Parkinson disease (PD) is a neurodegenerative disorder that affects approximately 1% of those older than 60 years of age. Improved recognition of both non-motor and motor symptoms can promote early diagnosis and treatment of PD. Importantly, early intervention leads to better quality of life for the patient, and this may be facilitated by improved understanding of PD pathophysiology, signs and symptoms, differential diagnosis, and therapeutic options. As a chronic condition, patients with PD have ongoing contact with their primary care provider for PD and non-PD related concerns. Additional aspects related to PD are likely to be encountered, including issues with medications prescribed to control PD symptoms, comorbid conditions, and polypharmacy. This course will review all of the relevant aspects of PD diagnosis and treatment necessary for the optimal care of patients with the disease.
This course is designed for all healthcare providers in the primary care setting who may encounter patients with Parkinson disease.
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This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.
The purpose of this course is to provide needed information about the assessment and treatment of Parkinson disease so healthcare professionals may implement the necessary interventions appropriately.
Upon completion of this course, you should be able to:
- Outline the history of Parkinson disease (PD) and scientific developments related to recognition of the disease.
- Review the epidemiology of PD in the United States.
- Analyze the pathophysiology of PD.
- Describe the time course of symptom development in patients with PD.
- Identify the early motor and non-motor signs and symptoms of PD.
- Outline the diagnostic workup of patients with suspected PD, including the diagnostic and staging criteria.
- Compare and contrast syndromes that may mimic PD and their differential diagnosis.
- Evaluate the drugs used in the management of PD.
- Review the approaches to managing PD throughout the course of the disease.
- Discuss the management objectives for non-motor symptoms of PD.
- Describe practice considerations when treating patients with PD, including long- term monitoring and safety precautions.
Mark Rose, BS, MA, is a licensed psychologist and researcher in the field of alcoholism and drug addiction based in Minnesota. He has written or contributed to the authorship of numerous papers on addiction and other medical disorders and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to various law firms on matters related to substance abuse, is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine, and is a member of several professional organizations.
Contributing faculty, Mark Rose, BS, MA, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
John M. Leonard, MD
Jane C. Norman, RN, MSN, CNE, PhD
Alice Yick Flanagan, PhD, MSW
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.
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#98770: Parkinson Disease
Parkinson disease (PD) is a neurodegenerative disorder that affects approximately 1% of those older than 60 years of age [1,2]. Improved recognition of both non-motor and motor symptoms can promote early diagnosis and treatment of PD. Importantly, early intervention leads to better quality of life for the patient, and this may be facilitated by improved understanding of PD pathophysiology, signs and symptoms, differential diagnosis, and therapeutic options [3,4]. As a chronic condition, patients with PD have ongoing contact with their primary care provider for PD and non-PD related concerns. Additional aspects related to PD are likely to be encountered, including issues with medications prescribed to control PD symptoms, comorbid conditions, and polypharmacy. This course will review all of the relevant aspects of PD diagnosis and treatment necessary for the optimal care of patients with the disease.
PD is a neurodegenerative disease first described in 1817 by the English physician James Parkinson as "the shaking palsy" . This disorder is prominently characterized by the motor symptoms of resting tremor, rigidity, and bradykinesia. The non-motor features are increasingly identified and include sensory, autonomic, and neuropsychiatric symptoms that appear before motor dysfunction is evident. The onset is insidious and often asymmetrical. Numerous, potentially disabling non-motor symptoms are often present, and diagnosis is made clinically. Treatment is symptomatic and involves multidisciplinary care.
Parkinsonism: A motor disorder syndrome and core clinical feature of PD that includes bradykinesia plus tremor, rigidity, and/or postural instability. Parkinsonism is non-specific to PD, as corticobasal degeneration, multisystem atrophy, and other neurodegenerative disorders can show parkinsonism features. Parkinsonism is required for a PD diagnosis because the motor symptoms directly reflect loss of dopamine neurons in brain motor control systems. All patients with PD have parkinsonism, but not all patients with parkinsonism have PD [1,6,7].
Idiopathic Parkinson disease: Synonymous with PD, the most common type of parkinsonism. Idiopathic means unknown cause, and idiopathic PD refers to parkinsonism not attributed to corticobasal degeneration, multisystem atrophy, or other neurologic disorder and not the direct result of gene mutation [1,6,7].
SporadicParkinson disease: PD without direct familial/genetic cause. Synonymous with idiopathic PD.
Bradykinesia: Slowness with initiating voluntary movement and progressive reduction in speed and amplitude with repetitive actions. The core motor symptom of PD.
Dementia: The progressive decline in cognitive function due to neurologic damage or disease, with decline greater than expected from normal aging.
Dyskinesia: Involuntary movements with a rotatory, writhing appearance that can affect the limbs, trunk, or face. Dyskinesias are typically associated with dopaminergic therapy in later PD.
"On" and "off" states: With long-term levodopa use in later PD, many patients develop fluctuating drug response, termed "on" and "off" motor states. "On" describes optimal motor response to medication (typically levodopa); "on with dyskinesias" describes involuntary writhing movements during medication efficacy. "Off" describes resurgent motor symptoms and impairment, sometimes accompanied by non-motor symptoms such as low mood or fatigue. "Off" episodes commonly occur during loss of medication effect before the next dose [1,6,7].
Sporadic (idiopathic) PD is the second most frequent neurodegenerative disorder after Alzheimer disease . Roughly 1 million Americans currently have the disease, with 60,000 diagnosed each year. The mean age of onset is around 60 years. The population prevalence is 1% in persons 60 years of age or older and up to 4% in those 80 years of age or older. While mostly occurring in the elderly, persons in their 30s and 40s can develop PD. Women develop PD at lower rates and with later onset than men; the delayed onset has been attributed to the neuroprotective effects of estrogen on the nigrostriatal dopaminergic system [1,2]. The variable prevalence of PD throughout the world suggests that environmental and genetic factors interact with ethnic differences in disease pathogenesis .
The incidence of PD varies by age, race, and ethnicity. The ratio of men to women is roughly 2:1 . As noted, the incidence is markedly higher in each decade after 60 years of age, peaking after 80 years of age. The rate is highest among Hispanic individuals, followed by non-Hispanic whites, Asians, and black persons . However, there is some variation in the incidence in each racial/ethnic group when divided by sex, with black men and Asian women at greater risk than their other-sex counterparts.
The United States has the fourth highest annual death rate from PD in the world. In 2011, 23,111 people died from PD, the 14th most common cause of death in the United States. From 1999 to 2011, there was a 30% increase in the annual death rate from PD (from 5.2 to 7.4 per 100,000 persons) . Between 2000 and 2013, age-adjusted death rates from PD per 100,000 increased for men (8.8 to 11.0) and women (3.9 to 4.8) .
Idiopathic PD, like other neurodegenerative diseases, has a complex pathogenesis involving the interaction of several genetic contributions, each with minor impact, with environmental factors . Risk factors associated with the development of PD include other medical conditions, abnormal physiologic processes, and exposure to specific substances and environmental toxins. Genetic associations are less robust, but several gene mutations confer greater risk of PD (Table 1).
RISK AND GENETIC FACTORS ASSOCIATED WITH PARKINSON DISEASE
|Medical conditions and lifestyle factors||
|Inflammatory, immune, and oxidative processes||
Current understanding of how environmental factors increase or mitigate risk of developing PD was accelerated by a series of studies from two distinct lines of investigation. These investigations identified specific protective and risk factors, greatly contributing to the knowledge of pathogenesis and pathophysiology in PD.
The first line of investigation began in the early 1960s, with an unexpected finding that linked cigarette smoking with protection against PD. This association between smoking and neuroprotection from PD has been replicated in numerous epidemiologic, pre-clinical, and case-control studies. These studies also identified coffee drinking (and caffeine) as a factor that reduced risk of developing PD .
In these studies, risk of developing PD is shown as odds ratio (OR), where the odds of developing PD in cigarette or coffee users was compared to non-user reference groups. An OR of 1.00 signifies no difference from the reference group, while a number greater than 1 means increased odds of developing PD and a number less than 1 indicates decreased odds of PD.
In one study, smoking, other lifestyle behaviors, family history of PD, and their interaction were examined for possible association with risk of PD diagnosis by comparing 1,808 patients in Denmark with PD diagnosis with 1,876 matched population controls . Strong inverse associations were found between cigarette smoking and risk of PD, even in smokers who quit 10 years before PD diagnosis. Compared with never-smokers without PD family history, the OR was 2.81 in never smokers with family history, versus 1.60 in smokers with family history. Duration had the greatest effect in modulating the smoking-PD relationship. Current smokers who smoked 40 years or more had ORs as low as 0.30. Unlike the correlation between longer smoking and lower PD odds, smoking more than 10 cigarettes per day did not further reduce odds.
Moderate coffee intake (3.1 to 5 cups per day) (vs. no coffee intake) showed an OR of 0.45. Moderate alcohol intake (3.1 to 7 units per week) (vs. no alcohol use) was associated with an OR of 0.60; higher daily alcohol did not further reduce the odds of developing PD. Stronger negative OR for PD was found in smokers with medium-high coffee or moderate alcohol intake than with each alone. Coffee intake association with lower PD odds was found in men and women; only men showed lower risk estimates with caffeine and alcohol, largely attributed to beer consumption .
These findings were consistent with numerous prior studies, including publications from the prospective NIH-AARP Diet and Health Study [7,15]. In this study, 306,895 participants (58.8% male, 50 to 71 years of age) were evaluated in 1995–1996 and again in 2000–2006 for development of PD.
One NIH-AARP study examined caffeine intake, risk of PD, and whether smoking affected this relationship . Higher caffeine use in 1995–1996 was associated with lower risk of PD diagnosis in 2000–2006 for men (OR=0.75) and women (OR=0.60). The linear trend for lower odds with higher caffeine was significant for both sexes .
The authors also performed a meta-analysis, which confirmed the inverse association between caffeine intake and risk for PD in men and women. Together with the study findings, this data led the researchers to conclude that gender differences do not influence caffeine risk reduction of PD. Smoking and caffeine may act independently to reduce PD risk .
Another NIH-AARP study examined cigarette smoking and risk of PD by comparing those who developed PD to those who did not. Odds for developing PD were 0.78 in past smokers and 0.56 in current smokers, with 0.47 in men and 0.74 in women. For few current smokers at baseline who developed PD, other comparisons were not relevant . The greatest reductions in odds for PD were found with current smoking and higher daily amount/duration of past smoking .
In the NIH-AARP study, amount and type of alcohol use was studied for risk of PD. Compared to non-drinkers, the odds ratio for developing PD was 0.73 with 1 to 1.99 drinks of beer per day, 1.22 with liquor, and 0.74 with wine. Beer and liquor consumption showed opposite effects .
Higher circulating levels of uric acid have also been associated with decreased incidence of PD and with slower rate of decline in patients with PD. This suggests a link to the neuroprotective effects of caffeine and the purinergic system [7,18].
A second line of investigation began when the first environmental risk factor was identified. In the early 1980s, a parkinsonism syndrome developed in persons who used a tainted street drug. An illicit lab produced a meperidine (Demerol) analog that contained 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxic impurity. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B. MPP+ is a neurotoxin that, following dopamine neuron uptake via the dopamine transporter, destroys striatal dopamine neurons by inhibiting mitochondrial complex I activity. Ten persons who ingested this batch developed a severe, irreversible parkinsonism syndrome [19,20]. Extensive evaluation of these patients at onset and over time led to many breakthroughs in the understanding of PD and related conditions. Also identified were several persons with MPP+ exposure who developed mild-to-moderate, but not severe, parkinsonism. For the first time, an environmental factor was linked to PD pathogenesis, initiating environmental risk factor research. The variable consequences from exposure also helped prompt research into protective factors [19,21,22,23].
Pesticides (i.e., herbicides, insecticides, fungicides, and rodenticides) that increase the risk for developing PD include paraquat and rotenone. Neurotoxic mechanisms have been proposed based on findings that substances such as MPTP cause selective damage to dopaminergic neurons in the nigrostriatal pathway through mitochondrial complex I toxicity .
Paraquat exposure induces reactive oxygen species formation, and while not shown to stimulate Lewy body formation, it accelerates alpha-synuclein misfolding, disrupts membrane conductance, and accelerates protein aggregation [24,25]. Rotenone inhibits mitochondrial complex I, enhances alpha-synuclein fibril formation, and increases alpha-synuclein aggregation, modification, misfolding, and toxicity [26,27]. The data suggest environmental factors that increase oxidative stress or inhibit mitochondrial function can lead to alpha-synuclein misfolding and nigrostriatal damage, processes that underlie PD .
A retrospective study of methamphetamine or amphetamine use as a risk factor for PD/parkinsonism/essential tremor was performed by examining statewide medical records in Utah (1996 through 2011) for all persons 30 years of age and older. A methamphetamine/amphetamine cohort and cocaine cohort were compared to a population control cohort unexposed to drugs or alcohol. Methamphetamine/amphetamine users showed increased risk compared to population controls; cocaine users did not exhibit elevated risk of PD compared to controls. The nearly three-fold increased risk of PD in methamphetamine/amphetamine users confirmed prior observations and suggests PD risk in users may be higher than previous estimates. A suggestion that female and male users may differ in PD susceptibility warrants further study .
Pre-clinical research identified nicotine exposure as a possible protective factor against methamphetamine-induced dopaminergic deficits . Using oral nicotine, researchers found that nicotine exposure from adolescence through mid-adulthood attenuated methamphetamine-induced striatal dopaminergic deficits associated with drug use in early adulthood. High-dose nicotine attenuated the negative effects of methamphetamine in late adolescence, but the protective effects did not persist. High-dose nicotine from post-adolescence to early adulthood did not protect against methamphetamine in very early adulthood, but high-dose nicotine from post-adolescence to full adulthood did protect against methamphetamine in mid-adulthood.
Nicotine neuroprotection is not due to nicotine alteration of methamphetamine pharmacology but from nicotine effects on nicotinic acetylcholine receptors (nAChRs). Imaging analysis found that nicotine increased striatal α4β2 nAChR expression, while methamphetamine and nicotine decreased striatal α6β2 nAChR expression. This suggests that nicotine protects against methamphetamine-induced striatal dopaminergic deficits by affecting α4β2 and/or α6β2 expression, with additional influence from nicotine exposure duration and the age of onset .
A meta-analysis of data from this study concluded that higher body mass index (BMI) in overweight (BMI 25–29.9) or obese (BMI ≥30) persons had no impact on the risk of developing PD .
Inherited genetic mutations are responsible for a small proportion of PD, with the most common genetic form of PD, PARK8, accounting for 2% of PD cases in the United States . Penetrance is incomplete in this inherited parkinsonism, and PD manifestation in carriers is determined by environmental exposure or other genetic factors .
Idiopathic PD is a sporadic disorder, and twin studies have not shown a strong genetic basis in patients older than 50 years of age. However, genetic mutations have been increasingly mapped, and rare autosomal dominant and recessive familial forms have been identified in small numbers of patients. These include the SNCA, Parkin, PINK-1, DJ-1, GBA, and LRRK2 genes that code various proteins, with some carrying the same name as the mutation and components of the ubiquitin-protease system. In addition, mutations in the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, confer a greater risk of PD [32,33].
The protein alpha-synuclein is a key element in Lewy pathology and contributes to familial and sporadic PD. Duplications and triplications of wild-type SNCA, the gene encoding alpha-synuclein, have been identified in typical and early-onset PD, suggesting SNCA overexpression is related to PD pathogenesis .
Gene-environment interactions in PD were examined by studying smoking and caffeine use interaction with 10 single nucleotide polymorphisms at or near four PD susceptibility genes in 584 patients with PD and 1,571 controls. Combining smoking and caffeine exposure showed significant interaction with one single nucleotide polymorphism at SLC2A13, near LRRK2. Each A allele was associated with a 35% increase in PD risk in never-smokers with low caffeine intake and a 32% lower risk in smokers with high caffeine intake. This study suggests a potential gene-environment interaction for PD .
History of traumatic brain injury also increases PD risk . The SNCA Rep1 variation may mediate the association between brain injury and PD risk. Pooled results from two case-control studies found head injury unrelated to risk of later PD, but relative to subjects with medium-length Rep1 alleles, head injury was strongly associated with PD in those with long Rep1 alleles. Those with both head injury and long Rep1 were diagnosed with PD an average of five years before those with neither risk factor. High levels of alpha-synuclein (as with Rep1 expansion) may initiate and/or accelerate neurodegeneration following head injury .
Unless otherwise stated, the following discussion pertains to sporadic (idiopathic) PD (i.e., cases lacking heritable/gene mutation cause).
PD is the most common neurodegenerative cause of parkinsonism, a syndrome characterized by progressive deterioration in motor abilities resulting from dopaminergic neuron loss in the substantia nigra pars compacta and ventral tegmental area. Dopamine neuron loss is most prominent in the ventral lateral substantia nigra; 60% to 80% of these neurons are lost when motor symptoms emerge and PD is diagnosed [8,12].
