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Parkinson's Disease

Chapter 446 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Cardinal motor features of PD are bradykinesia, rest tremor, rigidity, and postural instability.
  2. Pathologic hallmark is degeneration of dopaminergic neurons in substantia nigra pars compacta (SNc) and intraneuronal Lewy bodies (α-synuclein).
  3. MDS Clinical Diagnostic Criteria for PD require motor parkinsonism plus supportive criteria, exclusion criteria, and red flags.
  4. Genetic testing is indicated for early onset (<40 years), strong family history, or specific ethnic backgrounds (e.g., Ashkenazi Jews with GBA1/LRRK2).
  5. Pimavanserin (34 mg daily) is FDA-approved for psychosis in PDD; clozapine is an alternative for hallucinations.
  6. Atypical parkinsonism (MSA, PSP, CBS) presents with early falls, poor levodopa response, and autonomic/cerebellar signs.
  7. Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal marker for synucleinopathies.
  8. Cholinesterase inhibitors (rivastigmine, donepezil) are used for cognitive symptoms in dementia with Lewy bodies (DLB).
  9. Orthostatic hypotension is common in atypical parkinsonism and requires nonpharmacologic measures first.
  10. Environmental toxins (pesticides, solvents) and genetic factors (double-hit hypothesis) contribute to sporadic PD risk.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Schematic representation of how pathogenetic factors implicated in Parkinson’s disease interact in...
2 🖼 Figure Basal ganglia nuclei
3 🖼 Figure Changes in motor response associated with chronic levodopa shortening of the duration...
4 🖼 Figure Pathologic specimens from a patient with Parkinson’s disease (PD) versus control (left),...
5 🖼 Figure Pathologic specimens from a patient with Parkinson’s disease (PD) versus control (left),...
6 🖼 Figure [11C]Dihydrotetrabenazine positron emission tomography (a marker of VMAT2) in healthy control (A)...
7 🖼 Figure Pathologic specimens from a patient with Parkinson’s disease (PD) versus control (left),...
8 🖼 Figure Pathologic specimens from a patient with Parkinson’s disease (PD) versus control (left),...
9 🖼 Figure Basal ganglia nuclei
10 🖼 Figure [11C]Dihydrotetrabenazine positron emission tomography (a marker of VMAT2) in healthy control (A)...

1. DEFINITION & OVERVIEW

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease, exceeded only by Alzheimer's disease (AD). Its cardinal clinical features were first described by the English physician James Parkinson in 1817. Clinically, PD is characterized by bradykinesia (slowing), rest tremor, rigidity (stiffness), and gait dysfunction with postural instability. These are known as the classical or 'cardinal' features of PD. Pathologically, the hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), reduced striatal dopamine, and intraneuronal proteinaceous inclusions in cell bodies and axons that stain for α-synuclein (known as Lewy bodies and Lewy neurites; collectively as Lewy pathology). Neuronal degeneration with Lewy pathology can also affect cholinergic neurons of the nucleus basalis of Meynert (NBM), norepinephrine neurons of the locus coeruleus (LC), serotonin neurons in the raphe nuclei of the brainstem, and neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system.

1.1 Historical Context

James Parkinson was a general physician who captured the essence of this condition based on a visual inspection of a mere handful of patients, several of whom he only observed walking on the street and did not formally examine. It is estimated that the number of people with PD worldwide is ~10.8 million, and this number is expected to double within 20 years based on the aging of the population. The mean age of onset of PD is about 60 years, and the lifetime risk is ~3% for men and 2% for women. The frequency of PD increases with age, but cases can be seen in individuals in their twenties and even younger, particularly when associated with a pathogenic gene mutation.

1.2 Pathologic Hallmarks

Harrison's defines the hallmark features of PD as degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), reduced striatal dopamine, and intraneuronal proteinaceous inclusions in cell bodies and axons that stain for α-synuclein (known as Lewy bodies and Lewy neurites; collectively as Lewy pathology). While interest has focused on the dopamine system, neuronal degeneration with Lewy pathology can also affect cholinergic neurons of the nucleus basalis of Meynert (NBM), norepinephrine neurons of the locus coeruleus (LC), serotonin neurons in the raphe nuclei of the brainstem, and neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system.

2. EPIDEMIOLOGY

It is estimated that the number of people with PD worldwide is ~10.8 million, and this number is expected to double within 20 years based on the aging of the population. The mean age of onset of PD is about 60 years, and the lifetime risk is ~3% for men and 2% for women. The frequency of PD increases with age, but cases can be seen in individuals in their twenties and even younger, particularly when associated with a pathogenic gene mutation.

2.1 Global Burden

The number of people with PD worldwide is ~10.8 million. This number is expected to double within 20 years based on the aging of the population.

2.2 Age and Sex Distribution

The mean age of onset of PD is about 60 years. The lifetime risk is ~3% for men and 2% for women. The frequency of PD increases with age, but cases can be seen in individuals in their twenties and even younger, particularly when associated with a pathogenic gene mutation.

3. ETIOLOGY & PATHOPHYSIOLOGY

Most PD cases occur sporadically and are of unknown cause. Gene mutations are the only known causes of PD and may be found even in seemingly sporadic cases. Twin studies performed several decades ago suggested that environmental factors may play an important role in patients with an age of onset ≥50 years, with genetic factors being more important in younger-onset patients. However, the demonstration of genetic variants (e.g., LRRK2 and GBA1) causing later onset PD shows that certain monogenic forms can manifest as late as in the eighth or ninth decade. With the advent of new sequencing technologies (long-read sequencing), numerous monogenic causes of late-onset neurodegenerative diseases have recently been identified. It is likely that genetic factors could modify age at onset and severity of both genetic and nongenetic forms of PD. The environmental hypothesis received some support in the 1980s with the demonstration that MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine), a by-product of the illicit manufacture of a heroin-like drug, caused a PD syndrome in addicts in northern California. MPTP is transported into the central nervous system, where it is oxidized to form MPP+, a mitochondrial toxin that is selectively taken up by, and damages, dopamine neurons, but typically without the formation of Lewy bodies. Importantly, MPTP or MPTP-like compounds have not been linked to sporadic PD. Epidemiologic studies have reported an increased risk of developing PD in association with exposure to pesticides, solvents, rural living, farming, and drinking well water, but study results have been inconsistent. Additionally, doses of other associations have also been reported in individual studies. To date, no environmental factor has yet been proven to be a cause of PD. Some possible protective factors have also been identified in epidemiologic studies, including caffeine, cigarette smoking, intake of nonsteroidal anti-inflammatory drugs, and calcium channel blockers.

