Jack J. Chen and David M. Swope
KEY CONCEPTS
Thoughtful consideration of selection of initial therapy, management of drug dosing, and use of adjunctive therapies throughout the course of idiopathic Parkinson’s disease (PD) is necessary to optimize long-term therapeutic outcomes and minimize adverse effects.
The optimal time to start drug therapy in PD varies, but in general, treatment should be initiated when the disease begins to interfere with activities of daily living, employment, or quality of life.
Surgery is reserved for patients who require additional symptomatic relief or control of motor complications despite receiving medically optimized therapy.
Anticholinergic medication is useful for mild tremor-predominant PD but should be used with caution in the elderly and in those with preexisting cognitive difficulties.
As monotherapy, amantadine and monoamine oxidase type B (MAO-B) inhibitors provide benefits in early PD, but the symptomatic effect is less than that of dopamine agonists and carbidopa/levodopa (L-dopa).
Carbidopa/L-dopa is the most effective medication for symptomatic treatment, and eventually all patients with PD will require it.
Most carbidopa/L-dopa–treated patients will develop motor complications (e.g., fluctuations and dyskinesias).
MAO-B inhibitors and catechol-O-methyl-transferase inhibitors attenuate motor fluctuations in carbidopa/L-dopa–treated patients.
Dopamine agonists are effective and, compared to L-dopa, associated with less risk of developing motor complications but more risk to cause psychiatric symptoms, such as hallucinations and impulse control disorders.
The presence of tremor at rest, rigidity, bradykinesia, and postural instability (instability of balance) are considered the hallmark motor features of idiopathic Parkinson’s disease (PD). These clinical features of PD were adeptly described in 1817 by James Parkinson.1
EPIDEMIOLOGY
Up to 1 million individuals in the United States have PD. The approximate annual incidence of PD (i.e., number of persons diagnosed with PD per year) is age-dependent and ranges from 10 per 100,000 persons in the sixth decade of life (i.e., 50 to 59 years of age) to 120 per 100,000 persons in the ninth decade of life (i.e., 80 to 89 years of age).2 Likewise, the prevalence of PD also increases with age, affecting 1% of people older than age 65 years and 2.5% of those older than age 80 years. The usual age at time of diagnosis ranges between 55 and 65 years. A higher incidence is reported among males, with a male-to-female ratio of up to 2:1.
ETIOLOGY
The true etiology of PD is unknown, but is likely the result of interactions between aging, genetic constitution, and environmental factors. In PD, a key histopathologic feature is degeneration of dopaminergic neurons in the substantia nigra that project to the striatum (i.e., the nigrostriatal pathway).3 Additionally, neuronal vulnerability in PD extends beyond the nigrostriatal pathway and includes specific neurons in autonomic ganglia, basal ganglia, spinal cord, and neocortex.4 In humans and primates, administration of the compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in a form of parkinsonism. The MPTP compound is converted by monoamine oxidase (MAO)-B to 1-methyl-4-phenylpyridinium ion (MPP+), a potent neurotoxin. MPP+ is toxic to neurons by inhibiting mitochondrial complex 1 of the electron transport chain, which results in the generation of excessive reactive oxygen species and cell death.5 Several synthetic pesticides have a molecular structure similar to that of MPTP. Although PD is sporadic, extensive epidemiologic research associates environmental factors, such as chronic exposure to pesticides, with an elevated risk for lifetime development of PD.6–8 Interestingly, epidemiologic studies have consistently associated an inverse correlation between cigarette smoking and caffeine consumption for development of PD.9,10
Intrinsically, the substantia nigra pars compacta (SNc) is a region characterized by high levels of oxidative stress because free radicals are generated from dopamine degradation (mediated by MAO; Figure 43-1). Several antioxidative molecules (e.g., glutathione) are present in the SNc to limit damage produced by free-radical reactions, but in PD, such protection might be overwhelmed or impaired. Thus, cellular damage from oxidant stress has long been discussed as an etiopathologic component of PD.11 The SNc is also rich in iron and copper, essential cofactors in the biosynthesis and metabolism of dopamine. The oxidation–reduction cycle of iron can also generate free radicals and toxic metabolites (Fig. 43-1). In addition, apoptosis (programmed cell death), excitotoxicity, inflammation, mitochondrial dysfunction, nitric oxide toxicity, proteosomal dysfunction, and autophagic cellular mechanisms are also implicated etiopathologic mechanisms in PD.
FIGURE 43-1 Dopamine metabolism results in hydrogen peroxide (H2O2) formation. If the glutathione system is deficient or excess hydrogen peroxide is present, hydrogen peroxide accepts an electron from ferrous iron (Fe2+), forming ferric iron (Fe3+), and the hydroxyl free radical (OH*). The hydroxyl free radical can cause lipid peroxidation, thereby damaging neuronal cell membranes. (DOPAC, 3,4-dihydroxyphenylacetic acid; GSH, glutathione; GSSG, glutathione disulfide; H2O, water; OH–, the hydroxide ion; MAO-B, monoamine oxidase B.)
Genetic susceptibility also plays a role. Although rare, several forms of familial parkinsonism have been linked to specific genetic mutations.12,13 For example, autosomal dominant forms of parkinsonism are associated with mutations of the α-synuclein: PARK1/PARK4 and leucine-rich repeat kinase 2 (LRRK:PARK8) gene loci. Autosomal recessive forms are associated with mutations of parkin:PARK2 and PTEN-induced putative kinase 1 (PINK1:PARK6) gene loci. Although less well defined, ongoing studies indicate that genetic polymorphisms also modify an individual’s risk for idiopathic PD.
