NON-MOTOR SYMPTOMS OF PARKINSON’S DISEASE Parkinson’s Disease Research, Education and Clinical Center, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX, USA In addition to the typical motor symptoms (resting tremor, cogwheel rigidity, bradykinesia, postural instability)of Parkinson’s disease (PD), non-motor symptoms are sources of considerable burden in people with PD, espe-cially in elderly patients. The usual non-motor symptoms include cognitive declines, psychiatric disturbances(depression, psychosis, impulse control), autonomic failures (gastrointestinal, cardiovascular, urinary, sexualability, thermoregulation), sleep difficulties, and pain syndrome. This review article discusses the characteris-tics, pathophysiology, epidemiology, and management of these symptoms. [International Journal ofGerontology 2007; 1(2): 53–64] Key Words: dementia, depression, dysautonomia, non-motor symptoms, Parkinson’s disease, psychosis, sleep may appear even before the motor symptoms are firstnoticed. But they are more troublesome in the more Parkinson’s disease (PD), first described by James advanced stages of PD, when they can become major Parkinson in 1817, is a chronic, progressive neurodegen- problems for the patients and often pose a challenge erative disorder1. The pathologic hallmark is a deterio- to the treating physicians3,4. With multiple medications ration of the substantia nigra of yet unknown causes, often being used to treat PD, their side effects may resulting in a deficiency of dopamine, an important neurotransmitter for the basal ganglia circuit. Its typicalclinical symptoms are resting tremor, cogwheel rigidity,bradykinesia, and postural instability. Many affected patients are older than 55 years of age, and men seem tobe slightly more predominantly affected than women2.
Because of the varieties of symptoms, the prevalence of While PD is mainly regarded as a movement disor- non-motor symptoms in PD patients is difficult to delin- der, patients suffer from not only motor symptoms, eate precisely. It is estimated that about 16–70% of but also the non-motor symptoms which are also patients suffer from neuropsychiatric problems, includ-common and can significantly debilitate patients’ activ- ing depression, anxiety, apathy or psychosis5–7. Cogni- ities as well as the quality of life. These complications tive deficits affect at least 20–40% of PD patients8–10. include cognitive, psychiatric, autonomic, sleep and Sleep disturbances occur in more than a third of PD sensory disorders (Table). The non-motor symptoms patients11,12. Dysautonomia, including constipation,orthostatic hypotension, urinary and sexual dysfunc-tions, is reported in more than half of the PD patients, *Correspondence to: Dr Jyh-Gong Gabriel Hou, Parkinson’s Disease according to a questionnaire-based study13. This Euro- Research, Education and Clinical Center, Michael E. DeBakey pean study and other studies also suggest that auto- VA Medical Center, Baylor College of Medicine, Houston, TX nomic failures, including orthostatic dizziness, bladder dysfunctions, erectile dysfunctions and hyperhidrosis, are E-mail: [email protected]: March 30, 2007 more prevalent in PD patients than control individuals International Journal of Gerontology | June 2007 | Vol 1 | No 2 The non-motor symptom complex of Parkinson’s disease dysfunction; erectile impotence; hypersexuality (possibly drug induced) Modified from Chaudhuri et al.3. REM = rapid eye movement. without PD. These symptoms had a huge impact on ganglia-thalamocortical circuits involving different their quality of life13–15. Using a comprehensive symp- regions of the prefrontal cortex. Lewy body formation tom survey, Siddiqui et al.16 reported a significantly is abundant in these regions21,22. Urinary control may be higher prevalence rate of increased salivation, dyspha- from frontal cortex degeneration or autonomic nervous gia, decreased bowel movement, and orthostatic dizzi- system dysfunction, and possibly in combination with ness in PD patients compared with controls. Two prostate enlargement. Orthostatic hypotension is likely studies showed that cardiac uptake of metaiodobenzyl- due to sympathetic denervation of the central control guanidine, an index of functional integrity and func- centers located at the dorsal vagal nucleus, nucleus tion of postganglionic neurons, was impaired in almost ambiguus, and other medullary centers (caudal raphe all patients with PD, independent of duration and sever- nuclei, rostral ventrolateral medulla, and ventromedial ity of their parkinsonian symptoms17,18.
medulla). These nuclei mainly control the sympatheticpre-ganglionic neurons via descending pathways23,24.
