Parkinson Disease 

Updated: Aug 29, 2019
Author: Robert A Hauser, MD, MBA; Chief Editor: Selim R Benbadis, MD 

Overview

Practice Essentials

Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years and causing progressive disability that can be slowed, but not halted, by treatment. The 2 major neuropathologic findings in Parkinson disease are loss of pigmented dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neurites. See the images below.

Lewy bodies are intracytoplasmic eosinophilic incl Lewy bodies are intracytoplasmic eosinophilic inclusions, often with halos, that are easily seen in pigmented neurons, as shown in this histologic slide. They contain polymerized alpha-synuclein; therefore, Parkinson disease is a synucleinopathy.
Stages in the development of Parkinson disease (PD Stages in the development of Parkinson disease (PD)-related pathology (path.). Adapted from Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004 Oct;318(1):121-34.

Signs and symptoms

Initial clinical symptoms of Parkinson disease include the following:

  • Tremor

  • Subtle decrease in dexterity

  • Decreased arm swing on the first-involved side

  • Soft voice

  • Decreased facial expression

  • Sleep disturbances

  • Rapid eye movement (REM) behavior disorder (RBD; a loss of normal atonia during REM sleep)

  • Decreased sense of smell

  • Symptoms of autonomic dysfunction (eg, constipation, sweating abnormalities, sexual dysfunction, seborrheic dermatitis)

  • A general feeling of weakness, malaise, or lassitude

  • Depression or anhedonia

  • Slowness in thinking

Onset of motor signs include the following:

  • Typically asymmetric

  • The most common initial finding is a resting tremor in an upper extremity

  • Over time, patients experience progressive bradykinesia, rigidity, and gait difficulty

  • Axial posture becomes progressively flexed and strides become shorter

  • Postural instability (balance impairment) is a late phenomenon

Nonmotor symptoms

Nonmotor symptoms are common in early Parkinson disease. Recognition of the combination of nonmotor and motor symptoms can promote early diagnosis and thus early intervention, which often results in a better quality of life.

See Clinical Presentation for more detail.

Diagnosis

Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on routine magnetic resonance imaging and computed tomography scans are unremarkable.

Clinical diagnosis requires the presence of 2 of 3 cardinal signs:

  • Resting tremor

  • Rigidity

  • Bradykinesia

See Workup for more detail.

Management

The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects.

Symptomatic drug therapy

  • Usually provides good control of motor signs of Parkinson disease for 4-6 years

  • Levodopa/carbidopa: The gold standard of symptomatic treatment

  • Monoamine oxidase (MAO)–B inhibitors: Can be considered for initial treatment of early disease

  • Other dopamine agonists (eg, ropinirole, pramipexole): Monotherapy in early disease and adjunctive therapy in moderate to advanced disease

  • Anticholinergic agents (eg, trihexyphenidyl, benztropine): Second-line drugs for tremor only

Treatment for nonmotor symptoms

  • Sildenafil citrate (Viagra): For erectile dysfunction

  • Polyethylene glycol: For constipation

  • Modafinil: For excessive daytime somnolence

  • Methylphenidate: For fatigue (potential for abuse and addiction)

Deep brain stimulation

  • Surgical procedure of choice for Parkinson disease

  • Does not involve destruction of brain tissue

  • Reversible

  • Can be adjusted as the disease progresses or adverse events occur

  • Bilateral procedures can be performed without a significant increase in adverse events

See Treatment and Medication for more detail.

Background

Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. There are 2 major neuropathologic findings: the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (see the following image). Most cases of Parkinson disease (idiopathic Parkinson disease [IPD]) are hypothesized to be due to a combination of genetic and environmental factors. However, no environmental cause of Parkinson disease has yet been proven. A known genetic cause can be identified in approximately 10% of cases, and these are more common in younger-onset patients.

Gross comparison of the appearance of the substant Gross comparison of the appearance of the substantia nigra between a normal brain and a brain affected by Parkinson disease. Note the well-pigmented substantia nigra in the normal brain specimen on the left. In the brain of a Parkinson disease patient on the right, loss of pigmented substantia nigra due to depopulation of pigmented neurons is observed.

The classic motor features of Parkinson disease typically start insidiously and emerge slowly over weeks or months, with tremor being the most common initial symptom. The 3 cardinal signs of Parkinson disease are resting tremor, rigidity, and bradykinesia. Postural instability (balance impairment) is sometimes listed as the fourth cardinal feature. However, balance impairment in Parkinson disease is a late phenomenon, and in fact, prominent balance impairment in the first few years suggests that Parkinson disease is not the correct diagnosis. (See Presentation.)

When a patient presents with tremor, the clinician evaluates the patient's history and physical examination findings to differentiate Parkinson disease tremor from other types of tremor. In patients with parkinsonism, careful attention to the history is necessary to exclude causes such as drugs, toxins, or trauma. (See Differential Diagnosis.) Other common causes of tremor include essential tremor, physiologic tremor, and dystonic tremor.

No laboratory or imaging study is required in patients with a typical presentation of Parkinson disease. Such patients are aged 55 years or older and have a slowly progressive and asymmetric parkinsonism with resting tremor and bradykinesia or rigidity. There are no red flags such as prominent autonomic dysfunction, balance impairment, dementia, or eye-movement abnormalities. In such cases, the diagnosis is ultimately considered confirmed once the patient goes on dopaminergic therapy (levodopa or a dopamine agonist) as needed for motor symptom control and exhibits a robust and sustained benefit. (See Workup.)

Imaging studies can be considered, depending on the differential diagnosis. Magnetic resonance imaging (MRI) of the brain can be considered to evaluate possible cerebrovascular disease (including multi-infarct state), space-occupying lesions, normal-pressure hydrocephalus, and other disorders.

Iodine-123–labeled fluoropropyl-2beta-carbomethoxy-3beta-4-iodophenyl-nortroptane (FP-CIT I123) (Ioflupane, DaTscan) single-photon emission computed tomography (SPECT) can be considered in cases of uncertain parkinsonism to help differentiate disorders associated with a loss of dopamine neurons (Parkinson disease and atypical parkinsonisms, including multiple system atrophy [MSA] and progressive supranuclear palsy [PSP]) from those disorders not associated with a loss of dopamine neurons (eg, essential tremor, dystonic tremor, vascular parkinsonism, medication-induced parkinsonism or tremor, psychogenic conditions).[1]

Levodopa coupled with a peripheral decarboxylase inhibitor (PDI), such as carbidopa, remains the gold standard of symptomatic treatment of motor features of Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However, its long-term use is associated with the development of fluctuations and dyskinesias. Moreover, the disease continues to progress, and patients accumulate long-term disability. (See Treatment.)

Dopamine agonists such as pramipexole (Mirapex) and ropinirole (Requip) can be used as monotherapy to improve symptoms in early Parkinson disease or as adjuncts to levodopa in patients who are experiencing motor fluctuations. Monoamine oxidase (MAO)-B inhibitors, such as selegiline (Eldepryl) and rasagiline (Azilect) provide mild benefit as monotherapy in early disease and as adjuncts to levodopa in patients with motor fluctuations. (See Medication.) Entacapone (Comtan), a catechol-o-methyltransferase (COMT) inhibitor, reduces the peripheral metabolism of levodopa, thereby making more levodopa available to enter the brain over a longer period; this agent is used as an adjunct to levodopa in patients with motor fluctuations.

Anatomy

Parkinson disease is predominantly a disorder of the basal ganglia, which are a group of nuclei situated at the base of the forebrain. The striatum, composed of the caudate and putamen, is the largest nuclear complex of the basal ganglia. The striatum receives excitatory input from several areas of the cerebral cortex, as well as inhibitory and excitatory input from the dopaminergic cells of the substantia nigra pars compacta (SNc). These cortical and nigral inputs are received by the spiny projection neurons, which are of 2 types: those that project directly to the internal segment of the globus pallidus (GPi), the major output site of the basal ganglia; and those that project to the external segment of the globus pallidus (GPe), establishing an indirect pathway to the GPi via the subthalamic nucleus (STN).

For an illustration of the subthalamic nucleus, see the image below.

Sagittal section, 12 mm lateral of the midline, de Sagittal section, 12 mm lateral of the midline, demonstrating the subthalamic nucleus (STN) (lavender). The STN is one of the preferred surgical targets for deep brain stimulation to treat symptoms of advanced Parkinson disease.

The actions of the direct and indirect pathways regulate the neuronal output from the GPi, which provides tonic inhibitory input to the thalamic nuclei that project to the primary and supplementary motor areas.

Pathophysiology

No specific, standard criteria exist for the neuropathologic diagnosis of Parkinson disease, as the specificity and sensitivity of its characteristic findings have not been clearly established. However, the following are the 2 major neuropathologic findings in Parkinson disease:

  • Loss of pigmented dopaminergic neurons of the substantia nigra pars compacta

  • The presence of Lewy bodies and Lewy neurites

The loss of dopamine neurons occurs most prominently in the ventral lateral substantia nigra. Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson disease emerge.

Some individuals who were thought to be normal neurologically at the time of their deaths are found to have Lewy bodies on autopsy examination. These incidental Lewy bodies have been hypothesized to represent the presymptomatic phase of Parkinson disease. The prevalence of incidental Lewy bodies increases with age. Note that Lewy bodies are not specific to Parkinson disease, as they are found in some cases of atypical parkinsonism, Hallervorden-Spatz disease, and other disorders. Nonetheless, they are a characteristic pathology finding of Parkinson disease.

Motor circuit in Parkinson disease

The basal ganglia motor circuit modulates the cortical output necessary for normal movement (see the following image).

Schematic representation of the basal ganglia - th Schematic representation of the basal ganglia - thalamocortical motor circuit and its neurotransmitters in the normal state. From Vitek J. Stereotaxic surgery and deep brain stimulation for Parkinson disease and movement disorders. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:240. Copyright, McGraw-Hill Companies, Inc. Used with permission.

Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical motor circuit and return to the same area via a feedback pathway. Output from the motor circuit is directed through the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). This inhibitory output is directed to the thalamocortical pathway and suppresses movement.

Two pathways exist within the basal ganglia circuit, the direct and indirect pathways, as follows:

  • In the direct pathway, outflow from the striatum directly inhibits the GPi and SNr; striatal neurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr

  • The indirect pathway contains inhibitory connections between the striatum and the external segment of the globus pallidus (GPe) and between the GPe and the subthalamic nucleus (STN); striatal neurons with D2 receptors are part of the indirect pathway and project to the GPe

The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr sends inhibitory output to the ventral lateral nucleus (VL) of the thalamus. Dopamine is released from nigrostriatal (substantia nigra pars compacta [SNpc]) neurons to activate the direct pathway and inhibit the indirect pathway. In Parkinson disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr via both the direct and indirect pathways (see the following image).

Schematic representation of the basal ganglia - th Schematic representation of the basal ganglia - thalamocortical motor circuit and the relative change in neuronal activity in Parkinson disease. From Vitek J. Stereotaxic surgery and deep brain stimulation for Parkinson disease and movement disorders. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:241. Used with kind permission. Copyright, McGraw-Hill Companies, Inc.

The increased inhibition of the thalamocortical pathway suppresses movement. Via the direct pathway, decreased striatal dopamine stimulation causes decreased inhibition of the GPi/SNr. Via the indirect pathway, decreased dopamine inhibition causes increased inhibition of the GPe, resulting in disinhibition of the STN. Increased STN output increases GPi/SNr inhibitory output to the thalamus.

Etiology

Although the etiology of Parkinson disease is still unclear, most cases are hypothesized to be due to a combination of genetic and environmental factors. Currently known genetic causes of Parkinson disease account for approximately 10% of cases.

Environmental causes

Environmental risk factors commonly associated with the development of Parkinson disease include use of pesticides, living in a rural environment, consumption of well water, exposure to herbicides, and proximity to industrial plants or quarries.[2]

A meta-analysis of 89 studies, including 6 prospective and 83 case-control studies, found that exposure to pesticides may increase the risk for PD by as much as 80%.[3, 4] Exposure to the weed killer paraquat or to the fungicides maneb or mancozeb is particularly toxic, increasing the risk for PD about 2-fold. Many of the agents studied are no longer used in the United States and Europe; however, some are still found in developing parts of the world.[3, 4]

In case-control studies, PD was associated with exposure to any type of pesticide, herbicide, insecticide, and solvent, with risks ranging from 33% to 80%.[3, 4] Increased PD risk was also associated with proxy conditions of exposure to organic pollutants, such as farming, well-water drinking, and rural living. In addition, risk seemed to increase with length of exposure.[3, 4]

The National Institutes of Health-AARP Diet and Health Study, as well as a meta-analysis of prospective studies, found that higher caffeine intake was associated with lower risk of Parkinson disease in both men and women. A similar association was found for smoking and Parkinson disease risk.[5] The biological mechanisms underlying the inverse relationship between caffeine or smoking and Parkinson disease risk are not well elucidated.

MPTPinterference with mitochondrial function

Several individuals were identified who developed parkinsonism after self-injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These patients developed bradykinesia, rigidity, and tremor, which progressed over several weeks and improved with dopamine replacement therapy. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B.[6]

MPP+ accumulates in mitochondria and interferes with the function of complex I of the respiratory chain. A chemical resemblance between MPTP and some herbicides and pesticides suggested that an MPTP-like environmental toxin might be a cause of Parkinson disease, but no specific agent has been identified. Nonetheless, mitochondrial complex I activity is reduced in Parkinson disease, suggesting a common pathway with MPTP-induced parkinsonism.

Oxidation hypothesis

The oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative metabolism, plays a role in the development or progression of Parkinson disease. The oxidative metabolism of dopamine by MAO leads to the formation of hydrogen peroxide. Normally, hydrogen peroxide is cleared rapidly by glutathione, but if hydrogen peroxide is not cleared adequately, it may lead to the formation of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage. In Parkinson disease, levels of reduced glutathione are decreased, suggesting a loss of protection against formation of free radicals. Iron is increased in the substantia nigra and may serve as a source of donor electrons, thereby promoting the formation of free radicals.

Parkinson disease is associated with increased dopamine turnover, decreased protective mechanisms (glutathione), increased iron (a pro-oxidation molecule), and evidence of increased lipid peroxidation. This hypothesis has raised concern that increased dopamine turnover due to levodopa administration could increase oxidative damage and accelerate loss of dopamine neurons. However, there is no clear evidence that levodopa accelerates disease progression.

Genetic factors

If genetic factors are important in a particular disease, concordance in genetically identical monozygotic (MZ) twins will be greater than in dizygotic (DZ) twins, who share only about 50% of genes. Early Parkinson disease twin studies generally found low and similar concordance rates for MZ and DZ pairs.

However, genetic factors in Parkinson disease appear to be very important when the disease begins at or before age 50 years. In a study of 193 twins, overall concordance for MZ and DZ pairs was similar, but in 16 pairs of twins in whom Parkinson disease was diagnosed at or before age 50 years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant.[7]

The identification of a few families with familial Parkinson disease sparked further interest in the genetics of the disease. In one large family in Salerno, Italy, 50 of 592 members had Parkinson disease; linkage analysis incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G substitution at base 209 of the alpha-synuclein gene.[8] Termed PD-1, this mutation codes for a substitution of threonine for alanine at amino acid 53. These individuals were characterized by early age of disease onset (mean age, 47.5 years), rapid progression (mean age at death, 56.1 years), lack of tremor, and good response to levodopa therapy.[8] Five small Greek kindreds were also found to have the PD-1 mutation.

In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C for G at base 88, producing a substitution of proline for alanine at amino acid 30) confirmed that mutations in the alpha-synuclein gene can cause Parkinson disease.[9] A few additional familial mutations in the alpha-synuclein gene have been identified and are collectively called PARK1. It is now clear that these mutations are an exceedingly rare cause of Parkinson disease.

A total of 18 loci in various genes have now been proposed for Parkinson disease. Mutations within 6 of these loci (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP 13A2) are well-validated causes of familial parkinsonism.[10] Inheritance is autosomal dominant for SNCA and LRRK2 (although LRRK2 mutations exhibit variable penetrance). Inheritance is autosomal recessive for PRKN, DJ1, PINK1, and ATP13A2. In addition, polymorphisms within SNCA and LRRK2, as well as variations in MAPT and GBA, are risk factors for Parkinson disease.[10]

(For more information on genes/loci underlying monogenic parkinsonism and susceptibility genes/loci for Parkinson disease, see Tables 1 and 2, respectively, in The Genetics of Parkinson Disease.[10] )

In one study of 953 patients with Parkinson disease with age at onset of 50 years or younger, 64 patients (6.7%) had a PRKN mutation, 1 patient (0.2%) had a DJ1 mutation, 35 patients (3.6%) had an LRRK2 mutation, and 64 patients (6.7%) had a GBA mutation.[11] . Mutations were more common in patients with age at onset of 30 years or younger (40.6%) than in those with age at onset between 31 and 50 years (14.6%); more common in patients of Jewish ancestry (32.4%) than in non-Jewish patients (13.7%); and more common in patients reporting a first-degree family history of Parkinson disease (23.9%) than in those without such a family history (15.1%).[11]

Although the mechanisms by which genetic mutations cause Parkinson disease is not known, evidence to date converges on mechanisms related to abnormal protein aggregation, defective ubiquitin-mediated protein degradation, mitochondrial dysfunction, and oxidative damage.

Alpha-synuclein conformational changes and aggregation

Abnormally aggregated alpha-synuclein is the major component of Lewy bodies and Lewy neurites, which are characteristic pathologic findings in Parkinson disease. Missense mutations and multiplications in the SNCA gene that encodes alpha-synuclein, although rare, cause autosomal dominant Parkinson disease. However, genome-wide association studies have also demonstrated a link between SNCA and sporadic Parkinson disease.