PATHOPHYSIOLOGY
In the SNc, the two hallmark histopathologic features of PD are depigmentation of dopamine-producing neurons (i.e., loss of SNc neurons) and presence of Lewy bodies (neuronal cytoplasmic filamentous aggregates composed of the presynaptic protein α-synuclein) in the remaining SNc neurons. Lewy bodies appear in degenerating neurons in association with adjacent gliosis and the distribution of pathology is proposed to occur in stages.4 In the premotor stage of PD, Lewy bodies are initially found in the medulla oblongata, locus coeruleus, raphe nuclei, and olfactory bulb. This may correlate with observations that anxiety, depression, and impaired olfaction are detectable in premotor stages of PD. As PD progresses, Lewy pathology ascends to the midbrain (particularly the SNc) and accounts for development of motor features. In advanced stages, Lewy pathology spreads to the cortex, and this may correlate with cognitive and additional behavior changes. The observation that Lewy pathology can spread into adjacent healthy neurons has given rise to the postulate that prion-like propagation of α-synuclein aggregates may be occurring.
Pathologic findings reveal a correlation between the extent of nigrostriatal dopamine loss and the severity of certain PD motor features (e.g., bradykinesia). The threshold for onset of clinically detectable PD appears to be the loss of 70% to 80% of SNc neurons.14 Functional neuroimaging studies suggest compensatory responses, such as upregulation of dopamine synthesis and downregulation of synaptic dopamine reuptake, occur as adaptive mechanisms beginning in the premotor stage of PD. These adaptive responses may help to explain why the motor features are not clinically detectable until profound depletion (70% to 80%) of SNc neurons has occurred.
Dopaminergic projections from the SNc to the striatum (putamen and caudate) synapse on two major populations of dopamine receptor-mediated efferent neurons (referred to as the direct and indirect pathways), which, in turn, mediate motor activity via a complex neuronal circuit involving the extrapyramidal system (Fig. 43-2). In PD, the degeneration of the SNc neurons results in reduced activity within these two efferent pathways. The direct pathway involves activation of striatal dopamine1 (D1) dopamine receptors (which are coupled to adenylate cyclase) and stimulates the inhibitory γ-aminobutyric acid (GABA)/substance P efferents to the globus pallidus interna (GPi) and substantia nigra pars reticulata. The GPi and substantia nigra pars reticulata efferents are inhibitory to the thalamus.15 In PD, the reduced activation of D1 receptors results in greater inhibition of the thalamus. The indirect pathway involves activation of striatal dopamine2 (D2) dopamine receptors (which are coupled to a guanosine triphosphate-binding protein that opens potassium channels to hyperpolarize neurons, thereby reducing the excitability of the neuron).15 Activation of striatal D2 receptors inhibits GABA/enkephalin efferents (medium spiny neurons) to the globus pallidus externa. The globus pallidus externa projects GABA neurons to the subthalamic nucleus. Here, excitatory glutamatergic neurons project to the GPi. GPi output is inhibitory on the glutamatergic thalamic projections. In PD, the reduced activation of D2 receptors translates into greater inhibition of the thalamus. In PD, restoring activity at the D2 receptor appears to be of more importance than the D1 receptor for mediating clinical improvements. Overall, loss of the presynaptic nigrostriatal dopamine neurons in PD results in inhibition of thalamic activity and reduced activation of the motor cortex. Dopaminergic therapies help to restore motor activity.
FIGURE 43-2 A. The normal balance of the basal ganglia–thalamocortical circuit. B. With nigrostriatal degeneration (dashed line), there is loss of inhibition of the GPi by the direct pathway and activation of the GPi via the indirect pathway, resulting in decreased activation of the cortex. See the text for details. (GPe, globus pallidus externa; GPi, globus pallidus interna; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VA, ventroanterior nuclei of the thalamus; VL, ventrolateral nuclei of the thalamus.)
CLINICAL PRESENTATION Idiopathic Parkinson’s Disease
General Features
• The patient exhibits bradykinesia and at least one of the following: resting tremor, rigidity, or postural instability. Asymmetry of motor features is supportive
Motor Symptoms
• The patient experiences decreased manual dexterity, difficulty arising from a seated position, diminished arm swing during ambulation, dysarthria (slurred speech), dysphagia (difficulty with swallowing), festinating gait (tendency to pass from a walking to a running pace), flexed posture (axial, upper/lower extremities), “freezing” at initiation of movement, hypomimia (reduced facial animation), hypophonia (reduced voice volume), and micrographia (diminution of handwritten letters/symbols; Fig. 43-3)
Autonomic and Sensory Symptoms
• The patient experiences bladder and anal sphincter disturbances, constipation, diaphoresis, fatigue, olfactory disturbance, orthostatic blood pressure changes, pain, paresthesia, paroxysmal vascular flushing, seborrhea, sexual dysfunction, and sialorrhea (drooling)
Mental Status Changes
• The patient experiences anxiety, apathy, bradyphrenia (slowness of thought processes), confusional state, dementia, depression, hallucinosis/psychosis (typically drug induced), and sleep disorders (excessive daytime sleepiness, insomnia, obstructive sleep apnea, and rapid eye movement sleep behavior disorder)
Sleep Disturbances
• The patient experiences excessive daytime sleepiness, insomnia, obstructive sleep apnea, and rapid eye movement sleep behavior disorder
Laboratory Tests
• No laboratory tests are available to diagnose PD
Other Diagnostic Tests
• Genetic testing is not routinely helpful
• Neuroimaging may be useful for excluding other diagnoses
• Medication history should be obtained to rule out drug-induced parkinsonism
FIGURE 43-3 Example of micrographia in a patient with PD. As the sentence, “Today is a sunny day in California” is repeatedly handwritten, progressive diminution of letter size occurs (micrographia). The height of each lined row is approximately 5/16 inches (8 mm).(Courtesy of Jack J. Chen, PharmD, and David M. Swope, MD.)
In addition to dopamine, the synaptic organization of the basal ganglia also involves a variety of other neurotransmitters and neuromodulators, including acetylcholine, adenosine, enkephalins, GABA, glutamate, serotonin, and substance P. The potential role for drug modulation of these other neurotransmitters and receptor types is an active area of research and novel drug discovery for PD.16
Atypical parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy are characterized by damage to postsynaptic striatal neurons and dopamine receptors. Therefore, dopaminergic therapies provide less robust efficacy in atypical parkinsonism.