Substantia nigra pars compacta dopamine neuron loss and striatal dopaminergic deficits, including nicotinic receptor-mediated dopaminergic signaling, underlie motor symptom development in PD. The results of numerous studies linking cigarette smoking with protection against PD are explained by the actions of nicotine. Acetylcholine influences striatal dopamine release predominantly through action at nAChRs, and nicotine protects against nigrostriatal damage by stimulating nAChRs. Modulation of the nicotinic cholinergic system is an active area of PD research, also fueled by evidence that nAChR drugs may reduce PD progression and levodopa-induced dyskinesias [13,37].
The origin of motor dysregulation in PD is neuronal degeneration in the substantia nigra pars compacta and loss of dopaminergic regulation of the striatum. The striatum is an entry point for cortical projections into the basal ganglia, and the basal ganglia-thalamocortical motor circuit modulates the cortical output required for normal movement. Cortical signaling enters the striatum and is processed through the basal motor circuit; motor circuit output is relayed through the internal globus pallidus and the substantia nigra pars reticulata. The basal ganglia circuit involves two dopaminergic pathways:
The direct pathway of striatal neurons with dopamine D1 receptors, projecting to the globus pallidus and substantia nigra reticulata
The indirect pathway of striatal neurons with D2 receptors, projecting to the striatum/external globus pallidus connection and the external globus pallidus/subthalamic nucleus connection
In PD, striatal dopamine depletion deactivates the excitatory D1 direct pathway and hyperactivates the inhibitory D2 indirect pathway. Alterations in these two pathways inhibit voluntary movement [7,8,12].
Evidence consistently suggests primary contribution to neurodegeneration in PD from oxidative stress, mitochondrial dysfunction, and neuroinflammation. Environmental and genetic factors induce mitochondrial dysfunction, resulting in abnormal accumulation of miscoded proteins (mostly alpha-synuclein) and generation of oxidative stress in enteric, peripheral, and central nervous systems. In turn, oxidative stress, excitotoxicity, and mitochondrial dysfunction promote the destruction of dopamine neurons and dopaminergic function in midbrain systems [12,38,39,40].
Along with substantia nigra dopamine neuron loss, postmortem confirmation of PD diagnosis requires the presence of Lewy body pathology—intraneuronal aggregates of misfolded (pathogenic) forms of the protein alpha-synuclein. In addition to other pathologic effects, alpha-synuclein aggregates are associated with axonal and neuronal dysfunction, sequestration of vital neurotransmitter enzymes, and reduction or loss of cytoplasmic tyrosine hydroxylase and choline acetyltransferase. These effects compromise cellular integrity and fuel degeneration and contribute to neuronal death .
A third pathologic feature of PD is increased gliosis. Gliosis refers to an increased number and activation state of astrocytes and microglia, glial cell types that respond to injury or damage with altered morphology and production of inflammatory molecules. Increased gliosis is found in areas of neurodegeneration, which is not limited to the nigrostriatal pathway but evident throughout the brain to suggest a generalized neuroinflammation. Misfolded alpha-synuclein aggregates directly activate microglia, further linking alpha-synuclein and neuroinflammation to PD. These findings support a role of the innate immune system in the neurodegenerative process of PD .
Neuroscience findings have transformed the concept of PD, now recognized as a disease with pathology distributed throughout the enteric, peripheral, and central nervous systems. Nigrostriatal motor pathology is one pathophysiologic phase on a continuum of processes that begin long before motor symptoms emerge [7,12,42].
An essential initiating event for PD is induction of alpha-synuclein misfolding. This is followed by aggregation of misfolded alpha-synuclein and initial formation of alpha-synuclein aggregates in neurons. Very few neuron types are vulnerable to alpha-synuclein inclusions; the most vulnerable are projection neurons with long, thin, sparsely myelinated axons. Glutamatergic, gamma aminobutyric acid-ergic, dopaminergic, noradrenergic, serotonergic, histaminergic, and cholinergic projection cells can become involved, but within neurotransmitter types, some subgroups are selectively vulnerable (dopaminergic substantia nigra pars compacta neurons) while others are not (dopaminergic hypothalamic neurons) .
Neurons with the greatest exposure to potentially hostile environmental factors are selectively vulnerable to alpha-synuclein inclusions. Aggregates form in these enteric, peripheral, and central neurons and propagate trans-synaptically from neuron to neuron. A regional distribution pattern of aggregated alpha-synuclein emerges through specific involvement of susceptible and axonally interconnected projection neurons within the nervous system .
Evidence indicates that PD originates in structures outside the brain, including the enteric nervous system of the gastrointestinal tract and salivary glands. The olfactory bulb has very early involvement. A primary route of disease progression is through enteric nervous system neuronal connections to the vagal nerve motor nucleus in the lower brainstem. The pathology then spreads through visceromotor and somatomotor brainstem centers to the locus coeruleus, basal forebrain, striatum, basal ganglia-thalamocortical motor circuit, central amygdala, and cortical structures. Other routes are through spinal cord centers via descending projections from lower brainstem nuclei and from autonomic projections connecting the enteric nervous system with spinal cord peripheral ganglia and preganglionic nuclei [7,8,41].
A classification method was developed to identify the extent of postmortem pathology resulting from PD. This system uses six stages to roughly demarcate the sequence of anatomic involvement and symptom emergence throughout the disease course (Table 2). The stages occur in two phases: the pre-clinical phase (stages 1 through 3) and the clinical, or motor, phase (stages 4 through 6). Each stage includes newly affected regions along with those involved in previous stages [8,41,42,44,45].
STAGES OF PARKINSON DISEASE
|1||Lesions (Lewy body pathology/alpha-synuclein aggregates) develop in olfactory structures, salivary glands, enteric and peripheral autonomic nervous system, parasympathetic and sympathetic ganglion projection neurons, and lamina I of the spinal cord.|
|2||The pathological process enters the lower brainstem, including vagal nerve projection neurons that connect the enteric nervous system with the central nervous system, the lower raphe nuclei, and the locus coeruleus.|
|3||Lesions spread in the midbrain tegmentum, the basal forebrain, and into the substantia nigra|
|Clinical (motor) phase|
|4||The pathology is entrenched in the substantia nigra pars compacta and infiltrates the amygdala, the intralaminar thalamic nuclei, and the hippocampal CA2 sector.|
|5||Lesions spread in the cingulate and temporal cortex.|
|6||Lesions infiltrate the frontal and parietal cortex.|
PD is clinically diagnosed by the presence of cardinal motor features, broadly defined as bradykinesia, rest tremor, rigidity, and postural/gait impairment. The inclusion of postural/gait dysfunction in clinical criteria has been challenged, because it typically appears later in the disease course (instead of during the onset of motor symptoms) and is influenced by non-dopaminergic pathology primarily involving cortical cholinergic neurodegeneration .
The progression of disease and disability in PD varies and is partially influenced by patient factors such as age. In general, from the mean age at diagnosis of 61 years, the mean time to death is 14 years overall. Survival time is a mean 24 years for patients diagnosed in their 40s and 9.7 years for patients diagnosed in their 70s . With the onset of subclinical non-motor symptoms decades before diagnosis, pathologic processes that underlie PD are probably active over a 40-year period in many patients .
Throughout the disease course, all patients experience deterioration in motor function associated with increased impairment and disability and declining quality of life. The later stages of the disease are characterized by reduced oral medication efficacy, increased medication-related side effects, dysphagia, cognitive dysfunction with conversion of mild cognitive impairment to dementia, reduced mobility with increased tendency to fall, and in many, dependence on others for activities of daily living. The mode of death often involves respiratory compromise from bronchopneumonia or aspiration .
Mild cognitive impairment later progressing to dementia is very prevalent in patients with PD, and roughly 80% of patients develop dementia within 20 years of diagnosis. Cerebrospinal fluid levels of alpha-synuclein predict the progression of cognitive decline in PD . Dementia in PD and Alzheimer disease is associated with central nervous system (CNS) accumulation of protein aggregates such as b-amyloid peptide. B-amyloid peptide deposition in the striatum strongly correlates with dementia, suggesting this accumulation is a contributing factor to the development of cognitive impairment and neurodegeneration in PD . Subjects with PD and dementia show degeneration of several subcortical nuclei, including the cholinergic nucleus basalis of Meynert, the medial substancia nigra, and the noradrenergic locus coeruleus. Presence of secondary neuropathologies may further increase oxidative stress, decrease brain energy, and enhance brain degenerative processes in patients with PD .
PD is typically diagnosed following the onset of motor features (stage 4) that prompts the patient to seek medical attention. Pre-motor prodromal disease can manifest in non-motor features, such as depression, fatigue, rapid eye movement (REM) sleep behavior disorder, anosmia, and constipation, that reflect disease involvement in autonomic, enteric, or somatomotor systems. Visuospatial and cognitive dysfunction, especially mild cognitive impairment with dominant executive dysfunction manifested in diminished multitasking, planning, retrieval, concentration, and attention performance, are increasingly recognized as prevalent in earlier stages . As mentioned, appearance, severity, and progression of pre-motor and motor features corresponds to the nervous system and brain areas afflicted by pathologic infiltration [44,49,50,51].
Motor symptoms can also appear long before diagnosis. A prospective study found motor symptom onset 10 years before formal PD diagnosis. In this study, primary care patients were assessed for prodromal PD symptoms at three time points over 10 years. Symptom frequency was compared in patients later diagnosed with PD with those remaining PD-free (controls). Some symptoms were not analyzed . Ten years pre-diagnosis, tremor was 7.6 times more likely and constipation twice as likely in patients who developed PD than in controls. Five years pre-diagnosis, patients who developed PD were more likely to show tremor, balance impairments, constipation, hypotension, erectile dysfunction, urinary dysfunction, dizziness, fatigue, depression, and anxiety than controls.
PATHOLOGY AND NON-MOTOR SYMPTOMS IN VARIOUS STAGES OF PARKINSON DISEASE
|Non-Motor Symptoms||Stage||Symptoms/Signs||Affected Nervous System Areas|
|Olfaction||1||Decreased odor detection, identification (hyposmia)||
|Dorsal motor nucleus of the vagus Enteric ganglia|
|Sleep disorders||2, 3||
|Behavioral disorders||2, 3||
|Dementia||4, 5, 6||
It should be noted that PD is heterogeneous, and not all patients exhibit full-blown motor and non-motor syndromes. Some patients exhibit motor features that remain modest in severity for many years, or cognitive and behavioral functions that appear normal or minimally affected. Overall, the clinical features are most easily viewed as motor and non-motor components of the PD phenotype .
Several pre-motor symptoms have been studied for their relationship to disease process and PD diagnosis.
REM sleep behavior disorder is characterized by dream enactment behavior during sleep, including yelling, laughing, or crying; complex voluntary movements; falling out of bed; and even violent behaviors with injury. REM sleep behavior disorder is an extremely powerful predictor, or prodromal marker, of developing synuclein-mediated neurodegenerative diseases, which eventually occurs in at least 80% and most frequently involves PD [53,54].
A 16-year follow-up study of men diagnosed with REM sleep behavior disorder found that 80.8% eventually developed parkinsonism/dementia and were diagnosed with PD (62%); dementia with Lewy bodies (14%); multisystem atrophy (9.5%); clinically diagnosed, autopsy-confirmed Alzheimer disease plus Lewy body pathology (9.5%); or profound unspecified dementia (5%) . Of those who progressed to parkinsonism, the mean age of REM sleep behavior disorder onset was 57.7 years; the mean age of parkinsonism/dementia onset was 71.9 years. Overall, the mean interval from REM sleep behavior disorder onset to parkinsonism/dementia onset was 14.2 years (range: 5 to 29 years). In these patients, lower brainstem involvement, particularly the pons, appeared long before the onset of motor features .
The first published methodology with high accuracy in predicting PD development used data from patients with REM sleep behavior disorder. These patients were regularly evaluated throughout the 10-year period following their initial REM sleep behavior disorder diagnosis. Using this data, prodromal markers of PD were analyzed for predictive validity. Factors that highly predicted PD when combined were (in descending order of strength) subtle motor dysfunction, nonuse of antidepressants, abnormal color vision, olfactory loss, and advanced age. Factors found non-predictive when aggregated were mild cognitive impairment, depression, "Parkinson personality," treatment with clonazepam or melatonin (for REM sleep behavior disorder), autonomic markers, and male sex .
Studies of olfaction in PD have shown abnormalities in up to 100% of patients, making olfactory dysfunction the most robust predictor of developing PD. As noted, many patients complain of declining sense of smell long before parkinsonism onset. As it is not disabling and relatively nonspecific, anosmia has mostly failed to gain traction as a predictive and clinical feature of PD .
Constipation is a notoriously bothersome and common symptom in PD that results from peripheral autonomic involvement in the early pathogenic process . Compared to middle-aged men who reported more than two bowel movements per day, men who reported fewer than one bowel movement per day were prospectively identified as more than four times more likely to develop PD. This suggests lower bowel involvement is an early sign that, in some patients, predated PD by 15 years or more .
Excessive daytime sleepiness has also been identified as a midlife risk factor for PD, suggesting early brainstem involvement and subsequent sleep disturbances as a pre-diagnostic feature .
As noted, parkinsonism refers to the motor features of bradykinesia, tremor, rigidity, and postural instability resulting from nigrostriatal dopamine neuron loss in PD, as well as dementia with Lewy bodies, multisystem atrophy, progressive supranuclear palsy, and corticobasal degeneration. PD is the most common neurodegenerative cause of parkinsonism, comprising 80% of cases .
The centrality of the motor syndrome remains the core feature that defines clinical PD and by which PD is diagnosed. However, the pathologic process of PD is now established as beginning in non-dopaminergic structures of the brain or peripheral nervous system, during which non-motor features dominate. This is reflected in a new diagnostic classification, prodromal PD, now considered a true stage of PD, and in the 2015 International Parkinson and Movement Disorder Society (MDS) PD diagnostic criteria that incorporate non-motor manifestations of PD .
Non-motor symptoms of PD appear before motor symptoms and are usually present at diagnosis or develop and progress in severity through the disease course. Non-motor symptoms may appear as early as three decades before motor features, during the prodromal PD phase. They are present earlier in the neurodegenerative process than motor features, which require 60% to 80% loss of dopaminergic neurons to emerge . Criteria for prodromal PD have been published, and while early detection of PD before the onset of motor features could be immensely valuable, the absence of neuroprotective or disease-modifying therapy against PD, ethical issues from disclosure of disease risk, and the frequently shifting understanding of PD discourage any attempts to clinically diagnose the motor symptom prodrome of PD . Nonetheless, identification and treatment of non-motor symptoms are essential due to their potentially great negative impact on patient well-being [1,8].
Tremor at rest
Akinesia (i.e., bradykinesia and hypokinesia)
It is important to note that postural instability, while a cardinal motor feature, is seldom present at diagnosis, as it usually appears later in the disease course .
Bradykinesia, as typically defined, combines the definitions of bradykinesia (slowness) and hypokinesia (decreased movement amplitude) . Bradykinesia is reduced speed in initiating and executing movement, and altered fine motor control and dexterity. It is not just slowness in movements, but slowness in initiating voluntary movement, with progressive fatiguing during repetitive movements that presents in reduced speed and amplitude during finger or foot tapping. Slowness of movements, progressive reduction in speed and amplitude of repeated movements, delay in initiating movements, and freezing gait eventually occur in 80% to 90% of patients with PD .
Bradykinesia is the defining feature of parkinsonism and the essential clinical sign because the slowed, disordered motor movements directly correlate with functional abnormality in basal ganglia-cortical neuronal circuits, where aberrant dopamine-mediated firing patterns within indirect and direct pathways inhibit activity in cortical motor system neurons [4,7]. The slowed, small-amplitude movements in bradykinesia interfere with limb control, dexterity in tying shoes or buttoning shirts, and swallowing (dysphagia). It may also present as decreased facial expression and eye blinking (hypomimia), weak voice (hypophonia), and progressively smaller handwriting (micrographia) [4,62,64].
Rigidity is increased muscle tone in flexor and extensor muscle groups at rest and resistance to passive stretch movement in flexor and extensor muscles with the limb relaxed. Rigidity is present in 80% to 90% of patients with PD, usually unilaterally at the onset of motor symptoms. It often, but not always, co-occurs with tremor. Rigidity results from altered firing rates in the basal ganglia, a fundamental feature of parkinsonism. The resultant motor system output reflects inappropriate activation of agonist and antagonist muscles that present in bradykinesia and rigidity . In early-stage disease, rigidity may manifest as pain, such as frozen shoulder or low back pain, obscuring the diagnosis of a CNS disorder .
Rest tremor, an initial symptom in 70% to 90% of patients, refers to a 4–6 Hz tremor in the fully resting limb, suppressed during movement initiation. Rest tremor is a rhythmic, oscillatory involuntary movement and one of the most characteristic signs in clinical medicine. The most distinguishing rest tremor is the "pill-rolling" type, with rubbing movements of thumb and index fingers against each other. Rest tremor is thought to initiate with nigrostriatal degeneration and subthalamic nucleus or globus pallidus disinhibition, or disrupted thalamo-cortical-cerebellar circuits leading to abnormal thalamic pacemaker cell function [4,7].
Tremor in parkinsonism is distinct from other forms of tremor by its asymmetry, speed, dominance at rest, reduction or cessation during action, re-emergence when maintaining a posture, and increased amplitude during tasks requiring mental concentration .