Lewy bodies have been found in the myenteric plexus in PD patients. This explains the reason for constipationbecause of the loss of dopaminergic cells throughout Since non-motor symptoms comprise a variety of symptoms in different aspects, their involvement must PD is characterized by a dopaminergic degenera- be related to diffuse or multiple brain dysfunctions.
tive process affecting neurons in the substantia nigra.
Hallucination and psychosis can be related to the do- This results in the disruption in the basal ganglia cir- paminergic system in the prefrontal region. Depression cuitry. How the degenerative processes damage both is likely due to the decreased numbers of serotonin the nigrostriatal system and other brain regions is not5-hydroxyindolacetic acid (5-HT) neurons in the dorsal completely clear. Braak et al.26 hypothesized that the raphe nucleus and reduced dopamine neurons in the degenerative process starts from the base of the brain.
ventral tegmental area19,20. Cognitive function may be The olfactory bulbs may be the first to be involved, related to the depletion of dopamine in the head of followed by the lower brain stem that affects autonomic the caudate nucleus, which participates in the basal functions as well as sleep. Subsequently, substantia nigra International Journal of Gerontology | June 2007 | Vol 1 | No 2 and other nuclei in the midbrain are affected, thus man- patients with right-sided motor symptoms35,36. Further- ifesting the typical motor symptoms of PD. Eventually, more, greater depression is probably associated with the limbic system and frontal neocortex are involved, greater motor symptom severity in PD37.
resulting in cognitive and psychiatric symptoms in the Reactive depression is another form of depression advanced PD stages. Although yet to be confirmed, experienced by newly diagnosed PD patients and others Braak et al.’s hypothesis nicely illustrates the evolving with more advanced disease who are losing independ- symptoms in PD, including both motor and non-motor ence and control because of changes in motor func- tioning and feelings of helplessness6,25. Other socialfactors, including job loss with subsequent changes inincome or loss of identity, may also contribute to depres- sion. Concurrent memory difficulty, communicationproblems, and sleep interruptions, all add to the severity Depression is a very common feature in patients with of depression and anxiety. They contribute substantially PD. The reported prevalence from various studies is to increased morbidity and caregiver burdens.
between 16% and 70%5–7. Such variations are due to Treating PD patients with depression has not been the different diagnostic criteria used in different studies.
different from treating patients with other forms of Major depressive disorder defined by DSM-IV may not depressive disorders. Selective serotonin reuptake inhib- be very common in PD patients, but depressive symp- itors (SSRIs) are most frequently used. This is generally toms certainly have a high prevalence rate in PD. It is safe, although a small number of patients were reported thought that complex interactions between norepi- to develop serotonin syndrome from combined use of nephrine, serotonin and dopamine systems are inter- SSRI and selegiline, a monoamine oxidase B inhibitor38.
rupted in brains of PD patients. The mechanisms are not The effectiveness of SSRI in the treatment of PD clear yet. Some studies revealed decreased concentra- depression is still not determined. There have not been tions of 5-HT, a serotonin metabolite, in the cere- large-scale, of double-blind, placebo-controlled studies brospinal fluid and reduced cortical 5-HT1A receptor conducted. A meta-analysis found disappointing bene- binding in PD29. Another study suggested the role of fits of SSRI treatment in older PD patients with depres- an allelic variation in the serotonin transporter gene30.
sion39. Other treatments of choice include tricyclic The diagnosis of depression in PD can be challeng- antidepressants. While this class of medications has the ing, since flat affect, psychomotor slowing, fatigue, and additional benefit in reducing tremor by their anti- decreased libido may be frequently mistaken for PD cholinergic action, the side effects, including confusion, motor symptoms. The characteristics of depression in orthostatic hypotension, dry mouth or constipation, PD are decreased energy and motivation, losing interest, often limit their use. Rarely, electroconvulsive therapy is feelings of sadness, helplessness and hopelessness, used in patients with medication-refractory depression.