CLINICAL PRESENTATION
Although PD is unmistakable in its advanced form, recognizing PD during the early stages can be challenging. The clinical diagnosis of PD is based on the presence of bradykinesia and at least one of three other features: muscular rigidity, resting tremor, and postural instability (Table 43-1).17 Asymmetry of motor features is a supportive finding. It is important to note that tremor is not always present at the time of diagnosis, and postural instability typically occurs in later stages of PD. Overall, a diagnosis of PD can be made with a high level of confidence in a patient who has bradykinesia (along with rest tremor and/or rigidity), prominent asymmetry, and a good response to dopaminergic therapy. For the diagnosis of PD, other conditions must be reasonably excluded (Table 43-1). Medication-induced parkinsonism can mimic PD, so it is important to establish if such medications have been used (especially drugs that block D2 receptors, such as antipsychotics, metoclopramide, or phenothiazine antiemetics).18 Neurologic conditions that can be mistaken for PD include atypical parkinsonisms (e.g., corticobasal ganglionic degeneration, forms of multiple system atrophy, progressive supranuclear palsy) and essential tremor. Because the management and prognosis of PD differs from these other conditions, an accurate diagnosis is important. When the diagnosis is in doubt, referral to a movement disorders specialist is recommended.
TABLE 43-1 Diagnostic Criteria for Parkinson’s Disease and Differential Diagnosis
PD develops insidiously and progressively worsens. Over many years, symptoms can worsen to the point of severe disability, necessitating placement in a skilled nursing facility (especially with the development of dementia or frequent falling). However, the majority of patients remain community dwelling.
Tremor of an upper extremity occurring at rest (and occasionally an action or postural tremor) is often the sole presenting complaint; however, only two thirds of patients with PD have tremor on diagnosis, and some never develop this sign. Tremor in PD is present most commonly in the hands, sometimes with a characteristic pill-rolling motion. Less commonly, tremor may involve the jaw or legs. Like other motor features of PD, resting tremor often begins unilaterally and becomes bilateral with disease progression. Stressful or emotional (either negative or positive) situations often increase the tremor amplitude and severity. Usually, volitional movement abolishes resting tremor, and tremor is absent during sleep. Although resting tremor is visibly noticeable in PD and may cause social embarrassment for the patient, it often is the least physically disabling of the motor features.
Rigidity is the increased muscular resistance to passive range of motion and commonly affects the upper and lower extremities. If tremor is present in the affected extremity, the rigidity is associated with a cogwheel or ratchet-like quality upon examination. Facial muscles also are affected, resulting in hypomimia (masking of facial expressions) that may be erroneously interpreted as apathy, depression, or unfriendliness.
Bradykinesia refers to slowness of movement. Movement in PD is often slow throughout an intended action, and difficulty with the initiation of movement also occurs. A progressive slowing and decline in dexterity may impair tasks such as hand clapping, finger tapping, and handwriting (Fig. 43-3). Intermittent immobility (freezing) is another common characteristic. Freezing is especially likely to occur in situations such as when walking through a narrow doorway or initiating a turn. Patients also may experience a slow shuffling gait with difficulty halting their steps while in motion (festinating gait).
Postural instability, most common in advanced stages of PD, is one of the most disabling problems of PD because it increases the fall risk and is least amenable to pharmacotherapy. Testing for impaired postural responses by means of the pull test (in which a patient is unable to recover balance after sudden backward displacement at the shoulders) can help to identify the risk for falling. Many patients with impaired postural responses also have tendencies for propulsive gait (festination) and freezing, which also increases the risk of falling.
Although PD is known predominantly as a movement disorder, neuropsychiatric abnormalities also develop. Cognitive deterioration is not inevitable in PD; however, some patients deteriorate in a manner indistinguishable from Alzheimer’s disease and other dementing conditions.19 PD patients are also at increased risk for anxiety and depression.20 Although the disabilities of PD may provoke depression in some instances, the underlying biochemical changes in the brain associated with PD pathophysiology also predisposes for endogenous depression.
TREATMENT
Desired Outcomes
The goal in the management of PD is to improve motor and nonmotor symptoms so that patients are able to maintain the best possible quality of life.21 Specific objectives to consider when selecting an intervention include preservation of the ability to perform activities of daily living; improvement of mobility; minimization of adverse effects, treatment complications, putative disease modification; and improvement of nonmotor features such as cognitive impairment, depression, fatigue, and sleep disorders. To accomplish some of these objectives, consultation with a specialist is helpful (e.g., movement disorders, physical therapy, psychiatry, and sleep medicine).
General Approach to Treatment
Once a correct diagnosis of PD is made, nonpharmacologic and pharmacologic interventions must be considered. Thoughtful consideration of selection of initial therapy, management of drug dosing, and use of adjunctive therapies throughout the course of PD is necessary to optimize long-term therapeutic outcomes and minimize adverse effects. The optimal time to start drug therapy in PD varies, but in general, treatment should be initiated when the disease begins to interfere with activities of daily living, employment, or quality of life. Figure 43-4 illustrates a general treatment approach for early and advanced PD, Table 43-2 summarizes antiparkinsonian medications and mechanisms of action, and Table 43-3 summarizes monitoring parameters for potential adverse effects. Treatment guidelines and monographs are updated frequently to keep up with new information and changes in treatment paradigms.22—26
FIGURE 43-4 General approach to the management of early to advanced Parkinson’s disease.
TABLE 43-2 Dosing of Drugs Used in Parkinson’s Diseasea
TABLE 43-3 Monitoring of Potential Adverse Reactions to Drug Therapy for Parkinson’s Disease
Clinical Controversy…
The question of when to initiate L-dopa therapy is a matter of debate. Generally, initial therapy with a non–L-dopa agent is often recommended for patients younger than 65 years of age. Proponents for initiating non-L-dopa agents first and then adding L-dopa at a later point, cite evidence suggesting that long-term L-dopa therapy is associated with an increased risk of motor complications that can be disabling and challenging to manage. Additionally, drugs such as rasagiline and dopamine agonists provide sufficient symptom control for mild to moderate PD. The counterargument is that L-dopa is inexpensive, more effective, and the development of motor complications is an acceptable trade-off. Age alone should not be the major deciding factor, and ultimately, individualized considerations of a patient’s disability should guide all interventions for PD.