3.1 Genetic Factors

Large studies show that about 15% of PD cases are familial in origin, and mutations in several PD-linked genes have been identified. While uncommon pathogenic variants in PD genes (i.e., mutations) have been shown to be causative of PD or to contribute to PD risk, a plethora of common genetic variants—alone or in combination as part of polygenic risk scores—are associated with an increased risk of developing PD. These include variants in the SNCA, LRRK2, MAPT, and GBA1 genes and may be ethnicity-specific, such as a strong risk variant confined to the African or African-admixed population. It has been proposed that many cases of PD may be due to a 'double hit' involving an interaction between (1) one or more genetic risk factors that induce susceptibility and (2) exposure to a toxic environmental factor that may induce epigenetic or somatic DNA alterations or has the potential to directly damage the dopaminergic system. In this scenario, two factors (or more) are required for PD to ensue, while the presence of either one alone is not sufficient to cause the disease. While the 'double-hit' hypothesis is of interest, there is no direct evidence for its support at this time. Furthermore, even if a genetic or environmental risk factor doubles the risk of developing PD, this only results in a lifetime risk of 4–6% or lower, and thus cannot presently be used for individual patient counseling. Thus, the bulk of accumulating evidence suggests that genetic factors play an important role in both familial and 'sporadic' forms of PD, while the role of environmental factors remains unsettled.

Table 1 — Table 446-4 Confirmed Genetic Causes of Parkinson's Disease (PD) with a Clinical Presentation Similar to Idiopathic PD

Designation and Reference GeneReviews and OMIM Reference Clinical Clues Comments
Dominantly Inherited PD PARK-SNCA Median AAO: 46 years (range 19–77 years); 25th/75th percentile: 36/54 years. Gene duplications cause classical PD. Most missense mutations and triplications cause early-onset, severe parkinsonism with prominent cognitive dysfunction Very rare form of PD, α-synuclein protein main component of Lewy bodies, the pathological hallmark of PD
PARK-LRRK2 Median AAO: 56 years (range 20–95 years); 25th/75th percentile: 47/64 years. Clinically typical PD with slightly slower progression Most common known genetic form of PD
PARK-VPS35 Median AAO: 52 years (range 26–75 years); 25th/75th percentile: 45/61 years. Clinically typical PD Very rare form of PD
PARK-CHCHD2 Likely clinically typical PD. Systematic MDSGene review not yet available Very rare form of PD, predominantly found in Asia
PARK-RAB32 Likely clinically typical PD, possibly more frequent dementia. Systematic MDSGene review not yet available Most recently found form of PD. All currently identified patients and families carry the same founder pathogenic variant
PARK-GBA1 Clinically overall typical PD; however, faster progression and greater risk of cognitive impairment. Systematic MDSGene review not yet available Strongest known genetic risk factor for PD; incomplete penetrance
Recessively Inherited PD PARK-PRKN Median AAO: 31 years (range 3–81 years); 25th/75th percentile: 23/38 years. Often presents with dystonia, typically in a leg Most common early-onset form of genetic PD. Protein name: Parkin
PARK-PINK1 Median AAO: 32 years (range 9–67 years); 25th/75th percentile: 24/40 years. Prominent psychiatric features have been described in several families Clinically very similar to PARK-PRKN
PARK-PARK7 Median AAO: 27 years (range 15–40 years); 25th/75th percentile: 22/34 Clinically very similar to PARK-PRKN and PARK-PINK1, but rarest of all forms. Protein name: DJ-1

3.2 Environmental Factors

Most PD cases occur sporadically and are of unknown cause. Epidemiologic studies have reported an increased risk of developing PD in association with exposure to pesticides, solvents, rural living, farming, and drinking well water, but study results have been inconsistent. To date, no environmental factor has yet been proven to be a cause of PD. Some possible protective factors have also been identified in epidemiologic studies, including caffeine, cigarette smoking, intake of nonsteroidal anti-inflammatory drugs, and calcium channel blockers.

3.3 Alpha-Synuclein Pathology

The α-synuclein gene (SNCA) was the first to be linked to PD and is also the most intensely investigated with respect to causative mutations, risk variants, function, and role in the etiopathogenesis of PD. Shared clinical features of patients with SNCA mutations include earlier age of disease onset than in nongenetic PD, a faster progression of motor signs that are mostly levodopa-responsive, early occurrence of motor fluctuations, and presence of prominent nonmotor features, particularly cognitive impairment. Importantly, duplication or triplication of the wild-type SNCA gene also causes PD, with triplication carriers being more severely affected than carriers of duplications. These findings indicate that increased production of the normal protein alone can cause PD. Intriguingly, α-synuclein constitutes the major component of Lewy bodies, implicating the protein in sporadic forms of PD as well. In a remarkable study, Lewy pathology was discovered to have developed in healthy embryonic dopamine neurons that had been implanted into the striatum of PD patients, suggesting that the abnormal protein had transferred from affected cells to healthy unaffected dopamine neurons. Based on these findings, it has been proposed that the α-synuclein protein may be a prion and PD a prion disorder. In this model, α-synuclein can misfold to form β-rich sheets, join to form toxic oligomers and aggregates, polymerize to form amyloid plaques (i.e., Lewy bodies), and cause neurodegeneration with spread to unaffected neurons. Evidence also suggests that in some cases α-synuclein pathology might begin peripherally within the GI tract and spread by way of the vagus nerve to the lower brainstem (dorsal motor nucleus of the vagus) and ultimately to the SNc to cause the motor features of PD (the Braak hypothesis). There is also interest in the possibility that the gut microbiome in PD patients can cause inflammatory changes that promote α-synuclein misfolding with spread to the brain via the vagus nerve.