changes in weight, sleep and appetite, irritability, and It may improve motor function in PD patients40,41.
thoughts of suicide. Approximately 7–32% of PD patientsare diagnosed with major depression, according toDSM-IV diagnostic criteria31. However, the depression is reported to be qualitatively different in that manydepressed PD patients have greater rates of anxiety, pes- There can be periodic anxiety and panic attacks. Anxiety simism, irrationality, and less guilt and self-reproach, disorders are more prevalent in PD patients than compared with those of non-PD patients with major age-matched controls, although it is often under- depression32,33. There can be fluctuations between a diagnosed42. The prevalence rate is at least 40%43. Panic normal affect and a depressive state in their emotions.
attacks easily occur in patients who develop erratic The episodes of depression may be more frequent dur- motor fluctuations during “off” periods. It usually ing the “off” medication stage and may improve when improves after the patient achieves the “on” state44. “On” the motor symptoms are better treated34. Interestingly, state dyskinesia may also induce anxiety. Thus, anxiety depression has been found to be more prevalent in attacks seem more related with the motor fluctuations patients with the akinetic-rigid type of PD, compared in PD patients. Benzodiazepine, buspirone, and SSRI with those with the tremor-predominant type, and in may help reduce such anxiety45. However, better control International Journal of Gerontology | June 2007 | Vol 1 | No 2 of PD motor symptoms may be more helpful in reduc- deficits. These symptoms are summarized as “dysexecu- tive syndrome”, in which acquisition and delayed recallare defective, while recognition memory remains intact52.
However, the distinctions usually may not be very clear.
About 15–30% of demented patients with PD may alsohave coexisting Alzheimer’s disease and exhibit symp- Dementia in PD may not be evident until the later toms of impaired language, memory, and visuospatial stages. Although the cognitive decline reported in PD functioning earlier in the course of the disease, includ- is subtle and does not often interfere with daily func- ing the presence of aphasia, agnosia, and apraxia53,54.
tioning, PD patients have been shown to demonstrate Another important differential diagnosis is dementia cognitive slowing and executive dysfunctioning prob- with Lewy bodies (DLBs), which also manifests demen- lems at earlier stages46. Longitudinal research has tia, autonomic failure, and parkinsonian symptoms.
described PD-related cognitive deficits in language, As a general rule, DLB patients show fluctuations in men- visuospatial functioning, long-term memory, and execu- tal symptoms, visual hallucinations, and more promi- tive functioning that are greater than those expected nent lower body parkinsonism. The motor symptoms from normal aging. The percentage of patients with of parkinsonism usually occur together with cognitive cognitive deficits is estimated to be approximately decline55. Again, the clinical features are frequently 20%8,10. However, the prevalence varies widely according not reliable in making a clear differentiation. A con- to different studies. For example, a Norwegian study firmed diagnosis usually depends on the results of of PD patients indicated that the 8-year prevalence in autopsy. A typical pathologic picture of DLBs shows widespread Lewy bodies located in the neocortex and The cognitive dysfunction in PD may be a conse- quence of disruption not only in the primary motor Rivastigmine, an acetylcholinesterase inhibitor that circuit but also in a number of interconnected path- has been used in the symptomatic treatment of patients ways from the basal ganglia to the cortex. Dopamine with mild to moderate Alzheimer’s disease, was also depletion in the lateral orbitofrontal and dorsolateral shown to be effective in the treatment of dementia in prefrontal circuits has been suggested as a possible PD57,58. Other cholinesterase inhibitors may also be mechanism of cognitive impairment in PD48. Cholinergic beneficial, although large-scale randomized controlled cell loss in the nucleus basalis of Meynert is prominent studies have yet to be conducted59. Memantine, which in PD. The disturbances of dopamine–acetylcholine is an N-methyl-D-aspartate receptor antagonist benefi- dependent alterations in synaptic plasticity may also cial in Alzheimer’s dementia, has not been shown to be responsible for dementia in PD49.
