Abstract
Behavioral and psychiatric problems associated with idiopathic Parkinson’s disease (PD) include cognitive dysfunction, drug-related psychosis, depression, anxiety, apathy, fatigue and sleep disturbance. These nonmotor symptoms are a significant cause of disability at all stages of illness. Cognitive dysfunction spans a continuum from circumscribed cognitive impairments to severe global dementia which can occur in up to 10±30% of advanced PD patients. Psychosis develops in 20±30% of PD patients receiving chronic antiparkinsonian therapy.
Visual hallucinations and paranoid delusions are the most frequent symptoms. The gradual elimination of drugs of lesser priority that may affect cognition and/or cloud the sensorium constitutes the first step in the management of cognitive and psychotic symptoms. Atypical neuroleptic agents are an invaluable tool in those cases in which maximum drug regimen simplification is not adequate or results in unacceptable immobility. Depression and anxiety often go unrecognized although they are eminently treatable and may be important contributors to the morbidity of PD. They are present in 30±40% of PD patients and frequently occur together in association with other nonmotor symptoms such as apathy, fatigue and sleep disturbance. A combination of early recognition, counseling, antidepressant therapy, antianxiety and well-balanced antiparkinsonian therapy sets the stage for improved quality of life for patients with PD.
1. Introduction
There are a wide range of behavioral disturbances associated with idiopathic Parkinson’s disease (PD) including depression [1], anxiety [2], fatigue [3], sleep disturbances [4], cognitive dysfunction [5,6] and drug-related psychosis [7]. Collectively these symptoms affect the majority of patients with PD [1-7]. While PD is traditionally described as a motor disorder, there is increasing awareness that the behavioral non-motor symptoms constitute an important source of disability. Early recognition and effective management of the non-motor symptoms of PD is integral to the quality of life of both patients and caregivers [8]. We will review the current knowledge in this expanding field, focusing on the practical issues involved in the delicate balance of managing both motor and non-motor symptoms in PD.
2. Cognitive dysfunction
Cognitive dysfunction in Parkinson’s disease (PD) spans a continuum that ranges from circumscribed cognitive impairments that may be observed relatively early in the disease process to global dementia in the late stages of the disease. Although estimates vary, dementia occurs in 10±30% of advanced PD patients [5,6,9], while more discrete cognitive impairments not only occur earlier, but also, affect the large majority of patients. These cognitive changes may not be fully appreciated if targeted testing with a broad neuropsychological battery is not performed [10].
The age standardized ratio of dementia in PD patients compared to controls was 4.6 in a recent study conducted in France [11]. Mayeux et al. [12] in a re-evaluation of the clinic-based sample 5 years after his prevalence analysis [10], indicated that the incidence of dementia was 69 per 1000 person years of observation, which was almost 6 times that expected in an aged-matched cohort.
Several risk factors have been associated with the development of dementia in PD including older age at the onset of PD [10,11,13], severity of extrapyramidal signs, especially bradykinesia [14,15], family history of dementia [16,17], depression [13,14,18], psychological stress [19] and low socioeconomic or educational attainment [20].
Cognitive dysfunction in PD is primarily attributed to defects of subcortical processing as opposed to cognitive impairment in Alzheimer’s disease (AD) which is attributed to cortical dysfunction [21]. The dementia associated with PD is characterized by impairment of executive functions (e.g. planning, sequencing, monitoring and shifting between responses), visuomotor skills, visuospatial skills, free recall of both verbal and nonverbal material and verbal fluency. Cortical functions such as praxis, calculations, orientation, cued recall, recognition memory and certain other aspects of language are relatively spared [22]. Perhaps the main distinguishing factor between patients with PD and those with AD is performance on delayed recall as compared to immediate recall. PD is characterized by relatively good retention of ewly acquired information following a delay, while patients with AD tend to rapidly forget it. This supports he belief that the memory impairment associated with PD is primarily a retrieval deficit as opposed to AD, which is characterized by deficient encoding or consolidation of information. The poor retrieval of new information by PD patients may be secondary to a form of executive dysfunction, consisting of the inability to initiate a systematic search of memory, reflecting a dysfunction of subcorticofrontal circuits [23].
The relatively circumscribed cognitive problems seen in many PD patients may or may not progress to global dementia [22]. Risk factors associated with the development of dementia were previously described. Additional neuropsychological predictors of later decline have also been identified including the individual’s performance on tests of letter, category and verbal fluency [24,25]. The progression of the milder and more circumscribed cognitive deficits seen in many PD patients towards more global impairments appears to represent not only a quantitative change but also, a qualitative shift in the pattern of cognitive domainsinvolved [26]. This concept is supported by neuropathological evidence of damage extending beyond the dopaminergic system in PD patients with advanced dementia [27,28].
3. Drug-related psychosis
Drug-related psychosis occurs in 20±30% of PD patients following chronic antiparkinsonian therapy [36]. The mechanisms responsible for its appearance are not well understood but dopaminergic (especially mesolimbic) and serotoninergic systems are likely to be involved [36].
