Prevalence and pattern of occurrence
Apathy and fatigue can present as a feature of another condition or as independent and clinically significant symptoms. Most studies have used symptom rating scales to define the presence of apathy. Reported prevalence, ranging from 17% to 70%[1
], is influenced by the extent of cognitive impairment and depressive symptoms in the sample, the assessment tools used, and the rater (i.e., a clinician, family member, or patient)[1
]. Apathy symptoms in the absence of depression occur in 4% to 30% (14% average prevalence), whereas reported prevalence for depression in the absence of apathy is 6% to 28% and for the combination of apathy and depression is 12% to 47%[1
]. Apathy, also a feature of dementia, delirium, and demoralization, and can occur in the absence of cognitive decline[4
]. The longitudinal course of apathy has not been studied.
Fatigue, the single most disabling symptom reported by up to 1/3 of patients with PD[61
], has a prevalence of 32% to 58% that is also influenced by inconsistent definitions of fatigue and which assessment instrument was used[61
]. Fatigue is present early in the course of PD and may even predate onset of motor features[65
]. Once present, fatigue can be chronic or intermittent, but lifetime prevalence increases over time[64
]. Fatigue in PD is also associated frequently with depression, cognitive deficits, and daytime sleepiness[64
]. Despite its prevalence and impact, fatigue is under-recognized clinically[68
Apathy refers to a set of behavioral, emotional and cognitive features that involve reduced interest and motivation in goal-directed behaviors, indifference, and flattened affect[69
]. Some studies emphasize lack of motivation whereas others focus on lack of emotional responsiveness as a core feature. Patients typically show poor motivation with reduced initiative, effort, and perseverance as well as indifference to their circumstances. This is manifest as a lack of spontaneous engagement or early withdrawal in activities, a lack of concern for ones own health, or the absence of curiousness about others or new experiences. The impact of apathy is considerable; the patient is generally inactive, and this passivity leads to further functional decline and greater debility[1
]. Families misattribute signs of apathy as evidence of laziness, entitlement, or contrariness. Thus, providing care can be unrewarding and lead to resentment, especially when apathy remains undiagnosed[60
The role of depressive disturbances in the presentation of apathy is an important consideration. Reports are inconsistent as to whether the combination of apathy and depression is more common than apathy without depression or depression without apathy[54
]. At issue is whether loss of goal-oriented cognition, a feature of Marin's criteria for an apathy diagnosis[70
], qualitatively represents the same phenomenon as the reduced interest and anhedonia that is characteristic of depressive disorders. In addition to overlapping diagnostic criteria, symptom rating scales also include items that overlap features of depression and apathy. The Neuropsychiatric Inventory is an exception in this regard, but apathy and depressive subscores were still significantly correlated in a study involving PD subjects[55
]. By contrast, apathy and depression were more clearly dissociated in other disorders in that study, such as progressive supranuclear palsy.
Cognitive impairment, another important clinical factor in apathy, is also a general feature of PD. Apathy in PD is associated with bradyphrenia, global cognitive impairment, and executive dysfunction[54
]. However, motor severity, l-dopa dose, physical disability, and PD duration are less likely to be associated with apathy[56
There are two main classifications of fatigue: peripheral and central[43
]. Peripheral fatigue is a physiological phenomenon that involves lack of energy associated with muscular fatigue. It is objectively measured by decreased force generation or the inability to sustain repetitive movements[65
]. More clinically relevant in most cases is central fatigue, which is generally described as an abnormal degree of persistent tiredness, weakness, or exhaustion that is mental, physical or both in the absence of motor or physical impairment.[65
] Central fatigue is a subjective experience (in contrast to apathy, which is generally an observed phenomenon) with two subtypes, physical and mental. Physical fatigue represents the sense of physical exhaustion and lack of energy to perform physical tasks despite ability to do so. Mental fatigue refers to the effects experienced during and after prolonged periods of demanding cognitive activities that require sustained mental efficiency. Given its subjective nature, the overlap between physical and mental fatigue is not always clear.