Nonpharmacologic Therapy
Surgical Therapy
Currently, surgery should be considered as an adjunct to pharmacotherapy when patients are experiencing frequent motor fluctuations or disabling dyskinesia or tremor despite an optimized medical regimen. There are several patient-selection criteria for surgery, including a diagnosis of levodopa (L-dopa)–responsive PD. Anatomic targets include the thalamus, GPi, and the subthalamic nucleus. Bilateral, chronic, high-frequency electrical stimulation of a target site, also known as deep-brain stimulation (DBS), is the preferred surgical modality.27
In DBS surgery, a battery-powered neurostimulator (pacemaker-like device) is implanted subcutaneously below the clavicle and provides constant electrical stimulation, via electrode wires, to the targeted brain structure. Thalamic DBS is very effective for suppressing tremor (specifically arm tremor), but it does not significantly improve the other parkinsonian features (bradykinesia, rigidity, motor fluctuations, or dyskinesias). Although debatable, subthalamic nucleus DBS is favored over GPi DBS because it is considered more effective. Subthalamic nucleus DBS is associated with improvements in tremor, rigidity, bradykinesia, motor fluctuations, and dyskinesia, as well as lowering of antiparkinsonian medications. However, problems with gait and postural instability may not improve significantly with DBS (or pharmacotherapy).
DBS procedures require routine adjustment of the electrical stimulation parameters (e.g., voltage, frequency, and pulse width) to achieve optimal control while minimizing side effects. The electrical stimulation parameters (or “electrical dosage”) are adjusted via a programmable handheld device to meet each patient’s needs and are performed by physicians as well as other trained individuals, including nurse practitioners and clinical pharmacists.
In recent years, cell-based restorative procedures have appeared promising (implantation of dopamine-producing cells such as human fetal mesencephalon tissue or retinal pigmented epithelial cells into the striatum) but have yielded disappointing clinical results.28 Gene-based therapies are currently under investigation and remain highly experimental.29
Pharmacologic Therapy
Anticholinergic Medications
Because dopamine provides negative feedback to acetylcholine neurons in the striatum, the degeneration of nigrostriatal dopamine neurons also results in a relative increase of striatal cholinergic interneuron activity. This increased cholinergic activity (caused by dopamine depletion) is believed to contribute to the tremor of PD. The anticholinergic drugs (e.g., benztropine and trihexyphenidyl) are considered effective against tremor, but no more so than dopaminergic agents.22 Sometimes dystonic symptoms associated with PD are also improved by anticholinergic agents. Use of anticholinergic agents is limited due to the development of intolerable side effects, necessitating dosage reduction or drug discontinuation. Common adverse effects include blurred vision, confusion, constipation, dry mouth, memory difficulty, sedation, and urinary retention (Table 43-3). Younger patients are better able to tolerate anticholinergic side effects, whereas patients with preexisting cognitive deficits and advanced age are less tolerant. Anticholinergic drugs can be used alone or in conjunction with L-dopa and other antiparkinson agents.
Amantadine
Amantadine provides modest symptomatic benefit for tremor, as well as rigidity and bradykinesia. The precise mechanism of action of amantadine is unknown, but enhancement of dopamine release from presynaptic terminals and inhibition of glutamatergic N-methyl-D-aspartate (NMDA) receptors are implicated. Amantadine is typically administered 300 mg/day in divided doses. Amantadine is also useful for suppressing L-dopa–induced dyskinesia.25The antidyskinetic properties of amantadine are presumed to be mediated by antiglutamate activity which, in the setting of dyskinesias, appears to dominate over dopaminergic activity. Amantadine is eliminated renally, and a reduced dose should be administered when renal dysfunction is present (100 mg/day with creatinine clearances of 30 to 50 mL/min [0.50 to 0.84 mL/s], 100 mg every other day for creatinine clearances of 15 to 29 mL/min [0.25 to 0.49 mL/s], and 200 mg every 7 days for creatinine clearances of less than 15 mL/min [0.25 mL/s], and patients on hemodialysis).
Common side effects of amantadine include confusion, dizziness, dry mouth, and hallucinations. The elderly are particularly prone to develop confusion. Not uncommonly, amantadine may cause livedo reticularis, a reversible condition characterized by diffuse mottling of the skin affecting the upper or lower extremities and often accompanied by lower-extremity edema (Table 43-3).
Carbidopa/L-Dopa
L-Dopa is the immediate precursor of dopamine and, in combination with a peripherally acting L-amino acid decarboxylase inhibitor (carbidopa or benserazide), remains the most effective drug for the symptomatic treatment of PD.22 L-Dopa crosses the blood–brain barrier, whereas dopamine, carbidopa, and benserazide do not. The combination of L-dopa with carbidopa or benserazide reduces the unwanted peripheral conversion of L-dopa to dopamine. As a result, increased amounts of L-dopa are transported into the brain, and peripheral adverse effects of dopamine, such as nausea, are reduced. In the SNc, L-dopa is converted, via decarboxylation, to dopamine by the enzyme L-amino acid decarboxylase (Fig. 43-5). The converted dopamine is stored in the presynaptic SNc neurons until stimulated to be released into the synaptic cleft whereupon it binds to the D1 and D2 postsynaptic receptors. Dopamine activity is terminated primarily by reuptake back into the presynaptic neuron by means of a dopamine transporter. The enzymes MAO and catechol-O-methyltransferase (COMT) also inactivate dopamine.
FIGURE 43-5 Dopamine metabolism in presynaptic dopamine neuron. (3OMD, 3-O-methyldopa; AC, adenylate cyclase; AD, aldehyde dehydrogenase; COMT, catechol-O-methyl transferase; D1–D3, dopamine receptors; DA, dopamine; DAT, dopamine transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; L-AAD, L-aromatic amino acid decarboxylase; MAO-B, monoamine oxidase B; TH, tyrosine hydroxylase.)