Almost all of the drugs used to treat PD may induce psychosis although individual patients commonly demonstrate particular sensitivity to individual medications. The emergence of drug related psychotic ideation requires careful monitoring since this problem can be severely disabling and is more likely to lead to nursing home placement than either motor dysfunction or dementia [37]. In addition, there is a marked increase in the mortality rate of PD patients with drug-related psychosis [38].
3.1. Clinical features
The clinical features of drug-related psychosis in PD patients tend to be fairly stereotypical [39]. Visual hallucinations and delusions are both common [40]. Visual hallucinations often include people and are usually not threatening. The single most common hallucination is that of strangers who sit silently and observe the patient. These images tend to occur most commonly in the evening and do not interact with the patient. They will disappear when touched. Patients have a variable level of insight into the hallucinations. The level of insight has a profound impact on the patient’s functional level. Auditory hallucinations, a frequent manifestation in schizophrenic patients, are not a common occurrence in drug-induced psychosis. Delusions are often paranoid in nature. The most common delusions involve spousal infidelity and money loss [36]. Other symptoms include vivid dreams, nightmares, nocturnal vocalizations, and agitation. Psychotic symptoms frequently seen in schizophrenia, such as thought broadcasting, megalomania and pressured speech are not seen in the PD drug-related psychosis. The initial manifestations of an emerging psychosis may be subtle. Focused questioning by the astute clinician is often necessary to uncover the presence of hallucinations or paranoid delusions that the patient fails to spontaneously report. Patients should be specifically questioned about the presence of vivid dreams, the appearance of fleeting shadowy figures in the periphery of the visual field or the presence of recurrent suspicious thoughts, all of which may represent early symptoms of an emerging psychosis.
Drug-induced psychosis may either arise abruptly or insidiously. Symptoms often appear following the addition of a new drug or an increment in the dose of an old antiparkinsonian medication. Other precipitants include the onset or exacerbation of an unrelated medical condition (e.g. flu, urinary tract infection) as well as changes in the nonparkinsonian medication regimen (e.g. sedatives, tranquilizers). A common source of sudden confusion and psychotic ideation in the elderly is a change of environment. Restoration of the home environment is often therapeutic in itself, to reorient the patient and reduce the frequency and severity of hallucinations and delusions. In some situations, no clear precipitating factor can be identified. When a drug-related psychosis develops gradually, a continuum of signs and symptoms are often observed. Vivid dreaming is often the first symptom prior to overt visual hallucinations. This may be followed by a nonconfusional organic psychotic state and eventually an organic confusional psychosis.
The rate and speed of progression through this sequence is highly variable. The prevalence of hallucinations is about 20±30% of treated PD patients whereas florid psychosis is seen in 5-8%. Although drug-related psychosis is more common among the elderly and demented patients, it also occurs in younger individuals without prior psychiatric history or evidence of cognitive deterioration [41].
4. Neurobehavioral symptoms
4.1. Depression
Depression is the most common neuropsychiatric disturbance in PD. The prevalence of depression reported in PD has varied considerably depending on the diagnostic methodology employed [58]. A review of the literature shows a mean frequency of about 40-50% (4-70%) including patients with major depression, minor depression and dysthymia [1,59,60]. Depression may be difficult to recognize in patients with PD because the signs of both disorders may overlap. Slowness, sad appearance, sleeplessness, weight loss, apathy, anhedonia, sexual dissatisfaction, poor short term memory and loss of energy are manifestations of both depression and PD itself [8,61,62].
Therefore, depressive signs and symptoms are commonly overlooked and conversely, emerging symptoms of PD may be misdiagnosed as depression. A high index of suspicion is necessary to identify depression in patients with PD. Routine questioning about depressive symptoms during the history or in a brief screening questionnaire, as well as standardized instruments such as the Beck Depression Inventory (BDI) or the Hamilton Depression Rating Scale will improve recognition of depression. The BDI is the only standardized instrument that has been validated for use among patients with PD [63].
Risk factors for depression in PD include: younger age at onset of PD symptoms [64], female gender, right-sided parkinsonism [65], akinetic-rigid presentation [66], impaired cognitive function and the presence of a psychosis [67]. Curiously, severity of disability may correlate with minor depressive episodes but not with persistent major depression [33,68]. The presence of depression in PD patients has been correlated with worse functional status as measured by activities of daily living (ADLs) [69] and
motor performance test series (MPTS) [76]. Cognitive functions are also adversely affected by the coexistence of depression, with more consistent deficits in tasks of immediate recall, semantic fluency, shifts of cognitive set and abstract reasoning [70-73]. It has been suggested that depression influences the quantity rather than the quality of cognitive impairment associated with PD. [70] The neurobehavioral symptoms of PD are closely interrelated; comorbidity is common amongst the symptoms of depression,
anxiety, fatigue and sleep disturbance [33].