Dysfunction of alpha-synuclein appears to play a central role in the pathogenesis of Parkinson disease, and understanding its relationship to the disease process holds major promise for the development of a cure.

Alpha-synuclein is a 140-amino-acid protein that is unfolded at neutral pH. However, when bound to membranes or vesicles containing acidic phospholipids, it takes on an alpha-helical structure. Normally, alpha-synuclein is found mainly in neuronal presynaptic terminals and may play a role in assembly and function of SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) proteins that are involved in neurotransmitter release.

Under certain conditions, alpha-synuclein aggregates into oligomers that are gradually converted to the beta–sheet-rich fibrillary structures that form Lewy bodies and neurites in Parkinson disease. Most evidence currently suggests that it is the intermediate soluble oligomers that are toxic to neurons.

Multiple mechanisms have been suggested as to how abnormally aggregated alpha-synuclein could exert neurotoxicity.[12] One hypothesis suggests that oligomeric alpha-synuclein can promote formation of ion-permeable pores on neuronal membranes, leading to increased calcium influx. Aberrant pore formation could also lead to neurotransmitter leaks from synaptic vesicles into the cytosol. In addition, overexpression of alpha-synuclein has been demonstrated to impair mitochondrial complex I activity, and oligomeric alpha-synuclein may have a direct effect on mitochondrial membranes. Other lines of evidence suggest that oligomerization of alpha-synuclein could cause cytoskeletal disruption, possibly by an effect on the microtubule-stabilizing protein, tau.[13]

Elevated levels of alpha-synuclein promote abnormal aggregation. levels are normally regulated by a balance between synthesis and degradation. SNCA multiplications lead to increased synthesis of alpha-synuclein and can cause Parkinson disease. Alpha-synuclein appears to be degraded by the ubiquitin proteasome system and the autophagy-lysosome pathway. Several genetic mutations associated with Parkinson disease may lead to decreased alpha-synuclein degradation. For example, increased risk of Parkinson disease in carriers of GBA (beta-glucocerebrosidase gene) mutations, which encode for the lysosomal enzyme glucocerebrosidase, may be due to lysosomal dysfunction and consequent alpha-synuclein accumulation and oligomerization.

How the Parkinson disease process begins is not known. Once it is initiated, however, it may propagate by a prionlike process in which misconformed proteins induce the templated misfolding of other protein molecules. In Parkinson disease, synuclein pathology begins in the lower brainstem and olfactory bulb, ascends up the midbrain, and eventually affects the neocortex. One set of observations in support of a prionlike process comes from experience with fetal dopaminergic grafts transplanted into the striata of patients with Parkinson disease, because these grafts develop Lewy bodies, suggesting host-graft transmission of disease.[14]

Preventing the propagation of abnormal alpha-synuclein aggregation may be the key to slowing or stopping Parkinson disease progression.

Melanoma

For years, there has been speculation about a relationship between PD and melanoma. Initially, it was theorized that the drug levodopa led to an increased risk of skin cancer, but studies did not confirm this. However, subsequent trials have since found an increased risk for melanoma in patients with PD. One particular study conducted in 2017 found that Parkinson patients have about a 4-fold increased risk of having preexisting melanoma.[15, 16] Another study found the risk to be 7-fold.[17]

Diabetes

In a large cohort study, researchers found that individuals with type 2 diabetes had a 32% increased risk of developing later Parkinson's disease than those without diabetes. The study involved 2 million people with type 2 diabetes and compared them to a reference cohort of 6,173,208 people without diabetes and results showed significantly elevated rates of Parkinson's disease in the type 2 diabetes cohort (hazard ratio [HR], 1.32, 95% confidence interval [CI], 1.29 - 1.35; P < .001). The relative increase was greater in patients with diabetic complications and in younger individuals with type 2 diabetes aged 25 to 44 years.[18]

Epidemiology

Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. The incidence of Parkinson disease has been estimated to be 4.5-21 cases per 100,000 population per year, and estimates of prevalence range from 18 to 328 cases per 100,000 population, with most studies yielding a prevalence of approximately 120 cases per 100,000 population. The wide variation in reported global incidence and prevalence estimates may be the result of a number of factors, including the way data are collected, differences in population structures and patient survival, case ascertainment, and the methodology used to define cases.[19]

The incidence and prevalence of Parkinson disease increase with age, and the average age of onset is approximately 60 years. Onset in persons younger than 40 years is relatively uncommon. Parkinson disease is about 1.5 times more common in men than in women.

Prognosis

Before the introduction of levodopa, Parkinson disease caused severe disability or death in 25% of patients within 5 years of onset, 65% within 10 years, and 89% within 15 years. The mortality rate from Parkinson disease was 3 times that of the general population matched for age, sex, and racial origin. With the introduction of levodopa, the mortality rate dropped approximately 50%, and longevity was extended by many years. This is thought to be due to the symptomatic effects of levodopa, as no clear evidence suggests that levodopa stems the progressive nature of the disease.[20, 21]

The American Academy of Neurology notes that the following clinical features may help predict the rate of progression of Parkinson disease[22] :

  • Older age at onset and initial rigidity/hypokinesia can be used to predict (1) a more rapid rate of motor progression in those with newly diagnosed Parkinson disease and (2) earlier development of cognitive decline and dementia; however, initially presenting with tremor may predict a more benign disease course and longer therapeutic benefit from levodopa

  • A faster rate of motor progression may also be predicted if the patient is male, has associated comorbidities, and has postural instability/gait difficulty (PIGD)

  • Older age at onset, dementia, and decreased responsiveness to dopaminergic therapy may predict earlier nursing home placement and decreased survival

Patient Education

Patients with Parkinson disease should be encouraged to participate in decision making regarding their condition.[23] In addition, individuals and their caregivers should be provided with information that is appropriate for their disease state and expected or ongoing challenges.[21] Psychosocial support and concerns should be addressed and/or referred to a social worker or psychologist as needed.

Prevention of falls should be discussed. The UK National Institute for Health and Clinical Excellence has several guidance documents including those for patients and caregivers.

Other issues that commonly need to be addressed at appropriate times in the disease course include cognitive decline, personality changes, depression, dysphagia, sleepiness and fatigue, and impulse control disorders. Additional information is also often needed for financial planning, insurance issues, disability application, and placement (assisted living facility, nursing home).

For patient education information, see the Brain & Nervous System Center, as well as Parkinson's Disease Dementia.

 

Presentation

History

Onset of motor signs in Parkinson disease is typically asymmetric, with the most common initial finding being an asymmetric resting tremor in an upper extremity. Over time, patients notice symptoms related to progressive bradykinesia, rigidity, and gait difficulty. The first affected arm may not swing fully when walking, and the foot on the same side may scrape the floor. Over time, axial posture becomes progressively flexed and strides become shorter.

Some nonmotor symptoms commonly precede motor signs in Parkinson disease. Most Parkinson disease patients have a substantial reduction in olfactory function (smell) by the time motor signs emerge. However, either this is not noticed by the patients or patients may not realize that it is part of the disease. Another common premotor symptom is rapid eye movement (REM) behavior disorder (RBD). In this condition, individuals exhibit movements during REM sleep that are often described as hitting or kicking motions. There are also a number of midlife risk factors for the later development of Parkinson disease. These include constipation and excessive daytime sleepiness, although they are far from specific for Parkinson disease.

In a British study, the frequency of nonmotor symptoms in 159 patients with newly diagnosed Parkinson’s disease was found to be significantly greater than that in 99 healthy age-matched control patients (mean, 8.4 vs 2.8).[24] The most commonly experienced nonmotor symptoms in patients with early Parkinson disease in this study included the following[25] :

  • Excessive saliva

  • Forgetfulness

  • Urinary urgency

  • Hyposmia

  • Constipation

Initial clinical symptoms in Parkinson disease include the following:

  • Tremor

  • A subtle decrease in dexterity; for example, a lack of coordination with activities such as playing golf or dressing (about 20% of patients first experience clumsiness in one hand)

  • Decreased arm swing on the first-involved side

  • Soft voice

  • Decreased facial expression

  • Sleep disturbances

  • RBD, in which there is a loss of normal atonia during REM sleep: In one study, 38% of 50-year-old men with RBD and no neurologic signs went on to develop parkinsonism[26] ; patients “act out their dreams” and may kick, hit, talk, or cry out in their sleep

  • Decreased sense of smell

  • Symptoms of autonomic dysfunction, including constipation, sweating abnormalities, sexual dysfunction, and seborrheic dermatitis

  • A general feeling of weakness, malaise, or lassitude

  • Depression or anhedonia

  • Slowness in thinking

Common early motor signs of Parkinson disease include tremor, bradykinesia, rigidity, and dystonia.

Tremor

Although tremor is the most common initial symptom in Parkinson disease, occurring in approximately 70% of patients, it does not have to be present to make the diagnosis. Tremor is most often described by patients as shakiness or nervousness and usually begins in one upper extremity and initially may be intermittent. Upper extremity tremor generally begins in the fingers or thumb, but it can also start in the forearm or wrist. After several months or years, the tremor may spread to the ipsilateral lower extremity or the contralateral upper extremity before becoming more generalized; however, asymmetry is usually maintained.

Tremor can vary considerably, emerging only with stress, anxiety, or fatigue. Classically, the tremor of Parkinson disease is a resting tremor (occurring with the limb in a resting position) and disappears with action or use of the limb, but this is not seen in all patients. Initially, the tremor may be noticed during activities such as eating or reading a newspaper. Although Parkinson disease is a rare cause of tremor affecting the head or neck, tremors of the chin, lip, or tongue are not uncommon. As with other tremors, the amplitude increases with stress and resolves during sleep.

Bradykinesia

Bradykinesia refers to slowness of movement. Symptoms of bradykinesia are varied and can be described by patients in different ways. These may include a subjective sense of weakness, without true weakness on physical examination; loss of dexterity, sometimes described by patients as the "message not getting to the limb"; fatigability; or achiness when performing repeated actions.

Facial bradykinesia is characterized by decreased blink rate and facial expression. Speech may become softer, less distinct, or more monotonal. In more advanced cases, speech is slurred, poorly articulated, and difficult to understand. Drooling is an uncommon initial symptom in isolation but is reported commonly (especially nighttime drooling) later in the disease course.

Truncal bradykinesia results in slowness or difficulty in rising from a chair, turning in bed, or walking. If walking is affected, patients may take smaller steps and gait cadence is reduced. Some patients experience a transient inability to walk, as though their feet are frozen to the floor. This "freezing" is seen commonly in patients with more advanced disease; it is more prominent as patients attempt to navigate doorways or narrow areas and can result in patients getting trapped behind furniture or being unable to cross a door threshold easily.

In the upper extremities, bradykinesia can cause small, effortful handwriting (ie, micrographia) and difficulty using the hand for fine dexterous activities such as using a key or kitchen utensils. In the lower extremities, unilateral bradykinesia commonly causes scuffing of that foot on the ground, as it is not picked up during leg swing. This may also be described as dragging of one leg.

Rigidity

Some patients may describe stiffness in the limbs, but this may reflect bradykinesia more than rigidity. Occasionally, individuals may describe a feeling of ratchety stiffness when moving a limb, which may be a manifestation of cogwheel rigidity.

Dystonia

Dystonia is a common initial symptom in young-onset Parkinson disease, which is defined as symptom onset before age 40 years. Dystonia in Parkinson disease commonly consists of a foot involuntary turning in (inversion) or down (plantar flexion), often associated with cramping or aching in the leg. Dorsiflexion of the big toe may also occur. Another common dystonia in Parkinson disease is adduction of the arm and elbow, causing the hand to rest in front of the abdomen or chest. Dystonic postures can wax and wane, occurring with fatigue or exertion.

Whether stooped posture is due to truncal dystonia is a matter of debate. One study suggests that the stooped posture may be due to vertebral fractures resulting from vitamin D deficiency with compensatory hyperparathyroidism.[27] Vitamin D supplementation may reduce the risk for stooped posture.

Physical Examination

There are 4 cardinal signs of Parkinson disease, with 2 of the first 3 listed below required to make the clinical diagnosis. The fourth cardinal sign, postural instability (balance difficulty), emerges late in the disease, usually after 8 years or more.

  • Resting tremor

  • Rigidity

  • Bradykinesia

  • Postural instability

Resting tremor

Resting tremor is assessed by having patients relax their arms in their lap while in a seated position. Having patients count aloud backward from 10 may help bring out the tremor. The arms should also be observed in an outstretched position to assess postural tremor, and kinetic tremor (tremor with voluntary movement) can be observed during the finger-to-nose test. Although a resting tremor is the tremor characteristic of Parkinson disease, many Parkinson disease patients also have some postural and/or kinetic tremor.

Rigidity

Rigidity refers to an increase in resistance to passive movement about a joint. The resistance can be either smooth (lead pipe) or oscillating (cogwheeling). Cogwheeling is thought to reflect tremor rather than rigidity and may be present with tremors not associated with an increase in tone (ie, essential tremor). Rigidity is usually tested by flexing and extending the patient's relaxed wrist and can be made more obvious by having the patient perform voluntary movements, such as tapping, with the contralateral limb.

Bradykinesia

Bradykinesia refers to slowness of movement but also includes reduced spontaneous movements and decreased amplitude of movement. Bradykinesia is also expressed as micrographia (small handwriting), hypomimia (decreased facial expression), decreased blink rate, and hypophonia (soft speech). Thus, the patient’s blink rate and facial expression should be observed.

In addition, speed and amplitude of movements are assessed by having the patient open his or her hand (each limb is assessed individually) and tap his or her thumb and index finger repetitively, trying to perform the movement as big and as fast as possible. Similarly, the patient should be asked to tap the toes of each foot as big and as fast as possible. Finally, the patient should be asked to arise from a seated position with the arms crossed to assess the ability to arise from a chair. The patient is then observed while walking to assess stride length and speed, as well as arm swing.

Postural instability

Postural instability refers to imbalance and loss of righting reflexes. Its emergence in a patient with Parkinson disease is an important milestone, because it is poorly amenable to treatment and a common source of disability in late disease. Postural stability is typically assessed by having patients stand with their eyes open and then pulling their shoulders back toward the examiner. Patients are told to be ready for the displacement and to regain their balance as quickly as possible. Taking 1 or 2 steps backward to regain balance is considered normal. The examiner should be ready to catch patients if they are unable to regain balance.

Laryngeal dysfunction and dysphagia

As the patient is speaking, the vocal loudness, intonation, and quality, including fluidity of speech and articulation, should be assessed. Sustaining vowel phonation (eg, "ah") for maximum duration, counting to 50, and reading a passage that tests articulation (eg, the rainbow passage) provide reasonable speech samples. Closely listening for reduced or diminishing loudness and intonation and increasing breathiness and hoarseness helps differentiate Parkinson disease from hyperkinetic disorders such as spasmodic dysphonia.[28]

A soft, monotone voice, vocal tremor, poor articulation, variable speech rate, trouble with the initiation of speech, and stuttering-like qualities are all characteristics of Parkinson disease. Perhaps the most telling vocal symptom is the marked contrast between habitual vocal volume (soft and diminishing) and the patient's response to a request to increase loudness. A request to "say that again, twice as loud" often results in increased loudness, improved voice quality, and a dramatic improvement in speech intelligibility.

Dysphagia is common, especially in advanced Parkinson disease. Manifestations may range from drooling to aspiration.

An otolaryngologist can perform a more detailed assessment of laryngeal dysfunction in patients with Parkinson disease, using neurolaryngeal examination and stroboscopy. Because distortion can occur when the tongue is held forward during rigid stroboscopy, the neurolaryngeal examination is best performed by viewing the larynx with a flexible laryngoscope. The larynx is evaluated for vocal fold mobility, paresis or paralysis, coordination of movement, agility, fatigability, flexibility, and use of accessory muscles during phonation while the patient says various phrases and syllables. Hyperfunctional and hypofunctional disorders can often be differentiated by isolating the abductor and adductor muscle groups. The larynx is also visualized at rest.

Rigid stroboscopy plays a key role in the assessment of the vibratory characteristics of the vocal folds, including the presence of masses, lesions, or scar and glottic configuration abnormalities, including an elliptical closure pattern, phase asymmetry, and abnormal phase closure. Stroboscopy and neurolaryngeal examination are complementary in the evaluation of the patient with Parkinson disease. Common stroboscopy findings in Parkinson disease include true vocal fold atrophy or other evidence of glottal incompetence, including a chasing wave or a shorter closed phase.

Pooling of secretions, decreased sensation, and aspiration are also characterizations of the Parkinson disease larynx. A paralyzed vocal fold suggests Parkinson-plus syndrome (PPS) as the etiology for the parkinsonism if other aspects of the diagnosis are present.

Perez et al found that vocal tremor is present in 55% of patients with Parkinson disease.[29] Interestingly, only 35% of patients with Parkinson disease exhibited a resting vocal cord tremor, whereas the remainder exhibited kinetic tremor. The tremor is primarily a vertical laryngeal movement. PPS was found to carry a higher incidence of vocal tremor (64%), with most tremors located in the arytenoids. The authors found no vertical laryngeal tremor in patients with PPS.[29]

Autonomic dysfunction

Autonomic dysfunction is common in patients with Parkinson disease. Orthostatic hypotension often becomes a concern in late disease, and impaired intestinal motility can lead to constipation and, sometimes, vomiting or impaired absorption. Urinary symptoms, retention, and bladder infection can occur, and erectile dysfunction is not uncommon. In addition, many patients note episodes of sweating.

Prominent autonomic dysfunction, especially frank urinary incontinence or profound orthostatic hypotension, may suggest multiple system atrophy (MSA) rather than Parkinson disease.

Cardiopulmonary impairment

The flexed posture of patients with Parkinson disease can lead to kyphosis, cause a reduction in pulmonary capacity, and produce a restrictive lung disease pattern.