Regardless of what the initial therapeutic agent is, ultimately all patients with PD will require L-dopa at some point. An initial maintenance L-dopa regimen of 300 mg/day (in divided doses and in combination with carbidopa or benserazide) often is adequate. With regard to carbidopa, about 75 mg/day is required to sufficiently inhibit the peripheral activity of L-amino acid decarboxylase, but some patients require more. Therefore, the usual initial maintenance carbidopa/L-dopa regimen is 25/100 mg three times daily. As the motor features of PD become progressively more severe, use of higher dosages is required. There is no maximum allowable total daily L-dopa dose; however, the usual maximal dose needed by patients, even those with severe PD, is 800 to 1,000 mg/day. Slow buildup of dose (e.g., increments of 100 mg L-dopa per week) can help to minimize treatment emergent side effects, such as drowsiness, nausea, postural hypotension, vivid dreaming, and vomiting (Table 43-3).
For patients with difficulty swallowing tablets, an orally disintegrating tablet preparation of carbidopa/L-dopa is available. Although this formulation rapidly dissolves on contact with saliva, the carbidopa/L-dopa does not undergo transmucosal absorption and must reach the proximal duodenum for absorption.
Pharmacokinetics There is marked intra- and intersubject variability in the time to peak plasma concentrations after oral L-dopa, and this may in part be attributed to differences in gastric emptying. L-Dopa is absorbed primarily in the proximal duodenum by a saturable large neutral amino acid transport system. Competition for this transporter by dietary or supplemental large neutral amino acids (e.g., leucine, phenylalanine) can interfere with L-dopa bioavailability.
L-Dopa is not bound to plasma proteins. Active transport across the blood–brain barrier occurs by the large neutral amino acid transporter system. Because large amounts of dietary large neutral amino acids may compete for transport across the blood–brain barrier and interfere with the clinical response to L-dopa, separation of L-dopa administration from high protein meals or amino acid dietary supplements have been recommended. However, in patients with early PD, this interaction is generally not significant. In advanced PD, special diets involving protein restriction or redistribution may improve L-dopa responsiveness and are sometimes implemented. A metabolite of L-dopa, 3-O-methyldopa, also competes for transport, but it is not clear how this affects L-dopa clinical response.
When peripheral decarboxylation of L-dopa is inhibited by carbidopa or benserazide, 3-O-methylation (via COMT) becomes the predominant catabolic pathway. The elimination half-life of L-dopa is about 1 hour, and this is extended to about 1.5 hours with the addition of carbidopa or benserazide. With the addition of a COMT inhibitor such as entacapone to carbidopa/L-dopa, the elimination half-life is extended to about 2 to 2.5 hours.
Motor Complications of L-Dopa Long-term L-dopa therapy is associated with a variety of motor complications, of which end-of-dose “wearing off” (motor fluctuations) and L-dopa peak-dose dyskinesias are the two most commonly encountered.30 These motor complications can be disabling and challenging to manage. The approximate risk of developing either motor fluctuations or dyskinesia is 10% per year of L-dopa therapy.31,32 However, motor complications can occur as early as 5 to 6 months after starting L-dopa therapy, especially if excessive doses are used initially.33 Table 43-4 lists the motor complications associated with long-term treatment with L-dopa and suggested initial management strategies. Initiating therapy with the controlled-release (CR) form of carbidopa/L-dopa does not reduce the development of motor complications compared with standard-release carbidopa/L-dopa.23
TABLE 43-4 Common Motor Complications and Possible Initial Treatments
End-of-Dose Wearing Off The terms “off” and “on” refer to periods of poor movement (i.e., return of tremor, rigidity, or slowness) and good movement, respectively. End-of-dose wearing off prior to a dose of medication is a common type of response fluctuation. This phenomenon is related to the increasing loss of neuronal storage capability for dopamine as well as the short half-life of L-dopa. Initially, exogenous L-dopa is taken up by the remaining SNc neurons, converted to dopamine, and stored in synaptic vesicles. With progressive loss of SNc neurons, storage capacity, and synthesis of endogenously derived dopamine, patients become more dependent on exogenous L-dopa. Hence the peripheral pharmacokinetic properties of L-dopa increasingly become the determinant of central dopamine synthesis. With advancing PD, the duration of action of a single carbidopa/L-dopa dose progressively shortens, and in some cases may produce benefits for as little as 1 hour. As a result, carbidopa/L-dopa needs to be given more frequently so as to minimize daytime off episodes and to maximize on time. In addition to administering L-dopa doses more frequently, other options are available (see Table 43-4). In particular, the addition of the COMT inhibitor entacapone or the MAO-B inhibitor rasagiline extends the action of L-dopa, and either should be considered.23 A CR L-dopa product is available, but is not considered very effective for management of motor fluctuations.23 Currently, a reformulated extended-release carbidopa/L-dopa capsule (i.e., IPX066) is investigational and expected to be available in the near future.
A dopamine agonist (e.g., pramipexole, ropinirole, and rotigotine) also can be added to a carbidopa/L-dopa regimen in an attempt to minimize the occurrence of wearing off. For acute off episodes, a subcutaneously administered short-acting dopamine agonist, apomorphine, is available and possesses a rapid onset of effect (within 20 minutes). It is administered as needed.34 Alternatively, chronic subcutaneous apomorphine infusion (not available in the United States) provides stable and continuous systemic and central drug concentrations and improves motor fluctuations and dyskinesias. Long-term therapy is limited by injection site skin reactions.35 In addition, a carbidopa/L-dopa intestinal (jejunal) gel (not yet available in the United States) has been demonstrated to be an effective and safe therapy for patients with persistent, on/off fluctuations.36 Although not commonly performed, sipping small amounts of carbidopa/L-dopa solution very frequently throughout the day is also a method for managing on/off fluctuations. A solution that is stable for 72 hours at room temperature can be prepared by adding 10 crushed tablets of carbidopa/L-dopa 10/100 (or 25/100) mg and 2 g crystalline ascorbic acid to 1 L of water.37
Often, off episodes occur during the night, and patients will awaken in an off state (as a consequence of an overnight decline of drug levels). Bedtime administration of a dopamine agonist or a drug formulation that provides sustained drug levels overnight (e.g., carbidopa/L-dopa CR, ropinirole XL, pramipexole ER, rotigotine transdermal patch) can help reduce nocturnal off episodes and improve functioning upon awakening.
