sleep at the wheel (SOS). Their alarming results showed that of the patients holding a driver’s license, 15% had experienced SOS at the wheel in the past 5 years, and in 11% of cases, the episode led to an accident. The risk of accidents in this study was correlated with an increased score on the Epworth Sleepiness Scale (ESS).
Parkinson Disease
When evaluating already-diagnosed PD patients, it is important not to allow their motor symptoms, including bradykinesia, resting tremor, rigidity, and postural instability, to monopolize an office visit. Studies have shown that nonmotor symptoms of PD, such as fatigue, can have just as negative an impact on QoL as motor symptoms. It is also important to keep in mind that there is no clear correlation between the severity of motor symptoms and the presence or severity of fatigue, so the clinician must ask about nonmotor symptoms even in PD patients without severe motor symptoms. There is evidence that the presence of nonmotor symptoms may actually predict the development of PD. In fact, fatigue is usually encountered early in the disease, often before an official diagnosis of PD is made.
It is well known that patients with PD already walk at a slower speed, have increased episodes of fall, and have less of an ability to multitask while walking than those without the disease. Contributing to this body of knowledge, 1 study showed that performance of additional tasks while walking resulted in a reduction of walking speed and mean step length in PD patients over the general population. Physical fatigue showed a significant relationship with gait speed in this study; however, it was balance that accounted for most of the variance in walking speed. Another study found that increased levels of fatigue were associated with decreased levels of leisure physical activity, lower frequency of vigorous physical activity, and less time performing ADLss. This relationship between activity and fatigue in PD patients remains unclear, however. One study showed that although PD patients experience significantly greater levels of fatigue than those of controls for a given amount of physical activity, this was not associated with a decrease in physical activity when given the opportunity. These data underscore the fact that an assessment of physical activity level and exercise tolerance should be part of every fatigue evaluation.
Stroke
Assessment of fatigue in post-stroke patients is perhaps the most difficult of all neurologic entities because many patients will have trouble distinguishing peripheral fatigue from muscle weakness secondary to the stroke. Careful use of language and good communication are especially important while conducting this interview.
Lynch and colleagues propose case definitions of post-stroke fatigue, which correlated well with substantially higher fatigue scores on 4 common FSSs. They differentiated between patients in the community and hospitalized patients. Their proposed case definition for post-stroke fatigue in community patients is “Over the past month, there has been at least a 2-week period when patient has experienced fatigue, a lack of energy, or an increased need to rest every day or nearly every day. This fatigue has led to difficulty taking part in everyday activities.”
It is important not to neglect the possibility of post-stroke fatigue in patients who have had mild strokes. Carlsson and colleagues showed that after mild stroke involving minimal or no motor or cognitive impairments, 75% of their subjects still stated that their stroke affected everyday life. Astheno-emotional disorder (AED), with fatigue being the most important symptom, was found in 72% of the sample. Carlsson and colleagues went on to further characterize AED the following year and concluded that although fatigue was a pervasive element of this syndrome, it was often hidden to others. This finding highlights the importance of asking about this symptom during office visits.
Traumatic Brain Injury
In the assessment of fatigue after TBI, high yield correlates that require evaluation and treatment include sleep disturbance, hormonal disorders, and pain.
Insomnia, or difficulty initiating or maintaining sleep, is reported with a frequency of 27% to 70% or higher in those with higher frequencies early post injury. Disordered sleep can have adverse behavioral, physical, and cognitive consequences. Endocrine dysfunction has been shown to be as high as 59% after TBI. Growth hormone deficiency and hypogonadism are associated with decreased bone mineral densities, aerobic capacity, muscle strength, lower QoL, and cognitive impairments as well as fatigue. The relationship between fatigue and neuroendocrine dysfunction is still evolving.
Scales
Several scales are available to help quantify the magnitude and impact of fatigue in general. Some of the more commonly used scales include the FSS (see Table 3 ) , the ESS, the FIS, and the Modified Fatigue Impact Scale (MFIS). In the FSS, the patient is asked to rate 9 statements about fatigue on the degree of agreement, and then the score is averaged. People with depression alone score about 4.5, but people with fatigue related to multiple sclerosis (MS), for example, average about 6.5. The ESS measures the likelihood of a subject dozing during certain mundane daily activities, such as watching television or being a passenger in a car ride lasting for 1 hour. The test subjects must rate each activity based on how likely they feel they would be able to doze off while engaged in that activity. The FIS is a 40-item questionnaire that separates functional categories into physical, cognitive, and psychosocial subsets. Each question is rated 1 to 4. The MFIS is a shorter, 21-item derivative of the FIS and has most frequently been used in the MS population.
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