4. CLINICAL FEATURES

Clinically, PD is characterized by bradykinesia (slowing), rest tremor, rigidity (stiffness), and gait dysfunction with postural instability. These are known as the classical or 'cardinal' features of PD. Additional clinical features can include freezing of gait, speech difficulty, swallowing impairment, and a series of nonmotor features that include autonomic disturbances, sensory alterations, mood disorders, sleep disorders, and cognitive impairment/dementia. Pathologically, the hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), reduced striatal dopamine, and intraneuronal proteinaceous inclusions in cell bodies and axons that stain for α-synuclein (known as Lewy bodies and Lewy neurites; collectively as Lewy pathology). While interest has focused on the dopamine system, neuronal degeneration with Lewy pathology can also affect cholinergic neurons of the nucleus basalis of Meynert (NBM), norepinephrine neurons of the locus coeruleus (LC), serotonin neurons in the raphe nuclei of the brainstem, and neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system. This 'nondopaminergic' pathology is likely responsible for the nonmotor clinical features listed above and in Table 446-1. It has been postulated that in some cases Lewy pathology can begin in the peripheral autonomic nervous system, gastrointestinal (GI) tract, olfactory system, or dorsal motor nucleus of the vagus nerve and then spread in a predictable and sequential manner to affect the SNc and cerebral hemispheres (Braak staging). These studies suggest that the classic degeneration of SNc dopamine neurons and the cardinal motor features of PD may develop at a mid-stage of the illness. Indeed, epidemiologic studies suggest that clinical symptoms reflecting early involvement of ganglia, the specific pathologic characteristics, and the clinical picture can precede the onset of the classic motor features of PD by several years if not decades. Originally it was considered that these represent risk factors for developing PD, but based on pathological findings, it is now considered likely that they represent an early premotor form of the disease. These observations have led to the notion of 'body-first' and 'brain-first' forms of PD based on whether pathology initially develops in the brain or periphery.

Table 2 — Table 446-1 Clinical Features of Parkinson's Disease

Cardinal Motor Features Other Motor Features Nonmotor Features
Bradykinesia Micrographia Anosmia
Rest tremor Masked facies (hypomimia) Sensory disturbances (e.g., pain, hyposmia)
Rigidity Reduced eye blinking Mood disorders (e.g., depression, anxiety, apathy)
Postural instability Drooling Sleep disturbances (e.g., fragmented sleep, RBD)
Soft voice (hypophonia) Autonomic disturbances
Orthostatic hypotension
Gastrointestinal disturbances
Genitourinal disturbances
Sexual dysfunction
Cognitive impairment/dementia
Falling
Dysphagia
Freezing

4.1 Cardinal Motor Features

Bradykinesia, Rest tremor, Rigidity, Postural instability.

4.2 Other Motor Features

Micrographia, Masked facies (hypomimia), Reduced eye blinking, Drooling, Soft voice (hypophonia), Dysphagia, Freezing, Falling.

4.3 Nonmotor Features

Anosmia, Sensory disturbances (e.g., pain, hyposmia), Mood disorders (e.g., depression, anxiety, apathy), Sleep disturbances (e.g., fragmented sleep, RBD), Autonomic disturbances, Orthostatic hypotension, Gastrointestinal disturbances, Genitourinal disturbances, Sexual dysfunction, Cognitive impairment/dementia.

5. DIFFERENTIAL DIAGNOSIS

Parkinsonism is a term that is used to define a syndrome manifest by bradykinesia with rigidity and/or tremor. The differential diagnosis includes PD, atypical parkinsonisms such as multiple-system atrophy (MSA) and progressive supranuclear palsy (PSP), secondary parkinsonism, and parkinsonism associated with other neurodegenerative conditions in which parkinsonian features are present. These conditions affect the basal ganglia, a group of subcortical nuclei that include the striatum (putamen and caudate nucleus), subthalamic nucleus (STN), globus pallidus pars externa (GPe), globus pallidus pars interna (GPi), and the SNc. They differ, however, in the precise site of involvement within the basal ganglia. Among the different forms of parkinsonism, PD is the most common. Historically, PD was diagnosed based on the presence of two of three parkinsonian features (tremor, rigidity, bradykinesia). However, postmortem studies found a 24% error rate when diagnosis was based solely on these criteria. Clinicopathologic correlation studies subsequently determined that parkinsonism (bradykinesia and rigidity) associated with rest tremor, asymmetry of motor impairment, and a good response to levodopa is much more likely to predict the correct pathologic diagnosis. With these revised criteria (known as the U.K. Brain Bank Criteria), a clinical diagnosis of PD could be confirmed pathologically in >90% of patients. Imaging of the dopamine system and new biomarkers further increase diagnostic accuracy. The International Parkinson's Disease and Movement Disorder Society (MDS) has proposed revised clinical criteria for PD (known as the MDS Clinical Diagnostic Criteria for Parkinson's disease), which are thought to increase diagnostic accuracy even further, particularly in early cases where levodopa has not yet been introduced. While motor parkinsonism has been retained as the core feature of the disease, in these criteria, the specific diagnosis of PD relies on three additional categories of diagnostic features: supportive criteria (features that increase confidence in the diagnosis of PD), absolute exclusion criteria, and red flags (which must be counterbalanced by supportive criteria to permit a diagnosis of PD). Utilizing these criteria, two levels of certainty have been delineated: clinically established PD and clinically probable PD.

Table 3 — Table 446-2 Differential Diagnosis of Parkinsonism

Parkinson's disease Atypical parkinsonism Secondary parkinsonism Other neurodegenerative disorders associated with parkinsonism
Sporadic Multiple-system atrophy (MSA) Drug-induced parkinsonism Wilson's disease
Genetic Cerebellar type (MSA-c) Tumor Huntington's disease
PD with dementia/dementia with Lewy bodies Parkinson type (MSA-p) Infection Neurodegeneration with brain iron accumulation
Parkinsonian variant Progressive supranuclear palsy Vascular SCA 3 (spinocerebellar ataxia)
Richardson variant Corticobasal syndrome Normal-pressure hydrocephalus Fragile X–associated ataxia-tremor-parkinsonism
Corticobasal syndrome Trauma Liver failure Prion diseases
Toxins (e.g., carbon monoxide, manganese, MPTP, cyanide, hexane, methanol, carbon disulfide) X-linked dystonia-parkinsonism
Alzheimer's disease with parkinsonism
Dopa-responsive dystonia

Table 4 — Table 446-3 Features Suggesting an Atypical or Secondary Cause of Parkinsonism