Postural instability is defined as difficulty adjusting to postural change, and together with gait impairment and postural abnormalities, it comprises the axial motor signs of PD . Postural instability and other axial signs do not usually present in early PD, reflecting pathophysiology beyond dopamine motor neuron loss . As such, the inclusion of axial signals in the cardinal motor features required for the parkinsonism diagnosis in PD has been challenged .
Postural and gait impairment result from loss of postural reflexes, which leads patients to adopt a stooped posture. The loss of postural reflexes is also a major contributor to falls . In PD, the gait is slow, with short shuffling steps on a narrow base that appears as if the patient is chasing his or her own center of gravity. Patients show decreased arm swing; turning around is slow, with multiple small steps, and freezing gait can occur, especially in crowded or narrow places. Festination, a very fast succession of steps with the patient only able to stop when meeting an obstacle, may also be present. Walking and turning becomes difficult or impossible in patients with PD when additional cognitive load, such as dual tasking, is imposed [67,68].
Brainstem pathology is now recognized as a major contributor to the clinical features in PD. Postural control problems with imbalance, falls, and freezing gait tend to occur later in PD and reflect cholinergic neuron degeneration and dysfunction outside of the basal ganglia . Persons with parkinsonism or other extrapyramidal neurodegenerative disorders frequently develop problems with balance and may experience frequent falls. The vestibular system controls balance and is synaptically linked to the extrapyramidal system, possibly contributing to posture and balance dysfunction .
The frequency and diversity of non-motor symptoms in PD is substantial, and includes autonomic, neuropsychiatric, olfactory, sensory, and sleep disorders that occur in 80% to 90% of patients (Table 4). Non-motor symptoms can manifest before, during, or after motor symptoms and may result in greater impairment of quality of life. The prevalence of cognitive, autonomic, and mood disorders is very high; progression can result in patients requiring care in a supervised environment .
NON-MOTOR SYMPTOMS IN PARKINSON DISEASE
A 2010 survey found that up to 62% of patients with PD do not volunteer symptoms such as apathy, pain, sexual dysfunction, bowel incontinence, constipation, or sleep disorders either through embarrassment or unawareness of symptom relevance to PD. Clinicians may not understand that these symptoms require assessment. Their under-reporting has important therapeutic and societal implications, as most are treatable. Left unaddressed, non-motor symptoms detrimentally affect patient quality of life, frequently lead to hospitalization and institutionalization, and quadruple the cost of PD care .
Disease-specific screening tests or biomarkers for PD are not yet available, and definitive diagnosis is only possible at autopsy by confirmation of striatal dopamine neuron loss and Lewy body pathology . Idiopathic PD is diagnosed through patient history and physical examination. History or physical findings inconsistent with features of idiopathic PD are explored further to rule out or confirm an alternate diagnosis. Clinicians with limited experience caring for patients with PD should consider referring a patient with suspected disease to a physician with expertise in movement disorders to confirm diagnosis .
The UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria have been the most widely used diagnostic criteria for PD, recommended for use in North America and Europe as a straightforward, objective, and accurate approach (Table 5) [4,63,71]. With these criteria, three major steps are required for PD diagnosis. The presence of parkinsonism must be established, but parkinsonism is non-specific to PD and additional steps are required for a PD diagnosis.
UK BRAIN BANK CLINICAL DIAGNOSTIC CRITERIA FOR PARKINSON DISEASE
|Step 1: Diagnosis of parkinsonian syndrome||
Bradykinesia and one or more of the following:
|Step 2: Exclusion criteria for Parkinson disease||
|Step 3: Supportive positive criteria of Parkinson diseasea||
|aThree or more required for diagnosis of definite PD.|
However, the UK Brain Bank diagnostic criteria were established more than 20 years ago (in 1992) and solely address motor symptoms, leading many to consider them outdated. This led to the 2015 publication of new PD diagnostic criteria by the MDS Task Force, comprised of North American and European experts. These criteria better reflect current understanding of PD as a multi-system disorder affecting all parts of the nervous system, often with a genetic component and a very slow progression of neurodegenerative processes reflected in a long prodromal period. These aspects are incorporated in the new criteria .
The first essential criterion of the MDS Clinical Diagnostic Criteria for PD is parkinsonism, defined as bradykinesia with rest tremor and/or rigidity . Examination of cardinal motor features should follow as described in the MDS-United Parkinson Disease Rating Scale (UPDRS) . After parkinsonism is diagnosed, PD may be diagnosed as either clinically probable or established based on the presence or absence of absolute exclusion criteria, supportive criteria, and guideline-defined "red flags" (Table 6) . Clinically probable PD diagnosis requires :
Absence of absolute exclusion criteria
Presence of no more than two red flags counterbalanced by supportive criteria
If one red flag is present, there must also be at least one supportive criterion
If two red flags, at least two supportive criteria are needed
MDS CLINICAL DIAGNOSTIC CRITERIA FOR PD
|Absolute exclusion criteria||
Clear, dramatic benefit to dopaminergic therapy. During initial treatment, patient returned to normal or near-normal level of function. In the absence of documented initial response, dramatic response can be classified as:
A diagnosis of clinically established PD is made if the patient displays :
Absence of absolute exclusion criteria
At least two supportive criteria
No red flags
The MDS PD criteria note that the establishment of parkinsonism motor features remains the foundation of PD diagnosis, but several pre-motor features are woven into the overall criteria . While postural instability is a feature of parkinsonism, it is not a criterion for parkinsonism in the MDS guideline. Dementia with Lewy bodies is not considered an alternative parkinsonian syndrome; these patients can be diagnosed as PD (dementia with Lewy bodies subtype).
Idiopathic PD is diagnosed by history and physical examination. The first step in the diagnostic process is taking a careful history by thoroughly questioning the patient and/or family members regarding [1,4,62]:
Symptoms that emerged, their sequence, and perceived anatomical involvement, including symptoms that suggest bradykinesia, rigidity, resting tremor, and/or postural instability
The presence and onset of pre-motor symptoms:
Past and present medical disorders
Family history, including neurological disorders and ethnic ancestry, as monogenic forms of PD are more frequent in some ethnic groups (e.g., LRRK2 in Ashkenazi Jews and North African Arabs)
Exposure to illicit drugs associated with parkinsonism (e.g., methamphetamine, amphetamine)
Environmental toxin exposure (e.g., manganese in welders)
It is also important to always assess for drug-induced parkinsonism. This is one of few reversible causes of the disorder, and identification by a complete medication evaluation will help avoid inappropriate treatment. The most frequent causes of drug-induced parkinsonism are typical antipsychotics (e.g., haloperidol, chlorpromazine), most atypical antipsychotics (e.g., riperidone, olanzapine), and the gastrointestinal agents prochlorperazine, promethazine, and metoclopramide. Infrequent causes are tetrabenazine, reserpine, methyldopa, flunarizine, cinnarizine, verapamil, valproic acid, and lithium.
To resolve drug-induced parkinsonism, identify and discontinue the culpable medication. Patients requiring an antipsychotic agent should receive clozapine, with quetiapine as a second-line option .
A neurologic examination is performed to provide objective evidence of motor symptoms in the absence of other abnormalities. Simple observation will often reveal a generalized slowness and lack of spontaneous movement. Findings of parkinsonism motor features supported by patient history, confirm a diagnosis of idiopathic PD. Idiopathic PD will demonstrate any combination of the following, and motor symptom findings are usually asymmetrical .
To assess bradykinesia, ask the patient to perform repetitive movements as quickly and widely as possible, such as opening and closing the hand, tapping thumb and index fingers, or tapping the foot on the ground. Progressive slowness and/or loss of amplitude should emerge and may bring the movement to full arrest (freezing). To globally assess bradykinesia, observe spontaneous movements while the patient is sitting, standing up from a chair, or walking [62,64]. To avoid misdiagnosis, distinguished clinical bradykinesia from simple slowness in patients with decreased muscle power, spasticity, or reduced motivation in depression or in normal elderly populations that reflect non-specific slowness [62,64].
Rigidity refers to "leadpipe" resistance, whereby velocity-independent resistance to passive movement is not influenced by an inability to relax (i.e., distinct from spasticity). This resistance is felt throughout the full range of movement, and unlike spasticity, it does not increase with higher mobilization speed. When resting tremor co-occurs with rigidity, "cog-wheel rigidity" can be felt during passive limb mobilization, especially in the wrist. When assessing rigidity, interruption of passive movement by a "cog-wheel" movement reflects the underlying 4–6 Hz tremor oscillation. In contrast, pyramidal tone (spasticity) is dependent on the velocity of passive movement and is described as ''clasp knife'' in quality because of the higher resistance during early acceleration of the passive movement followed by giving way, such as is seen when opening lock-blade knives . Rigidity is assessed by passive movement of a joint and reinforced by asking the patient to move the opposite limb in a circular motion or open/close a fist.
Resting tremor is often observed in patients with PD, and postural tremor and re-emergent resting tremor may be seen with arms outstretched. Resting tremor is best observed in the hands during patient focus on a mental task (e.g., eyes-closed countdown from 100) that facilitates muscle relaxation; in the legs with the patient seated on the edge of an exam table, with legs hanging and feet unsupported; and in the jaw when the patient is engaging another part of the body in activity [4,62].
Gait may be stooped or shuffling, with reduced arm swing. Patients often turn en bloc, requiring numerous steps to complete a 180° turn. The pull test (briskly pulling the patient backwards while standing) may be used to assess postural reflexes. Loss of postural reflexes generally occurs in later-stage disease.
Unless signs or symptoms are observed that are inconsistent with idiopathic PD (i.e., MDS absolute exclusion criteria or red flags), no further testing is needed with history and exam findings consistent with idiopathic PD. Imaging tests are used only to confirm absolute exclusion criteria findings or to rule out or confirm red flag findings .
However, there are a variety of tests available to confirm diagnosis, obtain additional information on disease type or severity, and differentiate PD from disease mimics (Table 7). Dopaminergic challenge tests with levodopa can confirm PD diagnosis with response of objective improvement, although support is not universal [63,73]. Olfactory testing can help substantiate a PD diagnosis, is inexpensive, is extensively validated, and contributes to the early diagnosis and differential diagnosis of PD. Although it can help identify patients with pre-motor symptoms of PD, use alone is not diagnostic [1,63,74].
EFNS/MDS-ES RECOMMENDATIONS FOR DIAGNOSTIC INSTRUMENT USE IN PARKINSON DISEASE
|Diagnostic Modality||Level of Evidence||Indications for Use|
|SNCA gene point mutations and multiplication||B||PD families suggestive of dominant inheritance|
|LRRK2 and known pathogenic variants||B||
|GBA mutations||B||Founder effect mutations in PD cases in specific populations (e.g., Ashkenazi Jewish) with or without positive family history|
|Parkin, PINK1, DJ-1 mutations||B||
|ATP13A2, PLA2G6, FBX07||B||Very early onset PD cases|
|University of Pennsylvania Smell Identification Test (with other diagnostic tests)||A||PD versus atypical and secondary parkinsonism|
|A||Idiopathic PD versus recessive PD forms|
|Collateral history from a carer, cognitive assessment, and screening of REM sleep behavior disorder, psychosis, severe depression||A||During initial evaluation to exclude other causes of parkinsonism in patients with suspected PD|
|Use with other diagnostic tests||A||Differential diagnosis of PD from atypical and secondary parkinsonism|
|A||Early diagnosis of PD|
|A||Detection of subjects at risk for PD|
|Magnetic resonance imaging (MRI) in differential diagnosis|
|Conventional 1.5-Tesla MRI||A||Differential diagnosis of multisystem atrophy from PD|
|B||Differential diagnosis of progressive supranuclear palsy from PD (detection of midbrain atrophy and/or SCP atrophy)|
|1.5-Tesla diffusion-weighted MRI||A||Differential diagnosis of multisystem atrophy from PD (identification of putaminal diffusivity changes)|
|B||Differential diagnosis of progressive supranuclear palsy from PD (identification of SCP diffusivity changes)|
|Single photon emission tomography (SPECT) in differential diagnosis|
|123Ioflupane SPECT||A||Differential diagnosis of essential tremor from PD and atypical parkinsonism|
|123I-MIBG SPECT||A||Differential diagnosis of PD from multisystem atrophy|
Recommendations for genetic testing in diagnosing PD are inconsistent. Some view this testing as questionable in benefit due to lack of clarity on which populations to test, the consequences of test results, and cost issues . Others highly recommend use of genetic testing to identify parkinsonism and PD genotypes that differ in clinical course, prognosis, and treatment response from idiopathic PD [63,74].
Some have suggested assessing all patients younger than 40 years of age with suspected PD for Wilson disease. Wilson disease is confirmed by low serum ceruloplasmin, elevated 24-hour urine copper, or the presence of Kayser-Fleischer rings on slit-lamp examination .
Screening tests are used to help identify common comorbidities, including depression and dementia in patients with PD. The American Academy of Neurology (AAN) recommends the following assessment tools when screening for comorbid conditions [75,76]:
Depression: Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), Geriatric Depression Scale (GDS)
Dementia: Cambridge Cognitive Examination (CAMCog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA)
The MDS-UPDRS is widely used in research and in clinical practice to standardize the neurological exam and present the findings as a pre-determined Likert scale. The UPDRS can be used to assess the clinical status of patients with PD during follow-up. This instrument assesses motor features, psychologic features, activities of daily living, and treatment complications. Increases of 2.5 and 4.3 points in UPDRS motor and total scores, respectively, indicate clinically relevant change [77,78].
If cognitive impairment is noted on mental status examination, magnetic resonance imaging (MRI) and neuropsychological testing should be used to distinguish PD with dementia from other neurodegenerative disorders .
Progressive supranuclear palsy
Dementia with Lewy bodies
Symptomatic syndromes of non-neurodegenerative underlying cause:
Infectious disease (acquired immunodeficiency syndrome, subacute sclerosing panencephalitis, postencephalitic parkinsonism, prion disease)
Neurotoxin exposure (carbon monoxide, manganese, MPTP)
Structural disorder (tumor, hydrocephalus, subdural hematoma, trauma)
Other secondary causes
Patient history and exam findings not normally associated with idiopathic PD require differential diagnosis to rule out or confirm an alternate diagnosis. The most common syndromes mimicking PD are essential tremor, vascular parkinsonism, Lewy body dementia, progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, and drug-induced parkinsonism (Table 8). Differentiating tests should be used to rule out or confirm the presence of conditions [1,2,63,79,80].
SYNDROMES THAT MAY MIMIC PARKINSON DISEASE
|Syndrome||Signs/Symptoms Resembling Parkinson Disease||Differentiating Tests|
|Drug-induced parkinsonism||Akinesia and bradykinesia||Patient medication history, particularly for dopamine antagonists (e.g., clozapine)|
|Lewy body dementia||
|Progressive supranuclear palsy||
|No tests required|
Identifying parkinsonism is the first step for considering therapeutic options, and differentiating PD from progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, and vascular parkinsonism will not expand the options for disease modifying or curative therapies. However, arriving at a definitive diagnosis is important for informing patients, caregivers, family, and the patient care team about prognosis, expected clinical progression, disease course, and potentially beneficial treatment. A definitive diagnosis gives a name to the condition. This is very important for the patient experience and helps in coming to terms with a chronic disease. An "atypical parkinsonism" or "parkinsonian syndrome" diagnosis are meaningless terms for patients and carers and fails to offer information about management or prognosis. A hierarchical list of diagnostic possibilities should be discussed if definitive diagnosis is elusive. Diagnostic criteria for progressive supranuclear palsy, corticobasal degeneration, and multisystem atrophy allow for possible and probable diagnostic categories, according to diagnostic certainty .
Since curative or disease-modifying agents are not yet available, PD is treated symptomatically. Treatment strategies for PD are influenced by disease stage, most problematic symptoms, and patient age, and clinical decision-making should balance possible efficacy with potential side-effect risk for each treatment option. Treatment decisions should be based on the best available evidence for each intervention. Pharmacotherapy should be accompanied by non-medical interventions, as needed, for gait and balance dysfunction, vocal impairment, and other motor, non-motor, and comorbid conditions .
Treatment of PD begins at the time of diagnosis but may not require immediate medical intervention. Early treatment should address information delivery, support, and counseling to facilitate in the patient a realistic view of PD, prognosis, and treatment outcome. These conversations usually take place over several visits and should include discussion of available medical therapies for PD. When possible, these initial meetings should include family members .
Initial treatment of early PD generally involves monotherapy, and motor control problems can be improved in many patients. Treatment of later PD becomes more complicated, with disease progression and prolonged dopaminergic drug administration. Requirements for dopamine replacement therapy become increasingly demanding as motor signs worsen. Patients initially well controlled using dopamine agonists require initiation of levodopa and, over time, increasing amounts given in higher doses with more frequent intervals. Patients initiated on levodopa will require the addition of dopamine agonists and/or other adjuncts that improve response to levodopa .
Levodopa therapy is commonly withheld until motor symptoms begin interfering with normal patient functioning. This is based on the assumptions that:
The period of improved motor control is finite, and levodopa therapy is more valuable in later disease, when symptom improvement is greater.
Deferring levodopa initiation defers the onset of dyskinesias.
Early symptomatic treatment has no effect on disease course.