Staging

Investigators have proposed a staging system to improve the assessment of overall Parkinson disease severity. In an observational, cross-sectional study of 933 patients with Parkinson disease, Ray Chaudhuri and colleagues found a wide discrepancy between the severity of nonmotor symptoms as measured by the NonMotor Symptoms Scale (NMSS) and motor symptoms as measured by the Hoehn and Yahr scale.[30, 31] The investigators proposed a staging system for nonmotor symptom burden based on NMSS scores, which was correlated with measures of disability and quality of life. The staging system rates nonmotor symptom burden (NMSB) on a scale of 0 (no NMSB) to 4 (very severe NMSB).[30, 31]

Depression

Given the high prevalence of mood disorders in Parkinson disease, these patients should be screened regularly for depression. However, assessment of depression in patients with Parkinson disease is complicated by the fact that some symptoms of Parkinson disease overlap with those of depression (eg, masklike facies, insomnia, psychomotor slowing, difficulty concentrating, fatigue). Guilt and self-reproach are less prominent in depression in patients with Parkinson disease, whereas anxiety and pessimism are more prominent.

Dementia

Hoops et al found that in Parkinson disease, the Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE) for screening for mild cognitive impairment or dementia.[32] MoCA and MMSE demonstrated similar overall discriminant validity for detection of any cognitive disorder, but as a screening instrument, MoCA was better than MMSE (64% vs 54% correct diagnoses).[32]

The prevalence of dementia in Parkinson disease ranges from 20-40%, with the disease conferring a 2- to 6-fold increased risk compared with control populations.[33] Many patients with Parkinson disease have some executive function impairment, even early in the disease.[33] Substantial cognitive impairment and dementia typically occur 8 years or more after the onset of motor features.

Dementia generally occurs late in Parkinson disease; substantial cognitive dysfunction within 1 year of onset of motor features suggests a diagnosis of Lewy body disease, a disease closely related to Parkinson disease and marked by the presence of cortical Lewy bodies. In the affected age group, comorbidity with other neurodegenerative disorders, particularly Alzheimer disease and cerebrovascular disease, is common. The relatively high prevalence of depression in patients with Parkinson disease is another confounder in the diagnosis of Parkinson disease dementia.

Executive function, short-term memory, and visuospatial ability may be impaired in patients with Parkinson disease dementia, but aphasia is not present. In a long-term Australian study that compared neuropsychologic measures between patients with Parkinson disease who had early dementia (< 10 years of disease onset) and those with late dementia, investigators reported that dementia in parkinsonism appears to occur at about age 70 years regardless of the time of onset of Parkinson disease.[34] However, although early and late dementia had similar effects in cognitive domains, individuals with early onset of parkinsonism had a preserved linguistic ability before the onset of dementia.[34]

Atypical Parkinsonisms

Atypical parkinsonisms, or Parkinson-plus syndromes, are primary neurodegenerative disorders that have parkinsonian features and are associated with complex clinical presentations that reflect degeneration in various neuronal systems. Patients with atypical parkinsonisms typically have a worse prognosis than those with Parkinson disease, and atypical parkinsonisms respond poorly to standard anti-Parkinson disease treatments.

(For more information, see Parkinson-Plus Syndromes for detailed information regarding clinical clues, workup, differential diagnosis, and treatment of atypical parkinsonisms, including multiple system atrophy, progressive supranuclear palsy, parkinsonism-dementia-amyotrophic lateral sclerosis complex, corticobasal ganglionic degeneration, and diffuse Lewy body disease.)

 

DDx

Diagnostic Considerations

The most common tremor disorders are Parkinson disease and essential tremor. When a patient presents with tremor, the clinician should pay particular attention to the body parts involved, positions/conditions in which the tremor occurs (ie, resting, postural, kinetic, intention), and the frequency of the tremor. It is also critical to look for potential associated signs. The patient should be examined for evidence of parkinsonism (bradykinesia, rigidity, postural instability), dystonia, and other neurologic signs.

An 8-12 Hz action (postural/kinetic) tremor of the upper extremities that is temporarily relieved by drinking alcohol is characteristic of essential tremor, whereas the presence of a pill-rolling rest tremor, bradykinesia, and rigidity is consistent with Parkinson disease and argues against essential tremor.

In patients with parkinsonism, careful attention to the history is necessary to exclude secondary causes such as medications, toxins, or trauma. Medications that block striatal dopamine receptors, such as metoclopramide and neuroleptics, can cause drug-induced parkinsonism. Certain toxins such as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and manganese (at high levels of exposure) can also cause parkinsonism.

Consider evaluating patients with parkinsonism for osteoporosis and osteopenia. In a meta-analysis of 23 studies, Tornsey and colleagues found evidence that individuals with Parkinson disease have an increased risk for osteoporosis and osteopenia.[35, 36] A pooled analysis of 2 of the studies, for example, indicated that in patients with Parkinson disease, the odds ratio for developing osteoporosis, when compared with healthy controls, was 2.61, although the increase was lower in men than in women.

Analysis of 14 studies found bone mineral densities in patients with Parkinson disease to be significantly lower at the hip, lumbar spine, and femoral neck, whereas, after an examination of 9 studies, the investigators estimated that bone fracture risk is doubled in Parkinson patients.[35, 36]

Early clinical features that suggest an atypical parkinsonism rather than Parkinson disease include the following[22] :

  • Falls at presentation or early in the disease

  • Poor response to levodopa

  • Symmetry at disease onset

  • Rapid disease progression

  • No tremor

  • Dysautonomia (eg, urinary incontinence, fecal incontinence, catheterization for urinary retention, persistent erectile failure, prominent symptomatic orthostatic hypotension)

The atypical parkinsonisms are usually associated with little or no tremor, relatively early speech and balance difficulty, and little or no response to dopaminergic medications. Multiple system atrophy (MSA) is relatively symmetric and characterized by parkinsonism, often with some combination of autonomic, corticospinal, and cerebellar dysfunction. Progressive supranuclear palsy (PSP) is relatively symmetric and characterized by parkinsonism with early falls (often in the first year) and a supranuclear gaze palsy in which the patient has difficulty with voluntary down-gaze. Corticobasal ganglionic degeneration (CBD) is typically very asymmetric and characterized by both cortical (difficulty identifying objects, apraxias) and basal ganglionic (usually marked rigidity in an arm) features.

Lewy body disease is characterized by substantial cognitive dysfunction within 1 year of onset of parkinsonism. Hallucinations are common.

Patients with onset of parkinsonism before age 40 years should be tested for Wilson disease, starting with serum ceruloplasmin measurement and ophthalmologic evaluation for Kayser-Fleischer rings.

Differential Diagnoses

 

Workup

Approach Considerations

Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on routine magnetic resonance imaging (MRI) and computed tomography (CT) scan are unremarkable. Positron emission tomography (PET) and single-photon emission CT (SPECT) may show findings consistent with Parkinson disease, and olfactory testing may provide evidence pointing toward Parkinson disease, but these studies are not routinely needed. (Olfactory testing can reveal hyposmia, which may precede the motor signs of Parkinson disease by several years.[37] However, olfactory loss is not specific and can also occur in Alzheimer disease.)

No laboratory or imaging study is required in patients with a typical presentation. Such patients are aged 55 years or older and have a slowly progressive and asymmetric parkinsonism with resting tremor and bradykinesia or rigidity. Patients who do not have tremor should generally be considered for MRI evaluation to exclude brain lesions such as stroke, tumor, or demyelination.

In patients with an unusual presentation, diagnostic testing may be indicated to exclude other disorders in the differential diagnosis. Such tests may include serum ceruloplasmin, sphincter electromyography, or lumbar puncture.

Serum ceruloplasmin concentration is obtained as a screening test for Wilson disease in patients younger than 40 years who present with parkinsonian signs. If the ceruloplasmin level is low, measurement of 24-hour urinary copper excretion and slit-lamp examination for Kayser-Fleischer rings must be performed. Abnormal results on urinary sphincter electromyography have been noted in patients with multiple system atrophy (MSA).

A substantial and sustained response to dopamine medications (dopamine agonists or levodopa) helps confirm a diagnosis of Parkinson disease. It is unclear whether acute levodopa or apomorphine challenge has any advantage over clinical diagnostic criteria.[22] Over time, diagnostic accuracy improves as the progression of signs and symptoms and response to medications unfolds.

In the general community, there is a high diagnosis error rate between Parkinson disease and essential tremor. For movement disorder neurologists, when an erroneous diagnosis of Parkinson disease is made, the most likely correct diagnoses are the atypical parkinsonisms (MSA, progressive supranuclear palsy [PSP], corticobasal ganglionic degeneration [CBD]). Early in the disease course, it may be very difficult to distinguish between Parkinson disease and the atypical parkinsonisms. These disorders also do not have laboratory biomarkers, and, therefore, distinguishing among them is based on clinical criteria. Olfactory testing may help differentiate Parkinson disease from PSP and CBD, but olfaction is also reduced in MSA.

Radiologic Studies

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is useful to exclude strokes, tumors, multi-infarct state, hydrocephalus, and the lesions of Wilson disease. MRI should be obtained in patients whose clinical presentation does not allow a high degree of diagnostic certainty, including those who lack tremor, have an acute or stepwise progression, or are younger than 55 years.

The following MRI indicates where a thalamic stimulator is typically placed.

Axial, fast spin-echo inversion recovery magnetic Axial, fast spin-echo inversion recovery magnetic resonance image at the level of the posterior commissure. The typical target for placing a thalamic stimulator is demonstrated (cross-hairs).

Below is a coronal MRI following bilateral subthalamic nuclei deep brain stimulation.

Postoperative coronal magnetic resonance image (MR Postoperative coronal magnetic resonance image (MRI) demonstrating desired placement of bilateral subthalamic nuclei-deep brain stimulation (STN-DBS) leads.

PET and SPECT scanning

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scanning are useful diagnostic imaging studies, but these are not routinely required. Different radioligands permit imaging of different components or abnormalities within the brain.

At the onset of motor signs, patients with Parkinson disease show an approximately 30% decrease in18 F-dopa (fluorodopa) uptake on PET imaging in the contralateral putamen.18 F-Dopa is taken up by the terminals of dopamine neurons and converted to18 F-dopamine. The rate of striatal18 F accumulation reflects transport of18 F-dopa into dopamine neurons and its decarboxylation to18 F-dopamine, which is stored in dopamine nerve terminals in the striatum. Thus,18 F-dopa PET imaging provides an index of remaining dopamine neurons. However, this study is not widely available, is usually not covered by insurance, and is currently generally considered a research tool.

Carbon-11 (11 C)-nomifensine and cocaine analogues such as123 I-beta-CIT (iodine-123-labeled carboxymethoxy-3beta-4-iodophenyl-nortropane) and123 I-FP-CIT (fluoropropyl-CIT) bind to dopamine reuptake sites on nigrostriatal terminals and provide an index of the remaining dopamine neurons. Ioflupane (123 I) (DaTscan) is a radiopharmaceutical agent that is indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adults with suspected Parkinsonian syndromes (PSs). This agent may be used to help differentiate essential tremor from tremor due to PSs (idiopathic Parkinson disease [IPD] and Parkinson-plus syndromes [PPS]).[1] Analysis of data from 2 clinical trials demonstrated that the use of ioflupane with iodine-123 and single-photon emission computed tomography (SPECT) scanning to diagnose early-stage Parkinson's disease performed as well as clinical assessment at 1-year follow-up.[38, 39]

Deficits on123 I SPECT scans indicate a dopamine deficiency syndrome but do not differentiate Parkinson disease from atypical parkinsonisms, including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Ioflupane SPECT imaging reveals a dopamine deficiency in Parkinson disease, MSA, PSP, corticobasal ganglionic degeneration, and Lewy body disease. This study is normal in essential tremor, dystonic tremor, medication-induced parkinsonism or tremor, psychogenic disorders, and in normal individuals.

Histologic Findings

Classic pathologic findings in Parkinson disease include degeneration of the neurons containing neuromelanin, especially in the substantia nigra and the locus ceruleus. Surviving neurons often contain eosinophilic cytoplasmic inclusions called Lewy bodies (see the following image). The primary biochemical defects are loss of striatal dopamine, which results from degeneration of dopamine-producing cells in the substantia nigra, as well as hyperactivity of the cholinergic neurons in the caudate nucleus.

Lewy bodies are intracytoplasmic eosinophilic incl Lewy bodies are intracytoplasmic eosinophilic inclusions, often with halos, that are easily seen in pigmented neurons, as shown in this histologic slide. They contain polymerized alpha-synuclein; therefore, Parkinson disease is a synucleinopathy.
Lewy bodies in the locus coeruleus from a patient Lewy bodies in the locus coeruleus from a patient with Parkinson disease.

Alpha-synuclein is a major structural component of Lewy bodies; all Lewy bodies stain for alpha-synuclein, and most also stain for ubiquitin. Lewy bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos and dense cores. The presence of Lewy bodies within pigmented neurons of the substantia nigra is characteristic, but not pathognomonic, of Parkinson disease. Lewy bodies are also found in the cortex, nucleus basalis, locus ceruleus, intermediolateral column of the spinal cord, and other areas.

According to the Braak hypothesis, Lewy body pathology in the brain begins in the olfactory bulb and lower brainstem and slowly ascends to affect dopamine neurons in the substantia nigra and, ultimately, the cerebral cortex.[40] Lewy body pathology is also observed in autonomic nerves of the gut and heart.

Lumbar Puncture

Lumbar puncture should be considered if signs of normal-pressure hydrocephalus (NPH) are observed (eg, incontinence, ataxia, dementia). In NPH, clinical signs characteristically improve after removal of about 20 mL of cerebrospinal fluid.

Dopa-responsive dystonia should be considered in patients with juvenile-onset dystonia and parkinsonism, particularly with diurnal fluctuations in symptoms. In such patients, a trial of levodopa is critical. Additional tests for this condition include measurement of CSF concentrations of biopterin, neopterin, and the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). In both forms of dopa-responsive dystonia, an altered pattern of decreases in these compounds is observed.

In the "Parkinson's Progression Markers Initiative" cross-sectional study of 63 drug-naive patients with early-stage PD and 39 healthy controls, CSF levels of the Alzheimer's biomarkers β-amyloid 1-42 (Aβ1-42), total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and α-synuclein were lower in the PD patients than in the controls. Aβ1-42 and P-tau181 were significant predictors of Parkinson's disease, and T-tau and α-synuclein were associated with the severity of motor dysfunction. In particular, lower Aβ1-42 and P-tau181 concentrations were associated with the postural instability–gait disturbance–dominant PD phenotype, but were not associated with the tremor-dominant or intermediate phenotypes.[41, 42]

See Lumbar Puncture for detailed information on indications for the procedure, contraindications, and a step-by-step discussion containing images and video on how to perform the procedure.

 

Treatment

Approach Considerations

The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects. Studies demonstrate that a patient's quality of life deteriorates quickly if treatment is not instituted at or shortly after diagnosis.[43]

Symptomatic and neuroprotective therapy

Pharmacologic treatment of Parkinson disease can be divided into symptomatic and neuroprotective (disease modifying) therapy. At this time, there is no proven neuroprotective or disease-modifying therapy.

Levodopa, coupled with carbidopa, a peripheral decarboxylase inhibitor (PDI), remains the gold standard of symptomatic treatment for Parkinson disease. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic circulation, allowing for greater levodopa distribution into the central nervous system. Levodopa provides the greatest antiparkinsonian benefit for motor signs and symptoms, with the fewest adverse effects in the short term; however, its long-term use is associated with the development of motor fluctuations (“wearing-off”) and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve.

Monoamine oxidase (MAO)-B inhibitors can be considered for initial treatment of early disease. These drugs provide mild symptomatic benefit, have excellent adverse effect profiles, and, according to a Cochrane review, have improved long-term outcomes in quality-of-life indicators by 20-25%.[44]

Dopamine agonists (ropinirole, pramipexole) provide moderate symptomatic benefit and delay the development of dyskinesia compared with levodopa. Proactively screen patients receiving oral dopamine agonists for adverse events. A review of the Cochrane and PubMed databases from 1990 to 2008 found that these agents caused a 15% increase in adverse events such as somnolence, sudden-onset sleep, hallucinations, edema, and impulse control disorders (eg, pathologic gambling, shopping, and Internet use; hypersexuality; and hoarding).[45] Note that patients may be reluctant to mention these events or may not attribute them to their treatment.

Symptomatic anti-Parkinson disease medications usually provide good control of motor signs of Parkinson disease for 4-6 years. After this, disability often progresses despite best medical management, and many patients develop long-term motor complications, including fluctuations and dyskinesias. Additional causes of disability in late disease include postural instability (balance difficulty) and dementia. Thus, symptomatic therapy for late disease requires different strategies.

Neuroprotective therapy aims to slow, block, or reverse disease progression; such therapies are defined as those that slow underlying loss of dopamine neurons. Although no therapy has been proven to be neuroprotective, there remains interest in the long-term effects of MAO-B inhibitors. Other agents currently under investigation include creatine and isradipine.

The younger the patient, the more emphasis the authors place on long-term considerations to guide early treatment. Young patients have a longer life expectancy and are more likely to develop motor fluctuations and dyskinesias. For older patients and those with cognitive impairment, less emphasis is placed on long-term considerations; instead, the focus is on providing adequate symptomatic benefit in the near term, with as few adverse effects as possible.