Nonadherence to medications also contributes to the frequency of off episodes. Therefore, engaging and supporting patients and caregivers in overcoming barriers to medication adherence is important.
“Delayed-On” and “No-On” Response “Delayed-on” or “no-on” (a delayed or absent onset of drug effect, respectively) responses to individual doses of carbidopa/L-dopa can be a result of delayed gastric emptying or decreased absorption in the duodenum. Chewing a tablet or crushing it and then drinking a full glass of water, or using the orally disintegrating tablet formulation on an empty stomach, can help mitigate effects of delayed gastric emptying. Additionally, subcutaneously administered apomorphine may be used as rescue therapy from delayed-on or no-on periods. A drug-free period (“drug holiday”) has been investigated in an attempt to modify postsynaptic dopamine receptors and thus decrease unpredictable off states. Although not commonly performed because of discomfort (to the patient) and medical risks, when drug holidays are performed, it should be under close medical supervision.
Freezing “Freezing,” or a sudden, episodic inhibition of lower-extremity motor function, may occur and will interfere with ambulation and increase the risk of falls. Patients may report that their “feet suddenly feel stuck to the floor” during ambulation or that they have difficulty initiating steps (start hesitation) or turns (turn hesitation). Freezing often is exacerbated by anxiety or when perceived obstacles (e.g., doorways, turnstiles) are encountered. Although changes to the antiparkinson drug regimen may be attempted, improvements are unlikely. Physical therapy along with assistive walking devices and sensory cues are helpful.
Dyskinesias Another complication of L-dopa therapy is “on” period dyskinesias (involuntary choreiform movements involving usually the neck, trunk, and lower/upper extremities). If patients report “shakiness,” it is important to clarify if they are referring to tremor or dyskinesias. Dyskinesias usually are associated with peak striatal dopamine levels (peak-dose dyskinesia) and, simplistically, can be thought of as too much movement secondary to extension of the pharmacologic effect resulting in excessive striatal dopamine receptor stimulation. Less commonly, dyskinesias also can develop during the rise and fall of L-dopa effects (the dyskinesia–improvement–dyskinesia or diphasic pattern of response). In the case of peak-dose dyskinesias, use of lower individual doses of L-dopa is beneficial. With the lowering of the L-dopa dose, dyskinesias improve but at the cost of returning parkinsonian features, thereby necessitating an increase in dosage frequency or addition of another agent to counteract the effects of using a lower L-dopa dose. Glutamate overactivity may also be involved, as suggested by the antidyskinesia effect of amantadine (NMDA receptor antagonist) and positive results of investigational studies of antiglutamate ligands in animal models.38 For severe dyskinesias (despite pharmacologically optimized therapy), surgery should be considered.
“Off-Period” Dystonia In PD, dystonias (sustained muscle contractions) can occur and more commonly affect a distal lower extremity (e.g., clenching of toes or involuntary turning of a foot). Dystonias often occur in the early morning hours (as a result of waning drug levels) and improve with the first L-dopa dose of the day. Remedies for early morning dystonia include bedtime administration of a long acting dopamine agonist, sustained-release carbidopa/L-dopa, baclofen, or focal injections of botulinum toxin type A or B (for persistent focal dystonia).
Monoamine Oxidase B Inhibitors
Two selective MAO-B inhibitors, rasagiline and selegiline, are available in the United States for management of PD. The selective inhibition of MAO-B in the brain interferes with the degradation of dopamine and results in prolonged dopaminergic activity. Both drugs contain a propargylamine moiety, which is essential for conferring irreversible inhibition of MAO-B. At therapeutic doses, these agents preferentially and irreversibly inhibit MAO-B over MAO-A.
A common concern with use of these agents is the potential for interactions with drugs that possess serotonergic activity. Concomitant use of MAO-B inhibitors with meperidine and other selected opioid analgesics is contraindicated because of a small risk of serotonin syndrome. However, concomitant use of other agents that enhance serotonin levels (e.g., antidepressants) is not contraindicated, and these drugs can be used concomitantly when clinically warranted.39
Selegiline, also known as L-deprenyl, is marketed for extending L-dopa effects and is typically administered 5 mg twice daily. Selegiline is also available as an orally disintegrating tablet formulation administered 1.25 to 2.5 mg once daily. A transdermal formulation of selegiline is also available but is not indicated for PD. As monotherapy in early PD, conventional selegiline provides modest improvements in motor function.22 In more advanced PD, the adjunctive use of conventional selegiline can provide up to 1 hour of extended on time for patients with wearing off, although the data are inconsistent.23 This inconsistent effect of conventional selegiline may be explained, in part, by poor and erratic bioavailability of the parent drug.
As an amphetamine pharmacophore, selegiline undergoes first-pass hepatic metabolism (predominantly via cytochrome P450 [CYP450] 2B6 and 2C19) to end products of L-methamphetamine and L-amphetamine. Adverse effects of selegiline are minimal but can include insomnia (especially if administered at bedtime), hallucinations, and jitteriness (Table 43-3). Selegiline also increases the peak effects of L-dopa and can worsen preexisting dyskinesias or psychiatric symptoms such as delusions. With the selegiline orally disintegrating tablet formulation, first-pass hepatic metabolism is bypassed as a consequence of transmucosal absorption of the drug. Hence, bioavailability characteristics of the parent drug are improved and formation of amphetamine metabolites is reduced. Thus, the selegiline orally disintegrating tablet formulation may provide an improved response relative to conventional selegiline.