However, there is some evidence that initiating levodopa in early PD and maintaining the dose less than 400 mg/day reduces dyskinesia onset, and early use of levodopa has been shown to be the most effective treatment for motor symptoms, with long-term risk of dyskinesia minimally affected by early use of less than 400 mg/day. It appears that disease stage has a greater influence on the development of levodopa-induced dyskinesia than medication duration [81,82,83].
Some PD motor symptoms show preferential dopaminergic response. For example, bradykinesia and rigidity show the most robust levodopa response. Rest tremor severity correlates poorly with the other cardinal symptoms and extent of dopamine neuron loss and inconsistently responds to dopaminergic therapy. This sign may originate from a trigger in the basal ganglia, with contributions from cerebellothalamic pathways. Freezing gait and imbalance with frequent falls also poorly respond to dopaminergic treatment .
Added complexity comes with progression from later to advanced PD. The onset of motor fluctuations and motor complications (e.g., dyskinesia, freezing) create the greatest challenge to treatment efforts to maintain mobility and function in earlier disease. Predicting the onset of motor complications and fluctuations in individual patients is very difficult, but disease duration and stage, dose and duration of levodopa exposure, sex, and body weight are contributing factors .
Even if motor symptoms are well controlled, numerous non-motor components of PD will emerge and can be intensely burdensome to patients. Many non-motor symptoms lack response to dopaminergic medications, reflecting progression beyond the dopamine neuron motor system and extensive disease involvement in the cortical and frontal lobes and widespread central neuropathology. Only recently have non-motor symptoms received adequate research attention, and for some of these syndromes, effective treatments have been identified and become available or their final regulatory evaluation is in progress [77,81].
An important issue, unaddressed by practice guidelines, is medication non-adherence in patients with PD. While the prevalence of non-adherence broadly varies by assessment method, the figures range from 15% to 20% using patient self-report to 67% or more using pharmacy refill data and pill counts . An important dimension in PD treatment is timing adherence, as dopaminergic medications should be taken at the evenly spaced intervals instructed by the prescribing physician. Timing non-adherence is probably very common and contributes to unwanted dopamine variability implicated in earlier onset of motor fluctuations . The overall consequence of non-adherence is worse motor control, with diminishing mobility, greater fluctuations, dyskinesias, and declining quality of life .
In chronic diseases, highest medication adherence occurs with once-daily formulations, but this sharply decreases with each added daily dose . Polypharmacy in PD is normative, with most patients taking two or more antiparkinsonian drugs and additional medications for non-motor symptoms and comorbidities. In addition to the risk of non-adherence that directly correlates with the number of prescriptions and daily doses per prescription, many patients with PD experience depression and/or cognitive impairment, both of which are strong independent risk factors for medication non-adherence .
Medication non-adherence among patients with PD should be recognized as a common, under-reported, detrimental, and costly cause of suboptimal disease control. Reliance on clinical judgment to identify non-adherence is demonstrably inaccurate, and healthcare professionals should use nonjudgmental interviewing skills that encourage patient admission of their non-adherence without fear or concerns of disapproval or termination of care. Barriers to adherence should be explored and clinical resources applied to surmount them. These include simple explanations of how medications optimally work when taken correctly and referral to non-adherence counseling. To avoid unnecessary dose escalations, adverse effects, and increased patient and healthcare costs, non-adherence should be explored before a drug regimen is deemed ineffective .
For the purpose of supplementing depleted brain dopamine to manage PD motor symptoms, exogenous dopamine is unable to cross the blood-brain barrier and is ineffective. Instead, levodopa is used for this purpose. Levodopa is a dopamine prodrug that crosses the blood-brain barrier, is converted by aromatic amino acid decarboxylase (AAAD) to dopamine in the substantia nigra pars compacta, and is stored in presynaptic dopamine neurons for subsequent use. Depleted striatal dopamine concentrations are increased, and parkinsonism symptoms are reduced. Levodopa was introduced for use in PD in the late 1960s, and remains the gold-standard treatment .
Levodopa is extensively metabolized to dopamine in the gut, causing only 30% to reach systemic circulation and distribution to the brain. Levodopa is always combined with carbidopa, a peripherally acting AAAD inhibitor. Carbidopa reduces peripheral conversion of levodopa to dopamine, which triples levodopa bioavailability and lowers dosage requirements. Carbidopa 75–100 mg/day is required to inhibit peripheral conversion of levodopa to dopamine. Carbidopa also decreases acute peripheral dopamine side effects, such as nausea, vomiting, and hypotension, and improves tolerability .
Levodopa carries a higher risk for the development of motor complications, and keeping the dose as low as possible for symptomatic management is suggested. No evidence has been found that using an extended-release levodopa/carbidopa formulation, or adding a catechol-O-methyltransferase (COMT) inhibitor, delays or prevents the development of motor fluctuations .
Because levodopa is absorbed in the proximal small intestine, food may delay absorption. Levodopa also competes with dietary proteins for transport into the brain. High-protein meals should be kept separate from levodopa dosing, and daily dietary protein intake should be reduced to approximately 0.8 g/kg (of body weight). Levodopa is metabolized in the gastrointestinal tract, kidneys, and liver, with 70% excreted in the urine. Levodopa half-life is roughly one hour. Dosing should be reduced 10% to 30% when other dopaminergic agents are added to carbidopa/levodopa. Available formulations in the United States are :
Carbidopa/levodopa tablet (Sinemet)
Carbidopa/levodopa orally disintegrating tablets (Parcopa ODT)
Carbidopa/levodopa sustained-release tablet (Sinemet CR)
Carbidopa/levodopa extended-release tablet (Rytary ER)
Carbidopa/levodopa enteral suspension (Duopa)
Potential adverse events associated with levodopa/carbidopa can be generally categorized as CNS, gastrointestinal, or other. Adverse effects involving the CNS include confusion, sedation, vivid dreams, dizziness, hallucinations, psychosis, and depression. Gastrointestinal effects may include nausea, vomiting, and changes in bowel habits. Orthostasis, leg edema, dyskinesia, dystonia, hemolytic anemia, and leukopenia may also occur. All patients taking levodopa should be monitored for changes in blood pressure, pulse, mental status, and clinical response.
Dopamine D2/3 receptor agonists bind post-synaptic striatal dopamine receptors to increase dopaminergic neurotransmission and reduce parkinsonism symptoms. Ropinirole (oral), pramipexole (oral), and rotigotine (transdermal) are the most widely used agents. In advanced disease, subcutaneous apomorphine is continuously delivered via external pump or is used for rapid rescue therapy (via injection). The ergot derivative dopamine agonists cabergoline, pergolide, and bromocriptine are not recommended as first-line dopamine agonist therapy, and bromocriptine is associated with the development of fibrotic tissue. Ergot derivatives require specialized side effect monitoring, but they remain options for patients lacking benefit or tolerability with other dopamine agonists [74,90].
Dopamine agonists are the second most potent drug class (after levodopa) for motor symptom control in PD and are effective at all stages of the condition. Initial dopaminergic therapy using dopamine agonists (versus levodopa) is associated with reduced/delayed treatment-related complications, such as levodopa-induced dyskinesia and motor fluctuations [7,91].
However, poor tolerability can limit the use of dopamine agonists. While dopamine agonists are less likely to lead to motor fluctuations in early disease than levodopa, they are less effective for motor symptoms and carry greater risk of side effects such hallucinations, psychosis, hypotension, peripheral edema, excessive daytime somnolence, and impulse control disorders. In patients older than 70 years of age, dopamine agonists should be used with caution or avoided entirely . All patients taking ropinirole, pramipexole, or rotigotine should be monitored for changes in blood pressure, daytime alertness, weight, and heart rate .
Ropinirole undergoes hepatic metabolism, with a half-life of about six hours. It is associated with various adverse effects in various systems, including the gastrointestinal system (nausea, vomiting, dyspepsia, abdominal pain, constipation) and the CNS (dizziness, somnolence, headache, syncope, confusion, hallucinations, impulse control disorders, sleep attacks). Other potential adverse effects include fatigue, asthenia, dependent/leg edema, viral infection, pain, increased sweating, orthostatic symptoms, pharyngitis, abnormal vision, and urinary tract infection .
Pramipexole is administered orally for PD and is available in immediate- and extended-release formulations. The half-life in healthy adults is about 8 hours, but this is extended to 12 hours in elderly patients. It is excreted in the urine primarily as unchanged drug, and dose adjustment is required in renal impairment. Overnight switch from immediate- to extended-release is successful in 80% of patients . Potential adverse effects include nausea, abdominal pain/discomfort, constipation, dizziness, somnolence, headache, hallucinations, impulse control disorders, dyskinesia, orthostatic hypotension, xerostomia, peripheral edema, and muscle spasms .
Rotigotine is available as a transdermal patch for the treatment of PD. It undergoes extensive metabolism via conjugation and N-dealkylation. The initial half-life is three hours, with the terminal half-life five to seven hours after patch removal. Potential adverse effects have included nausea, vomiting, somnolence, dizziness, application-site reactions, dyskinesia, anorexia, hyperhidrosis, visual disturbance, and peripheral edema, and all patients should be monitored for skin reactions. Patients with sulfa allergy should not be prescribed rotigotine, and patches contain aluminum and should be removed prior to MRI .
Apomorphine for PD is given as a subcutaneous injection into the abdominal wall, upper arm, or upper leg; the injection site should be rotated. It is indicated for hypomobility and "off" episodes associated with PD.
Apomorphine undergoes extensive first-pass metabolism, with a terminal half-life of about 40 minutes. Nausea, vomiting, drowsiness, somnolence, dizziness, orthostatic hypotension, hallucinations, confusion, dyskinesia, rhinorrhea, and edema/swelling of extremities may occur. It is important to avoid use of apomorphine with serotonin blockers, as co-ingestion may cause profound hypotension. All patients taking this agent should be monitored for orthostatic hypotension and drowsiness .
Bromocriptine mesylate is taken orally and is metabolized by the liver. The half-life is approximately 5 to 15 hours. Potential adverse effects include nausea, vomiting, abdominal discomfort, abnormal involuntary movements, ataxia, hallucinations, confusion, "on-off" phenomenon, dizziness, syncope, drowsiness, insomnia, depression, visual disturbance, hypotension, shortness of breath, constipation, vertigo, and asthenia. Long-term treatment with this drug is associated with pleural thickening (fibrosis). As such, patients' pulmonary function should be monitored during treatment .
MAO-B is an enzyme that inactivates dopamine by breaking it down into metabolic byproducts. MAO-B inhibitors block the breakdown of dopamine, slowing the loss of dopamine and several of the effects of PD. MAO-B inhibitors are generally considered for initial treatment of early PD as monotherapy and as adjunctive therapy to augment the effects of levodopa in later PD. The preferred agents are selegiline and rasagiline, both of which have shown symptomatic benefit and multiple neuroprotective effects in pre-clinical research [7,89,92].
In the treatment of PD, selegiline may be used as monotherapy or combined with levodopa. This agent blocks the breakdown of dopamine via MAO-B inhibition. It is metabolized via CYP450 enzymes to amphetamines, with a half-life of 10 hours. In high doses, it may precipitate a hypertensive crisis. Other potential adverse effects include nausea, weight loss, dyspepsia, hypotension, decreased heart rate, headache, hallucinations, vivid dreams, dizziness, insomnia, flu-like symptoms, dyskinesias, dystonia, rash, and photosensitivity . All patients undergoing treatment with selegiline should be monitored for rash, drug interactions, and changes in blood pressure, cardiac status, and mental status (i.e., increased anxiety) .
In addition to a capsule/tablet, selegiline is available as an orally disintegrating tablet. Pharmacology, potential adverse effects, and monitoring are similar, but metabolism of the disintegrating tablet bypasses the liver to reduce formations of amphetamine metabolites, which reduces the risk of insomnia side effects .
Oral rasagiline may be used in monotherapy or combination therapy for patients with PD. This agent inhibits the breakdown of dopamine via MAO-B inhibition and is metabolized via CYP1A2. The half-life is three hours. The potential adverse effects and patient monitoring requirements are the same as with selegiline .
COMT is an enzyme that converts levodopa in peripheral circulation to 3-O-methyl-DOPA (3-OMD). This metabolite cannot be converted to dopamine and accumulates in plasma during levodopa therapy. Inhibition of COMT increases the bioavailability of levodopa, allowing a larger amount of the drug to reach the brain and consequently raise dopamine levels. COMT inhibitors are always taken in combination with levodopa because they lack intrinsic dopaminergic activity. They are used in PD to potentiate levodopa effects when "wearing off" or other motor complications appear during carbidopa/levodopa therapy .
As a COMT inhibitor, entacapone inhibits the peripheral metabolism of levodopa. It is metabolized to active isomer and undergoes glucuronidation to inactive metabolites, with a half-life of two hours. Potential adverse effects include exacerbation of levodopa adverse effects, brown/orange urine, and diarrhea. All patients should be monitored for changes in blood pressure and mental status. A fixed-dose combination of entacapone with carbidopa/levodopa is available and reduces the number of tablets needed for treatment, which may improve adherence .
Tolcapone inhibits peripheral and central metabolism of levodopa. It has a half-life of about three hours and is metabolized via glucuronidation and CYP2A6 and CYP3A4 enzymes. The adverse effects are the same as those described for entacapone, plus transient elevations in liver enzymes and fulminant liver failure. In addition to the monitoring recommended for entacapone, these patients should be regularly tested for liver enzymes and function .
Opicapone is a novel, once-daily, third-generation COMT inhibitor. Research has compared opicapone with entacapone and placebo as a levodopa adjunct. In a study involving 590 patients with PD-associated motor fluctuations, the mean reduced times in "off" state were 56 minutes for placebo, 96.3 minutes for entacapone, and 116.8 minutes for opicapone after 14 to 15 weeks. Opicapone 50 mg was statistically superior to placebo and non-inferior to entacapone, but lower-dose opicapone did not differ from placebo .
The most common adverse events with opicapone are dyskinesia, insomnia, and constipation. Serious adverse events were reported in six patients with placebo, eight with entacapone, and four with opicapone 50 mg. In addition to "off" time efficacy, an advantage of opicapone is the once daily dosing .
Anticholinergic agents used in PD treatment include benztropine (Cogentin) and trihexyphenidyl. Anticholinergics may be helpful as a symptomatic treatment in younger patients with early PD and severe tremor or dystonia, but they should not be drugs of first choice due to their narrow range of efficacy. Adverse effects from nonselective cholinergic receptor blockade are a major drawback and include CNS-related side effects of cognitive impairment, exacerbation of dementia, delirium, sedation, and hallucinations. Other side effects include constipation, xerostomia, blurred vision, and urinary retention; higher doses may cause or worsen orthostatic hypotension and palpitations. Elderly patients are especially prone to these side effects plus confusion and memory difficulties, and anticholinergic agents are not recommended in this population .
Amantadine is an N-methyl-d-aspartate (NMDA) antagonist with modest benefit in early PD and efficacy in suppressing levodopa-induced dyskinesia in later/advanced PD. The mechanism of action is thought to involve augmentation of pre-synaptic dopamine release and NMDA glutamatergic antagonism. Common side effects include pedal edema and livedo reticularis (violet, lace-like coloration) .
Amantadine is the only agent demonstrated to suppress levodopa-induced dyskinesia without worsening parkinsonism, and the American Academy of Family Physicians recommends that amantadine should be considered for treatment of dyskinesias in patients with advanced PD . However, use in frail elderly patients with advanced PD may result in confusion, hallucinations, and/or worsening motor symptoms .
The acetylcholinesterase inhibitor rivastigmine is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of mild-to-moderate PD dementia. Other approved drugs for dementia, including donepezil, galantamine, and memantine, have been evaluated for the treatment of PD dementia, but their efficacy has not been clearly shown .
Rivastigmine has shown significant improvement in PD dementia that was maintained through 48- and 76-week follow-up in different trials. In long-term trials comparing rivastigmine capsules (12 mg/day) versus transdermal patch (9.5 mg/24 hours), the rates of adverse effects from worsening PD were 36.1% with the capsule (tremor in 24.5%) versus 31.9% with the patch (tremor in 9.7%). Both formulations showed a 2.1-point worsening on the UPDRS-III motor scale [96,97].
A2A receptors are co-localized on dopamine D2 receptors and may be over-activated in PD. Thus, A2A receptor antagonism may reduce PD motor symptoms . Istradefylline was the first A2A antagonist evaluated in PD, but it received a "not approvable" letter from the FDA due to lack of clinical benefit and association with dyskinesias. A subsequent review concluded istradefylline 50 mg had clinical potential as a levodopa adjunct in PD, with support from a clinical trial showing significant reduction in "off" time and good tolerance [95,99].
There has been interest in glutamate receptor antagonists for the treatment of PD based on the finding that PD is linked to glutamate overactivation in basal ganglia circuits, resulting in oxidative stress and cell death. Riluzole, an NMDA receptor antagonist approved for the treatment of amyotrophic lateral sclerosis, was studied in PD, but it lacked significant effects on survival or disease progression .