Symptoms/Signs Alternative Diagnosis to Consider
Early speech and gait impairment (lack of tremor, lack of motor asymmetry, early falls) Atypical parkinsonism
Exposure to neuroleptics Drug-induced parkinsonism
Onset prior to age 40 years Genetic form of PD, Wilson's disease, DRD
Liver disease Wilson's disease, non-Wilsonian hepatolenticular degeneration
Hallucinations and dementia which precede the development of PD features Dementia with Lewy bodies
Diplopia, impaired vertical gaze PSP
Poor or no response to an adequate trial of levodopa Atypical or secondary parkinsonism
Prominent orthostatic hypotension MSA
Prominent cerebellar signs MSA-c
Slow saccades with impaired downgaze PSP
High-frequency (6–10 Hz) symmetric postural tremor with a prominent kinetic component Essential tremor

5.1 Atypical Parkinsonism

Atypical parkinsonism refers to a group of neurodegenerative conditions that are usually associated with more widespread pathology than found in PD (e.g., degeneration potentially involving the striatum, globus pallidus, cerebellum, and brainstem as well as the SNc). These conditions include MSA, PSP, and corticobasal syndrome (CBS). As a group, they tend to present with features that typically differ from classical PD include early involvement of speech and gait, absence of rest tremor, lack of motor asymmetry, poor or no response to levodopa, and a more aggressive clinical course. They can be difficult to distinguish from PD in the early stages where levodopa has not yet been tried and in some cases that show a modest benefit from levodopa, but the diagnosis usually becomes clear as the disease evolves over time. Atypical parkinsonism includes MSA (Chap. 451), PSP (Chap. 443), and corticobasal syndrome (CBS) (Chap. 443).

5.2 Secondary Parkinsonism

Secondary parkinsonisms occur as a consequence of other etiologic factors such as drugs, stroke, tumor, infection, or toxins (e.g., carbon monoxide, manganese) that cause basal ganglia dysfunction. Clinical features reflect the region of the basal ganglia that has been damaged. For example, strokes or tumors that affect the SNc may have a clinical picture that is very similar to PD, whereas toxins such as carbon monoxide or manganese that damage the globus pallidus more closely resemble atypical parkinsonism and have a poor response to levodopa. Dopamine-blocking agents such as neuroleptics are the most common cause of secondary parkinsonism. These drugs are most widely used in psychiatry, but physicians should be aware that drugs such as metoclopramide, which are primarily used to treat GI problems, are also neuroleptic agents and may induce secondary parkinsonism. These drugs can also cause acute and tardive dyskinesias. Other drugs that can cause secondary parkinsonism include tetrabenazine, calcium channel blockers (flunarizine, cinnarizine), amiodarone, and lithium. Parkinsonism can also be seen as a feature of dopa-responsive dystonia (DRD), a condition that typically results from pathogenic variants in the GTP-cyclohydrolase 1 gene, which lead to a defect in a cofactor for tyrosine hydroxylase with impairment in the manufacture of dopamine and dopamine. While it typically presents as dystonia, it can present as a biochemically based form of parkinsonism (due to reduced synthesis of dopamine) closely resembling PD. DRD patients respond to levodopa, but abnormalities on fluorodopa PET (FD-PET) are typically not seen, nor are drug-induced dyskinesias, reflecting a biochemical abnormality without degeneration of the underlying anatomic structures. DRD should be considered in individuals aged <20 years who present with parkinsonism, particularly if there are dystonic features. Finally, parkinsonism can be seen as a feature of a variety of other neurodegenerative disorders such as Wilson's disease, Huntington's disease (especially the juvenile form known as the Westphal variant), certain spinocerebellar ataxias, and neurodegenerative disorders with brain iron accumulation such as pantothenate kinase (PANK)–associated neurodegeneration (formerly known as Hallervorden-Spatz disease). It is particularly important to rule out Wilson's disease, as progression can be prevented with the use of copper chelators.

5.3 Other Neurodegenerative Disorders

Other neurodegenerative disorders associated with parkinsonism include Wilson's disease, Huntington's disease, neurodegeneration with brain iron accumulation, SCA 3 (spinocerebellar ataxia), fragile X–associated ataxia-tremor-parkinsonism, prion diseases, X-linked dystonia-parkinsonism, Alzheimer's disease with parkinsonism, and dopa-responsive dystonia.