Rasagiline is a second-generation, irreversible, selective MAO-B inhibitor administered at 0.5 or 1 mg once daily.40 Rasagiline is effective as monotherapy in early PD and also as add-on therapy for managing motor fluctuations in advanced PD. In a large, placebo-controlled, 18-month, delayed-start clinical trial, patients initiated on rasagiline monotherapy early in PD had less functional decline than did patients whose treatment was delayed for 9 months.41 This suggests that earlier initiation with rasagiline (even before the onset of functional impairment) may be associated with better long-term outcomes. For the management of patients with motor fluctuations, the efficacy of rasagiline appears similar to that of entacapone, offering approximately 1 hour of extra on time during the day.42 Consequently, when an adjunctive agent is required for managing motor fluctuations, rasagiline is considered a first-line agent (as is entacapone).23 Overall, rasagiline is well tolerated with minimal GI or neuropsychiatric side effects. Rasagiline is metabolized by hepatic CYP1A2 to aminoindan, which is inactive and devoid of amphetamine-like properties.40
MAO-B inhibitors with a propargylamine molecular scaffolding have been investigated for neuroprotective properties (clinically referred to as disease modification). These agents inhibit the oxidative deamination of dopamine, which generates hydrogen peroxide and, ultimately, oxyradicals capable of damaging nigrostriatal neurons (see Fig. 43-1). Because MAO-B inhibition diverts dopamine catabolism to an alternate route that does not generate peroxide, MAO-B inhibitor therapy may spare neurons from oxidative stress. Additionally, MAO-B inhibitors have demonstrated antiapoptotic properties in laboratory experiments, further suggesting the possibility of disease modification. Clinical studies to demonstrate disease modification with selegiline have yielded inconclusive results, perhaps contributed in part by selegiline amphetamine metabolites as well as inadequate study methodology. Results with rasagiline 1 mg/day from a clinical study utilizing methodology (i.e., delayed start) intended to demonstrate disease modification were positive, but the issue of disease-modifying properties of rasagiline is surrounded by controversy.41
Clinical Controversy…
Great interest and debate surround the putative disease-modifying effects of the MAO-B inhibitors. A large clinical study demonstrated that earlier initiation of rasagiline is associated with better outcomes as compared to delaying therapy, and this was attributed to a disease-modifying effect (as opposed to a symptomatic effect). Whether this is a class effect of MAO-B inhibitors is not known. However, selegiline is metabolized to amphetamine derivatives, which have been demonstrated to neutralize neuroprotective effects in various preclinical studies. In a clinical study of the dopamine agonist pramipexole in patients with early PD, no benefit of earlier initiation over delayed initiation was observed.
COMT Inhibitors
Two COMT inhibitors, entacapone and tolcapone, have been developed to extend the effects of L-dopa and are indicated for managing wearing off.23 Both reduce the peripheral conversion of L-dopa to dopamine, thus enhancing central L-dopa bioavailability. Consequently, in the absence of L-dopa, they have no effect on PD symptoms. For patients with wearing off, these agents can decrease off-time significantly by increasing the L-dopa area under the curve by approximately 35%.43 COMT inhibition is considered more effective than CR carbidopa/L-dopa in providing consistent extension of L-dopa effect.23 A triple-combination product of carbidopa/L-dopa/entacapone offers convenience for some patients (i.e., fewer tablets to administer).
Tolcapone inhibits both peripheral and central COMT. Its use is limited by reports of fatal hepatotoxicity, such that strict monitoring of hepatic function, especially during the first 6 months of therapy, is required (Table 43-3).39Because of the hepatotoxicity risk, tolcapone is reserved for patients with fluctuations that are not responding to other therapies.
Entacapone has a shorter half-life than tolcapone, and 200 mg needs to be given with each dose of carbidopa/L-dopa up to a maximum of eight times per day. In clinical trials, both tolcapone and entacapone increased total daily on time by about 1 to 2 hours.44,45 Dopaminergic adverse effects may occur and generally are manageable by reduction of the carbidopa/L-dopa dosage. With both agents, brownish-orange urinary discoloration may occur. Also, delayed onset of diarrhea (weeks to months later) can occur in up to 5% of patients. Unlike tolcapone, entacapone is not associated with hepatotoxicity, and if an adjunctive agent is needed for managing motor fluctuations, entacapone is considered one of the first choices.23
Dopamine Agonists
Dopamine agonists fall into two pharmacologic subtypes: ergot-derived agonists (bromocriptine) and the nonergot agonists (pramipexole, ropinirole, and rotigotine). The nonergot dopamine agonists are safer than the ergot-derived agonists46 and are useful as monotherapy in mild-moderate PD, and also as adjuncts to L-dopa therapy in patients with motor fluctuations.22,23 The dopamine agonists reduce the frequency of off periods and may allow reductions in L-dopa dosage.
Investigations comparing initial monotherapy with either L-dopa or a dopamine agonist in patients with PD have revealed a significantly reduced risk of developing motor complications associated with dopamine agonists.47,48 Younger patients are more likely to develop motor complications; consequently, dopamine agonists are preferred over L-dopa. Older patients are more likely to experience intolerable side effects (e.g., confusion, hallucinations, and orthostatic hypotension) from the dopamine agonists; consequently, carbidopa/L-dopa is preferred, particularly if cognitive problems or dementia is present.
Common adverse effects of dopamine agonists include nausea, confusion, hallucinations, light-headedness, lower-extremity edema, postural hypotension, sedation, and vivid dreaming (Table 43-3). Less common but serious adverse effects include impulsive behaviors (e.g., pathologic gambling or shopping, hypersexuality), psychosis, and sleep attacks (sudden, unexpected episodes of sleep). Hallucinations and delusion can be managed using a stepwise approach (Table 43-5) that often involves the use of an atypical antipsychotic medication, such as clozapine or quetiapine.20 The addition of a dopamine agonist to L-dopa therapy also can increase the frequency and severity of L-dopa–induced dyskinesias, especially in patients with preexisting dyskinesias.
TABLE 43-5 Stepwise Approach to Management of Drug-Induced Hallucinosis and Psychosis in Parkinson’s Disease
Initiation of a dopaminergic agonist is best performed by slow titration to minimize side effects. Pramipexole is initiated at a dose of 0.125 mg three times a day and increased every 5 to 7 days, as tolerated, to a maximum of 1.5 mg three times a day. An extended-release pramipexole formulation is also available. Immediate-release ropinirole is initiated at 0.25 mg three times a day and increased by 0.25 mg three times a day on a weekly basis to a maximum of 24 mg/day. An extended-release ropinirole formulation also is available.