For patients who have motor fluctuations and dyskinesias that cannot be adequately managed with medication manipulation, surgery is considered. The principal surgical option is deep brain stimulation (DBS), which has largely replaced neuroablative lesion surgeries. Levodopa/carbidopa intestinal gel infusion is available in some countries and is in clinical trials in others, including the United States.[12]

Nonmotor symptoms

It is now recognized that in Parkinson disease, nonmotor symptoms may be as troublesome as, or more troublesome than, motor symptoms. Nonmotor symptoms can be categorized as autonomic, cognitive/psychiatric, and sensory[46] and may include depression, dementia, hallucinations, rapid eye movement (REM) sleep behavior disorder (RMD), orthostatic hypotension, and constipation. Nonmotor symptoms can also fluctuate, especially depression, pain, numbness, paresthesia/dysesthesia, akathisia, and restless-legs syndrome. Recognition of nonmotor symptoms of Parkinson disease is essential for appropriate management.[46]

Screen Parkinson disease patients for depression, and treat it when present. An evidence-based guideline from the American Academy of Neurology (AAN) reports that physician recognition of depression is low in Parkinson disease, at less than 30% of clinically proven cases. There are many factors that confound its diagnosis in these patients; and depression has the single largest effect on the quality of life of patients with Parkinson disease.[26, 47]

In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations included the following[48] :

  • Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction

  • Polyethylene glycol may be considered to treat constipation

  • Modafinil should be considered for patients who subjectively experience excessive daytime somnolence

  • For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters that are not affected by motor symptoms; evidence is also insufficient to support or refute the use of melatonin for poor sleep quality

  • Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but there are insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that of restless-legs syndrome

  • Methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction)

  • Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, anxiety, and RMD

Symptomatic Therapy, Early Disease

Medications commonly used for symptomatic benefit of motor symptoms in early Parkinson disease include levodopa, monoamine oxidase (MAO)-B inhibitors, and dopamine agonists.

Levodopa

Levodopa, coupled with a peripheral dopa decarboxylase inhibitor such as carbidopa, remains the standard of symptomatic treatment for Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short term. However, long-term use of levodopa is associated with the development of fluctuations and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve. These adverse effects are the reason to consider delaying the initiation of levodopa if other alternatives are able to control symptoms.

Levodopa/carbidopa is introduced at a low dose and escalated slowly. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic circulation, allowing for greater levodopa delivery into the central nervous system.

Currently available levodopa preparations in the United States include levodopa/carbidopa immediate-release (IR) tablets (Sinemet), levodopa/carbidopa controlled-release (CR) tablets (Sinemet CR), and levodopa/carbidopa orally disintegrating tablets (Parcopa). The orally disintegrating tablet is bioequivalent to oral levodopa/carbidopa IR, but it dissolves on the tongue without the need to swallow it with water. The orally disintegrating tablet is not absorbed in the mouth but travels in the saliva to absorption sites in the proximal small bowel (where other levodopa preparations are also absorbed).

Levodopa/carbidopa is also available in combination with entacapone, a catechol-O-methyltransferase (COMT) inhibitor. When entacapone is given in conjunction with levodopa and carbidopa, plasma levels of levodopa are higher and more sustained than after administration of levodopa and carbidopa alone. Levodopa/carbidopa/entacapone is useful in advanced Parkinson disease in patients with motor fluctuations. In the STRIDE-PD (STalevo Reduction In Dyskinesia Evaluation) study, patients with early Parkinson disease treated with levodopa/carbidopa/entacapone (Stalevo) developed more dyskinesia than patients treated with levodopa/carbidopa; therefore, levodopa/carbidopa/entacapone is not recommended for treatment of early disease.[49]

Levodopa in combination with a dopa decarboxylase inhibitor is started at a low dose and slowly titrated to control clinical symptoms. Most patients experience a good response on a daily levodopa dosage of 300–600 mg/day (usually divided 3 or 4 times daily) for 3–5 years or longer. Doses higher than those necessary to control symptoms adequately should be avoided, because higher doses increase the risk for the development of dyskinesia.[50] If nausea occurs, the levodopa dose can be taken immediately following a meal. Additional measures to alleviate nausea include adding extra carbidopa or introducing domperidone (available outside the United States). Other side effects include dizziness and headache. In elderly patients, confusion, delusions, agitation, hallucinations, and psychosis may be more commonly seen.

MAO-B inhibitors

MAO-B inhibitors, such as selegiline and rasagiline, may be used for early symptomatic treatment of Parkinson disease. These medications provide mild symptomatic benefit, have excellent adverse effect profiles, and may improve long-term outcomes. These characteristics make MAO-B inhibitors a good choice as initial treatment for many patients. When the MAO-B inhibitor alone is not sufficient to provide good control of motor symptoms, another medication (eg, a dopamine agonist or levodopa) can be added.

Selegiline is indicated as adjunctive therapy (5 mg every morning; maximum, 10 mg/day) in the treatment of Parkinson disease in patients being treated with levodopa/carbidopa. Rasagiline is indicated for the treatment of the signs and symptoms of Parkinson disease as initial monotherapy (1 mg/day) and as adjunctive therapy (0.5-1.0 mg/day) to levodopa. Potential side effects include nausea, headaches, and dizziness.

Dopamine agonists

Initial treatment with a dopamine agonist, to which levodopa can be added as necessary, is associated with fewer motor fluctuations and dyskinesias than levodopa alone in prospective, double-blind studies. Subsequent analyses of these studies indicate that the benefit of dopamine agonists in delaying motor symptoms is due to their ability to delay the need for levodopa/carbidopa.[51, 52] Commonly used dopamine agonists include pramipexole and ropinirole.

Dopamine agonists provide symptomatic benefit that is comparable to that with levodopa/carbidopa in early disease, but these agents lack sufficient efficacy to control signs and symptoms by themselves in more advanced disease. Dopamine agonists provide moderate symptomatic benefit and rarely cause fluctuations and dyskinesias by themselves, but they have more adverse effects than levodopa, including sleepiness, hallucinations, edema, and impulse control disorders. However, these adverse effects resolve upon lowering the dose or discontinuing the medication.

Dopamine agonists are commonly reserved for younger individuals (< 65-70 years) who are cognitively intact. When the dopamine agonist (with or without an MAO-B inhibitor) no longer provides good control of motor symptoms, levodopa can be added. However, dopamine agonists may provide good symptom control for several years before levodopa is required.

For patients aged 65-70 years, the authors make a judgment based on general health and cognitive status. The more robust and cognitively intact the patient, the more likely the authors are to treat with a dopamine agonist before levodopa and add levodopa/carbidopa when necessary. For patients with cognitive impairment and those older than 70 years—who may be prone to adverse effects, such as hallucinations, from dopamine agonists—and for those likely to require treatment for only a few years, the authors may elect not to use a dopamine agonist and instead depend on levodopa/PDI (peripheral decarboxylase inhibitor) as primary symptomatic therapy.

When introducing a dopamine agonist, it is important to start at a low dose and escalate slowly. The dose should be titrated upward until symptoms are controlled, the maximum dose is reached, or adverse effects emerge.

The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension, hallucinations, somnolence, and impulse control disorders. Nausea can usually be reduced by having the patient take the medication after meals. Domperidone, a peripheral dopamine agonist available outside the United States, is very helpful in relieving refractory nausea.

Patients on dopamine agonists should be routinely asked about sleepiness, sudden onset of sleep, and impulse control disorders such as pathologic gambling, shopping, internet use, and sexual activity. These adverse effects typically resolve with reduction in dose or discontinuation of the medication. Patients should be warned not to drive if they are experiencing undue sleepiness. They should also be warned about the possibility of impulse control disorders and the need to let their physician know if such an effect occurs.

Anticholinergic agents

Anticholinergic agents can be used for patients who have disability due to tremor that is not adequately controlled with dopaminergic medication, but these are not first-line drugs, because of their limited efficacy and the possibility of neuropsychiatric side effects. Anticholinergic medications provide good tremor relief in approximately 50% of patients but do not meaningfully improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication but not another, a second anticholinergic agent usually can be tried if the first is not successful. These medications should be introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion, and hallucinations. Adverse cognitive effects are relatively common, especially in elderly persons.

One of the most commonly used anticholinergic is trihexyphenidyl. The initial dose of trihexyphenidyl should be low and gradually increased. It is recommended to begin therapy with a single 1-mg dose. Dosage can be titrated by 1 mg each week or so, until a total of 4-6 mg is given daily or until satisfactory control is achieved. Some patients may require higher doses. Benztropine (Cogentin) is also commonly used, with an initial dose of 0.5-1 mg daily at bedtime. Dose can be titrated at weekly intervals in increments of 0.5 mg to a maximum of 6 mg/day.

Amantadine

Amantadine is an antiviral agent that has antiparkinsonian activity. Its mechanism of action is not fully understood, but amantadine appears to potentiate CNS dopaminergic responses. It may release dopamine and norepinephrine from storage sites and inhibit the reuptake of dopamine and norepinephrine. Amantadine may offer additional benefit in patients experiencing maximal or waning effects from levodopa.

Amantadine is commonly introduced at a dose of 100 mg per day and slowly increased to an initial maintenance dose of 100 mg 2 or 3 times daily. The most concerning potential side effects of amantadine are confusion and hallucinations. Common side effects include nausea, headache, dizziness, and insomnia. Less frequently reported side effects include anxiety and irritability, ataxia, livedo reticularis, peripheral edema, and orthostatic hypotension.

In a small, double-blind crossover study, amantadine was found to ameliorate pathologic gambling associated with Parkinson disease.[53] However, in a large cross-sectional study, amantadine was associated with a higher prevalence of impulse control disorders, including gambling.[54] Thus, further research is needed to understand the role of amantadine as a treatment or cause of impulse control disorders in patients with Parkinson disease.

Symptomatic Therapy, Advanced Disease

Motor fluctuations

Patients initially experience stable, sustained benefit through the day in response to levodopa. However, after several months to years, many patients notice that the benefit from immediate-release (IR) levodopa/carbidopa wears off after 4-5 hours. Over time, this shortened duration of response becomes more fleeting, and clinical status fluctuates more and more closely in concert with peripheral levodopa concentration. Ultimately, benefit lasts only about 2 hours. The time when medication is providing benefit for bradykinesia, rigidity, and tremor is called "on" time, and the time when medication is not providing benefit is called "off" time.

Treating motor fluctuations in the absence of peak-dose dyskinesia is relatively easy. Several different strategies, either alone or in combination, can be used to provide more sustained dopaminergic therapy. Possible strategies include the following:

  • Adding a dopamine agonist, catechol-O -methyltransferase (COMT) inhibitor, monoamine oxidase (MAO)-B inhibitor, or selective adenosine antagonist

  • Dosing levodopa more frequently

  • Increasing the levodopa dose

  • Adding intermittent levodopa inhaled doses

  • Switching from immediate-release (IR) to sustained-release (CR) levodopa/carbidopa or levodopa/carbidopa/entacapone

  • Continuous intrajejunal infusion of a carbidopa/levodopa enteral suspension[55]

In January 2015, the FDA approved a carbidopa/levodopa enteral suspension (Duopa) that is infused into the jejunum by a portable pump. The efficacy of the enteral suspension to decrease off-time and increase on-time was shown in a multicenter, international study. From baseline to 12 weeks, mean off-time decreased by 4.04 hours for 35 patients allocated to the levodopa/carbidopa intestinal group compared with a decrease of 2.14 hours for 31 patients allocated to immediate-release oral levodopa/carbidopa (p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 hours in the intestinal gel group and 2.24 hours in the immediate-release oral group (p=0.0059).[55]

Safinamide (Xadago), a MAO-B inhibitor, was approved by the FDA in March 2017 as add-on treatment for patients with Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. It is the first new chemical entity approved in the United States in more than 10 years. Approval was based on 2 phase-III trials that included nearly 1200 patients who had PD with motor fluctuations. Results showed that safinamide as add-on treatment to levodopa/carbidopa provided a significant reduction in off-time and a significant increase in on-time without troublesome dyskinesia in patients experiencing motor fluctuations.[56, 57]

Levodopa inhaled (Inbrija), a dopamine agonist, was approved in December 2018 for intermittent treatment of "off" episodes in patients who are already treated with oral carbidopa/levodopa. The inhaled dosage form bypasses the digestive system, thereby providing a quick onset of action as soon as 10 minutes. Approval was based on the phase 3 SPAN-PD trial (N = 339). The change at week 12 in UPDRS III score was -9.83 for patients receiving the 84-mg dose compared with -5.91 for the group taking placebo (P = 0.009).[58]

Istradefylline (Nourianz), a selective adenosine A2A antagonist, was approved by the FDA in August 2019 as adjunctive treatment to levodopa/carbidopa in adults with PD experiencing “off” episodes. Approval was based on four randomized, placebo-controlled trials (n=1143) in patients stabilized on levodopa/carbidopa with or without other medications for their Parkinson disease. Results showed statistically significant decreases in OFF time in the istradefylline treatment groups compared with placebo.[59, 60, 61]  

Unless limited by the emergence of peak-dose symptoms such as dyskinesia or hallucinations, dopaminergic therapy should be increased until off-time is eliminated. Once-daily formulations of the dopamine agonists ropinirole and pramipexole are now available. These medications appear to provide efficacy and safety similar to the IR formulations that are administered 3 times daily.[62]

Dyskinesia

By several months to years after the introduction of levodopa, many patients develop peak-dose dyskinesia consisting of choreiform, which is twisting/turning movements that occur when levodopa-derived dopamine levels are peaking. At this point, increasing dopamine stimulation is likely to worsen peak-dose dyskinesias, and decreasing dopamine stimulation may worsen Parkinson disease motor signs and increase off time. The therapeutic window lies above the threshold required to improve symptoms (on threshold) and below the threshold for peak-dose dyskinesia (dyskinesia threshold). The therapeutic window narrows over time because of a progressive decrease in the threshold for peak-dose dyskinesia.

Although many patients prefer mild dyskinesia to off time, the clinician should recognize that dyskinesias can be sufficiently severe to be troublesome to the patient, either by interfering with activities or because of discomfort. Asking patients how they feel during both off time and time with dyskinesia is important in titrating medication optimally. Having patients fill out a diary may be helpful; the diary should be divided into half-hour time periods on which the patient denotes whether they are off; on without dyskinesia; on with non-troublesome dyskinesia; or on with troublesome dyskinesia (see the following image). The goal of medical management is to minimize off time and time on with troublesome dyskinesia. Stated another way, the goal is to maximize on time without troublesome dyskinesia.

Parkinson disease diary. The patient or caregiver Parkinson disease diary. The patient or caregiver should place 1 check mark in each half-hour time slot to indicate the patient's predominant response during most of that period. The goal of therapeutic management is to minimize off time and on time with troublesome dyskinesia. Copyright Robert Hauser, 1996. Used with permission.

Treatment of motor fluctuations with dyskinesia

The treatment of patients with both motor fluctuations and troublesome peak-dose dyskinesia can be difficult. The goal of treatment in this situation is to provide as much functional time throughout the day as possible. This is accomplished by maximizing on time without troublesome dyskinesia. An attempt is made to reduce both off time and time with troublesome or disabling dyskinesia. Unfortunately, a decrease in dopaminergic therapy may increase off time, and an increase in dopaminergic therapy may worsen peak-dose dyskinesia.

For patients on the levodopa/carbidopa CR formulation, switching to levodopa/carbidopa IR often provides a more consistent and predictable dosing cycle and allows finer titration. In general, smaller levodopa doses are administered more frequently. A dose should be sought that is sufficient to provide benefit without causing troublesome dyskinesia. The time to wearing-off then determines the appropriate interdose interval. The extreme of this strategy is using liquid levodopa, a solution with which the dose can be titrated finely and administered every hour.

COMT inhibitors inhibit the peripheral metabolism of levodopa to 3-O -methyldopa (3-OMD), thereby prolonging the levodopa half-life and making more levodopa available for transport across the blood-brain barrier over a longer period. Because of the potential risk of hepatotoxicity with tolcapone (Tasmar), liver function test monitoring is required, and this medication should be used only in patients who are experiencing motor fluctuations on levodopa that cannot be adequately controlled with other medications. If dyskinesia occurs, the levodopa dose should be reduced. In patients who already have dyskinesia, the levodopa dose often is reduced by 30-50% at the time tolcapone is introduced.

Entacapone (Comtan) is a COMT inhibitor that does not cause hepatotoxicity; liver function tests are not required with this medication. Levodopa/carbidopa/entacapone (Stalevo) is currently available as a drug combination for Parkinson disease.

Similarly, dopamine agonists can be added to levodopa to try to smooth the response. If the patient has both fluctuations and dyskinesias on levodopa, adding a dopamine agonist is likely to decrease the disease severity and could delay dyskinesias and motor fluctuations; then, an attempt can be made to lower the levodopa dose.

The FDA approved amantadine (Gocovri) extended-release (ER) capsules for the treatment of dyskinesia in Parkinson disease patients receiving levodopa-based therapy, with or without concomitant dopaminergic medications. Amantadine ER, previously known as ADS-5102, is the first drug FDA-approved for this indication.

The safety and efficacy of amantadine ER was seen in two Phase 3 controlled trials in Parkinson disease patients with dyskinesia. In the Easy LID trial, amantadine ER-treated patients had statistically significant and clinically relevant reductions in dyskinesia as per the Unified Dyskinesia Rating Scale (UDysRS) total score vs. placebo at Week 12 (37% vs. 12%). In the Easy LID 2 trial, amantadine ER-treated patients had a 46% reduction in UDysRS compared with 16% in the placebo arm. For both studies, treatment with amantadine ER increased functional time daily (ON time without troublesome dyskinesia) for patients at Week 12 (3.6 hours and 4.0 hours, respectively) vs. placebo (0.8 hour and 2.1 hours, respectively).[63, 64]

This should be considered for patients who have clinically relevant dyskinesia and who appear likely to be able to tolerate this medication. Results from the 3-month, parallel-group, washout AMANDYSK (AMANtadine for DYSKinesia) study showed that amantadine treatment maintained its antidyskinetic effect over several years in patients with Parkinson disease and levodopa-induced dyskinesia.[65, 66]

The principal side effects of amantadine are hallucinations and confusion, so the drug is usually not appropriate for patients with preexisting cognitive dysfunction.