6. INVESTIGATIONS & DIAGNOSIS

Imaging of the brain dopamine system can be helpful in diagnosing PD and is performed using positron emission tomography (PET) or single-photon emission computed tomography (SPECT). These studies typically show reduced and asymmetric uptake in the striatum, particularly in the posterior putamen with relative sparing of the caudate nucleus. These findings reflect the degeneration of nigrostriatal dopaminergic neurons and the loss of their striatal terminals. Imaging is useful in patients where there is diagnostic uncertainty (e.g., early-stage disease, essential tremor, dystonic tremor, psychogenic tremor) or in research studies in order to ensure diagnostic accuracy, but it is not routinely required in clinical practice. There is also some evidence suggesting that a diagnosis of PD, and even prodromal PD, may be made based on the presence of increased iron in the SNc using transcranial sonography or special magnetic resonance imaging (MRI) protocols. There have been intensive efforts to image α-synuclein in the brain but, in contrast to beta-amyloid or tau imaging in Alzheimer's disease, this has proven difficult as most of the abnormal α-synuclein protein is located within cells. This makes it difficult to develop a marker that binds to α-synuclein and that can be detected with imaging. There has been a longstanding interest in developing a biomarker for PD that could aid in diagnosis, differentiate PD from other parkinsonian conditions, potentially assess the effects of a putative disease-modifying therapy, and be used as an endpoint in clinical trials. Considerable interest has focused on detecting abnormal α-synuclein deposits in cerebrospinal fluid (CSF), blood, muscle, and other tissues, but results to date have been inconsistent. The development of the α-synuclein seeding amplification assay (SAA) has provided a novel means to support a clinical diagnosis of PD. The SAA was developed for use on CSF and skin and provides a binary result indicating the presence or absence of endogenous α-synuclein sufficient to result in aggregation upon addition of α-synuclein 'seeds.' This assay has very high sensitivity and specificity and is able to distinguish PD from other parkinsonisms. At present, the test has been primarily applied in a research setting, but the development of a blood-based assay may extend its use into a clinical role. This assay also has the potential to permit diagnosis in early-stage and even prodromal PD. Genetic testing can be helpful for establishing a diagnosis but is not routinely employed as monogenic forms of PD are relatively uncommon and account for only 5% of cases, although this increases to 15% when pathogenic variants in the strongest known risk gene, glucocerebrosidase (GBA1), are included (see discussion below), and this number may increase as more knowledge is acquired. A genetic form of PD should be considered in patients with a strong positive family history, early age of onset (<40 years), and a particular ethnic background (see below), and in research studies. Genetic variants of GBA1 are the most common genetic association with PD. They are present in ~10% of PD patients and in 25% of Ashkenazi PD patients. However, only ~20–30% of people with GBA1 variants will develop PD, and PD risk is correlated with the severity of the variant effect. Pathogenic variants in the LRRK2 gene have also attracted particular interest as they are responsible for ~3% of typical sporadic cases of the disease. LRRK2 mutations are a particularly common cause of PD (~25%) in Ashkenazi Jews and North African Berber Arabs; however, there is considerable variability in penetrance, and ~40–50% of carriers never develop clinical features of PD. Interestingly, some PD cases associated with LRRK2 mutations and other genetic causes have been described without Lewy bodies. Genetic testing is of particular interest for identifying at-risk individuals in a research setting and for defining enriched populations for clinical trials of therapies directed at a pathogenic mutation or pathway. In patients presenting with cognitive disturbances, it is always necessary to rule out treatable causes of dementia such as drugs, infections, or metabolic disturbances. Magnetic resonance imaging (MRI) of the brain can be helpful to rule out vascular parkinsonism or subdural hematomas, or support the diagnosis of other disorders such as MSA (i.e., pontine 'hot-cross buns' sign). The biomarkers that can help diagnose LBD include the following: a polysomnogram showing RBD without atonia, seed amplification assays (SAAs) to detect αSyn in cerebrospinal fluid (CSF), demonstrating skin deposition of α-synuclein, iodine-123-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy showing cardiac postganglionic sympathetic denervation, and dopamine transporter imaging using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) or, if associated with AD, increased CSF or blood levels of phospho-tau217 or phospho-tau181.

6.1 Diagnostic Criteria

The International Parkinson's Disease and Movement Disorder Society (MDS) has proposed revised clinical criteria for PD (known as the MDS Clinical Diagnostic Criteria for Parkinson's disease), which are thought to increase diagnostic accuracy even further, particularly in early cases where levodopa has not yet been introduced. While motor parkinsonism has been retained as the core feature of the disease, in these criteria, the specific diagnosis of PD relies on three additional categories of diagnostic features: supportive criteria (features that increase confidence in the diagnosis of PD), absolute exclusion criteria, and red flags (which must be counterbalanced by supportive criteria to permit a diagnosis of PD). Utilizing these criteria, two levels of certainty have been delineated: clinically established PD and clinically probable PD.

6.2 Imaging and Biomarkers

Imaging of the brain dopamine system can be helpful in diagnosing PD and is performed using positron emission tomography (PET) or single-photon emission computed tomography (SPECT). These studies typically show reduced and asymmetric uptake in the striatum, particularly in the posterior putamen with relative sparing of the caudate nucleus. These findings reflect the degeneration of nigrostriatal dopaminergic neurons and the loss of their striatal terminals. Imaging is useful in patients where there is diagnostic uncertainty (e.g., early-stage disease, essential tremor, dystonic tremor, psychogenic tremor) or in research studies in order to ensure diagnostic accuracy, but it is not routinely required in clinical practice. The biomarkers that can help diagnose LBD include the following: a polysomnogram showing RBD without atonia, seed amplification assays (SAAs) to detect αSyn in cerebrospinal fluid (CSF), demonstrating skin deposition of α-synuclein, iodine-123-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy showing cardiac postganglionic sympathetic denervation, and dopamine transporter imaging using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) or, if associated with AD, increased CSF or blood levels of phospho-tau217 or phospho-tau181.

6.3 Genetic Testing

Genetic testing can be helpful for establishing a diagnosis but is not routinely employed as monogenic forms of PD are relatively uncommon and account for only 5% of cases, although this increases to 15% when pathogenic variants in the strongest known risk gene, glucocerebrosidase (GBA1), are included (see discussion below), and this number may increase as more knowledge is acquired. A genetic form of PD should be considered in patients with a strong positive family history, early age of onset (<40 years), and a particular ethnic background (see below), and in research studies. Genetic variants of GBA1 are the most common genetic association with PD. They are present in ~10% of PD patients and in 25% of Ashkenazi PD patients. However, only ~20–30% of people with GBA1 variants will develop PD, and PD risk is correlated with the severity of the variant effect. Pathogenic variants in the LRRK2 gene have also attracted particular interest as they are responsible for ~3% of typical sporadic cases of the disease. LRRK2 mutations are a particularly common cause of PD (~25%) in Ashkenazi Jews and North African Berber Arabs; however, there is considerable variability in penetrance, and ~40–50% of carriers never develop clinical features of PD. Interestingly, some PD cases associated with LRRK2 mutations and other genetic causes have been described without Lewy bodies. Genetic testing is of particular interest for identifying at-risk individuals in a research setting and for defining enriched populations for clinical trials of therapies directed at a pathogenic mutation or pathway.