Pramipexole is renally excreted with an 8- to 12-hour half-life. The initial dosage must be adjusted in renal insufficiency (0.125 mg twice daily for creatinine clearances of 35 to 59 mL/min [0.58 to 0.99 mL/s], 0.125 mg once daily for creatinine clearances of 15 to 34 mL/min [0.25 to 0.57 mL/s]). Ropinirole has a 6-hour half-life and is metabolized by CYP1A2. Potent inhibitors (e.g., fluoroquinolone antibiotics) and inducers (e.g., cigarette smoking) of this enzyme likely will lead to alterations in ropinirole clearance. Rotigotine transdermal patch is initiated at 2 mg once daily and increased weekly by 2 mg increments to achieve desired therapeutic effect. The rotigotine transdermal patch provides continuous release of drug over a 24-hour period.49 Patch application sites should be rotated to minimize skin irritation and rash. Rotigotine disposition is not affected by hepatic or renal impairment and CYP-mediated drug interactions are not significant.
Apomorphine is an injectable nonergot dopamine agonist. It is an aporphine alkaloid originally derived from morphine but lacks narcotic properties.34 Because of extensive hepatic first-pass metabolism, apomorphine is not suitable for oral administration and is administered subcutaneously. Apomorphine should not be injected IV. For patients with advanced PD who are experiencing intermittent off episodes despite optimized therapy, administration of subcutaneous apomorphine effectively triggers an “on” response within 20 minutes.34 The effective dose ranges from 2 to 6 mg per injection, with most patients requiring approximately 0.06 mg/kg. Sites of injection (abdomen, upper arm, and upper thigh) should be rotated to avoid development of subcutaneous nodules. The metabolic pathway of apomorphine remains unknown. Apomorphine elimination half-life is approximately 40 minutes, and the duration of benefit can be up to 100 minutes. Nausea and vomiting are common side effects, and prior to the initiation of apomorphine, patients should be premedicated with the antiemetic trimethobenzamide.
PERSONALIZED PHARMACOTHERAPY
Currently, there are no pharmacogenomic parameters utilized to guide PD pharmacotherapy. Personalized therapy should take into account patient-specific factors including age, level of functional impairment, disability, desired therapeutic outcomes, comorbidities, employment status, drug tolerability, presence of motor complications, fall risk, cognitive impairment, need for skilled assistance, health-related economics, and patient preferences. The definition of functional impairment is highly patient specific. The lowest dose of anti-PD medication that provides satisfactory symptomatic results should be used and, for patients already on carbidopa/L-dopa, optimization of the L-dopa regimen should be attempted before adding adjunctive agents. As side effects and the severity, level of disability, and related comorbidities increase, therapy adjustments are expected and desired therapeutic endpoints should be reassessed.
For mild functional impairment, initial monotherapy may be initiated with an MAO-B inhibitor, such as rasagiline, with the addition of other therapeutic agents as PD motor symptoms progressively worsen. Therapy with rasagiline in early stage PD provides sufficient symptomatic benefit and is well tolerated. Dopamine agonist monotherapy is more potent than rasagiline or amantadine and provides greater symptomatic benefit for patients with greater than mild to moderate impairment. However, dopamine agonists are less well tolerated in older patients. For patients who are older, cognitively impaired, intolerant of dopamine agonists, or experiencing moderate or severe functional impairment, L-dopa (e.g., carbidopa/levodopa) is preferred. Ultimately, all patients will require the use of L-dopa (either as monotherapy or in combination with other agents). With the development of motor fluctuations, patients should administer L-dopa more frequently. Alternatively, addition of a COMT inhibitor, MAO-B inhibitor, or dopamine agonist to the L-dopa regimen should be considered. For management of L-dopa induced peak-dose dyskinesias, a reduction in L-dopa dose should be attempted. Alternatively, addition of amantadine should be considered. Surgery is considered only in patients who need more symptomatic control or who are experiencing severe motor complications despite pharmacologically optimized therapy.
The treatment plan evolves as the disease progresses and must include consideration of short-term symptomatic relief as well as long-term effects. Patient education should be communicated with realistic optimism. For example, it should be explained that although there is no cure for PD, modern medicine has many medications that can provide relief of symptoms. Nonpharmacologic interventions such as exercise should be encouraged, and problematic nonmotor features of PD should always be addressed.
EVALUATION OF THERAPEUTIC OUTCOMES
Pharmaceutical care related to PD improves patient outcomes.50 Table 43-6 lists the monitoring parameters for PD therapy. Patient and caregiver satisfaction is an important component of evaluating therapeutic outcomes. Toward this end, establishing appropriate treatment expectations is important, patients and caregivers should be educated that PD is a neurodegenerative disease that progresses with time, and that some features will respond less well to pharmacotherapy (e.g., freezing, gait, and postural instability). Patients and caregivers can participate in treatment by recording medication administration times as well as the duration of on and off times that can be reviewed at each visit. Periodic review of all medications that the patient is taking should be performed to identify use of medications (e.g., D2-receptor blockers) that can exacerbate PD motor features. If the patient reports memory problems, the medication profile should be screened for medications with anticholinergic properties and, if present, eliminated when possible. Assessment of the patient’s general level of functioning, including activities of daily living and mobility, is important to determine when medication adjustments or physical therapy interventions are needed. Screening for anxiety or depressive disorders will help to determine if antidepressant or antianxiety therapy is needed. If falling is a problem, it is important to investigate whether falls are secondary to insufficient motor control or drug side effects, such as dizziness and orthostatic hypotension. The former may necessitate an increase in dose of antiparkinson agents, and the latter a reduction in drug dosage. Physical therapy is also helpful for strengthening ambulation and balance skills to minimize falls. The patient should be questioned about any difficulties with their antiparkinson medications, including presence of adverse effects. Recommendations always should be made in view of the patient’s perception of the severity of symptoms and effect on quality of life.
TABLE 43-6 Monitoring Parkinson’s Disease Therapy
ABBREVIATIONS
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