Safinamide is an alpha-aminoamide developed as adjunct therapy to dopamine agonist or levodopa therapy in patients with PD. This drug shows dopaminergic and non-dopaminergic activity, including MAO-B inhibition, sodium channel antagonism, and inhibition of glutamate release. Clinical trials have shown significantly improved motor symptoms versus placebo. The FDA reviewed the new drug application for safinamide (under the brand name Xadago) and has requested additional research on the drug's abuse liability and dependence/withdrawal effects be conducted prior to final decision .
Cannabidiol, the primary non-psychoactive constituent in Cannabis, has been evaluated for treatment efficacy in several non-motor PD conditions. In patients with PD-associated psychoses of at least three months' duration, oral cannabidiol treatment ≤400 mg/day for four weeks significantly reduced psychotic symptoms. No cognitive or motor side effects were found in study participants .
A small case series of patients with PD and REM sleep behavior disorder examined treatment response to oral cannabidiol 75 mg/day or 300 mg/day for six weeks. In this sample, symptoms of REM sleep behavior disorder included swearing, laughing, yelling, pushing, kicking, or punching during REM sleep, occurring two to seven times per week. After six weeks of cannabidiol, REM sleep behavior disorder symptom frequency was no times per week in 75% and one time per week in 25% of patients. All patients reported elimination of nightmares. Shortly after cannabidiol cessation, symptom frequency returned to baseline level in all patients. No side effects were observed .
The antioxidant urate precursor inosine has been associated with lower risk of PD and slower PD progression and was suggested as neuroprotective in laboratory assays. The effects of inosine on PD are currently in phase III clinical trial evaluation in the Safety of Urate Elevation in Parkinson Disease (SURE-PD) study .
In addition to investigational new drugs, several FDA-approved medications have been studied for their off-label use in the treatment of PD. Calcium-channel blockers are one such group. In one study, the calcium-channel blocker isradipine was found to reduce risk of PD in patients 65 years of age or older . Isradipine, a calcium-channel blocker in use as hypertension therapy, may be neuroprotective in PD. The drug is currently in phase III trials (known as STEADY-PD) to determine its utility in treating early PD .
Evidence for the role of neuroinflammation in the pathogenesis of PD have prompted trials of several anti-inflammatory agents. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be protective against PD, but the overall evidence of neuroprotective effect with aspirin or NSAIDs in PD is inconsistent .
The stimulant methylphenidate has been found in limited studies to improve gait hypokinesia and freezing in patients with PD receiving deep brain stimulation of the subthalamic nucleus .
Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes. In a 12-month trial of 45 patients with moderate PD, subcutaneous exenatide showed clinically relevant improvements in PD across motor and cognitive measures versus untreated controls [105,106].
Zonisamide is an anticonvulsant with neurotransmitter effects, including stimulation of dopamine synthesis, and is approved in Japan for the treatment of PD. Use as an adjunct to levodopa found improvements in "off" time .
Beta-blockers are considered a therapeutic option for PD tremor, although some patients may not benefit from or tolerate these agents .
The therapeutic objective in patients with early PD is symptomatic treatment of motor symptoms to restore more normalized motor function and to optimize and maintain patients' ability in perform activities of daily living. Therapy initiation is individualized, based on patient age, handedness, employment status, and functional status. Tremor is often the symptom that brings patients to medical attention and diagnosis, but it is dominant at rest and infrequently a source of disability or reason to initiate treatment. Rigidity and bradykinesia are more frequently associated with the functional limitations and mobility impairments that influence a patient to initiate treatment . Initial therapy should also target the most disruptive and impairing symptoms in each patient, which can differ with tremor versus rigidity .
Initial therapeutic options for motor symptoms, in descending order by potency of effect, are levodopa, dopamine agonists, and MAO-B inhibitors. Dopaminergic agents (levodopa and dopamine agonists) remain the mainstay of symptom control but are not always first-line treatment. The timing of dopaminergic therapy initiation depends on patient preference, degree of disability, and potential side effects. In general, early dopaminergic treatment is recommended, and the choice, depending on age and overall cognition, is between levodopa preparations, dopamine agonists, and MAO-B inhibitors .
The assumption that dyskinesia strictly arose from long-term levodopa use led to the common practice of delaying its initiation until the onset of significant motor symptoms in order to save the window of efficacy before dyskinesia begins. As noted, it is now thought that disease stage has greater influence than medication duration on development of levodopa-induced dyskinesia. This has led to earlier levodopa initiation, although MAO-B inhibitors or dopamine agonists are often preferred as initial early PD therapy .
The choice of drug depends on the impact of improving motor disability (better with levodopa) compared with the risk of motor complications (more common in younger patients, delayed by agonists) and neuropsychiatric complications (more common in older and cognitively impaired patients, greater with agonists). Levodopa is the most effective symptomatic drug. However, controlled-release formulations or adding entacapone is not effective for delaying the onset of motor complications. Other treatments include MAO-B inhibitors (e.g., selegiline, rasagiline) or oral or transdermal dopamine agonists (e.g., pramipexole, ropinirole, rotigotine). Initial treatment with an agonist can be recommended in younger patients. Ergot derivatives (e.g., bromocriptine, cabergoline) are not recommended due to the increased risk of fibrotic development . Amantadine and anticholinergic agents are also options. Rehabilitation in early-stage disease has seldom been evaluated, and therefore a recommendation for or against its use cannot be made .
Dose adjustments with dopamine agonists and levodopa preparations are made in response to clinical effect, emerging symptoms, and/or side effects. Risks of psychiatric side effects and dyskinesias are greater at higher doses, and treatment with the lowest dose possible to achieve benefit is favored; this better maintains patient function and quality of life. Patients older than 50 years of age who receive levodopa doses greater than 600 mg/day are more likely to develop dyskinesia .
Patients who initiate treatment with an MAO-B inhibitor, anticholinergic agent, amantadine, or their combination will, at some point, require levodopa or a dopamine agonist added. If patients on dopaminergic therapy require treatment intensification, the options are to increase the dose, switch to another agonist, or add levodopa. Patients who are initiated on levodopa may be better managed by an increase in the dose, the addition of an agonist, or the addition of a COMT inhibitor . If significant tremor persists in patients with disabling tremor, add or initiate with :
Beta-blocker (e.g., propranolol)
Deep brain stimulation
Later stage PD is clinically characterized by diminished efficacy of dopaminergic therapy and the emergence of motor fluctuations and dyskinesias. In patients with PD, the initial response to carbidopa/levodopa therapy is usually positive, because dopaminergic systems are relatively intact and produce sufficient endogenous dopamine to "buffer" the exogenous carbidopa/levodopa. With disease progression, combined effects from dopaminergic neuron loss, receptor alteration, modifications in circuitry, and desensitization of receptors lead to inconsistent and unpredictable carbidopa/levodopa response and the development of motor fluctuations. At some point, virtually all patients with PD develop motor fluctuations that include wearing off, delayed onset dyskinesias and dystonias [110,111,112].
As PD progresses, the duration of benefit from each levodopa dose becomes increasingly shorter. "End of dose deterioration," "wearing-off," "off periods," or simply "off" refers to the waning or absent effects of levodopa within four hours of the last dose. As "off" periods increase, "on" periods (levodopa-related motor symptom control) decrease .
While early PD can be effectively managed with levodopa for many years, disease progression invariably leads to peak-dose dyskinesias, including tics, tremors, and other involuntary movements . In addition to levodopa, dyskinesias can also develop with dopamine agonists or MAO-B inhibitors. Men and younger patients have higher risk of dyskinesias. Mild dyskinesias do not require specific treatment, but more severe cases may respond to a reduction in levodopa dose or addition of an NMDA antagonist or dopamine receptor agonist .
When patients develop end-of-dose deterioration (symptom relapse) or peak-dose dyskinesias, motor complications begin to dominate the clinical picture. Several potential mechanisms contribute to the development of motor complications. Low plasma levels of dopaminergic drugs lead to "off" periods, while high levels increase peak-dose dyskinesia; the levodopa therapeutic window is narrowed. Motor complications accrue in an estimated 10% of patients with PD per year, with an estimated 50% prevalence with five years of levodopa treatment. Other motor signs and symptoms can emerge, including axial motor symptoms of gait and postural abnormalities, that increase the risks of falling, dysphagia, dysarthria, and cognitive problems .
Axial motor signs/symptoms of gait impairment, postural instability, and postural abnormalities are common and debilitating in patients with later PD. Unlike the cardinal motor symptoms of rest tremor, bradykinesia, and rigidity, dopaminergic therapy and physiotherapy minimally benefit axial motor symptoms. This is probably due to mediation of motor control of axial and cardinal functions by different anatomical-functional pathways .
Freezing gait often appears later in the disease course and can lead to significant declines in quality of life. Walking requires shifting from one leg to the other, and patients with freezing gait experience a sense of falling every time they lift a foot up off the floor. Every step forward resembles a controlled fall. Research has shown that auditory stimuli (e.g., sound of a metronome) or visual cues (e.g., a flash of light or lines on the floor indicating stride length) can reduce episodes of freezing, but how these cues work is unknown .
When motor complications emerge, manipulation of levodopa dose or frequency is often the first strategy, but the initial improvement is eventually precluded by the emergence of dyskinesias.
Studies comparing immediate- and modified-release levodopa found roughly 25% less levodopa absorbed with the modified-release formulation, and this should be considered when switching between preparations. Erratic levodopa absorption in later PD and significant reduction in doses per day with modified-release levodopa can result in delayed or no "on" responses. Modified-release levodopa has greatest benefit in reducing overnight wearing-off .
The next strategy is adding adjunctive therapies to levodopa to control fluctuating motor response. Wearing-off symptoms can be reduced by adding MAO-B inhibitors, COMT inhibitors, or dopamine agonists. The MAO-B inhibitor rasagiline reduces "off" time by around 1.5 waking hours per day; the same results were found with the COMT inhibitor entacapone . The COMT inhibitors entacapone and tolcapone can improve CNS delivery of levodopa by inhibiting its peripheral degradation to 3-OMD. Entacapone is most widely used due to rare hepatic failure associated with tolcapone, although the latter agent may be more effective [7,74]. COMT inhibitors can increase ''on'' time, but these drugs lack intrinsic antiparkinsonism efficacy as monotherapy .
The dopamine agonists pramipexole and ropinirole reduce "off" time by around 15% but can cause problematic side effects, including drowsiness, sudden onset of sleep, and impulse control disorders, in 15% or more of patients. Patients should be screened for pre-existing drowsiness and tendencies toward compulsive disorders (e.g., gambling) before prescribing a dopamine agent. Patients should be monitored for the development of impulse control disorders throughout the course of treatment. Apomorphine can be administered by continuous infusion or intermittently to treat sudden "off" periods unresponsive to other medications .
Deep brain stimulation is effective against motor fluctuations and dyskinesia . However, because the risk for adverse events is elevated, this modality is only recommended in patients younger than 70 years of age without major psychiatric or cognitive problems. Other options include subcutaneous apomorphine administered via penject or pump or intrajejunal levodopa/carbidopa enteric gel administered through percutaneous gastrostomy .
Deep brain stimulation of the subthalamic nucleus is effective to manage unpredictable "on-off" symptoms . In treatment studies for wearing-off, patients with unpredictable "on-off" have been excluded or were uncommon. Thus, there is insufficient evidence to conclude if the results are valid for unpredictable "on-off." The strategies described for dyskinesia and wearing-off should be considered. For delayed "on," dispersible levodopa and subcutaneous apomorphine injections have some value . Reducing or redistributing dietary proteins may be helpful, but a more practical approach is to take levodopa on an empty stomach one hour before, or at least one hour after, each meal.
Management options for "off" freezing are the same as for wearing-off. However, freezing during "on" often does not respond to dopaminergic strategies. Visual or auditory cues are empirically useful for facilitating the start of motor acts .
The first step in managing dyskinesias is to reduce the levodopa dose. This elevates the risk of increasing "off," but it can be compensated for by increasing the number of doses or adding a dopamine agonist. MAO-B or COMT inhibitors should also be reduced or discontinued at the risk of worsening wearing-off .
Amantadine (an NMDA antagonist) is the sole effective agent in suppressing levodopa-induced dyskinesia without worsening parkinsonism and should be initiated at 200–400 mg/day [74,95]. In younger patients, an anticholinergic agent may be prescribed .
Deep brain stimulation of the subthalamic nucleus also reduces dyskinesia symptoms and dopaminergic dosing. Stimulation of the globus pallidus pars interna may reduce severe dyskinesia.
Clozapine or quetiapine may be added. Clozapine is associated with potential serious adverse events (e.g., agranulocytosis, myocarditis) and requires monitoring. Intrajejunal levodopa infusion is another option. Continuous subcutaneous infusion of apomorphine allows reduction of levodopa .
Biphasic dyskinesias can be very difficult to treat, and well-designed treatment studies are sparse. Deep brain stimulation of the subthalamic nucleus appears effective . The strategies described for managing peak-dose dyskinesias may also be considered.
Another option is increasing the size and frequency of levodopa dosing, at the risk of increasing peak-dose dyskinesia. However, larger and less frequent doses may give more predictable responses. Apomorphine and intrajejunal levodopa infusion may be tried .
The strategies for wearing-off can be applied to patients with off-period dystonias. Additional levodopa or dopamine agonist doses at night may be effective if the symptoms are worst in the morning. Deep brain stimulation is recommended, and botulinum toxin injection may be employed .
Advanced PD is defined as the onset of persistent and severe motor complications despite optimized oral pharmacologic and behavioral management . The development of motor complications during later disease progresses to advanced disease. The underlying pathophysiologic mechanisms result in a narrowing therapeutic window whereby low plasma and striatal levels of dopaminergic drugs lead to "off" periods and high levels lead to increases in peak-dose dyskinesia. Patients experience increasing dose failures from absorption problems [7,95]. Dyskinesias become more frequent and severe in advanced disease, appearing in 59% of patients after 10 years of levodopa treatment. Even small dose increases in levodopa to improve motor function may produce dyskinesias. Management of dyskinesias and "off" periods by lowering the levodopa dose and shortening the time intervals between doses becomes increasingly ineffective in advanced disease .
Long-acting dopamine agonists taken once daily have become popular with patients. In theory, long-acting dopamine agonists should allow a stable release of drug, with continuous dopaminergic stimulation reducing plasma fluctuations and decrease motor complications. Many experts state this theory is unsupported by observations in clinical practice, and the presumptive advantage of long-acting dopamine agonists has not been proven. Dopamine agonists should not be prescribed to patients with dementia, hallucinations, autonomic dysfunction, or sleep disorders, and impulse control disorders are a potential side effect with this drug class .
With disease progression in advanced PD, the development of wearing-off symptoms and dyskinesias can produce severe, disabling motor fluctuations uncontrollable with oral medications. Advanced therapies are considered at this point, including deep brain stimulation or infusional therapies such as subcutaneous apomorphine or intraduodenal levodopa gel infusions. Such therapies are generally reserved for patients who no longer improve with available oral and transdermal therapies and who lack cognitive or psychiatric dysfunction .
Apomorphine, intraduodenal levodopa, and deep brain stimulation can substantially improve motor fluctuations by decreasing daily "off" time and dyskinesias. Despite benefits that may continue several years after initiation, the underlying pathology progresses, and even patients with excellent response can experience the emergence of advancing disease with postural instability and falls, cognitive disturbance, autonomic dysfunction, and swallowing and speech dysfunction .
While large head-to-head studies comparing invasive procedures are lacking, deep brain stimulation has the highest level of supportive evidence from the largest number of randomized controlled trials. Before any decision is made to use invasive therapies, a multidisciplinary team should examine the patient and carefully weigh the relative risks and potential benefits of each therapy .
With apomorphine, the rapid onset of action makes it an effective intervention for "off" periods with use as a rescue injection. Apomorphine is also available as a continuous infusion treatment, suggested by clinical trials as effective in treating motor symptoms and some non-motor advanced PD symptoms .
With FDA approval in 2015, intestinal gel is the most recent formulation of levodopa/carbidopa to improve its blood concentration consistency and stability. In advanced PD, delayed and unpredictable spontaneous gastric emptying interferes with the passage of oral medication from the stomach to the small intestines for absorption and circulation to the brain. Levodopa/carbidopa intestinal gel (Duodopa) was developed to bypass this problem by delivering the drug directly to the proximal jejunum via a percutaneous endoscopic gastrojejunostomy tube connected to a portable infusion pump .
Compared to conventional immediate-release levodopa, levodopa/carbidopa intestinal gel has been found superior in improving motor fluctuations and quality-of-life scores. For example, 71 patients with advanced PD were randomized to levodopa/carbidopa intestinal gel plus oral placebo or oral levodopa/carbidopa plus placebo intestinal gel. After 12 weeks, the levodopa/carbidopa intestinal gel group showed a significant reduction in "off" time (-4.04 hours/day), versus the active oral/placebo gel group (+2.14 hours/day). This extent of improvement was also observed in "on" time without troublesome dyskinesia, and in "on" time without dyskinesia. Most side effects involved complications related to the percutaneous gastrojejunostomy therapy pump .