7. MANAGEMENT & TREATMENT

Although there are currently no disease-modifying agents to prevent, slow, or cure LBD-related dementias, several symptomatic treatments are available. By addressing the substantial cholinergic deficit in DLB, cholinesterase inhibitors such as rivastigmine (target dose 6 mg twice daily or 9.5 mg patch daily) or donepezil (target dose 10 mg daily) often improve cognition, reduce hallucinosis, and stabilize delusional symptoms. The atypical antipsychotic pimavanserin is frequently helpful to treat the psychosis and does not worsen parkinsonism; it is approved by the U.S. Food and Drug Administration (FDA) for patients with PDD and is often used off-label for DLB. Pimavanserin (34 mg daily) is a selective inverse agonist of the serotonin 5-HT2A receptor that does not block dopamine receptors but carries an FDA warning regarding an increase in risk of death, especially in older patients. Low-dose clozapine (begin at 6.25 mg, increasing up to 25 mg, daily) is also effective for treating hallucinations and delusions, but requires frequent blood draws due to the risk of agranulocytosis. Patients with LBD are sensitive to dopaminergic medications, which must be carefully titrated; tolerability may be improved with concomitant use of a cholinesterase inhibitor. Patients with DLB should not be exposed to typical neuroleptics, which can lead to a neuroleptic malignant syndrome and death, or anticholinergics or dopamine agonists that can exacerbate their symptoms. RBD usually responds to melatonin, requiring at times 20 mg/d. If melatonin is not effective, clonazepam, gabapentin, or codeine can be used with caution due to the possibility of worsening cognition or falls. Antidepressants, especially those with strong anxiolytic properties (escitalopram, paroxetine, duloxetine, or venlafaxine; see Chap. 463), are often necessary for mood and anxiety symptoms. Orthostatic hypotension may require treatment with nonpharmacologic measures (diet high in salt and liquids, a 30° elevation of the head of the bed) or pharmacologic therapies (i.e., fludrocortisone, midodrine, droxidopa). Physical therapy can maximize motor function and protect against fall-related injury. Home safety assessments and transfer instruction should also be provided. Education for patients and caregivers and social worker support are also important. Therefore, the care of patients with LBD requires a multidisciplinary approach.

7.1 Pharmacologic Treatment for Psychosis

The atypical antipsychotic pimavanserin is frequently helpful to treat the psychosis and does not worsen parkinsonism; it is approved by the U.S. Food and Drug Administration (FDA) for patients with PDD and is often used off-label for DLB. Pimavanserin (34 mg daily) is a selective inverse agonist of the serotonin 5-HT2A receptor that does not block dopamine receptors but carries an FDA warning regarding an increase in risk of death, especially in older patients. Low-dose clozapine (begin at 6.25 mg, increasing up to 25 mg, daily) is also effective for treating hallucinations and delusions, but requires frequent blood draws due to the risk of agranulocytosis. Patients with LBD are sensitive to dopaminergic medications, which must be carefully titrated; tolerability may be improved with concomitant use of a cholinesterase inhibitor. Patients with DLB should not be exposed to typical neuroleptics, which can lead to a neuroleptic malignant syndrome and death, or anticholinergics or dopamine agonists that can exacerbate their symptoms.

7.2 Treatment of RBD

RBD usually responds to melatonin, requiring at times 20 mg/d. If melatonin is not effective, clonazepam, gabapentin, or codeine can be used with caution due to the possibility of worsening cognition or falls.

7.3 Treatment of Mood and Anxiety

Antidepressants, especially those with strong anxiolytic properties (escitalopram, paroxetine, duloxetine, or venlafaxine; see Chap. 463), are often necessary for mood and anxiety symptoms.

7.4 Treatment of Autonomic Dysfunction

Orthostatic hypotension may require treatment with nonpharmacologic measures (diet high in salt and liquids, a 30° elevation of the head of the bed) or pharmacologic therapies (i.e., fludrocortisone, midodrine, droxidopa).

7.5 Physical Therapy and Safety

Physical therapy can maximize motor function and protect against fall-related injury. Home safety assessments and transfer instruction should also be provided. Education for patients and caregivers and social worker support are also important. Therefore, the care of patients with LBD requires a multidisciplinary approach.

8. PROGNOSIS & COMPLICATIONS

Atypical parkinsonism refers to a group of neurodegenerative conditions that are usually associated with more widespread pathology than found in PD (e.g., degeneration potentially involving the striatum, globus pallidus, cerebellum, and brainstem as well as the SNc). These conditions include MSA, PSP, and corticobasal syndrome (CBS). As a group, they tend to present with features that typically differ from classical PD include early involvement of speech and gait, absence of rest tremor, lack of motor asymmetry, poor or no response to levodopa, and a more aggressive clinical course. They can be difficult to distinguish from PD in the early stages where levodopa has not yet been tried and in some cases that show a modest benefit from levodopa, but the diagnosis usually becomes clear as the disease evolves over time. The rate of progression is typically more aggressive than in classic PD. Pathologically, MSA is characterized by degeneration of the SNc, striatum, cerebellum, and inferior olivary nuclei coupled with characteristic glial cytoplasmic inclusions (GCIs) that stain positively for α-synuclein aggregates (Lewy bodies), which accumulate in oligodendrocytes rather than in SNc neurons as in PD. There is currently no established evidence for any gene mutation or genetic risk factor for MSA, and no specific treatment exists. PSP is characterized by the features noted above coupled with slow ocular saccades, eyelid apraxia, and restricted vertical eye movements with impairment of downward gaze. Patients frequently experience hyperextension of the neck with early gait disturbance and falls. In later stages, speech and swallowing difficulty and cognitive impairment may become evident. Two clinical forms of PSP have been identified: a 'Parkinson' form that can closely resemble PD in the early stages and can include a positive response to levodopa, and the more classic 'Richardson' form that is characterized by the features described above with little or no response to levodopa. MRI may reveal a characteristic atrophy of the midbrain with relative preservation of the pons on mid-sagittal images (the so-called 'hummingbird sign'). Pathologically, PSP is characterized by degeneration of the SNc, striatum, STN, midline thalamic nuclei, and pallidum, coupled with neurofibrillary tangles and inclusions that stain for the tau protein. Mutations in the MAPT gene encoding the tau protein have been detected in some familial cases. CBS is a relatively uncommon condition that usually presents with asymmetric dystonic contractions, and clumsiness of one hand coupled with cortical sensory disturbances manifest as apraxia, agnosia, focal limb myoclonus, or alien limb phenomenon (where the limb assumes a position in space without the patient being aware of its location or recognizing that the limb belongs to them). Dementia may occur at any stage of the disease. Both cortical and basal ganglia features are required to make this diagnosis. MRI frequently shows asymmetric cortical atrophy, but this must be carefully sought and may not be obvious on casual inspection. Pathologic findings include achromatic neuronal degeneration with tau deposits. Considerable overlap may occur both clinically and pathologically between CBS and PSP, and they may be difficult to distinguish without pathologic confirmation.