be effective in PD dementia60. One study even sug- PD patients at a higher risk of developing demenia gested that it worsened both the motor and cognitive include: (1) age older than 70 years; (2) Unified Parkin- son’s Disease Rating Scale motor score of more than25 (moderate to advanced impairment); (3) coexistingdepression; (4) development of mania, agitation, dis- orientation or psychosis when treated with levodopa;(5) facial masking at presentation; (6) exposure to psy- Hallucination occurs in PD, more frequently in the chologic stress; (7) presence of cardiovascular abnor- advanced stages. Psychosis and visual hallucination malities; (8) low socioeconomic status and educational are common, dose-dependent adverse effects of anti-PD level; and (9) predominant bradykinesia, and postural medications, in combination with disease progression and gait disturbance. Tremor or other parkinsonian and medical illnesses62. Risk factors include advancing signs are less associated with dementia10,50,51.
age, presence of dementia, and polypharmacy. Patients Cognitive impairment in PD is usually distinguished who experience hallucination generally have a certain from that of Alzheimer’s type, which reveals more degree of cognitive decline. They also have a worse amnestic quality of memory loss. In contrast, PD patients prognosis, with higher mortality rates63. In addition, encompass the clinical symptoms of cognitive slowing, delusions, paranoid ideation, and delirium may also impaired memory recall and retrieval, and executive become more frequent as the disease progresses.
International Journal of Gerontology | June 2007 | Vol 1 | No 2 Hallucination is usually visual in nature, in contrast Interestingly, the movements during REM sleep show to auditory hallucination in schizophrenia64. Patients little signs of parkinsonism. This could be attributed may report seeing small animals, insects, children, or to the motor signals from the cortex during REM sleep their deceased relatives or friends. In the early stages, bypassing the extrapyramidal system76. Management patients retain insight that the hallucinations are not of this disorder requires adjusting dopaminergic med- real. Symptoms are commonly more severe toward ications to smaller dosages, especially toward the night.
the evening, known as “sun-downing”65. Patients may Long-acting dopamine agonists may also be consid- experience frightening dreams or night terrors that can ered77,78. Clonazepam has been widely used in this con- lead to acting or lashing out during the dream state.
dition, but side effects such as excessive sedation have Another common delusion is that of spousal infidelity, for either male or female patients64,66. These symptoms Excessive daytime sleepiness (EDS) is common. In can be aggravated by dopaminergic and other psychoac- addition to fatigue that many PD patients experience, tive medications. Any medical illness, even as mild as the lack of sleep during the night also sets up a vicious an upper respiratory tract infection or diarrhea, may cycle for poor sleep hygiene. This sleepiness can be trigger or worsen the demented or psychotic symp- disabling, often approaching levels observed in dis- toms. They are best managed by either simplifying the orders of sudden-onset sleep, namely narcolepsy/ patient’s psychoactive medications or reducing the cataplexy. Polysomnographic studies have shown tran- sition from wakefulness to stage II sleep within sec- Typical neuroleptics significantly increase extrapyra- onds79. In addition, dopaminergic drugs, especially midal symptoms in PD and should not be used.
dopamine agonists, can further cause sedation and sud- Atypical neuroleptics, such as quetiapine or clozapine, den onset of sleep80–82. Management is usually by adjust- may be used in the evening to relieve such symp- ing the timing of medications, or breaking the vicious toms67–69. However, not all atypical neuroleptics are safe cycle by improving patients’ night-time sleep. Modafinil or free from extrapyramidal side effects. Olanzapine may help relieve EDS. However, while this medicine does and risperidone were both shown to worsen the not deteriorate PD symptoms, several randomized motor symptoms in PD and should not be used70,71.
controlled trials revealed that it either had no significantbenefit or produced only modest improvement83–85.
A significant portion of patients may suffer restless leg syndrome (RLS) that results in sleep disturbance86–88.