Surgical treatment is considered in patients with advanced PD when optimized medical treatment has failed to control motor symptoms. Initial surgical interventions involved lesions to the basal ganglia, with thalamotomy for tremor and pallidotomy for levodopa-induced dyskinesias. Surgical lesions showed a high risk of permanent side effects, and while pallidotomy or thalamotomy remain options in carefully selected patients, deep brain stimulation is now the surgical treatment of choice for patients with advanced PD . Unlike ablative surgery, deep brain stimulation can be modified over time to address changing disease presentation with progression, adverse effects are primarily reversible, and deep brain stimulation can be used bilaterally to improve symptoms .
Deep brain stimulation can reduce symptoms of motor fluctuations, dyskinesia, and tremor, but symptoms unresponsive to levodopa in advanced PD (e.g., cognitive impairment, gait instability, mood disorders, speech impairment, autonomic dysfunction) are unlikely to improve and may worsen with deep brain stimulation. Guidelines recommend that deep brain stimulation should only be performed in experienced centers .
The primary targets of deep brain stimulation are the subthalamic nucleus and the globus pallidus pars interna. Effectiveness of subthalamic nucleus stimulation in improving levodopa-responsive signs and symptoms has been reported by many short-term and long-term studies. The overall improvement of activities of daily living and motor UPDRS scores averaged 50% compared to pre-surgery. Levodopa-induced dyskinesias have been reduced by an average 69%. The most frequent post-surgical surgery-related adverse effects are infections (6.1%), migration or misplacement of the leads (5.1%), lead fractures (5%), intracranial hemorrhage (3%), and skin erosion (1.3%) .
Factors that contribute to deep brain stimulation outcome include clinical indications, patient selection, surgical targeting accuracy, stimulation programming, and medication management. The most frequently reported persistent complications possibly related to deep brain stimulation include eyelid opening apraxia (1.8% to 30%), dysarthria/hypophonia (4% to 17%), gait disturbances (14%), postural instability (12.5%), weight gain (8.4%), and verbal fluency decline (14%) [89,116]. As of 2016, more than 100,000 patients had undergone deep brain stimulation surgery for the treatment of PD and other movement disorders .
While deep brain stimulation was formerly offered only in late-phase disease (mean: 13 to 14 years post-diagnosis), several considerations have now moved the timing for surgery forward . Deep brain stimulation produces motor improvement in symptoms responsive to dopaminergic drugs, but unresponsive features usually predominate in later disease. Performing deep brain stimulation at advanced stages of illness can alleviate some motor dysfunction features but does not benefit ongoing problems in well-being and occupational, social, and role functioning. In addition, older patients are more likely to develop surgical complications and/or worsening of axial motor functions.
Earlier deep brain stimulation surgery was studied by comparing best medical treatment with deep brain stimulation of the subthalamic nucleus in 251 patients with early-stage motor fluctuation (mean: seven years post-diagnosis). Early and sustained improvement was found in quality of life for patients who received deep brain stimulation. Deep brain stimulation of the subthalamic nucleus has been proposed in patients less than four years after diagnosis without motor fluctuation, but this approach is less compelling, as it exposes patients to potentially dangerous side effects without improving motor function or quality of life. The long-term impact is also unclear .
Several trials comparing subthalamic nucleus and globus pallidus pars intera stimulation have helped define relative advantages between these two targets. While motor benefits are comparable, other parameters show advantages with subthalamic nucleus for more severe on-off symptoms and cost-efficacy, and advantages with globus pallidus pars intera for dyskinesia suppression, long-term stability of effects, and cognitive symptoms .
Experimental and clinical observations suggest contribution from the pedunculopontine nucleus to the pathophysiology of gait and stability impairment. However, pedunculopontine nucleus stimulation remains investigational, with several unresolved issues .
Early open-label studies reporting long-term (more than 10 years) outcomes in subthalamic nucleus stimulation consistently found durable benefits in motor fluctuation, dyskinesias, and the cardinal symptoms of PD (tremor, rigidity, and to a lesser extent, bradykinesia). A survival advantage was suggested when comparing eligible patients who chose deep brain stimulation versus those who continued medical treatment. However, subthalamic nucleus stimulation does not halt disease progression, and "long-term deep brain stimulation syndrome" with axial motor problems can emerge from long-term therapy. Reappraisal of current targets and investigation of new ones is ongoing .
As discussed, patients frequently develop diverse non-motor symptoms and syndromes throughout the clinical course of PD. Most non-motor symptoms cluster into broader groups of abnormality: neuropsychiatric disorders, autonomic dysfunction, sleep disorders, and pain.
Psychosis in PD is common and multifactorial in etiology. Up to 60% of patients with PD develop psychosis. Following its onset, PD psychosis remains a persistent, lifelong problem for most patients . Pharmacologic management is challenging, in part because dopaminergic agents required for motor control can exacerbate psychotic symptoms, and antipsychotic agents can exacerbate motor symptoms . The onset of psychosis in PD predicts a poor prognosis, including increased likelihood of nursing home placement and early mortality .
The early clinical manifestations of PD-associated psychosis differ from other psychotic disorders in that hallucinations are common and patients initially remain lucid and connected with reality. Visual hallucinations are the most prevalent form. Functional MRI performed on patients with PD who are experiencing visual hallucinations show several abnormalities: altered cortical visual processing; decreased occipital response and increased caudate and frontal cortical activation to visual stimuli; overactive visual association cortex; and decreased primary visual cortex activity .
Auditory, tactile, olfactory, and gustatory hallucinations do occur, though less commonly and usually in combination with visual hallucinations. Confusion states, delusions, paranoia, agitation, and delirium may also develop.
The stage of PD at which psychotic features emerge has some diagnostic import. In newly suspected or recently diagnosed (within three months) cases of PD, the appearance of psychotic symptoms suggests early-onset dementia with Lewy bodies, but could also indicate an alternative neuropsychiatric diagnosis, such as Alzheimer disease with extrapyramidal symptoms or underlying functional (psychiatric) psychosis. Differences in the initial presentation of PD-associated psychosis do not substantively change the management approach (with some caveats) .
Risk factors for PD-associated psychosis include cognitive impairment, dementia, advanced age, sleep disturbances, and disease duration/severity . Psychosis is unrelated to total dose or duration of dopaminergic medication, and no differences have been found in the incidence rate among patients receiving levodopa versus those on dopamine agonists or anticholinergic drugs .
The association between sleep disturbance and PD psychosis is sufficiently robust to suggest REM sleep behavior disorder manifests from an evolving synucleinopathy in patients with PD-associated psychosis or dementia. Both factors may develop from a single epiphenomenon, such as neurodegeneration. Evidence also suggests contribution to PD psychosis from non-dopaminergic neurotransmitters, including serotoninergic or cholinergic systems .
Visual hallucinations require medication adjustment and possibly specific therapies if they are troublesome, threatening, or associated with behavioral change . Triggering factors, such as infection, metabolic disorders, fluid/electrolyte imbalance, and sleep disorder, should be controlled. In addition, steps should be taken to reduce polypharmacy. Tricyclic antidepressants and anxiolytics/sedatives should be reduced or stopped. Antiparkinsonism drugs should also be reassessed. Anticholinergics and amantadine should be halted, while dopamine agonists and MAO-B and COMT inhibitors should be reduced or halted. The levodopa dose may be reduced [74,123].
Unfortunately, most commonly used antipsychotic drugs have side effects that exacerbate PD. Consequently, atypical antipsychotics are often key in the management of PD-associated psychosis. Almost all antipsychotic drugs can exacerbate PD. Clozapine is the only antipsychotic with high-level evidence of efficacy; in some patients, it also improves motor function . Clozapine is widely recommended as the first-line choice, but it is associated with potentially fatal agranulocytosis, which develops in 1% of patients and makes routine blood neutrophil counts mandatory. Less serious side effects include sedation, tachycardia, orthostatic hypotension, and sialorrhea. Low-dose clozapine (less than 50 mg) also has efficacy, with less frequent and more tolerable side effects and rare agranulocytosis [125,126].
The AAN states quetiapine can be considered in the treatment of PD-associated psychosis . However, some studies have found quetiapine no better than placebo in antipsychotic effect in this group of patients [127,128]. Despite clozapine superiority, quetiapine is the most frequently used antipsychotic for PD-associated psychosis in the United States, due to better safety and despite inconsistent antipsychotic benefit [75,119].
First-generation antipsychotics (e.g., haloperidol) should not be used. This drug class is a common cause of drug-induced parkinsonism, shows little to no psychotic symptom relief, and can worsen motor symptoms . Other atypical antipsychotic agents (e.g., olanzapine, risperidone) can worsen parkinsonism and should not be used . The FDA requires all atypical antipsychotics to carry black box warnings for increased risk of death in elderly patients with dementia .
Adding a cholinesterase inhibitor (e.g., rivastigmine, donepezil) is an option . In patients requiring sedation for severe agitation, non-neuroleptics such as lorazepam should be considered over standard agents like haloperidol [75,76].
Pimavanserin is an investigational drug with a novel mechanism of antipsychotic action as a selective serotonin 5-HT2A receptor inverse agonist. The activity of this drug does not block dopamine receptors and does not adversely affect PD. In clinical trials for the treatment of PD-associated psychosis, pimavanserin has shown efficacy and tolerability, including significant improvements in positive symptoms of psychoses, caregiver burden, and overall clinical improvement without worsening of motor function. No safety signals have emerged [95,129].
Dementia is the progressive decline in cognitive function (i.e., thinking, planning, organizing, problem solving) beyond what might be expected from normal aging. The dementia of PD takes two forms: an early, more rapidly progressive dementia characterized pathologically by an abundance of Lewy bodies within the brain (i.e., dementia with Lewy bodies), and a later onset, less rapid form characterized by neurodegenerative change and fewer Lewy bodies (i.e., PD dementia) . The cognitive signs of dementia with Lewy bodies begin within one year of motor symptom onset, while the cognitive problems associated with PD dementia begin one or more years after motor symptom onset.
Dementia affects a substantial portion of people with PD and has virtually no effective treatment . Cognitive impairment, autonomic dysfunction, and falls are all features of PD dementia that substantially affect function and quality of life and incompletely respond to medication manipulation .
In patients with typical PD dementia, there is an initial rapid loss of midbrain dopamine neurons followed by slow progression of Lewy body infiltration into the brain over decades. Dementia manifests later when Lewy bodies invade the neocortex. Patients diagnosed with PD after 70 years of age develop dementia earlier in the disease, show more alpha-synuclein-containing Lewy bodies throughout the brain, and often have additional age-related plaque pathology. In contrast, dementia with Lewy bodies occurs with PD diagnosed at a younger age, is more rapidly progressive, and shows substantial amounts of Lewy bodies and Alzheimer-type pathologies infiltrating the brain. These data suggest that age at symptom onset and the extent and type of age-related, Alzheimer-type pathology influence pathologic progression in PD .
Management involves discontinuation of potential aggravators, including anticholinergics, amantadine, tricyclic antidepressants, tolterodine, oxybutynin, and benzodiazepines [74,123]. A cholinesterase inhibitor, such as rivastigmine, donepezil, or galantamine, should be initiated. With idiosyncratic clinical response or side effects, an alternate agent may be tried. If cholinesterase inhibitors lack tolerability or efficacy, memantine should be added or substituted.
As many as 90% of patients with PD experience depression, which can appear in early and advanced disease. This neuropsychiatric problem has a major impact on both patients' and caregivers' quality of life. With many overlapping features between depression and PD before and during dopaminergic treatment (e.g., loss of facial expression, hypophonic speech, slowed movement, reduced appetite, sleep disorders), depression in PD often goes on unrecognized [89,130].
Tricyclic antidepressants may be the best choice for depression treatment in PD, followed by selective serotonin or norepinephrine reuptake inhibitors (SSRIs/SNRIs) or dopaminergic agonist therapy. Cognitive-behavioral therapy also appears promising. Most PD experts use an SSRI, SNRI, or tricyclic antidepressant and follow the patient closely for four to six weeks, adjusting as needed [95,131].
The potential of antidepressants to worsen PD motor symptoms has been debated, but studies show no significant increase in risk of motor deterioration. A review of tricyclic antidepressant and SSRI/SNRI treatment of depression in PD concluded possible efficacy in reducing levodopa-induced dyskinesia . There is a minor risk of impairing levodopa motor control, but this finding is inconsistent. The effect is usually minor when it happens and can be resolved by increasing levodopa dose . Nortriptyline has no effect on dyskinesia or motor symptoms.
Tricyclic antidepressants and SSRIs/SNRIs are probably effective for depression . The strongest evidence is for nortriptyline and paroxetine. SSRIs may not be the preferred drug class when rapid effect is needed, and quicker onset of therapeutic benefit is achieved with noradrenergic antidepressants. Tricyclic antidepressants and SSRIs/SNRIs are also beneficial in treating anxiety in patients with PD.
In other drug classes, the dopamine agonist pramipexole (up to 1 mg three times per day) significantly improved depression compared to placebo, an effect unrelated to motor improvement [95,131]. Depression symptoms confined to "off" time may respond well to any treatment that reduces motor fluctuations and improves "on" time. Electroconvulsive therapy remains a potentially lifesaving treatment in major depression and has been used successfully in PD, but sufficient trials in PD depression do not exist [95,131].
Apathy in non-demented and non-depressed patients with PD is not associated with dopamine transporter activity in the striatal sub-regions. It is more likely the result of extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits .
No established treatment for apathy is available. Levodopa, selegiline, and antidepressants have been suggested as useful. In a small clinical trial, rivastigmine 9.5 mg/day transdermal significantly improved apathy symptoms beyond placebo response. There was also improvement in activities of daily living and caregiver burden, but not quality of life. Methylphenidate is probably effective in treating apathy and fatigue in later PD . There is a lack of literature on the subject, many experts use a dopamine agonist for severe apathy, but with caution for impulsive behaviors [95,134].
Impulse control disorders and aberrant behaviors can develop during dopamine agonist treatment in PD and worsen patient and caregiver quality of life. Often, patients lack insight into the negative consequences of their behavior. Risk factors include male sex, younger age at onset, personality traits of high impulsivity and novelty seeking, and personal or family history of addictive disorders. In predisposed patients, overstimulation of mesocorticolimbic dopamine receptors by dopamine agonists leads to impulse control disorders and compulsive medication use. Impulse control disorders are more likely in early PD with normal-range medication dosing, while compulsive medication use is more commonly associated with fluctuations in advanced disease. Affected patients often lack noteworthy psychiatric histories and cognitive impairment, making identification difficult. Management requires reducing dopaminergic therapy, and psychosocial support is often necessary. SSRIs may help, while atypical antipsychotics have limited benefit. Prevention is based on the identification of at-risk individuals and active monitoring .
In a study of 203 patients with PD, the most common impulse control disorders were compulsive eating (14%), hypersexuality (10%), compulsive shopping (6%), and pathologic gambling (3%). Age younger than 68 years and exposure to dopamine agonists or MAO-B inhibitors were identified as risk factors for developing disorders of impulse control. Affected patients on dopamine agonists received a daily dose 60% higher than those without the disorders. Impulse control disorder symptoms showed a nonlinear dose-response relationship with dopamine agonists .
In patients with PD, constipation may develop due to impaired gastrointestinal motility and medication side effects. Treatment is often behavioral, with a focus on increasing fluid ingestion, fiber intake, and physical activity. If additional treatment is necessary, polyethylene glycol solution, fiber supplements (e.g., psyllium, methylcellulose), and/or osmotic laxatives are recommended. Short-term irritant laxatives may help in selected patients [74,123].
Management of dysphagia requires optimization of motor control approaches. Speech therapy is indicated for assessment, swallowing advice, and further investigations, if needed. Videofluoroscopy may be conducted in selected cases to exclude silent aspiration. In severe cases, enteral feeding options (e.g., short-term nasogastric tube, percutaneous endoscopic gastrostomy) may be considered [74,123].
Orthostatic hypotension is a symptomatic drop of 20 mm Hg systolic or 10 mm Hg diastolic blood pressure when rising to standing from sitting or lying down. Orthostatic hypotension is associated with lightheadedness, syncope, or nonspecific complaints including fatigue, unsteadiness, headache, neck tightness, or cognitive slowing. Because supine hypertension often accompanies orthostatic hypotension, the first step of treatment should be non-pharmacologic to avoid worsening supine hypertension. Patients should avoid, reduce, or eliminate large meals, alcohol, warm environments, volume depletion, diuretics, antihypertensive drugs, tricyclic antidepressants, nitrates, dopaminergic drugs (if possible), and alpha-blockers used for benign prostatic hypertrophy. Increasing salt intake may also help. Tilting the head of bed at night (30° to 40°) is recommended, as is exercise, as tolerated. Waist-high elastic stockings, abdominal compression bands, and counter-maneuvers (e.g., leg crossing, toe raising, thigh contraction) are effective prevention measures.
Urinary incontinence in patients with PD is thought to result from hyper-reflexia caused by basal ganglia dysfunction. When symptoms appear suddenly, it is important to rule out urinary tract infection. If incontinence occurs mainly at night, fluid intake should be reduced after 6 p.m. and the head of the bed should be tilted up for sleep.
Night-time dopaminergic therapy should be optimized, and if necessary, an anticholinergic drug may be added. Guidelines recommend trospium chloride (10–20 mg two to three times per day) or tolterodine (2 mg twice per day) [74,123]. However, trospium is less able to penetrate the blood-brain barrier, and cognition may worsen. Botulinum toxin type A injected in the detrusor muscle is also an option [74,123].