8.1 Atypical Parkinsonism Prognosis

Atypical parkinsonism (MSA, PSP, CBS) tends to have a more aggressive clinical course than classic PD. The rate of progression is typically more aggressive than in classic PD. There is currently no established evidence for any gene mutation or genetic risk factor for MSA, and no specific treatment exists.

8.2 PSP Clinical Forms

Two clinical forms of PSP have been identified: a 'Parkinson' form that can closely resemble PD in the early stages and can include a positive response to levodopa, and the more classic 'Richardson' form that is characterized by the features described above with little or no response to levodopa.

8.3 CBS Features

CBS is a relatively uncommon condition that usually presents with asymmetric dystonic contractions, and clumsiness of one hand coupled with cortical sensory disturbances manifest as apraxia, agnosia, focal limb myoclonus, or alien limb phenomenon. Dementia may occur at any stage of the disease. Both cortical and basal ganglia features are required to make this diagnosis.

9. SPECIAL CONSIDERATIONS

The majority of caregivers for individuals with DLB are women, often spouses, who frequently experience high levels of burden and depression. The severity of behavioral symptoms, sleep disturbances, and autonomic symptoms in the person with DLB is associated with higher caregiver burden, leading to a poorer quality of life for the caregiver. The most commonly reported caregiver concerns include the inability to plan for the future, prioritizing the needs of the person with DLB over their own, and worry about the person with DLB becoming too dependent on the caregiver, among others. Overall, caregivers expressed satisfaction with the support provided by the medical team, but they reported the lowest satisfaction with information about disease progression and the sharing of information among medical team members. Clinicians can address caregiver needs by providing support resources, educating caregivers about DLB, and developing management strategies for the range of troubling symptoms experienced by patients. Therefore, the care of patients with LBD requires a multidisciplinary approach.

9.1 Caregiver Burden

The majority of caregivers for individuals with DLB are women, often spouses, who frequently experience high levels of burden and depression. The severity of behavioral symptoms, sleep disturbances, and autonomic symptoms in the person with DLB is associated with higher caregiver burden, leading to a poorer quality of life for the caregiver. The most commonly reported caregiver concerns include the inability to plan for the future, prioritizing the needs of the person with DLB over their own, and worry about the person with DLB becoming too dependent on the caregiver, among others. Overall, caregivers expressed satisfaction with the support provided by the medical team, but they reported the lowest satisfaction with information about disease progression and the sharing of information among medical team members. Clinicians can address caregiver needs by providing support resources, educating caregivers about DLB, and developing management strategies for the range of troubling symptoms experienced by patients.

10. KEY PEARLS & CLINICAL TRAPS

Some features that suggest that parkinsonism might be due to a condition other than classic PD are shown in Table 446-3. These include early speech and gait impairment (lack of tremor, lack of motor asymmetry, early falls), exposure to neuroleptics, onset prior to age 40 years, liver disease, hallucinations and dementia which precede the development of PD features, diplopia, impaired vertical gaze, poor or no response to an adequate trial of levodopa, prominent orthostatic hypotension, prominent cerebellar signs, slow saccades with impaired downgaze, and high-frequency (6–10 Hz) symmetric postural tremor with a prominent kinetic component. It is particularly important to rule out Wilson's disease, as progression can be prevented with the use of copper chelators. Patients with DLB should not be exposed to typical neuroleptics, which can lead to a neuroleptic malignant syndrome and death, or anticholinergics or dopamine agonists that can exacerbate their symptoms. Patients with LBD are sensitive to dopaminergic medications, which must be carefully titrated; tolerability may be improved with concomitant use of a cholinesterase inhibitor. RBD usually responds to melatonin, requiring at times 20 mg/d. If melatonin is not effective, clonazepam, gabapentin, or codeine can be used with caution due to the possibility of worsening cognition or falls. Antidepressants, especially those with strong anxiolytic properties (escitalopram, paroxetine, duloxetine, or venlafaxine; see Chap. 463), are often necessary for mood and anxiety symptoms. Orthostatic hypotension may require treatment with nonpharmacologic measures (diet high in salt and liquids, a 30° elevation of the head of the bed) or pharmacologic therapies (i.e., fludrocortisone, midodrine, droxidopa). Physical therapy can maximize motor function and protect against fall-related injury. Home safety assessments and transfer instruction should also be provided. Education for patients and caregivers and social worker support are also important. Therefore, the care of patients with LBD requires a multidisciplinary approach.

10.1 Diagnostic Clues

Some features that suggest that parkinsonism might be due to a condition other than classic PD are shown in Table 446-3. These include early speech and gait impairment (lack of tremor, lack of motor asymmetry, early falls), exposure to neuroleptics, onset prior to age 40 years, liver disease, hallucinations and dementia which precede the development of PD features, diplopia, impaired vertical gaze, poor or no response to an adequate trial of levodopa, prominent orthostatic hypotension, prominent cerebellar signs, slow saccades with impaired downgaze, and high-frequency (6–10 Hz) symmetric postural tremor with a prominent kinetic component.

10.2 Treatment Pitfalls

Patients with DLB should not be exposed to typical neuroleptics, which can lead to a neuroleptic malignant syndrome and death, or anticholinergics or dopamine agonists that can exacerbate their symptoms. Patients with LBD are sensitive to dopaminergic medications, which must be carefully titrated; tolerability may be improved with concomitant use of a cholinesterase inhibitor.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Schematic representation of how pathogenetic factors implicated in Parkinson’s disease...

Caption: FIGURE 446-4 Schematic representation of how pathogenetic factors implicated in Parkinson’s disease interact in a network manner, ultimately leading to cell death. This to figure illustrates how interference with any one of these factors may not necessarily stop the cell death cascade. (Reproduced with permission from CW Olanow: The pathogenesis of cell death in Parkinson’s disease. Movement Disorders 22:S-335, 2007.) studies to date have not conclusively demonstrated a benefit using therapies directed against any of these targets. Moreover, it is not clear which of these factors is primary, if they are the same in all cases or to specific to individual subgroups, if they act by way of a network such of that multiple insults are required for neurodegeneration to ensue, or — Figure 446-1: Pathologic specimens from a patient with Parkinson's disease (PD) compared to a normal control demonstrating (A) reduction of pigment in substantia nigra pars compacta (SNc) in PD versus control, (B) reduced numbers of cells in SNc in PD compared to control, and (C) Lewy bodies within melanized dopamine neurons in PD.