For patients who have motor fluctuations and dyskinesia that cannot be adequately managed with medication manipulation, surgery is considered.

Tremor

Levodopa/carbidopa, dopamine agonists, and anticholinergics each provide good benefit for tremor in approximately 50-60% of patients. If a patient is experiencing troublesome tremor and if symptoms are not controlled adequately with one medication, another should be tried. If the tremor is not controlled adequately with medication, surgical therapy may be considered at any time during the disease.

Bradykinesia

A study published in Neurology found that laser shoes can improve freezing episodes in patients with PD. The shoes are specially designed to emit a laser beam on the ground ahead, providing a visual cue to the patient and a target to aim for. In the study, the shoes cut freezing episodes and their overall duration by 49.5% when patients were off medication and 37.7% when patients were on medication.[67]

Putative Neuroprotective Therapy

Neuroprotective therapies are defined as those that slow underlying loss of neurons. Currently, no proven neuroprotective therapies exist for Parkinson disease. If a neuroprotective therapy were available for Parkinson disease, it would be administered from the time of diagnosis onward. At the current time, the greatest interest in possible neuroprotection resides with the monoamine oxidase (MAO)-B inhibitors, selegiline, and rasagiline. Other agents of interest include creatine and isradipine. Clinical trials have not provided support for neuroprotective effects for vitamin E or coenzyme Q10.

Selegiline

Selegiline (Eldepryl, Zelapar) is an irreversible inhibitor of MAO-B. In humans, brain dopamine is metabolized by MAO-B, and the blockade of this enzyme will reduce the metabolism of dopamine. Selegiline was shown conclusively to delay the need for levodopa therapy in early Parkinson disease, in the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) study.[68, 69] The Parkinson Study Group evaluated the ability of selegiline and tocopherol to delay progression of clinical disability in early Parkinson disease by randomizing 800 patients to receive selegiline (10 mg/day) or placebo and tocopherol (2000 IU/day) or placebo. Patients who received selegiline, with placebo or with tocopherol, experienced a significant delay in the need for levodopa therapy. Patients who received placebo required levodopa at a projected median of 15 months from enrollment, whereas those who received selegiline required levodopa ataprojectedmedianof24monthsafterenrollment.Tocopherolhadnoeffectonprogression of disability.[68, 69]

Because selegiline was observed to provide a small but statistically significant symptomatic (early) benefit, it is not possible to determine whether a neuroprotective effect contributed to the delay in need for levodopa in the DATATOP study.[68, 69]

In another study, patients with early Parkinson disease who received selegiline over a 7-year period experienced less clinical progression and required less levodopa than patients receiving placebo.[70] In this study, patients with early Parkinson disease were randomized to selegiline or placebo, and levodopa was added as needed. After 5 years, patients who were treated with placebo had Unified Parkinson Disease Rating Scale (UPDRS) scores that were 35% higher (worse) than those treated with selegiline, even as they were receiving 19% higher doses of levodopa.[70] This is a striking finding, considering that as monotherapy in early disease, selegiline provides only modest symptomatic improvement.

Selegiline is the medication that first garnered wide interest as a possible neuroprotective agent for Parkinson disease. Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect for dopamine neurons independent of MAO-B inhibition. Selegiline was reported to protect dopamine cells in mice from MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity, even when the agent was administered after a delay sufficient to allow the oxidation of MPTP to MPP+ (1-methyl-4-phenylpyridinium),[71] an effect that cannot be attributed to MAO-B inhibition.

In cell-culture systems, selegiline's neuroprotective effect is mediated by new protein synthesis. Selegiline induces transcriptional events that result in increased synthesis of antioxidant and antiapoptotic proteins. Evidence indicates that one of selegiline's metabolites, desmethylselegiline, is the active agent for neuroprotection. It is possible that selegiline's amphetamine metabolites may interfere with its neuroprotective actions.

Rasagiline

Rasagiline (Azilect) is also an MAO-B inhibitor that exhibits neuroprotective effects in cell culture and animal models. Possible disease-modifying effects of rasagiline were studied in 2 large, delayed-start studies. In such studies, subjects are randomized to treatment with active study medication or to placebo followed by active study medication. This creates 2 phases within the study. In phase I, one group is on placebo, and the other is on active study medication; in phase II, both groups are receiving active study medication. If phase II is long enough to allow full wash-in of symptomatic effects, any differences between the groups at the end of the study should be due to enduring benefits (ie, disease modification) that accrue only to the group that received active study medication during phase I.

Stated another way, in a delayed-start design, half of the subjects in the study take the trial drug from day 1 and the other half take placebo. However, halfway through the study, the placebo group is switched from placebo to the trial drug. If the drug is truly beneficial in slowing progression of the disease, those that started the trial on placebo should never catch up, in terms of disease progression, to those who were given the trial drug from the beginning of the study.

ADAGIO and TEMPO studies

In October 2011, the US Food and Drug Administration’s (FDA’s) Peripheral and Central Nervous System Drugs Advisory Committee voted against approval of an indication for disease-modifying effects for rasagiline. The advisory committee determined that the 2 delayed-start rasagiline studies did not provide compelling evidence that rasagiline slows progression of Parkinson disease. These trials were the ADAGIO (Attenuation of Disease progression with Azilect Given Once-daily)[72, 73] and TEMPO (Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients)[74, 75] studies, which are discussed below.

In the TEMPO study, patients were randomized to treatment with rasagiline 1 mg/day for 12 months; rasagiline 2 mg/day for 12 months; or placebo for 6 months, followed by rasagiline 2 mg/day for 6 months.[74] Rasagiline administered at a dosage of 1 or 2 mg/day for the first 6 months resulted in improved Unified Parkinson Disease Rating Scale (UPDRS) scores relative to placebo; there was also a higher proportion of patients with treatment responses in the active treatment groups than in the placebo group.[74] In addition, both of the rasagiline groups showed significant differences, compared with the placebo group, in the motor and activities of daily living (ADL) subscales of the UPDRS and in the Parkinson Disease Quality of Life (PDQUALIF) scale.[74]

Over the 12 months of the TEMPO study, patients who were initially treated with placebo had a greater progression in clinical symptomatology as assessed by UPDRS scores than did patients who were treated with rasagiline for the full 12 months. This finding suggested that there was an effect over and above a simple symptomatic effect and potentially consistent with a disease-modifying effect.[76] When the TEMPO investigators looked at the long-term (6.5-year follow-up period) outcome of early rasagiline therapy relative to late therapy in early Parkinson disease, patients in the early rasagiline treatment group—who received the drug from the beginning of the TEMPO study—had significantly less worsening of their total UPDRS scores than patients in the delayed-start group, even as investigators added other antiparkinson medications as needed.[75]

In the large and rigorous delayed-start study called ADAGIO, patients with early Parkinson disease were randomized to rasagiline 1 mg/day for 18 months; rasagiline 2 mg/day for 18 months; placebo for 9 months, followed by rasagiline 1 mg/day for 9 months; or placebo for 9 months, followed by rasagiline 2 mg/day for 9 months. Results demonstrated that rasagiline at 1 or 2 mg/day was associated with a slower rate of worsening in the active drug groups, relative to the placebo groups.[73] Over 18 months, rasagiline 1 mg/day started early resulted in less worsening in mean total UPDRS score than when it was started late. However, for the groups that received rasagiline 2 mg/day, there was no difference at 18 months between the early-start and delayed-start groups.[73]

Based on their findings, the ADAGIO investigators concluded that early treatment with rasagiline at a dose of 1 mg/day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg/day did not.[73] They speculated that the effect of the 2-mg dose on symptoms may have masked any disease-modifying effects in patients with mild Parkinson disease; they also noted that it was possible that results with 1 mg/day were false positive, rather than the results with 2 mg/day being false negative.[73]

Thus, there remains interest as to whether selegiline and rasagiline improve long-term outcome for Parkinson disease patients, but this is not definitively proven, and the mechanism is unclear.

Levodopa

Clinical trial data suggest that levodopa therapy in early Parkinson disease can potentially slow progression or has a prolonged effect on the symptoms of the disease.[77] However, neuroimaging studies also indicate that loss of nigrostriatal dopamine nerve terminals may be accelerated or the dopamine terminals may be modified with use of levodopa.[77] In a study by Parkkinen et al that evaluated whether chronic levodopa use accelerates pathologic cerebral processes in parkinsonism, the investigators did not find such a progression based on nigral neuronal count and Lewy body pathology.[78] Nonetheless, the lowest dose that is necessary to maintain good function should be used to avoid motor complications.[23] Additional research is needed to determine whether levodopa accelerates, slows, or has no effect on disease progression.

Dopamine agonists

Dopamine agonists have been used to provide symptomatic relief in early Parkinson disease. In vivo experiments have demonstrated that the ergot and nonergot dopamine agonists protect cultured cells from death due to oxidative damage. Clinical data in patients with early Parkinson disease provide neuroimaging results that suggest a possible neuroprotective effect.[77, 79] Various studies have been conducted with ropinirole and pramipexole; however, definitive neuroprotection cannot be confirmed on the basis of these studies.[80, 81]

Deep Brain Stimulation

Deep brain stimulation (DBS) has become the surgical procedure of choice for Parkinson disease for the following reasons:

  • It does not involve destruction of brain tissue

  • It is reversible

  • It can be adjusted as the disease progresses or adverse events occur

  • Bilateral procedures can be performed without a significant increase in adverse events

Deep brain stimulation, a form of stereotactic surgery, has made a resurgence in the treatment of Parkinson disease largely because long-term complications of levodopa therapy result in significant disability over time. A better understanding of basal ganglia physiology and circuitry and improvements in surgical techniques, neuroimaging, and electrophysiologic recording have allowed surgical procedures to be performed more accurately and with lower morbidity.

Surgery for movement disorders previously involved predominantly destructive lesioning of abnormally hyperactive deep brain nuclei; however, the observation that high-frequency electrostimulation in the ventral lateral nucleus (VL) of the thalamus eliminates tremors in patients undergoing thalamotomy led to investigation of long-term DBS as a reversible alternative to lesioning procedures.

Continued refinement of the knowledge of basal ganglia circuitry and Parkinson disease pathophysiology has narrowed the focus of movement disorder surgery to 3 key gray-matter structures: the thalamus, the globus pallidus, and the subthalamic nucleus (STN). Currently, the STN is the most commonly targeted site for Parkinson disease. (See the following image.)

Sagittal section, 12 mm lateral of the midline, de Sagittal section, 12 mm lateral of the midline, demonstrating the subthalamic nucleus (STN) (lavender). The STN is one of the preferred surgical targets for deep brain stimulation to treat symptoms of advanced Parkinson disease.

DBS surgery includes subthalamic nucleus (STN) stimulation, globus pallidus interna (GPi) stimulation, and thalamic deep brain stimulation (see the following images). The UK National Collaborating Centre for Chronic Conditions notes the following indications for STN and GPi in patients with Parkinson disease[23] :

  • The presence of motor complications refractory to medical therapy

  • The absence of significant comorbidities in a biologically fit individual

  • The absence of significant mental health problems (eg, depression, dementia)

  • Response to levodopa

A key to patient selection is that appropriate patients still experience a good response to levodopa, but that response cannot be adequately maintained through the day or is complicated by excessive dyskinesia.

The deep brain stimulating lead is equipped with 4 The deep brain stimulating lead is equipped with 4 electrode contacts, each of which may be used, alone or in combination, for therapeutic stimulation.
Implantation of the deep brain stimulation (DBS) l Implantation of the deep brain stimulation (DBS) lead.
Insertion of an electrode during deep brain stimul Insertion of an electrode during deep brain stimulation for Parkinson disease.

Thalamic DBS has been used in patients with predominantly severe and disabling tremor.[23] However, this surgery is now rarely used in patients with Parkinson disease, because it has been shown that other symptoms continue to progress, causing significant disability that is not controlled by thalamic DBS.

Recent landmark studies have demonstrated the effectiveness of STN and GPi DBS for appropriate Parkinson disease patients.[82] In a randomized, controlled trial of 255 patients enrolled in the Veterans Affairs (VA) Cooperative Studies Program (CSP) trial for patients with advanced Parkinson disease, bilateral DBS (STN and GPi) was more effective than best medical therapy in improving on time without troublesome dyskinesia, motor function, and quality of life at 6 months; however, DBS was associated with an increased risk of serious adverse events.[83] In the same study, when the 2-year outcomes of 147 patients who received STN DBS and 152 patients who received GPi DBS were compared, motor function and adverse events were not significantly different between the 2 sites.[84] However, those who received STN DBS had a greater reduction in dopaminergic medications, and individuals who received GPi DBS had significantly less depression.[84]

Investigators from the EARLYSTIM Study Group reported that relative to medical therapy alone, STN DBS in conjunction with medical therapy offers benefits earlier in the course of PD, before the appearance of severe disabling motor complications.[85, 86] Moreover, subthalamic stimulation plus medical therapy was superior to medical therapy alone on several key measures of quality of life and motor function. However, 54.8% of the patients in the DBS group suffered serious adverse events, compared to 44.1% of those in the medical-therapy group[85, 86] ; 17.7% of patients suffered serious adverse events related to surgical implantation or the neurostimulation device.

A study by Foltynie assessed 79 consecutive patients who underwent bilateral subthalamic nucleus DBS at the National Hospital for Neurology and Neurosurgery using an MRI-guided surgical technique without microelectrode recording.[87] At a median follow-up period of 12-14 months, a mean improvement of 27.7 points (standard deviation, 13.8) was noted in the off-medication motor part of the Unified Parkinson Disease Rating Scale (UPDRS III), equivalent to a mean improvement of 52%. Significant improvements in dyskinesia duration, disability, and pain were noted. This suggests that in well-selected patients with Parkinson disease, image-guided STN DBS without microelectrode recording can lead to substantial improvements in motor disability and improvements in quality of life, with very low morbidity.

A randomized trial by Moreau et al assessed the effectiveness of the drug methylphenidate in improving gait disorders and freezing of gait in patients with advanced Parkinson disease without dementia who also received subthalamic nucleus stimulation (STN). Eighty-one patients from 13 movement disorders departments in France were randomly assigned to methylphenidate or placebo for 90 days. Compared with patients in the placebo group, patients in the methylphenidate group used fewer steps at 90 days. These results suggest methylphenidate may improve gait hypokinesia and freezing although further study is needed to determine long-term risks.[88]

There is evidence that long-term motor improvement from STN DBS is sustained overall. However, axial signs progressively decline over time and contribute to a waning of the initial benefit of this procedure.[89]

Although not specifically approved by the Food and Drug Administration (FDA) for pain, STN DBS may be effective in improving specific types of pain related to Parkinson disease,[90, 91] such as musculoskeletal pain[90, 92] and dystonic pain. However, there is a risk of postoperative deterioration of somatic pain exacerbated by Parkinson disease and radicular/peripheral neuropathic pain due to lumbar spine diseases. Patients with central pain have had a poor response to STN DBS.[90]

STN DBS may result in either a favorable or an unfavorable outcome in patients with Parkinson disease and impulse control and related disorders.[93] Although there may be resolution or improvement of impulse control disorders following STN DBS, the procedure may also induce, exacerbate, reveal, or have no effect on these conditions.[93]

In 2017, the FDA approved the Vercise DBS system to treat symptoms of Parkinson disease. The device is a rechargeable implantable pulse generator with a potential battery life of 15 years. It has been available in Europe since 2012.[94]

(See Deep Brain Stimulation forParkinson Disease for a more extensive discussion of deep brain stimulation in this setting, including mechanisms of action, advantages and disadvantages, and stages of the procedure.)

Neuroablative Lesion Surgeries

Lesion surgeries involve the destruction of targeted areas of the brain to control the symptoms of Parkinson disease. Lesion surgeries for Parkinson disease have largely been replaced by deep brain stimulation (DBS). During neuroablation, a specific deep brain target is destroyed by thermocoagulation. A radiofrequency generator is used most commonly to heat the lesioning electrode tip to the prescribed temperature in a controlled fashion.

Thalamotomy and pallidotomy

Thalamotomy involves destruction of a part of the thalamus, generally the ventralis intermedius (VIM), to relieve tremor. The VIM nucleus is considered the best target for tremor suppression, with excellent short- and long-term tremor suppression in 80-90% of patients with Parkinson disease. Thalamotomy has little effect on bradykinesia, rigidity, motor fluctuations, or dyskinesia. When rigidity and akinesia are prominent, other targets, including the globus pallidus interna (GPi) and subthalamic nucleus (STN), are preferred.

Svenillson and Leksell described ventral posterior pallidotomy in the 1960s[95] ; however, their report was largely overlooked. The original pallidotomy target was in the medial and anterodorsal part of the nucleus. This so-called medial pallidotomy effectively relieved rigidity but inconsistently improved tremor. Leksell subsequently moved the target to the posteroventral and lateral GPi, resulting in sustained improvement in as many as 96% of patients. In 1992, Laitinen et al reported reduced tremor, rigidity, akinesia, and levodopa-induced dyskinesia in 38 patients treated with pallidotomy, prompting a reappraisal of the procedure performed with more modern techniques.[96]

Pallidotomy involves destruction of a part of the GPi. Pallidotomy studies have demonstrated significant improvements in each of the cardinal symptoms of Parkinson disease (tremor, rigidity, bradykinesia), as well as a significant reduction in dyskinesia.