4.2. Anxiety
Anxiety has a higher prevalence in PD than is observed in either the general population [86,87] or many other chronic neurologic conditions, such as multiple sclerosis. Anxiety disorders, including generalized anxiety, panic and social phobia occur in up to 40% of patients with PD. The onset of anxiety in PD, and particularly panic attacks, tends to occur relatively late in PD patients when compared to individuals without concurrent PD . As with depression, PD symptomatology may overlap with symptoms of anxiety (e.g. postural dizziness, dry mouth, urinary frequency, tremulousness) contributing to nonrecognition or misdiagnosis .
Menza et al. found that 92% of PD patients who had anxiety also suffered from a concomitant depressive disorder while 67% of the depressed patients experienced an anxiety disorder. Anxiety has not been found to be associated with the presence of dementia. Disease severity and chronic levodopa therapy have been related to the presence of anxiety in some but not all studies.
The presence of anxiety symptoms is believed to be endogenous to the neuropathology of PD. In support of this, anxiety symptoms not infrequently predate the diagnosis of PD , anxiety has been observed to worsen during “off” periods in patients who experience motor fluctuations and in a recent study, levodopa infusion resulted in mood changes several minutes before any motor effects
could be detected.
Damage to the locus ceruleus and its dorsal ascending noradrenergic pathway may contribute to the prevalence of anxiety in PD. In addition, reduced serotonin concentration has been observed at the level of the raphe nuclei, basal ganglia and frontal cortex. Dopamine’s role may be suggested by the mood changes observed in patients with motor fluctuations .
SSRIs are generally effective and well tolerated in the treatment of anxiety in PD and they are particularly helpful when treating mixed depression and anxiety. Benzodiazepines should be used cautiously in PD patients since they may have detrimental effects on balance and cognitive functions.
4.3. Fatigue
Fatigue is more commonly reported by PD patients than by healthy adults and is the initial symptom of PD in a small number of patients . In a study of more than 100 patients with idiopathic PD, nearly one half of the study population reported clinically significant fatigue as measured by the Fatigue Assessment Instrument (FAI). Many of these patients reported that fatigue was among their three most disabling symptoms and that fatigue made their other symptoms worse. The severity of fatigue in PD was greater than that seen in healthy individuals but less than that reported in patients with multiple sclerosis or systemic lupus erythematosus. Fatigue was correlated with functional impairment as measured by the Unified Parkinson’s Disease Rating Scale. Fatigue was also associated with the presence of anxiety and unassociated with sleep disturbance or duration of PD. The relationship between depression and fatigue in PD patients remains unclear, with contradictory data from three clinical trials . Fatigue severity has also been reported to worsen during “off” periods in patients with motor fluctuations . At this time, no formal trials have been performed to assess treatment strategies for fatigue in PD patients.
4.4. Sleep disorders
Sleep disturbance adversely affects the quality of life of a significant number of PD patients as well as their bed partners . The most common problem is sleep fragmentation with frequent and prolonged awakenings followed by daytime sleepiness [4]. Nocturnal awakenings result from nocturia, difficulty turning over in bed, vivid dreams, nightmares, and painful dystonic cramping. Depression , motor fluctuations and levodopa dose have been shown to correlate with sleep disturbance. Controlledrelease levodopa appears to be less likely to cause nocturnal problems than standard levodopa, particularly in patients with mild-to-moderate PD [3]. Levodopa and dopamine agonists may have a dual effect on sleep in PD, causing sleep disruption in patients with mild-to-moderate disease, but having a beneficial effect on those nocturnal disabilities that cause sleep disruption (e.g. pain, stiffness, dificulty turning over) in more severely affected patients. Understanding the individual patient’s symptoms and sleep history will assist in planning therapy. Targeted therapy with a variety of drugs including controlled-release carbidopa/levodopa, urinary antispasmodics or muscle relaxants may be eficacious for the patient with immobility at night, frequent urination or dystonic foot cramping. Vivid reams and nightmares often improve with a reduction of antiparkinsonian medication, when this is feasible. In a patient taking selegiline, dosages should not be later than midday, since later dosages are associated with insomnia.
Physicians should be alert for symptoms of restless leg syndrome ( leg dysesthesias associated with an irresistible urge to move ) which frequently responds to dopamine receptor agonists.
5. Conclusion
Behavioral and psychiatric problems occur frequently in PD patients and are often a significant cause of disability. Accurate recognition and management poses a dificult clinical challenge since behavioral symptoms may be easily confused with manifestations of PD and effective treatment demands a careful balance between treating the nonmotor symptoms while preserving motor function. The goal of the linician is to interrupt the vicious cycle of hopelessness, helplessness and fatigue which results in PD symptom amplification and disruption of healthy adjustment to chronic illness. A combination of early recognition, counseling, antidepressants, antianxiety and well-balanced antiparkinsonian therapy sets the stage for improved quality of life for patients with PD.