Sexual dysfunction is common in men and women with PD and is a complex problem from diverse etiologies, including motor dysfunction, medication side effects, mood disorders, and autonomic dysfunction manifesting in erectile dysfunction, reduced genital sensitivity and lubrication, and difficulty reaching orgasm .
Erectile dysfunction is widespread in PD and affects at least 50% to 75% of men with PD. Good evidence supports the use of sildenafil citrate, and similar drug class members, such as tadalafil and vardenafil, are also likely to be effective .
Excessive daytime somnolence and sudden sleep onset can originate from the disease process, medications, or other sleep disorders. Excessive daytime somnolence can result from dopaminergic medications—more commonly dopamine agonists than levodopa. Patients with these symptoms should be assessed for nocturnal sleep disturbances. Nocturnal sleep may be improved by reducing akinesia, tremor, and urinary frequency.
Sedative drugs should be reduced or discontinued. All dopaminergic drugs may induce daytime somnolence, so the dose of the current dopamine agonist may be reduced or the patient may switch to another dopamine agonist. Modafinil and/or other wake-promoting agents (e.g., methylphenidate) should be added [74,123]. Patients with excessive daytime somnolence should be advised to stop driving.
Restless legs syndrome (RLS) is a movement disorder of the limbs whereby patients have a bothersome, irresistible urge to move the legs. RLS often interferes with sleep, leading to chronic sleep deprivation and stress. The prevalence of RLS was 12% in one study of patients with PD . Drugs considered the most efficacious for RLS include levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin; second-line options include rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine .
Insomnia in PD may be the result of mood disturbances, persistent tremor, night-time re-emergence of PD symptoms, nocturia, and reversal of sleep patterns . Levodopa/carbidopa may contribute to insomnia while improving sleep-related motor symptoms. Melatonin may be effective in improving patients' perception of sleep quality .
As discussed, REM sleep behavior disorder is a type of parasomnia characterized by the behavioral enactment of dreams during REM sleep. REM sleep behavior disorder is one of the most robust predictors of PD development and is very prevalent throughout the motor symptom phase of disease progression. Standard treatment is clonazepam or melatonin .
Among non-motor symptoms, 60% to 83% of patients with PD report pain of heterogeneous presentation and disabling effect on quality of life. Pain has received minimal attention in PD due to its association with the reappearance of motor symptoms and dystonic muscle contraction with dissipation of levodopa dose response. Pain also occurs as skeletal-muscle or neuropathic (peripheral or central) pain. Evidence suggests patients with PD have abnormal nociceptive processing in pain-free states, independent of parkinsonism motor symptom presence, that is unaffected by levodopa stimulation. Few therapeutic strategies for pain management in PD have been developed [139,140].
A concern in using opioids to treat pain in patients with PD is potential exacerbation of constipation, a common, burdensome symptom of autonomic dysfunction. To possibly mitigate this issue, an oral formulation combining prolonged-release oxycodone with naloxone has been evaluated. In an eight-week trial, patients with PD-associated chronic pain received low-dose oxycodone/naloxone (5 mg/2.5 mg) twice daily. Of the 87.5% who completed the trial, significant pain reduction was achieved, no adjustment of dopaminergic therapy was required, no significant changes were observed in bowel function and constipation symptoms, no changes were observed in sleep symptoms, and improvements were recorded in clinician impression of therapeutic effect .
A little-studied area of PD has been symptom manifestation with approaching death and factors related to their severity and progression. The course of non-dopaminergic PD symptoms in relation to age and death was prospectively studied in 378 patients with PD over five years. Patients who died (11%) during follow-up had more severe non-dopaminergic symptoms. The progression of cognitive and axial symptoms accelerated in older patients, and the progression of axial, cognitive, and psychotic symptoms accelerated before death. Improving understanding of these factors will hopefully make a positive impact on end-of-life care .
During end-stage PD, the focus of care is on palliation of symptoms and comfort. Patients with end-stage PD often exhibit cognitive impairment and progress to the point of requiring assistance with most activities. The best approach for patients with PD at the end of life is multidisciplinary palliative care with adequate physical, psychologic, and spiritual support. In earlier stages, the goal is to maintain patient independence for as long as possible; however, in end-stage PD, the focus is mainly on comfort and supportive care .
Non-motor symptoms such as depression, psychosis, urologic dysfunction, pain, and respiratory depression, become more common in end-stage PD. Over time, these symptoms may become the most prominent medical problem, leading to increasing decline in quality of life . The first step in managing these symptoms may be reduction or discontinuing triggering pharmacotherapeutic agents, such as anticholinergics, MAO-B inhibitors, and opioids.
In the last days, the goals of the healthcare team are to ensure a peaceful death for the patient and to support the family during the dying process and throughout grief and mourning. The focus for the patient is management of symptoms and emotional and spiritual ease, and the focus for the family is education to prepare them for the dying process.
A variety of nonpharmacologic, adjunctive interventions have been evaluated for management of PD. These include exercise programs and occupational, physical, and speech therapies. While clinical study design and control group issues have confounded the quality of evidence, clinical experience suggests that these approaches have value. The American Academy of Family Physicians recommends physical therapy, speech therapy, and occupational therapy be offered to patients with PD as part of an overall strategy for improving or maintaining function . The specific benefits for allied health professional interventions to patients with PD include :
Gait re-education, improving balance and flexibility
Increasing aerobic capacity
Improving movement initiation
Improving independent functioning, mobility, and daily activities
Advising on safety in the home environment
Maintaining work and family roles, home care, and leisure activities
Improving and maintain transfers and mobility
Improving self-care activities such as eating, drinking, washing, and dressing
Addressing environmental issues to improve safety and motor function
Cognitive assessment and appropriate intervention
Improving vocal loudness and pitch range (with programs such as Lee Silverman voice treatment)
Teaching strategies to optimize speech intelligibility
Ensuring effective means of communication maintained throughout the disease course, including use of assistive technologies
Reviewing and managing safe and efficient swallowing to minimise risk of aspiration
In patients with mild PD and balance problems, tai chi and exercise have been found to reduce balance impairments and falls. Cognitive training is likely helpful for other patients. Patient and family member education is a key component of PD management, as is the use of support groups .
Many patients with PD require hospital admission for problems unrelated to motor pathology. Their medical care is typically received on non-neurology wards from staff unfamiliar with PD management, increasing the risk of inappropriate medications that exacerbate PD. Among inpatients with PD, 43.8% received inappropriate anti-dopaminergic medication at some point, primarily haloperidol and metoclopramide. The highest prevalence occurred in patients with PD on chronic antipsychotics .
Nausea and vomiting, common adverse effects of levodopa and dopamine agonists, may require antiemetic use. The centrally acting dopamine antagonists metoclopramide and prochlorperazine should not be used; the peripheral dopamine antagonist domperidone is the antiemetic of choice. The serotonin receptor antagonist ondansetron is another option [74,75].
Healthcare professional education is suggested to improve the care of inpatients with PD. Pharmacists can play a key role in identifying inappropriate medications and in educating non-PD specialist professionals .
With disease progression, patients with PD become more reliant on medication to maintain their ability to function. In addition to regular monitoring for drug-specific side effects, clinicians should be careful not to abruptly withdraw dopaminergic medication . Patients and family should be educated on the importance of medication compliance and regular dosing so as to avoid rapid changes in efficacy. Special attention is required during periods of intercurrent illness, such as gastroenteritis or abdominal surgery, which may result in interruption of dosage or poor intestinal absorption. These measures help to avoid the potential development of acute akinesia or neuroleptic malignant syndrome. "Drug holidays" are not recommended due to the risk of developing neuroleptic malignant syndrome.
Considering the risks of sudden changes in dopaminergic medication, patients with PD admitted to hospitals or care facilities should receive their medication at the appropriate times or be allowed self-medication. Medication adjustment should be reserved for specialists in PD management .
In managing newly diagnosed patients, healthcare professionals should exhibit great sensitivity and understanding in describing disease symptoms and progression. As it progresses, PD complicates every aspect of daily living. Formerly routine tasks demand full attention and often cause frustration and anxiety. Over time, PD reduces work capacity, erodes earning potential, and may compromise social and family relationships. Disease progression leads to increased dependency and fosters feelings of being a burden to others. Increasing difficulties with writing and speaking, coupled with the loss of independence, often lead to social withdrawal, isolation, depression, frustration, and anger. Access to primary care, speech therapists, exercise programs, and emotional support is critical to managing the disease and living with dignity, and people living with PD require understanding and support as they struggle to maintain independence and adapt to living with a chronic condition .
Good communication is the foundation of care between patients with PD, their caregivers, and health professionals. Healthcare professional commitment to clear, compassionate communication can make a meaningful difference to their patients. When patients with PD understand healthcare professionals' recommendations, they can know what to expect and are better prepared to navigate the system, ask the right questions, and make the best personal choices .
Communicating effectively is more challenging when the patient's primary language differs from that of the practitioner. According to the U.S. Census Bureau, more than 31 million Americans speak a language other than English in the home, with approximately 9.4 million of them (11.7% of the population) speaking English less than "very well" . It has been suggested that when patients are first evaluated, they should be asked what language is spoken at home and if they speak English "very well" . In addition, patients should also be asked what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss symptoms in English . Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [146,147].
"Ad hoc" interpreters (untrained staff members, family members, friends) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, the reliability and specificity of information obtained through ad hoc interpreters is less than with professional interpreters . In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members . A systematic review of the literature has shown that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters .
Care decisions should be based upon best available evidence and provided by applicable professional standards. Issues to consider when communicating with people with PD and their caregivers include :
Style, manner, and frequency of communication that is compassionate and respectful
Ease of access for those receiving information in a timely and appropriate manner throughout the progression of the disease
Honesty and sensitivity in tailoring information to meet changing medical needs
Encouragement of self-management to meet individual needs and preferences
Inclusion of caregivers who are also impacted by PD and require information and support
Traditionally, management of PD has focused on drug treatment and interdisciplinary care for a long-term, slowly progressive disorder. Palliative care specialists have not routinely been involved. Due to the long duration of the disease and the difficulty in predicting the time of death, patients with PD are frequently refused access to hospice and palliative care services .
During the long natural history of PD, patients often receive medical care from non-neurologists for problems unrelated to the motor symptoms of PD. Provider unfamiliarity with the medications and management approaches can lead to medication prescribing that antagonizes PD therapy and exacerbates symptoms [75,119]. Optimal disease management is better ensured by improved healthcare provider knowledge of PD and related aspects relevant to these patients.
1. DeMaagd G, Philip A. Parkinson's disease and its management. Part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. PT. 2015;40(8):504-532.
2. Gazewood JD, Richards DR, Clebak K. Parkinson disease: an update. Am Fam Physician. 2013;87(4):267-273.
3. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol. 2011;26(Suppl 1):S1-S58.
6. Scottish Intercollegiate Guidelines Network. Diagnosis and Pharmacological Management of Parkinson's Disease: A National Clinical Guideline. Available at http://www.sign.ac.uk/pdf/sign113.pdf. Last accessed April 13, 2016.
7. Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA. Parkinson's disease. Subcell Biochem. 2012;65:389-455.
8. National Institute of Neurological Disorders and Stroke. Parkinson's Disease: Challenges, Progress, and Promise. Available at http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_research.htm. Last accessed April 13, 2016.
9. Van Den Eeden SK. Tanner CM, Bernstein AL, et al. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003;157(11):1015-1022.
10. Kochanek KD, Murphy SL, Xu JQ. Deaths: final data for 2011. Natl Vital Stat Rep. 2015;63(3):1-120.
11. Xu J. QuickStats: age-adjusted death rates for Parkinson disease—United States, 2000–2013. MMWR. 2015;64(36);1034.
12. Barreto GE, Iakov A, Moran VE. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease. Front Aging Neurosci. 2015;6:340.
13. Quik M, Huang LZ, Parameswaran N, Bordia T, Campos C, Perez XA. Multiple roles for nicotine in Parkinson's disease. Biochem Pharmacol. 2009;78(7):677-685.
14. Kenborg L, Lassen CF, Ritz B, et al. Lifestyle, family history, and risk of idiopathic Parkinson disease: a large Danish case-control study. Am J Epidemiol. 2015;181(10):808-816.
15. Liu R, Guo X, Park Y, et al. Caffeine intake, smoking, and risk of Parkinson disease in men and women. Am J Epidemiol. 2012;175(11):1200-1207.
16. Chen H, Huang X, Guo X, et al. Smoking duration, intensity, and risk of Parkinson disease. Neurology. 2010;74(11):878-884.
17. Liu R, Guo X, Park Y, et al. Alcohol consumption, types of alcohol, and Parkinson's disease. PLoS One. 2013;8(6):e66452.
18. Morelli M, Carta AR, Kachroo A, Schwarzschild MA. Pathophysiological roles for purines: adenosine, caffeine and urate. Prog Brain Res. 2010;183:183-208.
19. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology. 1985;35(7):949-956.
20. Carroll FI, Lewin AH, Mascarella SW, Seltzman HH, Reddy PA. Designer drugs: a medicinal chemistry perspective. Ann NY Acad Sci. 2012;1248:18-38.
21. Vingerhoets FJ, Snow BJ, Tetrud JW, Langston JW, Schulzer M, Calne DB. Positron emission tomographic evidence for progression of human MPTP-induced dopaminergic lesions. Ann Neurol. 1994;36(5):765-770.
23. Stern Y, Tetrud JW, Martin WR, Kutner SJ, Langston JW. Cognitive change following MPTP exposure. Neurology. 1990;40(2):261-264.
24. Fernagut PO, Hutson CB, Fleming SM, et al. Behavioral and histopathological consequences of paraquat intoxication in mice: effects of alpha-synuclein over-expression. Synapse. 2007;61(12):991-1001.
25. Feng LR, Maguire-Zeiss KA. Dopamine and paraquat enhance alpha-synuclein-induced alterations in membrane conductance. Neurotox Res. 2011;20(4):387-401.
26. Lu L, Gu L, Liang Y, Sun X, Duan C, Yang H. Dual effects of alpha-synuclein on neurotoxicity induced by low dosage of rotenone are dependent on exposure time in dopaminergic neuroblastoma cells. Sci China Life Sci. 2010;53(5):590-597.
27. Ma KL, Yuan YH, Song LK, et al. Over-expression of alpha-synuclein 98 triggers intracellular oxidative stress and enhances susceptibility to rotenone. Neurosci Lett. 2011;491(2):148-152.
28. Curtin K, Fleckenstein AE, Robison RJ, Crookston MJ, Smith KR, Hanson GR. Methamphetamine/amphetamine abuse and risk of Parkinson's disease in Utah: a population-based assessment. Drug Alcohol Depend. 2015;146:30-38.
29. Vieira-Brock PL, McFadden LM, Nielsen SM, et al. Chronic nicotine exposure attenuates methamphetamine-induced dopaminergic deficits. J Pharmacol Exp Ther. 2015;355(3):463-472.
30. Wang YL, Wang YT, Li JF, Zhang YZ, Yin HL, Han B. Body mass index and risk of Parkinson's disease: a dose-response meta-analysis of prospective studies. PLoS One. 2015;10(6):e0131778.
31. Tanner CM, Goldman SM, Ross GW, Grate SJ. The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk. Alzheimers Dement. 2014;10(3 Suppl):S213-S225.
32. Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: an etiologic study. JAMA. 1999;281(4):341-346.
33. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009;361:1651-1661.
34. Gao J, Nalls MA, Shi M, et al. An exploratory analysis on gene-environment interactions for Parkinson disease. Neurobiol Aging. 2012;33(10):1-6.
35. Goldman SM, Tanner CM, Oakes D, Bhudhikanok GS, Gupta A, Langston JW. Head injury and Parkinson's disease risk in twins. Ann Neurol. 2006;60(1):65-72.
36. Goldman SM, Kamel F, Ross GW, et al. Head injury, alpha-synuclein Rep1 and Parkinson's disease. Ann Neurol. 2012;71(1):40-48.
37. Perez XA. Preclinical evidence for a role of the nicotinic cholinergic system in Parkinson's disease. Neuropsychol Rev. 2015;25(4):371-383.
38. Camilleri A, Vassallo N. The centrality of mitochondria in the pathogenesis and treatment of Parkinson's disease. CNS Neurosci Ther. 2014;20(7):591-602.
39. Celardo I, Martins LM, Gandhi S. Unravelling mitochondrial pathways to Parkinson's disease. Br J Pharmacol. 2014;171(8):1943-1957.
40. Dexter DT, Jenner P. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med. 2013;62:132-144.
41. Del Tredici K, Braak H. Sporadic Parkinson's disease: development and distribution of α-synuclein pathology. Neuropatholo Appl Neurobiol. 2015;42(1):33-50.
42. Braak H, Del Tredici K. Invited article: nervous system pathology in sporadic Parkinson disease. Neurology. 2008;70(20):1916-1925.
43. Dickson DW, Braak H, Duda JE, et al. Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol. 2009;8(12):1150-1157.
44. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004;318(1):121-134.
45. Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson's disease. Parkinsonism Relat Disord. 2010;16(2):79-84.