Figure 2

Basal ganglia nuclei

Caption: FIGURE 446-2 Basal ganglia nuclei. Schematic (A) and postmortem (B) coronal pars compacta; STN, subthalamic nucleus. — Figure 446-2: Schematic and postmortem coronal sections illustrating the various components of the basal ganglia, including the striatum (putamen and caudate), subthalamic nucleus (STN), globus pallidus pars externa/interna, and substantia nigra pars compacta (SNc).

Figure 3

Changes in motor response associated with chronic levodopa shortening of...

Caption: FIGURE 446-6 Changes in motor response associated with chronic levodopa shortening of the duration of a beneficial motor response to levodopa (wearing off) and — Figure 446-3: [11C]Dihydrotetrabenazine positron emission tomography (PET) showing reduced and asymmetric uptake of tracer in the striatum, particularly the posterior putamen, in a Parkinson's disease patient compared to a healthy control.

Figure 4

Pathologic specimens from a patient with Parkinson’s disease (PD) versus...

Caption: FIGURE 446-1 Pathologic specimens from a patient with Parkinson’s disease (PD) versus control (left), (B) reduced numbers of cells in SNc in PD (right) compared to SNc, substantia nigra pars compacta. — Table 446-1: Clinical Features of Parkinson's Disease categorized into Cardinal Motor Features (bradykinesia, rest tremor, rigidity, postural instability), Other Motor Features (micrographia, masked facies, reduced eye blinking, drooling, soft voice, dysphagia, freezing, falling), and Nonmotor Features (anosmia, sensory disturbances, mood disorders, sleep disturbances, autonomic disturbances, gastrointestinal disturbances, genitourinal disturbances, sexual dysfunction, cognitive impairment/dementia).

Figure 5

Pathologic specimens from a patient with Parkinson’s disease (PD) versus...

Caption: FIGURE 446-1 Pathologic specimens from a patient with Parkinson’s disease (PD) versus control (left), (B) reduced numbers of cells in SNc in PD (right) compared to SNc, substantia nigra pars compacta. — Table 446-2: Differential Diagnosis of Parkinsonism comparing Parkinson's disease (sporadic, genetic, PD with dementia with Lewy bodies), Atypical parkinsonism (MSA, PSP, CBS), Secondary parkinsonism (drug-induced, tumor, infection, vascular, trauma, toxins), and Other neurodegenerative disorders (Wilson's disease, Huntington's disease, Alzheimer's disease with parkinsonism, etc.).

Figure 6

[11C]Dihydrotetrabenazine positron emission tomography (a marker of VMAT2) in healthy...

Caption: FIGURE 446-3 [11C]Dihydrotetrabenazine positron emission tomography (a marker of VMAT2) in healthy control (A) and Parkinson’s disease (B) patient. Note the reduced striatal uptake of tracer, which is most pronounced in the posterior putamen and tends to be asymmetric. (Courtesy of Dr. Jon Stoessl.) of of nigrostriatal dopaminergic neurons and the loss of their striatal terminals. Imaging is useful in patients where there is diagnostic uncertainty (e.g., early-stage disease, essential tremor, dystonic tremor, psychogenic tremor) or in research studies in order to ensure diagnos- tic accuracy, but it is not routinely required in clinical practice. This — Table 446-3: Features Suggesting an Atypical or Secondary Cause of Parkinsonism, listing symptoms/signs (e.g., early speech/gait impairment, poor levodopa response, hallucinations, diplopia, slow saccades) and corresponding alternative diagnoses (e.g., atypical parkinsonism, drug-induced parkinsonism, dementia with Lewy bodies, PSP, MSA, essential tremor).

Figure 7

Pathologic specimens from a patient with Parkinson’s disease (PD) versus...

Caption: FIGURE 446-1 Pathologic specimens from a patient with Parkinson’s disease (PD) versus control (left), (B) reduced numbers of cells in SNc in PD (right) compared to SNc, substantia nigra pars compacta. — Table 446-4: Confirmed Genetic Causes of Parkinson's Disease (PD) with Clinical Presentation Similar to Idiopathic PD, listing gene designations (PARK-SNCA, PARK-LRRK2, PARK-PRKN, etc.), median age at onset, clinical clues, and comments on penetrance and progression.

Figure 8

Pathologic specimens from a patient with Parkinson’s disease (PD) versus...

Caption: FIGURE 446-1 Pathologic specimens from a patient with Parkinson’s disease (PD) versus control (left), (B) reduced numbers of cells in SNc in PD (right) compared to SNc, substantia nigra pars compacta. — Figure 451-6 (referenced in text): MRI showing pontine 'hot-cross buns' sign characteristic of multiple-system atrophy (MSA-c), illustrating high signal change in the region of the external surface of the putamen or cerebellar and brainstem atrophy.

Figure 9

Basal ganglia nuclei

Caption: FIGURE 446-2 Basal ganglia nuclei. Schematic (A) and postmortem (B) coronal pars compacta; STN, subthalamic nucleus. — Figure referencing Braak staging: Diagram illustrating the sequential spread of Lewy pathology from peripheral autonomic nervous system/gastrointestinal tract/olfactory system to the substantia nigra pars compacta and cerebral hemispheres.

Figure 10

[11C]Dihydrotetrabenazine positron emission tomography (a marker of VMAT2) in healthy...

Caption: FIGURE 446-3 [11C]Dihydrotetrabenazine positron emission tomography (a marker of VMAT2) in healthy control (A) and Parkinson’s disease (B) patient. Note the reduced striatal uptake of tracer, which is most pronounced in the posterior putamen and tends to be asymmetric. (Courtesy of Dr. Jon Stoessl.) of of nigrostriatal dopaminergic neurons and the loss of their striatal terminals. Imaging is useful in patients where there is diagnostic uncertainty (e.g., early-stage disease, essential tremor, dystonic tremor, psychogenic tremor) or in research studies in order to ensure diagnos- tic accuracy, but it is not routinely required in clinical practice. This — Figure referencing dopamine system imaging: Visual representation of reduced and asymmetric uptake in the striatum (posterior putamen) with relative sparing of the caudate nucleus in Parkinson's disease versus normal control.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.