The most serious and frequent (3.6%) adverse effect of pallidotomy is a scotoma in the contralateral lower-central visual field. This complication occurs when the GPi lesion extends into the optic tract, which lies immediately below the GPi. The risk of visual-field deficit is reduced greatly by accurate delineation of the ventral GPi border by microelectrode recording. Less frequent complications (< 5%) include injury to the internal capsule, facial paresis, and intracerebral hemorrhage (1-2%). Abnormalities of speech, swallowing, and cognition may also be observed.

Bilateral pallidotomy is not recommended because complications are relatively common and include speech difficulties, dysphagia, and cognitive impairment.

Subthalamotomy

Hyperactivity of the excitatory STN projections to the GPi is a crucial physiologic feature of Parkinson disease. Subthalamotomy involves destruction of a part of the STN. Although lesioning the STN usually has been avoided because of the concern about producing hemiballismus, results obtained by experimental lesions of the STN in animals and humans suggest that subthalamotomy may be performed safely and may reverse parkinsonism dramatically. Subthalamotomy studies have shown significant improvements in the cardinal features of Parkinson disease, as well as the reduction of motor fluctuations and dyskinesia.

Preoperative Evaluation

Good surgical outcomes begin with careful patient selection and end with attentive, detail-oriented postoperative care. The authors believe that this level of care is best provided by a multidisciplinary team that includes a movement disorder neurologist, a neurosurgeon who is well-versed in stereotactic technique, a neurophysiologist, a psychiatrist, and a neuropsychologist. Additional support from neuroradiology and rehabilitation medicine is essential.

First, a neurologist with expertise in movement disorders evaluates the patient. Patient selection is particularly important for successful subthalamic nucleus (STN) deep brain stimulation (DBS), because a number of factors determine positive surgical outcome.[97, 98] These can be summarized as follows:

  • A diagnosis of Parkinson disease

  • Positive response to levodopa

  • Absence of atypical parkinsonian features

  • Advanced disease, virtually unmanageable with dopaminergic medications

  • Relatively young age; however, advanced age (>75 years) is not an absolute contraindication to surgery (if a patient otherwise meets the selection criteria for a procedure and the quality of life is predicted to improve substantially, surgery should be offered)

  • No significant cognitive impairment

  • Absence of active psychiatric disease

  • Good social support and access to programming

Potential surgical candidates are then evaluated by the neurosurgeon, who determines whether the patient is indeed a surgical candidate and decides which procedure(s) would benefit the patient most. Close collaboration between the neurologist and the neurosurgeon aids the decision-making process, minimizing patient confusion and stress. If the neurologist and neurosurgeon agree that the patient is a good surgical candidate, further workup includes the following:

  • Brain magnetic resonance imaging (MRI) to rule out comorbid conditions and to assess the degree of brain atrophy; significant atrophy may increase the risk of perioperative hemorrhage

  • Detailed neuropsychological testing to rule out cognitive impairment, which can be worsened by the surgical procedure

A psychiatrist with expertise in psychiatric complications of movement disorders may be consulted to rule out active psychiatric disease and screen for relevant past psychiatric history that may pose a contraindication to surgery (eg, major depression, suicidality).

A fluorodopa positron emission tomography (PET) scan may be performed in the unusual circumstance of diagnostic uncertainty. A medical evaluation is performed to determine the patient's general fitness for surgery.

Surgery is reserved for patients with disabling motor fluctuations and dyskinesia or disabling tremor that cannot be adequately controlled with medications. Key points to consider are as follows:

  • Ablative surgery such as thalamotomy, pallidotomy, and subthalamotomy have largely been replaced by DBS

  • Thalamic DBS is offered to the minority of patients with Parkinson disease who have predominant and disabling tremor (more commonly, this procedure is performed on patients with disabling essential tremor)

  • Bilateral STN DBS (or globus pallidus interna [GPi] DBS) is offered to patients with advanced Parkinson disease with disabling motor fluctuations and/or dyskinesia or disabling tremor that cannot be adequately controlled by medications; outcomes have been shown to be similar after STN and GPi DBS

  • Before surgery, the patient should be informed that these procedures do not cure Parkinson disease and that progression is expected

Neural Transplantation

Neural transplantation is a potential treatment for Parkinson disease, because the most significant neuronal degeneration is site and type specific (ie, dopaminergic); the target area is well defined (ie, striatum); postsynaptic receptors are relatively intact; and the neurons provide tonic stimulation of the receptors and appear to serve a modulatory function.

Transplantation of autologous adrenal medullary cells and fetal porcine cells has not been found to be effective in double-blind studies and has been abandoned. Although open-label studies of fetal dopaminergic cell transplantation yielded promising results, 3 randomized, double-blind, sham-surgery–controlled studies found no net benefit. In addition, some patients receiving these transplants developed a potentially disabling form of dyskinesia that persisted even after withdrawal of levodopa. Features such as gait dysfunction, freezing, falling, and dementia are likely due to nondopaminergic pathology and hence are unlikely to respond to dopaminergic grafts.[99]

Lewy body–like inclusions have been found in grafted nigral neurons in long-term transplant recipients; these inclusions stained positively for alpha-synuclein and ubiquitin and had reduced immunostaining for dopamine transporter, suggesting that Parkinson disease may affect grafted cells.[14]

Human retinal pigment epithelial cells produce levodopa, and retinal pigment epithelial cells in gelatin microcarriers have been implanted into the putamen in preliminary studies. A phase II double-blind, randomized, multicenter, sham-surgery–controlled study of this technique has been completed.[100, 101] Parkinson disease patients received no benefit from this procedure compared to sham surgery. In addition, in one case study, postmortem examination in a patient who died 6 months after surgical implantation of 325,000 retinal pigment epithelial cells found only 118 surviving cells.[102]

Gene Therapy

Several studies have demonstrated the safety of gene therapy as a treatment for Parkinson disease, and larger studies have been initiated to examine the efficacy of this procedure. Three investigational strategies that use gene transfer for targeted protein expression are as follows[103] :

  • Improving dopamine availability to the striatum using more continuous delivery,

  • Reducing STN activity with local induction of gamma-aminobutryic acid (GABA) expression

  • Protection/restoration of nigrostriatal neuronal function with trophic factor expression

A double-blind, phase II, randomized, controlled trial of gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) in Parkinson patients aged 30-75 years suggested mild efficacy. Further studies are ongoing.[104]

Management of Psychiatric Comorbidities

Dementia

Although no specific therapy exists for dementia, the American Academy of Neurology evaluated the evidence regarding the use of cholinesterase inhibitors in Parkinson disease dementia.[105] Based on their review, they suggested that rivastigmine (Exelon) and donepezil (Aricept) are probably effective in treating Parkinson disease dementia. Anticholinergic drugs used for the treatment of motor symptoms of Parkinson disease may exacerbate memory impairment. When possible, avoid these medications.

Depression

Depression is one of the most common nonmotor symptoms of Parkinson disease, occurring in approximately 35% of patients.[106, 107] This condition is more common in patients with Parkinson disease than in the general elderly population and in those with chronic conditions such as osteoarthritis. Depression in Parkinson disease has a profound impact on quality of life and is associated with reduced function, cognitive impairment, and increased caregiver stress.

A systematic review of prevalence studies of depression in Parkinson disease found that 17% of patients present with major depression, 22% with minor depression, and 13% with dysthymia[108] Moreover, multiple studies have found that a history of depression is a risk factor for the subsequent development of Parkinson disease.[109]

Imaging, cerebrospinal fluid, and autopsy studies indicate that depression in Parkinson disease is associated with dysfunction of basal ganglia dopaminergic circuits that project to the frontal lobes, as well as noradrenergic limbic and brainstem structures.[107] Whether serotonin (5-HT) dysfunction plays a role in depression in PD is unclear.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used medications to treat depression in Parkinson disease in clinical practice. However, several randomized controlled trials, systematic reviews, and meta-analyses have suggested that SSRIs may be no more effective than placebo in this situation.[47, 107, 110]

Positive results in randomized clinical trials have been demonstrated for nortriptyline (a tricyclic antidepressant [TCA] with serotoninergic and adrenergic activity), desipramine (a predominantly noradrenergic reuptake inhibitor TCA), venlafaxine (a serotonin-noradrenaline uptake inhibitor), citalopram (an SSRI), and paroxetine (an SSRI).[107] For example, in Parkinson disease patients that were diagnosed with depressive disorder or operationally-defined subsyndromal depression, venlafaxine extended release or paroxetine significantly reduced scores on the Hamilton Rating Scale for Depression compared to placebo. Both venlafaxine and paroxetine were well tolerated and did not worsen motor function.[111]

There is a suggestion that noradrenergic or dual action (noradrenergic/serotoninergic) antidepressants may be more effective for treating depression in Parkinson disease than SSRIs. However, whether this is an artifact of clinical-trials methodology is not yet clear, and more research is necessary.

Antiparkinsonian medications can also exert an antidepressant effect. In a large, randomized trial, pramipexole (mean daily dose, 2.18 mg) significantly reduced depression scores relative to placebo.[112] The monoamine oxidase (MAO)-B inhibitor selegiline was also demonstrated to provide an antidepressant effect in patients with early Parkinson disease who were not clinically depressed.[113]

Preliminary studies suggest that repetitive transcranial magnetic stimulation (rTMS) may be effective for depression in Parkinson disease, but more research is required. Electroconvulsive therapy (ECT) can be considered for refractory moderate to severe depression.

Psychotic symptoms (hallucinations or delusions)

Antiparkinsonian drugs can trigger psychosis in patients with Parkinson disease. In Parkinson disease patients with psychosis, antiparkinsonian medications other than levodopa should be withdrawn in an effort to resolve psychosis while maintaining motor control with levodopa. In individuals with only mild hallucinations that are well tolerated, active antipsychotic treatment may not be necessary.

Pimavanserin (Nuplazid) was approved in April 2016 for treatment of hallucinations and delusions associated with Parkinson disease psychosis. It is the first drug to be approved for this condition. It is a selective serotonin inverse agonists (SSIA). It not only preferentially targets 5-HT2A receptors, but also avoids activity at dopamine and other receptors commonly targeted by antipsychotics. Efficacy was shown in a 6-week clinical trial (n=199), where it was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor Parkinson disease symptoms (p=0.001).[114]

Use of some other typical antipsychotics can exacerbate motor symptoms of Parkinson disease and should be avoided.[23]

Quetiapine is the atypical neuroleptic agent most commonly used by movement-disorder experts, because it rarely exacerbates motor symptoms and blood monitoring is not required. However, its efficacy has not been confirmed in clinical trials. Quetiapine is used in Parkinson disease at doses much lower than those used in schizophrenia. It is usually introduced at a dose of 25 mg at bedtime and can be increased to 50 mg or more at bedtime as necessary.

Clozapine can also be used, but blood monitoring is required due to its potential for agranulocytosis and other severe side effects.[23, 115] For this reason, clozapine is usually reserved for patients who are not adequately controlled with quetiapine. Other atypical neuroleptics generally have more potential to worsen Parkinson disease motor symptoms than quetiapine and clozapine.

Anxiety

The 2010 American Academy of Neurology (AAN) practice parameter on the treatment of nonmotor symptoms in Parkinson disease found insufficient evidence to support or refute the treatment of anxiety in Parkinson disease with levodopa.[48] However, SSRIs and venlafaxine (Effexor, Effexor XR) may be beneficial. Buspirone is well tolerated but has not been studied in this population. Benzodiazepines can be considered, but adverse effects such as cognitive impairment, somnolence, and balance problems may be concerning. Behavior modification techniques can play an important role in the treatment of anxiety.[116]

Impulse behaviors

Cognitive-behavioral therapy (CBT) can help control impulse behaviors in PD. In a study of 45 patients with idiopathic PD and associated impulse control behaviors that had not responded to standard treatment, CBT significantly improved symptom severity, neuropsychiatric disturbances, and depression and anxiety levels. Of the 45 patients, 17 were randomly assigned to a 6-month wait list for CBT along with standard medical care and 28 were randomized to CBT starting immediately. Among the 28 patients in the treatment group, 58% completed all 12 sessions of CBT and 88% completed at least 6. Three-quarters of those receiving the treatment had improved symptom severity compared with only about a third of those who did not receive the therapy.[117, 118]

In a placebo-controlled pilot study of 50 patients with idiopathic PD who developed impulse control disorder (ICD) symptoms while receiving dopamine agonist treatment, Papay and colleagues found that the opioid antagonist naltrexone improved ICD symptoms, as measured on a PD-specific rating scale.[119, 120]

Naltrexone was administered at 50 mg daily for 4 weeks and then increased to 100 mg daily for 4 weeks in nonresponders. The difference in response rate on the Clinical Global Impression-Change (CGI-C) scale between the naltrexone (54.5%) and placebo (34.8%) groups was not significant (P = 0.23). Estimated changes on the patient-completed Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) from baseline to week 8, however, significantly favored naltrexone: a change of 14.9 points for naltrexone vs 7.5 points for placebo (P = 0.04). Nausea and headache were the most common side effects of naltrexone treatment.[119, 120]

Sleep disturbances

Benzodiazepines can be helpful in the treatment of rapid eye movement (REM) sleep behavior disorder (RBD), and obstructive sleep apnea (OSA) can be treated with positive airway pressure with either continuous pressure or bilevel pressure. Sleep hygiene techniques include avoiding stimulants/fluids near bedtime, avoiding heavy late-night meals, and following a regular sleep schedule.[116, 121] It is advised that patients with Parkinson disease and sudden-onset sleep avoid driving and take precautions against potential occupational hazards.[23]

The 2010 AAN practice parameter found insufficient evidence to support or refute beneficial effects from the treatment of RBD in Parkinson disease. Other sleep disorders may benefit from treatment. Levodopa/carbidopa should be considered to treat periodic limb movements of sleep. Modafinil may improve patients’ subjective perceptions of excessive daytime somnolence (EDS), and methylphenidate may be considered in patients with fatigue.[48]

Exercise and Physical Therapy

Exercise therapy in patients with Parkinson disease using a variety of physiotherapy interventions may play a role in improving gait, balance and flexibility, aerobic capacity, initiation of movement, and functional independence. Studies generally have suggested improvement in functional outcomes, but the observed benefits were small in magnitude and were not sustained following discontinuation of the exercise.[81]

A systematic review of 33 randomized trials involving 1518 patients evaluated various physiotherapy interventions, including general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. There were significant improvements for walking speed, walking endurance and step length, mobility (the Timed Up & Go test), and balance. Unified Parkinson’s Disease Rating Scale (UPDRS) scores were also improved with physiotherapy. There was no benefit observed for falls or patient-rated quality of life, and there was no evidence that one type of physiotherapy was superior to others.[122]

There has been a resurgence of interest in the potential benefit of exercise in Parkinson disease, including a possible neuroprotective effect.[123] Vigorous exercise in mid-life is associated with a reduced risk of subsequent Parkinson disease. In animal models, vigorous exercise provides a protective effect against a variety of toxins that cause parkinsonism. In addition, in healthy people, serum brain-derived neurotrophic factor (BDNF) increases after exercise, in proportion to the intensity of the activity. In Parkinson disease, BDNF levels in the substantia nigra are reduced, and in animal models of Parkinson disease, BDNF provides a neuroprotective effect. This is an area of active research.

Speech Therapy

The laryngeal manifestations of Parkinson disease often lead to decreased participation in the activities of daily living because of an inability to communicate effectively. During the course of the disease, 45-89% of patients report speech problems, and more than 30% find speech problems to be the most debilitating part of the disease.

Medications and surgery cannot effectively treat the laryngeal manifestations of Parkinson disease. For this reason, speech therapy plays a key role in the disease's vocal treatment regimen. Speech therapy is effective in treating the laryngeal manifestations of Parkinson disease, but despite the significant number of patients with vocal symptoms, only an estimated 3-4% of patients with Parkinson disease undergo speech therapy.

The Lee Silverman Voice Treatment (LSVT) is a program designed to increase vocal intensity in patients with Parkinson disease. The treatment focuses on a simple set of tasks that are practiced intensively, 4 sessions per week during a 4-week period, resulting in maximization of phonatory and respiratory functions. The goal of LSVT is to improve vocal performance for 6-24 months without interval intervention. LSVT focuses on maximizing vocal effort ("think loud, think shout") and maximizing sensory perception of vocal effort and loudness by therapists. Therapists who quantify results give constant feedback to patients during sessions and encourage patients to self-monitor and internally calibrate their loudness. After LSVT, patients with Parkinson disease speak at a normal volume and with a healthy voice quality despite the need to "think loud, think shout."

In studies with a 2-year follow-up, patients who received LSVT maintained or improved vocal intensity compared with pretreatment levels. Glottal incompetence and swallowing ability both improved after LSVT, without any significant change in supraglottal hyperfunction. Preliminary positron emission tomography (PET) scans after LSVT training in patients with Parkinson disease show reduced activity in the globus pallidus, an effect similar to pallidotomy. LSVT may also stimulate coordination of motor output beyond the phonatory system in the form of increased orofacial expression.

Other therapies have been suggested for the treatment of the vocal symptoms in Parkinson disease, but most data so far support LSVT as the most promising therapy for Parkinson disease laryngeal symptoms. Alternative methods of delivering therapy that do not involve 16 face-to-face sessions with a therapist are currently being studied. These methods incorporate webcam delivery of LSVT (eLOUD) and software programs that patients can perform at home. These technologically enhanced methods, when used to replace half of the face-to-face sessions, have documented outcomes that are equivalent to classic LSVT. The hope is that such alternatives will be implemented to allow a less transportation-intensive therapy course for the patient and to allow follow-up review of the LSVT techniques as needed.

A systematic review of clinical trials of speech and language therapy in Parkinson disease identified 3 randomized controlled trials that included 61 patients. The authors concluded that although improvements were noted, they were not able to conclusively confirm or refute the benefit of speech and language therapy in Parkinson disease due to the small number of patients in these trials, methodologic limitations, and possible publication bias.[124]

Dietary Considerations

Proper nutritional support is essential for patients with Parkinson disease, including adequate dietary fiber to prevent the common problem of constipation. Patients recently diagnosed with Parkinson disease are often confused regarding dietary protein, because they receive conflicting information.