In interviews of patients with PD, fatigue was described as unpredictable with respect to its onset, duration, and relationship to prior activity, but often exacerbated by physical, psychological, or social stressors[71
]. Inability to initiate and sustain activity associated with fatigue is distinct from sadness, sleepiness, or impaired motor function[71
]. Fatigue has adverse effects on quality of life, depression, and disability in PD[72
] and is the primary determinant of work-related disability[73
]. Relationships between fatigue and motor symptoms, daytime sleepiness, sleep quality, and physical activity are inconsistent[60
]. Surprisingly, fatigue is unrelated to exercise efficiency, activity level, or physical fatigue[65
Fatigue in patients with PD is associated with higher rates of depressive symptoms, sleep disturbances, and cognitive disturbances, but it is also highly prevalent in non-depressed patients[64
]. In one series, 43.5% of patients without depression, dementia, or sleep problems still reported fatigue, in contrast to 4.5% of controls[74
]. By definition, mental fatigue involves difficulties initiating and maintaining sustained cognitive performance and is often associated with motivational and attentional difficulties[65
]. For example, mental fatigue during driving may lead to reduced error monitoring In contrast to apathy, which appears to be associated with pre-existent cognitive impairment, especially executive dysfunction, fatigue occurs as a consequence of mental challenges. In particular, tasks involving increased attentional demands and multi-tasking may be more likely to be associated with fatigue[67
Diagnosis, Assessment and Classification
For both apathy and fatigue, co-existence of mood symptoms and cognitive deficits, and their overlap with motor signs of PD, contribute to diagnostic challenges. For example, loss of motivation, a lack of effort, and emotional indifference mimic bradykinesia, bradyphrenia, and masked facial expression of PD in the absence of apathy[60
]. Similarly, flattened affect and passivity can manifest as monotonous and reduced spontaneous speech, which can be functions of hypophonia or cognitive dysfunction.
Establishing the diagnosis of apathy can be challenging for additional reasons. Apathy, which can represent a transient clinical state or an isolated symptom or syndrome, is defined inconsistently in the literature and lacks standardized or validated criteria for apathy. Marin's criteria of reduced goal-directed behavior and cognition and emotional concomitants of goal-directed behavior are the most widely used[69
]. Controversy over the roles of an emotional dimension and cognitive deficits make it difficult to apply these criteria in PD. Discrete criteria for apathy are also lacking in the DSM-IV-TR.
Several rating scales, recently reviewed by a Movement Disorder Society task force, assist with evaluation[75
]. Rating instruments are generally useful as screening tools to be used with a secondary diagnostic interview. The rater (patient, caregiver, or clinician) influences the quality of the information obtained. For example, patients with apathy may be indifferent as to whether they have undergone behavioral changes. Distinguishing apathy from depression requires evidence for emotional features such as low mood, a reduced sense of pleasure, guilt, diminished self-attitude, and anxiety in patients with a concurrent depressive disorder.
The diagnosis of fatigue is challenging because of its recognition as an independent entity that can also be a feature of other disturbances. For example, fatigue is one of the criteria for diagnosing major depression. It can be impossible to distinguish fatigue due to depression from that related to other factors. However, assessments of fatigue must account for the possibility of a depressive disturbance.
A number of fatigue rating scales have been developed for the general population and for specific conditions[76
]. Unidimensional fatigue scales provide a single score that represents the range of symptoms and behaviors whereas multidimensional scales provide a profile of various qualitative and quantitative aspects of fatigue. The Parkinson's Fatigue Scale (PFS) was developed as a disease specific scale to overcome limitations of generic scales, which do not account for motor symptoms and to measure the single construct of physical fatigue[71
]. Most fatigue scales use set cut-off scores to define presence or absence of clinically significant fatigue.
Optimal management of apathy and fatigue involves vigilance for the symptoms of each, use of informants to obtain information to establish clinical diagnoses, and judicious use of assessment tools to screen for the presence of non-motor symptoms. Treatments for both include illness education to families and patients about depression, fatigue, apathy, and cognitive disturbances in PD, behavioral strategies to maximize executive functions, and use of medications to treat mood disorders and cognitive disturbances; improvements in co-morbid conditions may be sufficient to relieve apathy and fatigue when they do occur.
Studies on the specific treatment of apathy in PD are limited. Management is often difficult since patients are indifferent to the need to attend to their own health and well-being and their inactivity can be misconstrued as “characterological laziness”[77
]. Non-pharmacologic strategies involve providing an individualized daily schedule and structure with varied activities and group experiences that help to maintain a satisfactory activity level and enrichment. Campbell and Duffy underscore the role of the family as a therapeutic resource as patients benefit from a “goal-directed, reality-based, and paternalistic approach that essentially allows the caregiver to function as an `auxiliary executive'”[77
]. Possible medications include dopamine agonists, psychostimulants, modafanil, dopamine agonists, and testosterone[60
]. Deep brain stimulation effects on apathy are inconsistent[62
Few studies have investigated treatment of fatigue. In placebo-controlled trials, methylphenidate had a favorable effect on fatigue[78
] and l-dopa improved physical fatigue[79
]. Dopamine agonists have been helpful for some, but fatigue worsened in the placebo group compared to those who initiated levodopa therapy in early course untreated PD[80
]. Whereas modafanil, a wake-promoting drug, improved excessive daytime sleepiness but not fatigue in PD in a double-blind placebo-controlled trial[81
], nocturnally administered sodium oxybate improved fatigue and excessive daytime sleepiness in PD[82