It is characterized by an uncomfortable feeling of the Sleep disturbances are common problems in PD lower extremities that urges the patients to move. It patients. Because of depression and/or hallucination, occurs mostly when patients are at rest or during the patients may become restless at night and have diffi- night. Moving or walking will help patients feel better culty falling asleep. Those at higher risk for pathologic subjectively. It often occurs in combination with the sleep are male patients with advanced disease, cognitive symptoms of periodic limb movement during sleep, a impairment, drug-induced psychosis, and orthostatic repetitive, myoclonic jerky limb movement present hypotension72. After falling asleep, patients may still mainly when patients are asleep. Both conditions wake up frequently because of stiffness of their bodies severely affect the sleep quality of patients. Prevalence or urinary urgency at night. As a result, they have diffi- of RLS in PD patients was reported to be higher than that in other non-PD patients3,89,90. The pathophysiology Rapid eye movement (REM) behavior sleep disor- is still unclear, although various central dopaminergic der (RBD) is very likely to occur. It is characterized by systems are believed to be involved in both PD and RLS91.
loss of atonia during REM sleep, resulting in excess Dopamine agonists, such as ropinirole and pramipexole, motor activity during dreaming. It is highly related to are effective in controlling RLS92–95. Levodopa is also neurodegenerative disorders, including PD73,74. Recent effective in controlling the symptoms, although augmen- studies suggested RBD may occur well before the tation is a concern. This limits the usefulness of levodopa emergence of PD symptoms. Approximately half of the as a first-line choice for treatment of RLS. Other med- patients with RBD will eventually develop PD, and ications, including gabapentin, clonazepam and opi-so RBD may be an indicator of presymptomatic PD75.
ates, have been shown to relieve RLS symptoms96–98.
International Journal of Gerontology | June 2007 | Vol 1 | No 2 One study even reported that deep brain stimulation of the subthalamic nucleus also improved RLS99.
Gastrointestinal symptoms are a common problem inPD. Dysphagia, heartburn, medication-related nausea,and constipation are the predominant symptoms105.
Constipation is the most frequently encountered prob-lem. It can be one of the early signs even before the Autonomic dysfunctions in PD patients are manifested appearance of the motor symptoms of PD13,106. Slower in several different systemic symptoms. These gener- bowel movement and decreased mobility exacerbate ally include cardiovascular (orthostatic hypotension, the severity of constipation. This can especially be a cardiac arrhythmia), gastrointestinal (gastric dysmotil- serious problem for older patients, as they do not ity, indigestion, constipation, and regurgitation), urinary exercise enough and may not take adequate amounts (frequency, urgency or incontinence), sexual (impotence of fluid. At least 59% of PD patients suffer from consti- or hypersexual drive), and thermoregulatory (exces- pation as compared with 21% in age-matched non-PD sive sweating or intolerance of heat or cold) dysfunc- patients107. Byrne et al.108 reported that constipation tions4,25. The pathophysiology of dysautonomia in PD is in PD is commonly a consequence of anorectal sphinc- thought to be from degeneration and dysfunction of ter and pelvic floor dysfunctions108. Fewer than three the nuclei that mediate autonomic functions, such as the bowel passages in a week will raise the clinicians’ con- dorsal vagal nucleus, nucleus ambiguus, and other cern for constipation. Patients are advised to take plenty medullary centers (rostral ventrolateral medulla, ven- of high-fiber food (dietary bulk) and fluid. Reducing tromedial medulla, caudal raphe nuclei), which exert anticholinergic medications will also help. Regular exer- differential control on the sympathetic preganglionic cise can improve bowel motility. Stool softeners, laxa- tives, and enemas may also be used to relieve persistentsymptoms109,110.
Dysphagia may become more problematic as PD Orthostatic hypotension is a particular concern. The progresses and can lead to choking and aspiration pneu- symptoms include position-related dizziness, fatigue monia. Softening of foods may help, whereas others or even fainting. Position-related dizziness often leads may need to thicken their liquids. Evaluation by a speech to falls in PD patients. It may be a subtle sign in the early pathologist or otolaryngologist can be helpful. Patients stage of PD and may not manifest as a major problem are instructed not to rush, and to eat and chew thor- until later stages101. Dopaminergic medications usually oughly before swallowing111. However, for some patients do not significantly help. They may even worsen the with advanced disease, a feeding gastrostomy may be symptoms, especially with dopamine agonists102,103.