Levodopa is absorbed via a large neutral amino acid active carrier system and therefore competes with dietary proteins for absorption; this effect is generally relatively small and is not clinically important for most patients, especially those with early or moderate disease. However, as the disease progresses and patients become more and more sensitive to maintaining relatively narrow therapeutic serum concentrations of levodopa, this effect can become clinically relevant. These patients usually have significant motor fluctuations. Some report that when they are "on" and they eat a meal including protein, they turn "off." Others find that if they eat a protein meal, their next levodopa dose does not kick in. These patients may benefit from a low protein or a protein redistributed diet.

In a low-protein diet, the total daily protein intake is spread more or less equally over the day. In a protein-redistributed diet, individuals only consume food very low in protein during the day and then eat a high-protein meal in the evening. Unfortunately, these diets are difficult to follow; dietary consultation may be beneficial for patients in whom such diets are considered.

For patients with early and moderate Parkinson disease, the considerations are quite different. As with patients with more advanced Parkinson disease, patients with early and moderate Parkinson disease will get the most complete and consistent absorption of levodopa by taking their levodopa doses a half hour or more before meals or 1 hour or more after meals. However, most patients with early or moderate disease will not notice a difference in clinical benefit, whether they take their levodopa with meals or apart from meals.

Even if there is some reduction in clinical benefit when levodopa is taken with meals, this can be mitigated by increasing the levodopa dose, if necessary. In patients with early disease, the primary concern regarding levodopa is typically nausea, which is less likely to occur if they take their levodopa dose at the completion of meals. Therefore, in early Parkinson disease, it is common to instruct patients to take their levodopa after meals to reduce the likelihood of nausea as the dose is titrated to clinical effect.

Some studies have shown mild motor benefit with Mucuna pruriens (cowhage, velvet bean), which contain levodopa, and Vicia faba (broad or fava bean) may have short-term benefits.[81] However, additional studies are needed.

Vitamin E and coenzyme Q10 have not been shown to have a neuroprotective effect in Parkinson disease,[68, 125] and they are not currently recommended as dietary supplements for this condition.

Consultations

Generally, patients with Parkinson disease are best treated and monitored by a neurologist or movement disorder specialist. Depending on the patient, consultations may include the following:

  • Neurosurgeon

  • Psychiatrist

  • Urologist

  • Physiatrist

  • Nutritionist

  • Otolaryngologist

  • Gastroenterologist

  • Speech therapist

Neurosurgical consultation may be appropriate in patients with tremor, dyskinesias, motor fluctuations, or dystonia refractory to medical treatment. However, patients with dementia or significant psychiatric or behavioral problems are not candidates for current neurosurgical treatments for Parkinson disease.

Psychiatric consultation may be required to control mood disorders and psychiatric symptoms, especially in patients with refractory depression or psychosis.

A urologist is consulted for evaluation and treatment of urinary frequency, urgency, incontinence, or erectile dysfunction.

A physiatrist, physical therapist, or occupational therapist may be able to improve the patient's ability to perform activities of daily living, reduce pain, and avoid fractures and compression neuropathies from falls. Botulinum injections for limb dystonia can be very helpful and are administered by specially trained physiatrists or neurologists.

A nutritionist can help ensure adequate energy intake, particularly when low-protein diets are needed to avoid adverse effects of levodopa.

An otolaryngologist can offer vocal fold bulking procedures in the form of vocal fold injection or Gore-Tex thyroplasty as a possibility in treating refractory true vocal fold bowing. Bilateral injections to medialize the vocal fold can offer improvement, unless the patient is already aphonic due to advanced disease. Bilateral collagen, gel, fat, and hydroxyapatite injections have been used for this purpose.[126] Articulatory problems can persist, and the result of surgery can be disappointing.

A gastroenterologist and a speech therapist may be needed to evaluate dysphagia, a common complication in patients with more advanced Parkinson disease. Excessive sialorrhea can be treated with botulinum toxin injections into the salivary glands, usually administered by neurologists or otolaryngologists. In some patients, a gastrostomy may be needed to maintain adequate nutrition.

Long-Term Monitoring

Patients with Parkinson disease must have regular follow-up care to ensure adequate treatment of motor and behavioral abnormalities. Once patients are stable on a medication regimen, provide follow-up care at least every 3-6 months, and periodically adjust medication dosages as necessary. Patients also need to be monitored for adverse events, including somnolence, sudden-onset sleep, impulse control disorders, and psychosis. In addition, patients should be evaluated and treated for emergence of clinically relevant nonmotor symptoms, including dementia, psychosis, sleep disorders, and mood disorders.

Future Treatments for Parkinson Disease

Future treatments for Parkinson disease are covered in Future Treatments for Parkinson’s Disease: Surfing the PD Pipeline. This article provides a discussion of new therapies in clinical development that may alleviate motor features or slow disease progression, including A2a antagonists, levodopa formulations, other antiparkinsonian medications, antidyskinesia medications, and gene therapy.[127]

 

Guidelines

Guidelines Summary

American Academy of Neurology (AAN)

In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations included the following[48] :

  • Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction

  • Polyethylene glycol may be considered to treat constipation

  • Modafinil should be considered for patients who subjectively experience excessive daytime somnolence

  • For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters that are not affected by motor symptoms; evidence is also insufficient to support or refute the use of melatonin for poor sleep quality

  • Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but there are insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that of restless-legs syndrome

  • Methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction)

  • Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, anxiety, and RMD

 

Medication

Medication Summary

The cornerstone of symptomatic treatment for Parkinson disease (PD) is dopamine replacement therapy. The criterion standard of symptomatic therapy is levodopa (L-dopa), the metabolic precursor of dopamine, in combination with carbidopa, a peripheral decarboxylase inhibitor (PDI). This combination provides the greatest symptomatic benefit with the fewest short-term adverse effects.

Dopamine agonists such as pramipexole and ropinirole can be used as monotherapy to improve symptoms in early disease or as adjuncts to levodopa in patients whose response to levodopa is deteriorating and in those who are experiencing fluctuations in their response to levodopa.

Monoamine oxidase (MAO)-B inhibitors (eg, rasagiline, safinamide, selegiline) provide symptomatic benefit as monotherapy in early disease and as adjuncts to levodopa in patients experiencing motor fluctuations.

Catechol-O -methyl transferase (COMT) inhibitors inhibitors such as entacapone and tolcapone may be used to increase the peripheral half-life of levodopa, thereby delivering more levodopa to the brain over a longer time.

Anticholinergic medications can be used for the treatment of resting tremor. However, they are not particularly effective for bradykinesia, rigidity, gait disturbance, or other features of advanced Parkinson disease; and cognitive side effects are common. Therefore anticholinergics are usually reserved for the treatment of tremor that is not adequately controlled with dopaminergic medications.

Pimavanserin is the first medication approved by the FDA for hallucinations and delusions associated with PD. It is a selective serotonin inverse agonists (SSIA) which preferentially targets 5-HT2A receptors and avoids activity at dopamine and other receptors commonly targeted by antipsychotics.

Dopamine Agonists

Class Summary

Dopamine agonists are effective as monotherapy in early PD and as adjuncts to levodopa/PDI (peripheral decarboxylase inhibitor) in moderate to advanced disease. Dopamine agonists directly stimulate postsynaptic dopamine receptors to provide antiparkinsonian benefit. All available dopamine agonists stimulate D2 receptors, an action that is thought to be clinically beneficial. The role of other dopamine receptors is currently unclear.

Dopamine agonists are effective to treat motor features of early PD, and they cause less development of motor fluctuations and dyskinesia than levodopa. For patients with motor fluctuations on levodopa/PDI, the addition of a dopamine agonist reduces off time, improves motor function, and allows lower levodopa doses.

Carbidopa/levodopa (Sinemet, Sinemet CR, Rytary, Duopa)

Carbidopa/levodopa is approved for the treatment of symptoms of idiopathic PD, postencephalitic parkinsonism, and symptomatic parkinsonism that may follow injury to the nervous system by carbon monoxide and/or manganese intoxication. Levodopa, combined with a peripheral decarboxylase inhibitor (PDI) such as carbidopa, is the criterion standard of symptomatic treatment for PD; it provides the greatest antiparkinsonian efficacy in moderate to advanced disease with the fewest acute adverse effects. When administered alone, levodopa causes a high incidence of nausea and vomiting due to the formation of dopamine in the peripheral circulation. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the peripheral circulation thereby reducing nausea and allowing for greater levodopa distribution into the CNS. Carbidopa does not cross the blood-brain barrier.

Sustained-release capsules (Rytary) may improve drug delivery for patients unable to swallow effectively. The capsule may be either swallowed whole or opened and sprinkled on a small amount of applesauce for immediate consumption.

An enteral suspension (Duopa) is administered by a portable pump into the jejunum over a 16-hr period to improve on-time and decrease off-time in patients with motor fluctuations with advanced Parkinson disease.

Levodopa inhaled (Inbrija)

Powder for inhalation is systemically absorbed via lungs, and therefore bypasses GI absorption, which may be variable in patients with PD. Levodopa, the metabolic precursor of dopamine, crosses the blood-brain barrier and is converted to dopamine in the brain. It is indicated for intermittent treatment of "off" episodes in patients with Parkinson disease who are taking oral carbidopa/levodopa.

Apomorphine (Apokyn)

Apomorphine is a nonergoline dopamine agonist indicated for the acute, intermittent treatment of hypomobility "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) associated with advanced PD. It is administered by a subcutaneous injection. Although the exact mechanism by which apomorphine exerts its therapeutic effects in PD is unknown, it is thought to occur via activation of postsynaptic D2 receptors in the striatum.

Pramipexole (Mirapex, Mirapex ER)

Pramipexole is approved as monotherapy in early disease and as adjunctive therapy to levodopa/PDI in more advanced stages. The mechanism of action of pramipexole as a treatment for PD is unknown, although it is believed to be related to its ability to stimulate D2 dopamine receptors in the striatum. It is available as an immediate-release and an extended-release tablet.

Ropinirole (Requip and Requip XL)

Ropinirole is approved as monotherapy in early disease and as adjunctive therapy to levodopa/PDI in more advanced disease. Ropinirole is a nonergot dopamine agonist that has high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors; it binds with higher affinity to D3 than to D2 or D4 receptor subtypes. The mechanism of action of ropinirole is stimulation of dopamine D2 receptors in striatum. It is available as an immediate-release and an extended-release tablet.

Amantadine (Gocovri)

Amantadine is approved for the treatment of idiopathic PD, postencephalitic parkinsonism, and symptomatic parkinsonism, which may follow injury to the nervous system by carbon monoxide intoxication. The extended-release capsule is indicated for dyskinesia in patients with PD. Amantadine is available as a syrup, tablet, capsule, and an extended-release capsule. The exact mechanism of amantadine for the treatment of PD and dyskinesia associated with PD is unknown. Amantadine is a weak, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.

Rotigotine (Neupro)

Dopamine agonist stimulating D3, D2, and D1 receptors. Improvement in Parkinson-related symptoms thought to be its ability to stimulate D2 receptors within the caudate putamen in the brain. Indicated for the treatment of the signs and symptoms of idiopathic Parkinson disease (PD). Dosage ranges differ for early-stage PD and advanced-stage PD. Available as transdermal patch that provides continuous delivery for 24 h

Anticholinergic

Class Summary

Anticholinergics are commonly used as symptomatic treatment of PD, both as monotherapy and as part of combination therapy. Anticholinergic agents provide benefit for tremor in approximately 50% of patients but do not substantially improve bradykinesia or rigidity. If one anticholinergic does not work, try another.

Trihexyphenidyl

Trihexyphenidyl is indicated as an adjunct for all forms of parkinsonism (postencephalitic, arteriosclerotic, and idiopathic). It is often useful as adjuvant therapy when treating these forms of parkinsonism with levodopa.

It is a synthetic tertiary amine anticholinergic agent. It has a direct antispasmodic action on smooth muscle and has weak mydriatic, antisecretory, and positive chronotropic activities. In addition to suppressing central cholinergic activity, trihexyphenidyl may also inhibit reuptake and storage of dopamine at central dopamine receptors, thereby prolonging the action of dopamine. It is commonly used in combination with other antiparkinsonian agents. Generally, anticholinergic agents can help control tremor but are less effective for treating bradykinesia or rigidity.

Benztropine mesylate (Cogentin)

Benztropine mesylate is approved for use as an adjunct in the therapy of all forms of PD. It partially blocks striatal cholinergic receptors, and by blocking muscarinic cholinergic receptors in the CNS, benztropine reduces the excessive cholinergic activity present in parkinsonism and related states. It can also block dopamine reuptake and storage in CNS cells. In general, anticholinergic agents can help control tremor but are less effective for treating bradykinesia or rigidity.

MAO-B inhibitors

Class Summary

MAO-B inhibitors inhibit the activity of MAO-B oxidases that are responsible for inactivating dopamine.

Selegiline (Eldepryl, Zelapar)

Selegiline is approved as adjunctive therapy to levodopa/carbidopa in patients who exhibit deterioration in response to that therapy. For patients who are experiencing motor fluctuations on levodopa/carbidopa, the addition of selegiline reduces off time, improves motor function, and allows levodopa dose reductions. If a patient experiences an increase in troublesome dyskinesia, reduce the levodopa dose. Selegiline blocks the breakdown of dopamine and extends the duration of action of each dose of levodopa.

Rasagiline (Azilect)

Rasagiline is indicated for the treatment of the signs and symptoms of idiopathic PD as initial monotherapy and as adjunctive therapy to levodopa. Rasagiline is an irreversible MAO-B inhibitor that blocks dopamine degradation. Rasagiline at a dosage of 1 mg once daily is given as monotherapy. When it is given as adjunctive therapy, an initial dose of 0.5 mg once daily is administered. Dosage adjustments are required if clinical response is not seen.

Safinamide (Xadago)

Safinamide inhibits MAO-B activity, by blocking the catabolism of dopamine. It is indicated as add-on treatment for patients with Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes.

Acetylcholinesterase Inhibitors, Central

Class Summary

Pathologic changes in dementia associated with PD involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. These pathways may be involved in memory, attention, learning, and other cognitive processes. Acetylcholinesterase inhibitors may exert their therapeutic effect by enhancing cholinergic function through inhibition of acetylcholinesterase.

Donepezil (Aricept)

Donepezil is a reversible inhibitor of ACh and exerts its beneficial effects by enhancing cholinergic function. It is indicated for the treatment for dementia of the Alzheimer type.

Rivastigmine (Exelon)

Rivastigmine is indicated for the treatment of mild to moderate dementia associated with PD. In addition, it is also approved for the treatment of mild to moderate dementia of the Alzheimer type.

Rivastigmine is a selective, competitive, and reversible acetylcholinesterase (ACh) inhibitor. It may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in CNS and thereby enhance cholinergic function. The effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. It is available as a capsule and an extended-release transdermal.

Galantamine (Razadyne, Razadyne ER)

Galantamine is a competitive and reversible inhibitor of ACh. It is approved for the treatment of mild to moderate dementia of the Alzheimer type.

NMDA Antagonists

Class Summary

Persistent activation of CNS N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of dementia. Agents such as memantine, which is an NMDA receptor antagonist, can prevent activation of the NMDA receptors.

Memantine (Namenda, Namenda XR)

Memantine is approved for the treatment of moderate to severe dementia in Alzheimer disease. Initial dosage is 5 mg once daily for immediate-release tablets and 7 mg once daily for extended-release tablets. Dosage titration may be required based on clinical response.

Memantine is postulated to exert its therapeutic effect through its action as a low- to moderate-affinity, uncompetitive NMDA receptor antagonist. Blockade of NMDA receptors by memantine slows the intracellular calcium accumulation and helps prevent further nerve damage.

COMT Inhibitors

Class Summary

Catechol-O -methyl transferase (COMT) inhibitors inhibit the peripheral metabolism of levodopa, making more levodopa available for transport across the blood-brain barrier over a longer time. For patients with motor fluctuations on levodopa/carbidopa, the addition of a COMT inhibitor decreases off time, improves motor function, and allows lower levodopa doses.

Tolcapone (Tasmar)

Tolcapone is an adjunct to levodopa/carbidopa therapy in PD in patients who are experiencing motor fluctuations. Because of the risk of hepatotoxicity, tolcapone is reserved for patients who have not responded adequately to, or are not appropriate candidates for, other adjunctive medications. If improvement is not apparent within 3 weeks, this medication should be withdrawn.

Tolcapone is a selective and reversible inhibitor of COMT. In the presence of a decarboxylase inhibitor such as carbidopa, COMT is the major degradation pathway for levodopa. By inhibiting COMT, there are more sustained plasma levels of levodopa, as well as enhanced central dopaminergic activity.

Entacapone (Comtan)

Entacapone is approved as an adjunct to levodopa/carbidopa for patients who are experiencing signs and symptoms of end-of-dose "wearing-off." The mechanism of action of entacapone is related to its ability to inhibit COMT and alter plasma pharmacokinetics of levodopa. When given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor (eg, carbidopa), plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. These sustained plasma levels of levodopa may result in more constant dopaminergic stimulation in the brain. This may lead to greater effects on signs and symptoms of PD, as well as increased levodopa adverse effects (which sometimes require a levodopa dose decrease).

Carbidopa, levodopa, and entacapone (Stalevo)

Carbidopa/levodopa/entacapone is indicated for the treatment of PD to substitute (with equivalent strengths of each of the 3 components) for immediate-release carbidopa/levodopa and entacapone previously administered as individual products. It is also used to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" (only for patients taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias).