46. Bohnen NI, Frey KA, Studenski S, et al. Gait speed in Parkinson disease correlates with cholinergic degeneration. Neurology. 2013;81(18):1611-1616.
47. Stewart T, Liu C, Ginghina C, et al. Cerebrospinal fluid α-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort. Am J Pathol. 2014;184(4):966-975.
48. Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of alpha-synuclein staging. Neuropathol Appl Neurobiol. 2008;34(3):284-295.
49. Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson's disease in primary care: a case-control study. Lancet Neurol. 2015;14(1):57-64.
50. Braak H, Bohl JR, Muller CM, et al. Stanley Fahn Lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered. Mov Disord. 2006;21(12):2042-2051.
51. Williams DR, Lees AJ. How do patients with parkinsonism present? A clinicopathological study. Intern Med J. 2009;39(1):7-12.
52. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24(2):197-211.
53. Postuma RB, Gagnon JF, Bertrand JA, Genier Marchand D, Montplaisir JY. Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology. 2015;84(11):1104-1113.
54. Postuma RB, Gagnon JF, Montplaisir JY. REM sleep behavior disorder and prodromal neurodegeneration: where are we headed? Tremor Other Hyperkinet Mov (N Y). 2013;3.
55. Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series.Sleep Med. 2013;14(8):744-748.
56. Langston JW. The Parkinson's complex: parkinsonism is just the tip of the iceberg. Ann Neurol. 2006;59(4):591-596.
57. Abbott RD, Ross GW, White LR, et al. Environmental, lifestyle, and physical precursors of clinical Parkinson's disease: recent findings from the Honolulu-Asia Aging Study. J Neurol. 2003;250(suppl 3):III3-III39.
58. Abbott RD, Ross GW, White LR, et al. Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology. 2005;65(9):1442-1446.
59. Soto-Ortolaza AI, Ross OA. Genetic susceptibility variants in parkinsonism. Parkinsonism Relat Disord. 2016;22(Suppl 1):S7-S11.
60. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12):1591-1599.
61. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson's disease. Mov Disord. 2015;30(12):1600-1611.
62. Massano J, Bhatia KP. Clinical approach to Parkinson's disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med. 2012;2(6):a008870.
63. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease. Eur J Neurol. 2013;20(1):16-34.
64. Merello M. Parkinson's Disease and Parkinsonism. Available at http://www.movementdisorders.org/MDS/About/Movement-Disorder-Overviews/Parkinsons-Disease--Parkinsonism.htm. Last accessed April 13, 2016.
65. Fasano A, Aquino CC, Krauss JK, Honey CR, Bloem BR. Axial disability and deep brain stimulation in patients with Parkinson's disease. Nat Rev Neurol. 2015;11(2):98-110.
66. Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376.
67. Spildooren J, Vercruysse S, Desloovere K, Vandenberghe W, Kerckhofs E, Nieuwboer A. Freezing of gait in Parkinson's disease: the impact of dual-tasking and turning. Mov Disord. 2010;25(15):2563-2570.
68. Plotnik M, Giladi N, Dagan Y, Hausdorff JM. Postural instability and fall risk in Parkinson's disease: impaired dual tasking, pacing, and bilateral coordination of gait during the "ON" medication state. Exp Brain Res. 2011;210(3-4):529-538.
69. Todorova A, Jenner P, Chaudhuri KR. Non-motor Parkinson's: integral to motor Parkinson's, yet often neglected. Pract Neurol. 2014;14(5):310-322.
70. Ngo-Metzger Q, Massagli MP, Clarridge BR, et al. Linguistic and cultural barriers to care. J Gen Intern Med. 2003;18(1):44-52.
71. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55(3):181-184.
72. Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129-2170.
73. Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):968-975.
74. Ferreira JJ, Katzenschlager R, Bloem BR, et al. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease. Eur J Neurol. 2013;20(1):5-15.
75. Domingo-Echaburu S, Lertxundi U, Gonzalo-Olazabal E, et al. Inappropriate antidopaminergic drug use in Parkinson's disease inpatients. Curr Drug Ther. 2012;7(3):164-169.
76. Miyasaki JM, Shannon K, Voon V, et al. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson's disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):996-1002.
77. Bergquist F, Horne M. Can objective measurements improve treatment outcomes in Parkinson's disease? Eur Neurol Rev. 2014;9(1):27-30.
78. Shulman LM, Gruber-Baldini AL, Anderson KE, Fishman PS, Reich SG, Weiner WJ. The clinically important difference on the united Parkinson's disease rating scale. Arch Neurol. 2010;67(1):64-70.
79. Zupancic M, Mahajan A, Handa K. Dementia with Lewy bodies: diagnosis and management for primary care providers. Prim Care Companion CNS Disord. 2011;13(5).
80. Kalra S, Grosset DG, Benamer HT. Differentiating vascular parkinsonism from idiopathic Parkinson's disease: a systematic review. Mov Disord. 2010;25(2):149-156.
81. Jenner P. Treatment of the later stages of Parkinson's disease: pharmacological approaches now and in the future. Transl Neurodegener. 2015;4:3.
82. Olanow C, Kieburtz K, Rascol O, et al. Factors predictive of the development of levodopa-induced dyskinesia and wearing-off in Parkinson's disease. Mov Disord. 2013;28(8):1064-1071.
83. Kuhl MM. Get with the Times: Parkinson's Diagnosis Criteria Catches Up with Latest Understanding. Available at https://www.michaeljfox.org/foundation/news-detail.php?get-with-the-times-parkinson-diagnosis-criteria-catches-up-with-latest-understanding. Last accessed April 13, 2016.
84. Malek N, Grosset DG. Medication adherence in patients with Parkinson's disease. CNS Drugs. 2015;29(1):47-53.
85. Grosset KA, Grosset DG. Effect of educational intervention on medication timing in Parkinson's disease: a randomized controlled trial. BMC Neurol. 2007;7:20.
86. Fleisher JE, Stern MB. Medication nonadherence in Parkinson's disease. Curr Neurol Neurosci Rep. 2013;13(10):382.
87. Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency on adherence in chronic diseases. Am J Manag Care. 2009;15(6):e22-e33.
88. DeMaagd G, Philip A. Parkinson's disease and its management. Part 2: introduction to the pharmacotherapy of Parkinson's disease, with a focus on the use of dopaminergic agents. PT. 2015;40(9):590-600.
89. Grimes D, Gordon J, Snelgrove B, et al. Canadian guidelines on Parkinson's disease. Can J Neurol Sci. 2012;39(Suppl 4): S1-S30.
90. Fox SH, Katzenschlager R, Lim S-Y, et al. Update on Treatments for Motor Symptom of PD. Available at http://www.movementdisorders.org/MDS-Files1/PDFs/EBM-Papers/UPDATEFORWEBSITEMOTORTREATMENTFORPD_TEXT_9FEB2015_FINALTEXT.pdf. Last accessed April 13, 2016.
91. Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol. 2004;61(7):1044-1053.
92. Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med. 2009;361(13):1268-1278.
93. DeMaagd G, Philip A. Parkinson's disease and its management. Part 3: nondopaminergic and nonpharmacological treatment options. PT. 2015;40(10):668-679.
94. Ferreira JJ, Lees A, Rocha JF, et al. Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol. 2015; [Epub ahead of print].
95. Giugni JC, Okun MS. Treatment of advanced Parkinson's disease. Curr Opin Neurol. 2014;27(4):450-460.
96. Poewe W, Wolters E, Emre M, et al. Long-term benefits of rivastigmine in dementia associated with Parkinson's disease: an active treatment extension study. Mov Disord. 2006;21(4):456–61.
97. Emre M, Poewe W, De Deyn PP, et al. Long-term safety of rivastigmine in Parkinson disease dementia: an open-label, randomized study. Clin Neuropharmacol. 2014;37(1):9-16.
98. Shook BC, Jackson PF. Adenosine A2A receptor antagonists and Parkinson's disease. ACS Chem Neurosci. 2011;2(10):555-567.
99. Mizuno Y, Kondo T. Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson's disease. Mov Disord. 2013;28(8):1138-1141.
100. Drugs.com. Newron Receives Complete Response Letter from US FDA for Xadago (Safinamide). Available at http://www.drugs.com/nda/xadago_160329.html. Last accessed April 13, 2016.
101. Zuardi A W, Crippa J, Hallak J, et al. Cannabidiol for the treatment of psychosis in Parkinson's disease. J Psychopharmacol. 2009;23(8):979-983.
102. Chagas MH, Eckeli AL, Zuardi AW, et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. J Clin Pharm Ther. 2014;39(5):564-566.
103. Pasternak B, Svanström H, Nielsen NM, Fugger L, Melbye M, Hviid A. Use of calcium channel blockers and Parkinson's disease. Am J Epidemiol. 2012;175(7):627-635.
104. Moreau C, Delval A, Defebvre L, et al. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol. 2012;11(7):589-596.
105. Simuni T, Brundin P. Is exenatide the next big thing in Parkinson's disease? J Parkinsons Dis. 2014;4(3):345-347.
106. Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest. 2013;123(6):2730-2736.
107. Murata M, Hasegawa K, Kanazawa I. Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study. Neurology. 2007;68(1):45-50.
108. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670-1683.
109. Korczyn AD, Hassin-Baer S. Can the disease course in Parkinson's disease be slowed? BMC Medicine. 2015;13:295.
110. Stocchi F, Jenner P, Obeso JA. When do levodopa motor fluctuations first appear in Parkinson's disease? Eur Neurol. 2010;63(5):257-266.
111. Müller T. Motor complications, levodopa metabolism and progression of Parkinson's disease. Expert Opin Drug Metab Toxicol. 2011;7(7):847-855.
112. Gershanik OS. Clinical problems in late-stage Parkinson's disease. J Neurol. 2010;257(suppl 2):S288-S291.
113. Teichholtz H. FDA Approves Duopa, Carbidopa/Levodopa Enteral Suspension Method New to U.S. Market. Available at https://www.michaeljfox.org/foundation/news-detail.php?fda-approves-duopa-levodopa-carbidopa-intestinal-gel-delivery-method-new-to-market. Last accessed April 13, 2016.
114. Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13(2):141-149.
115. Moro E, Lozano AM, Pollak P, et al. Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease. Mov Disord. 2010;25(5):578-586.
116. Le Goff F, Derrey S, Lefaucheur R, et al. Decline in verbal fluency after subthalamic nucleus brain stimulation in Parkinson's disease: a microlesion effect of the electrode trajectory. J Parkinsons Dis. 2015;5(1):95-104.
117. Fasano A, Lozano AM. Deep brain stimulation for movement disorders: 2015 and beyond. Curr Opin Neurol. 2015;28(4):423-436.
118. Fénelon G, Soulas T, Zenasni F, de Langavant LC. The changing face of Parkinson's disease-associated psychosis: a cross-sectional study based on the new NINDS-NIMH criteria. Mov Disord. 2010;25(6):763-766.
119. Bhatti D, Torres-Russotto DR. Pharmacological management of psychosis in Parkinson disease: a review. Curr Drug Ther. 2012;7(3):151-163.
120. Forsaa EB, Larsen JP, Wentzel-Larsen T, Alves G. What predicts mortality in Parkinson disease? A prospective population-based long-term study. Neurology. 2010;75(14):1270-1276.
121. de Maindreville AD, Fénelon G, Mahieux F. Hallucinations in Parkinson's disease: a follow-up study. Mov Disord. 2005;20(2):212-217.
122. Fox SH, Visanji NP, Johnston TH, Gomez-Ramirez J, Voon V, Brotchie JM. Dopamine receptor agonists and levodopa and inducing psychosis-like behavior in the MPTP primate model of Parkinson disease. Arch Neurol. 2006;63(9):1343-1344.
123. Zesiewicz TA, Sullivan KI, Arnulf I, et al. Practice parameter: treatment of nonmotor symptoms of Parkinson disease. Neurology. 2010;74(11):924-931.
124. Frieling H, Hillemacher T, Ziegenbein M, Neundorfer B, Bleich S. Treating dopamimetic psychosis in Parkinson's disease: structured review and meta-analysis. Eur Neuropsychopharmacol. 2007;17(3):165-171.
125. The Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med. 1999;340(10):757-763.
126. The French Clozapine Parkinson Study Group. Clozapine in drug-induced psychosis in Parkinson's disease. Lancet. 1999;353(9169):2041-2042.
127. Ondo WG, Tintner R, Voung KD, Lai D, Ringholz G. Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson's disease. Mov Disord. 2005;20(8):958-963.
128. Rabey JM, Prokhorov T, Miniovitz A, Dobronevsky E, Klein C. Effect of quetiapine in psychotic Parkinson's disease patients: a double-blind labeled study of 3 months' duration. Mov Disord. 2007;22(3):313-318.
129. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540.
130. DeMaagd G, Philip A. Parkinson's disease and its management. Part 5: treatment of nonmotor complications. PT. 2015;40(12):838-846.
131. Troeung L, Egan SJ, Gasson N. A meta-analysis of randomised placebo-controlled treatment trials for depression and anxiety in Parkinson's disease. PLoS One. 2013;8(11):e79510.
132. Huot P, Fox SH, Brotchie JM. Monoamine reuptake inhibitors in Parkinson's disease. Parkinsons Dis. 2015;2015:609428.
133. Chung SJ, Lee JJ, Ham JH, Lee PH, Sohn YH. Apathy and striatal dopamine defects in non-demented patients with Parkinson's disease. Parkinsonism Relat Disord. 2016;23:62-65.
134. Devos D, Moreau C, Maltete D, et al. Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial. J Neurol Neurosurg Psychiatry. 2014;85(6):668-674.
135. Antonini A, Cilia R. Behavioural adverse effects of dopaminergic treatments in Parkinson's disease: incidence, neurobiological basis, management and prevention. Drug Saf. 2009;32(6):475-88.
136. Santiago P-L, Rey MV, Fabre N, et al. Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with Parkinson disease. Clin Neuropharmacol. 2012;35(6):261-265.
137. Nomura T, Inoue Y, Miyake M, Yasui K, Nakashima K. Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease. Mov Disord. 2006;21(3):380-384.
138. Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord. 2008;23(16):2267-2302.
139. Antonini A, Tinazzi M. Targeting pain in Parkinson's disease. Lancet Neurol. 2015;14(12):1144-1145.
140. Tinazzi M, Del Vesco C, Defazio G, et al. Abnormal processing of the nociceptive input in Parkinson's disease: a study with CO2 laser evoked potentials. Pain. 2008;136(1-2):117-124.
141. Madeo G, Schirinzi T, Natoli S, et al. Efficacy and safety profile of prolonged release oxycodone in combination with naloxone (OXN PR) in Parkinson's disease patients with chronic pain. J Neurol. 2015;262(9):2164-2170.
142. van Rooden SM, Verbaan D, Stijnen T, van Hilten JJ. The influence of age and approaching death on the course of nondopaminergic symptoms in Parkinson's disease. Parkinsonism Relat Disord. 2016;24:113-118.
143. National Collaborating Centre for Chronic Conditions. Parkinson's Disease: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care. London: National Institute for Health and Clinical Excellence; 2006.
144. U.S. Census Bureau. Selected Social Characteristics in the United States: 2010–2014 American Community Survey 5-Year Estimates. Available at http://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?pid=ACS_14_5YR_DP02&src=pt. Last accessed April 13, 2016.
145. Karliner LS, Napoles-Springer AM, Schillinger D, Bibbins-Domingo K, Pérez-Stable EJ. Identification of limited English proficient patients in clinical care. J Gen Intern Med. 2008;23(10):1555-1560.
146. Flores G. The impact of medical interpreter services on the quality of health care: a systematic review. Med Care Res Rev. 2005;62(3):255-299.
147. Karliner LS, Jacobs EA, Chen AH, Mutha S. Do professional interpreters improve clinical care for patients with limited English proficiency? A systematic review of the literature. Health Serv Res. 2007;42(2):727-754.
148. Flores G. Language barriers to health care in the United States. N Engl J Med. 2006;355(3):229-231.
1. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES recommendations for the diagnosis of Parkinson's disease. Eur J Neurol. 2013;20(1):16-34. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=43845. Last accessed April 29, 2016.
2. Wippold FJ II, Brown DC, Broderick DF, et al. ACR Appropriateness Criteria: Dementia and Movement Disorders. Reston, VA: American College of Radiology; 2014. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=48285. Last accessed April 29, 2016.
3. Oertel WH, Berardelli A, Bloem BR, et al. Early (uncomplicated) Parkinson's disease. In: Gilhus NE, Barnes MP, Brainin M (eds). European Handbook of Neurological Management. 2nd ed. Oxford: Wiley-Blackwell; 2011: 217-236.Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=34899. Last accessed April 29, 2016.
4. Oertel WH, Berardelli A, Bloem BR, et al. Late (complicated) Parkinson's disease. In: Gilhus NE, Barnes MP, Brainin M (eds). European Handbook of Neurological Management. 2nd ed. Oxford: Wiley-Blackwell; 2011: 237-267. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=34900. Last accessed April 29, 2016.
5. Preissner K. Occupational Therapy Practice Guidelines for Adults with Neurodegenerative Diseases. Bethesda, MD: American Occupational Therapy Association, Inc.; 2014. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=48512. Last accessed April 29, 2016.
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