necessary to improve nutrition and quality of life and Treatment of orthostatic hypotension is mostly symp- tomatic. For those patients who also take regular anti- Nausea troubles many PD patients, especially when hypertensive medications, the balance between these they suffer the side effects of levodopa, dopamine and Parkinson medications should be sought. Patients agonists or other parkinsonian medications. This can are encouraged to drink appropriate amounts of water be explained by the stimulation of dopaminergic and consume more salt. They should be taught to get up receptors in the brain stem nausea center and the slowly from a sitting position and wait for a while before peripheral tissues, including receptors on the gastroin- initiating their gait to prevent the sudden decrease of testinal tract, resulting in irregular peristalsis. To cor- blood pressure on positional changes. Compression rect this condition, sometimes simply changing the stockings may also improve the condition. In more medication schedule may help. Other options include severe cases, antihypotensive medications may be nec- extra carbidopa to block the conversion of levodopa essary to improve orthostatic hypotension symptoms.
to dopamine in the peripheral tissues more effectively.
The commonly used drugs are fludrocortisone (a salt- Certain antiemetic (or appetite-increasing) medications, retaining mineralocorticoid) or midodrine (a selective, like chlorpromazine, cisapride or metoclopramide, peripherally acting alpha-adrenergic agonist). In an epi- block dopaminergic receptors both peripherally and demiologic study, 9.1% of PD patients required such centrally and should be avoided as they will cause medications to treat orthostatic hypotension104.
International Journal of Gerontology | June 2007 | Vol 1 | No 2 (hyperhidrosis). A study found that complaints of Urinary urgency or incontinence due to a spastic bladder sweating disturbances were not correlated with dis- occurs in approximately 27–39% of PD patients114. A ease severity but did correlate with other symptoms of questionnaire-based study regarding autonomic func- autonomic dysfunction. Sweating problems occurred tions of PD patients versus a control group of elderly predominantly in “off” periods and in “on” periods with non-PD subjects found the PD patients with twofold dyskinesias. It was almost three times more common greater occurrence of bladder problems and fourfold than in controls who did not have PD126. Excessive risk of other autonomic problems, when compared with sweating occurred mainly on the face, head, and trunk.
the controls115. The patients complained of urinary It may be explained by decreased activation of sweat frequency and urgency, but with little urinary output glands in the palms of the hands, suggesting that axial each time. Prostate enlargement is common among hyperhidrosis can be a compensatory phenomenon older patients. It usually becomes an obstacle for empty- for reduced sympathetic function in the extremities127.
ing urine completely. Nocturnal urinary urgency is also This phenomenon results in reduced quality of life of common. Many patients have the urge to urinate fre- the patients, in the areas of daily activities as well as quently at night as their sleep becomes fragmented.
social interactions126. Botulinum toxin injections may Urinary incontinence will occur if patients walk slowly relieve local areas of hyperhidrosis, though it has no and cannot reach the bathroom in time. It seems that effect on the body function or thermoregulation.
the severity of bladder dysfunction is correlated with theprogression of PD116. Appropriate dosage of anticholin-ergics or alpha-blockers helps relieve the frequency prob- lems. The use of dopaminergic medications to improvebladder function has been reported but is generally Non-motor symptoms in PD are usually more compli- cated and difficult to manage than typical PD motor Sexual dysfunctions, including erectile difficulty, loss symptoms. However, they are usually overlooked and of libido, and anorgasmia, are common in male PD not properly treated. Physicians should be aware of patients119. Erectile dysfunction was nearly twice as the need to evaluate the neuropsychiatric, cognitive, frequent in PD patients, compared with controls from a autonomic, and sleep complications of PD. Early recog- questionnaire-based study115. Patients rarely give infor- nition of non-motor symptoms is essential, as effective mation despite its significance on quality of life. Silde- treatment can reduce morbidity and improve the nafil has been reported to be effective for erectile dysfunction in patients without obvious cardiovascu-lar risk factors120–122. Other patients may suffer a com-pletely opposite problem, which is sexual impulse control. Patients, particularly those taking dopaminergicmedications, may become obsessive and compulsive We thank Ellen Matthiesen for her editorial assistance.
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