Carbidopa inhibits dopa decarboxylation, thereby allowing more complete levodopa distribution to the CNS. Levodopa is a dopamine precursor capable of crossing the blood-brain barrier, thereby increasing CNS dopamine following conversion. Entacapone inhibits COMT, another enzyme that metabolizes levodopa. COMT inhibition increases and sustains levodopa plasma levels, enabling more blood-brain barrier penetration.

Selective Serotonin Inverse Agonists (SSIA)

Class Summary

SSIAs preferentially target 5-HT2A receptors, but does not affect activity of dopamine and other receptors commonly targeted by antipsychotics.

Pimavanserin (Nuplazid)

Pimavanserin is an SSIA which preferentially targets 5-HT2A receptors and avoids activity at dopamine and other receptors commonly targeted by antipsychotics. It is indicated for hallucinations and delusions associated with PD.

Adenosine Antagonists

Class Summary

Option for adjunctive use with levodopa/carbidopa to reduce Parkinson disease OFF episodes.

Istradefylline (Nourianz)

Selective adenosine A2A receptor antagonist. Precise mechanism by which it reduces OFF episodes is unknown. Istradefylline is indicated as adjunctive treatment to levodopa/carbidopa in adults with PD experiencing OFF episodes.

 

Questions & Answers

Overview

Which major neurological findings are characteristic of Parkinson disease (PD)?

Why is it important to recognize both motor and nonmotor symptoms in patients with suspected Parkinson disease (PD)?

What are the initial clinical symptoms of Parkinson disease (PD)?

What are the initial motor signs of Parkinson disease (PD)?

What are the diagnostic criteria for Parkinson disease (PD)?

What is the goal of medical management of Parkinson disease (PD)?

Which medications are used to control symptoms of Parkinson disease (PD)?

Which medications are used to control the nonmotor symptoms of Parkinson disease (PD)?

What is deep brain stimulation for Parkinson disease (PD)?

What causes Parkinson disease (PD)?

What are the three motor signs of Parkinson disease (PD)?

What causes of tremor should be considered in the differential diagnoses of Parkinson disease (PD)?

How is a diagnosis confirmed in patients with a typical Parkinson disease (PD) presentation?

When are imaging studies considered in the diagnosis of Parkinson disease (PD)?

Which medications are used to control the motor symptoms of Parkinson disease (PD)?

What part of the brain is affected by Parkinson disease (PD)?

What are the neuropathologic findings of Parkinson disease (PD)?

How does Parkinson disease (PD) affect the basal ganglia motor circuit?

What is the etiology of Parkinson disease (PD)?

Which environmental risk factors may increase the risk of developing Parkinson disease (PD)?

Does exposure to pesticides, herbicides, or other pollutants increase the risk of developing Parkinson disease (PD)?

Does high caffeine intake or smoking increase the risk of developing Parkinson disease (PD)?

Does 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause Parkinson disease (PD)?

What is the oxidation hypothesis of the etiology of Parkinson disease (PD)?

What is the role of genetic factors in the development of Parkinson disease (PD)?

Which gene mutations may be related to Parkinson disease (PD)?

Which genetic mechanisms are thought to cause Parkinson disease (PD)?

What is the role of alpha-synuclein in the pathogenesis of Parkinson disease (PD)?

What is the relationship between melanoma and Parkinson disease (PD)?

What is the incidence of Parkinson disease (PD)?

How does the incidence of Parkinson disease (PD) change with age, and are men and women equally affected?

What is the impact of levodopa treatment on the prognosis and mortality rate of Parkinson disease (PD)?

What factors are predictive of the rate of progression of Parkinson disease (PD)?

What educational information should be given to patients with Parkinson disease (PD)?

Presentation

What are the initial physical findings of Parkinson disease (PD)?

Which nonmotor symptoms precede the motor signs of Parkinson disease (PD)?

What are the initial clinical symptoms of Parkinson disease (PD)?

What is the typical presentation of tremors due to Parkinson disease (PD)?

What is bradykinesia in patients with Parkinson disease (PD)?

What are the characteristics of facial bradykinesia in patients with Parkinson disease (PD)?

What are the characteristics of truncal bradykinesia in patients with Parkinson disease (PD)?

How does bradykinesia manifest in activities of daily life in patients with Parkinson disease (PD)?

What is cogwheel rigidity in patients with Parkinson disease (PD)?

How does dystonia present in patients with Parkinson disease (PD)?

What are the cardinal signs of Parkinson disease (PD)?

How is resting tremor assessed in a physical exam in patients with Parkinson Disease (PD)?

How is rigidity assessed in a physical exam in patients with Parkinson disease (PD)?

How is bradykinesia assessed in a physical exam in patients with Parkinson disease (PD)?

How is postural instability assessed in patients with Parkinson disease (PD)?

Which speech tendencies should be assessed in patients with Parkinson disease (PD)?

What are manifestations of dysphagia in patients with Parkinson disease (PD)?

How is laryngeal dysfunction assessed in patients with Parkinson disease (PD)?

What are characterizations of the Parkinson disease (PD) larynx?

What is the prevalence of vocal tremor in patients with Parkinson disease (PD)?

Is autonomic dysfunction common in patients with Parkinson disease (PD)?

Does prominent autonomic dysfunction suggest an alternative diagnosis to Parkinson disease (PD)?

Which cardiopulmonary impairments may be caused by Parkinson disease (PD)?

How is Parkinson disease (PD) severity assessed and staged?

How is depression assessed in patients with Parkinson disease (PD)?

Which assessment is most effective in screening for mild cognitive impairment or dementia in patients with Parkinson disease (PD)?

What is the prevalence of dementia in patients with Parkinson disease (PD)?

When in the course Parkinson disease (PD) does dementia or other cognitive impairment typically occur?

What are atypical parkinsonisms (Parkinson-plus syndromes)?

What is the prognosis of atypical parkinsonisms (Parkinson-plus syndromes)?

DDX

How is essential tremor differentiated from Parkinson disease (PD)?

Which secondary causes of parkinsonism (Parkinson-plus syndromes) should be considered in the differential diagnoses of Parkinson disease (PD)?

Does Parkinson disease (PD) increase the risk of osteoporosis and osteopenia?

Does Parkinson disease (PD) increase the risk of bone fracture?

What features differentiate an atypical parkinsonism (Parkinson-plus syndromes) from Parkinson disease (PD)?

How is Lewy body disease characterized in patients with parkinsonism?

When should Wilson disease be considered in patients with parkinsonism?

What are the differential diagnoses for Parkinson Disease?

Workup

Which lab studies are useful in the diagnosis of Parkinson disease (PD)?

Are any lab tests or imaging studies required for the diagnosis of Parkinson disease (PD)?

What tests may be indicated in patients with an unusual presentation of Parkinson disease (PD)?

How is Wilson disease screened for in the evaluation of patients with suspected Parkinson disease (PD)?

How is the clinical diagnosis of Parkinson disease (PD) confirmed?

Why is there a high diagnosis error rate between Parkinson disease (PD) and other movement disorders?

When is MRI indicated in the evaluation of patients with suspected Parkinson disease (PD)?

What is the role of PET scanning and SPECT in the evaluation of patients with Parkinson disease (PD)?

What are the usual histologic findings in Parkinson disease (PD)?

What histologic findings i Lewy bodies in patients with Parkinson disease (PD)?

What were the results of the Parkinson&#39;s Progression Markers Initiative (PPMI)?

When is lumbar puncture considered in the evaluation of patients with suspected Parkinson disease (PD)?

When should dopa-responsive dystonia be considered in the evaluation of Parkinson disease (PD)?

Treatment

What is the goal of medical management of Parkinson disease (PD)?

Are there neuroprotective (disease modifying) treatment options for Parkinson disease (PD)?

What is the role of levodopa in the management of Parkinson disease (PD)?

What is the role of monoamine oxidase (MAO)-B inhibitors in the management of Parkinson disease (PD)?

What is the role of dopamine agonists (ropinirole, pramipexole) in the treatment of Parkinson disease (PD)?

How long are medications effective in controlling the motor signs of Parkinson disease (PD)?

What is neuroprotective (disease modifying) therapy in the context of Parkinson disease (PD)?

How does the management of Parkinson disease (PD) differ in younger patients?

What are the indications for surgery in patients with Parkinson disease (PD)?

How are the nonmotor symptoms of Parkinson disease (PD) categorized?

What are the American Academy of Neurology (AAN) guidelines for the treatment of nonmotor symptoms of Parkinson disease (PD)?

Which medications are commonly used to control motor symptoms in early Parkinson disease (PD)?

What are the long-term risks of levodopa for the management of Parkinson disease (PD)?

What is the benefit of combining carbidopa with levodopa in the management of Parkinson disease (PD)?

What are the available preparations of levodopa/carbidopa?

How is the combination of levodopa, carbidopa, and entacapone used in the management of Parkinson disease (PD)?

What is the recommended dosage for levodopa and a dopa decarboxylase inhibitor in the management of Parkinson disease (PD)?

What are the benefits of using MAO-B inhibitors (selegiline and rasagiline) in the treatment of Parkinson disease (PD)?

When are selegiline and rasagiline indicated in the treatment of Parkinson disease (PD)?

How effective are dopamine agonists in the treatment of Parkinson disease (PD)?

Should dopamine agonists be used in the treatment of Parkinson disease (PD) in patients older than 65 years?

What dosage is recommended for the introduction of a dopamine agonist in the treatment of Parkinson disease (PD)?

What are the adverse effects of dopamine agonists?

When are anticholinergic medications indicated in the treatment of Parkinson disease (PD)?

How effective are anticholinergic agents in the treatment of Parkinson disease (PD)?

What are the possible adverse effects of anticholinergic agents in patients with Parkinson disease (PD)?

What are the recommended dosages of anticholinergic agents in the treatment of Parkinson disease (PD)?

What is amantadine’s mechanism of action in controlling parkinsonian activity?

What is the recommended dosage for amantadine in the treatment of Parkinson disease (PD)?

What are the potential adverse effects of amantadine?

Does amantadine increase or decrease impulse control disorders in patients with Parkinson disease (PD)?

Which drugs reduce dyskinesis in patients with Parkinson disease (PD)?

Does the benefit of levodopa for the management of Parkinson disease (PD) decrease over time?

What options are available to provide more sustained dopaminergic therapy in patients with Parkinson disease (PD)?

How effective is carbidopa/levodopa enteral suspension (Duopa) in increasing the benefit of levodopa in the treatment of Parkinson disease (PD)?

How effective is safinamide (Xadago) in in increasing the benefit of levodopa in the management of Parkinson disease (PD)?

When should dopaminergic therapy be increased to eliminate off-time in patients with Parkinson disease (PD)?

What is peak-dose dyskinesia in patients with Parkinson disease (PD)?

Is it safe to continue increasing dosage of levodopa if the patient develops dyskinesia?

What is the goal of treating patients with Parkinson disease (PD) who experience both motor fluctuation and peak-dose dyskinesia?

What is the benefit of switching from levodopa/carbidopa CR to levodopa/carbidopa IR in the treatment of Parkinson disease (PD)?

What is the role of COMT inhibitors in the treatment of Parkinson disease (PD)?

Are dopamine agonists beneficial in the management of Parkinson disease (PD) patients with both motor fluctuation and peak-dose dyskinesia?

What are the potential adverse effects of amantadine?

Are there any surgical options for patients with Parkinson disease (PD) who have both motor fluctuations and dyskinesia?

What are the treatment options for tremor in patients with Parkinson disease (PD)?

What is the role of laser shoes in reducing freezing episodes among patients with Parkinson disease (PD)?

Are any neuroprotective therapies available for Parkinson disease (PD)?

Does selegiline (Eldepryl, Zelapar) have neuroprotective effects in patients with Parkinson disease (PD)?

Does rasagiline (Azilect) have neuroprotective effects in patients with Parkinson disease (PD)?

What were the results of the TEMPO (Rasagiline in Early Monotherapy for Parkinson&#39;s Disease Outpatients) study?

What were the results of the ADAGIO (Attenuation of Disease progression with Azilect Given Once-daily) study?

What are the potential neuroprotective effects of levodopa therapy in early Parkinson disease (PD)?

What are the potential neuroprotective effects of dopamine agonists in Parkinson disease (PD)?

Why is deep brain stimulation (DBS) the surgical procedure of choice for Parkinson disease (PD)?

Which gray-matter structures are involved in deep brain stimulation (DBS) surgery for Parkinson disease (PD)?

What are the indications for deep brain stimulation (DBS) surgery in patients with Parkinson disease (PD)?

How are patients with Parkinson disease (PD) selected for deep brain stimulation (DBS)?

Is thalamic deep brain stimulation (DBS) indicated for patients with Parkinson disease (PD)?

How effective is subthalamic nucleus (STN) stimulation and globus pallidus interna (GPi) deep brain stimulation (DBS) in the management of Parkinson disease (PD)?

How effective is bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease (PD)?

Is methylphenidate effective in improving gait disorders in patients with advanced Parkinson disease (PD)?

What is the long-term effectiveness of subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease (PD)?

Is subthalamic nucleus (STN) deep brain stimulation (DBS) effective for treating pain related to Parkinson disease (PD)?

Does subthalamic nucleus (STN) deep brain stimulation (DBS) increase or decrease impulse control disorders in patients with Parkinson disease (PD)?

When are lesion surgeries indicated in the treatment of Parkinson disease (PD)?

Is thalamotomy effective in the treatment of Parkinson disease (PD)?

Is pallidotomy effective in the treatment of Parkinson disease (PD)?

What are the potential adverse effects of pallidotomy?

Is bilateral pallidotomy recommended in patients with Parkinson disease (PD)?

Is subthalamotomy effective in the treatment of Parkinson disease (PD)?

Which specialists should provide care for a patient undergoing surgical procedures for the treatment of Parkinson disease (PD)?

What is the patient evaluation and selection process for individuals with Parkinson disease (PD) considering subthalamic nucleus (STN) deep brain stimulation (DBS)?

After patient selection, what is the process for determining the correct surgical procedure for management of Parkinson disease (PD)?

What is the role of a psychiatrist in the preoperative evaluation of a patient with Parkinson disease (PD)?

When is a fluorodopa positron emission tomography (PET) scan indicated in the preoperative evaluation of patients with Parkinson disease (PD)?

When is surgery indicated in the treatment of Parkinson disease (PD)?

How is neural transplantation used in the treatment of Parkinson disease (PD)?

What are the effects of neural transplantation in patients with Parkinson disease (PD)?

Is gene therapy safe and effective in the treatment of Parkinson disease (PD)?

How is dementia managed in patients with Parkinson disease (PD)?

What is the prevalence of depression in patients with Parkinson disease (PD)?

How is depression treated in patients with Parkinson disease (PD)?

Can medications for Parkinson disease (PD) trigger psychosis?

How is psychosis treated in patients with Parkinson disease (PD)?

How is anxiety treated in patients with Parkinson disease (PD)?

How are impulse behaviors treated in patients with Parkinson disease (PD)?

How are sleep disturbances treated in patients with Parkinson disease (PD)?

How effective is exercise and physical therapy in patients with Parkinson disease (PD)?

What is the prevalence of speech problems in patients with Parkinson disease (PD)?

What is the role of speech therapy in the treatment of Parkinson disease (PD)?

What is the Lee Silverman Voice Treatment (LSVT) program for Parkinson disease (PD)?

How effective is the Lee Silverman Voice Treatment (LSVT) program in improving laryngeal symptoms in patients with Parkinson disease (PD)?

Are there effective alternative therapies to the Lee Silverman Voice Treatment (LSVT) program?

Are speech and language therapy effective in the treatment of Parkinson disease (PD)?

Why is dietary fiber recommended for patients with Parkinson disease (PD)?

What is the effect of dietary protein on levodopa in patients with Parkinson disease (PD)?

How is levodopa-induced nausea avoided in patients with Parkinson disease (PD)?

Are there dietary options that are beneficial in the management of Parkinson disease (PD)?

Do vitamin E and coenzyme Q10 have a neuroprotective effect in patients with Parkinson disease (PD)?

What consultations may be indicated for patients with Parkinson disease (PD)?

When is a neurosurgical consultation indicated in patients with Parkinson disease (PD)?

When is a psychiatric consultation indicated in patients with Parkinson disease (PD)?

When is consultation with a urologist indicated in patients with Parkinson disease (PD)?

What is the benefit of consultation with a physiatrist, physical therapist, or occupational therapist in patients with Parkinson disease (PD)?

What is the benefit of consultation with a nutritionist in patients with Parkinson disease (PD)?

What is the benefit of an otolaryngologist consultation for patients with Parkinson disease (PD)?

How are dysphagia, excessive sialorrhea, or nutrition issues managed in patients with Parkinson disease (PD)?

How often should patients with Parkinson disease (PD) be monitored?

What types of treatments may be available in the future for Parkinson disease (PD)?

Guidelines

What are the AAN treatment guidelines for nonmotor symptoms of Parkinson disease (PD)?

Medications

Which medications are used in the treatment of Parkinson disease (PD)?

Which medications in the drug class Dopamine Agonists are used in the treatment of Parkinson Disease?

Which medications in the drug class Anticholinergic are used in the treatment of Parkinson Disease?

Which medications in the drug class MAO-B inhibitors are used in the treatment of Parkinson Disease?

Which medications in the drug class Acetylcholinesterase Inhibitors, Central are used in the treatment of Parkinson Disease?

Which medications in the drug class NMDA Antagonists are used in the treatment of Parkinson Disease?

Which medications in the drug class COMT Inhibitors are used in the treatment of Parkinson Disease?

Which medications in the drug class Selective Serotonin Inverse Agonists (SSIA) are used in the treatment of Parkinson Disease?

Which medications in the drug class Adenosine Antagonists are used in the treatment of Parkinson Disease?