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Disease/Disorder

Definition

Parkinson disease (PD) is a progressive neurodegenerative movement disorder that is distinguished by loss of dopaminergic neurons in the substantia nigra of the basal ganglia and by neuronal aggregations of the protein α-synuclein.1,2 Cardinal motor signs of the disorder are bradykinesia, rigidity, tremor, and postural instability.3

Etiology

Although PD was historically thought largely a sporadic disorder with environmental influences, it is now recognized that approximately 15% of PD patients have a first degree relative with this disease.2,4,5 Genetic mutations have been identified which result in classic autosomal dominant and recessive familial PD; on genomic wide analysis studies, sporadic PD has been associated with independent polygenic risk scores.6

Epidemiology including risk factors and primary prevention

The incidence of PD increases with age, peaking at ages 85-89, with 90% of individuals older than 45 years of age.1 The prevalence of PD is increasing, estimated at 6.1 million individuals worldwide in 2016, and is the second most common neurodegenerative disorder.1,17 The disease is not race-specific.1 Men are approximately 1.5 times more likely than women to be affected, although this relationship has not been found in non-Western populations.7

Toxin exposure and post encephalitic syndromes can produce symptoms similar to idiopathic PD.7 There are weak associations between PD development and environmental toxins (including pesticides, herbicides or heavy metals) or head injury. Caffeine use, smoking, physical activity, and use of nonsteroidal anti-inflammatory drugs are associated with decreased risk.1,7,17 There is emerging evidence of an association between PD and the immune system; in some patients, certain autoimmune diseases (including multiple sclerosis, amyotrophic lateral sclerosis, and Graves’ disease, amongst others) have been associated with increased risk of PD.8

Patho-anatomy/physiology

Key pathologic findings in PD include degeneration of dopamine-producing neurons from the pars compacta of the substantia nigra, and cell loss in other brain structures.7 Oxidative stress, excitotoxicity, mitochondrial dysfunction, and immune modulators are thought to potentially contribute to cell death.5 A majority of patients develop Lewy bodies: an abnormal aggregation of the protein α-synuclein within the neurons.5,7

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Though previously viewed as a motor disorder, it is now evident that nonmotor manifestations can present years before motor symptoms. Individuals may develop loss of smell and rapid eye movement (REM) sleep disorders early in the disease or even before motor involvement.7 PD motor symptoms begin insidiously and often unilaterally, with diminished fine motor control, tremor, foot dystonia, or decreased arm swing.3,7 Symptoms spread bilaterally, with the development of cardinal motor signs and progressive loss of motor function.  In late stages, individuals may demonstrate an expressionless face (hypomimia), hypophonia, stooped posture, and freezing of gait. Although the rate of motor progression is variable in patients, disease duration averages 15 years from diagnosis to death.9,17

The Hoehn and Yahr Scale is used to assess clinical disease severity10

  • Stage 1: unilateral involvement only, usually with minimal or no functional disability
  • Stage 2: bilateral or midline involvement without impairment of balance
  • Stage 3: bilateral involvement and mild to moderate disability with impaired postural reflexes
  • Stage 4: severely disabling, but still able to walk or stand unassisted
  • Stage 5: confinement to bed or wheelchair unless assisted

The Movement Disorder Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) is also used for more detailed clinical and research measurement over time or to assess interventions.

Differential diagnosis includes11

  • Essential tremor
  • Progressive supranuclear palsy
  • Multiple system atrophy
  • Corticobasal degeneration
  • Diffuse Lewy body dementia
  • Alzheimer’s disease
  • Drug-induced parkinsonism (neuroleptics, anti-psychotics)
  • Vascular parkinsonism
  • Environmental toxin exposure (pesticides, solvents, metals)
  • Normal pressure hydrocephalus
  • Wilson’s disease
  • Frontotemporal dementia with parkinsonism
  • Neurodegeneration with brain iron accumulation
  • Mitochondrial disorders
  • Idiopathic basal ganglia calcification
  • Functional parkinsonism
  • Vitamin deficiencies (B12)

Specific secondary or associated conditions and complications

Due to motor impairments, PD patients are at high risk for falls with potential fractures.  Dysphagia is common in advanced PD, and aspiration pneumonia is the most common cause of PD-related deaths.1 Nonmotor symptoms are frequently seen in PD; these include urge urinary incontinence, constipation, depression or anxiety disorder, cognitive impairment, sleep disorders and pain syndromes.

Essentials of Assessment

History

Tremor is the most common presenting motor symptom prompting evaluation for PD. Others include complaints of slowed movement (bradykinesia), hypophonia, “fatigue,” and rigidity reported as “stiffness.”7 Questioning regarding falls or near falls may identify individuals requiring fall-related interventions. Problems with balance and falls typically occur later in the disease course.4

Careful history may identify symptoms of constipation, urinary incontinence, postural dizziness, sleep dysfunction, loss of smell or depression, as these often precede motor symptoms. Sexual dysfunction, sweating and abnormal thermoregulation can also be reported. Pain, particularly back pain, is frequent and impacts quality of life.12

Physical examination

The resting, “pill-rolling” tremor is initially seen in the hand, unilaterally and distally.4 Tremors may involve the legs, lips, jaw and tongue, and are frequently exacerbated by stress and excitement. Rapid-alternating movements demonstrate decreased speed and amplitude with abnormal rhythm. Cogwheeling describes the “ratcheting” of the limb with passive movement while rigidity (velocity and direction-independent increased resistance to passive movement) is also seen.

Sensory impairments include decreased body and spatial awareness. Findings consistent with a length-dependent neuropathy may be identified on exam; Neuropathy related to PD, without any further underlying cause, appears to be associated with daily levodopa dose.13,14

Gait assessment may identify decreased walking speed, short shuffling steps, wide “en-bloc” and/or multi-step turns, decreased arm swing, mild arm flexion at the elbow and forward flexion of the trunk.7 Delayed movement initiation (freezing) is common. Festinating gait, characterized by increasing gait speed with movement of the center of gravity forward, can be found as well.

Other findings on exam include hyposmia, infrequent blinking, hypophonia, hypokinetic dysarthria, monotonous speech quality, micrographia, bradyphrenia, apathy, abulia, palilalia, sialorrhea, seborrhea, and camptocormia.7 Cognitive impairments can be seen as PD progresses, including changes in executive function, memory, and visuospatial processing.17 Visuospatial deficits may be identified, particularly in those with left-sided disease onset.15  

Clinical functional assessment: mobility, selfcare cognition/behavior/affective state

  • Reduced manual dexterity may impair buttoning clothes, tying shoelaces, writing and computer use.
  • Mobility deficits in addition to gait include difficulty with transitional movements such as sit to stand, and bed, bath and car transfers.
  • Patients may have slower or more abnormal mobility with dual tasking.
  • Other functional issues include swallow dysfunction and communication impairment related to dysarthria and hypophonia.
  • Driving safety assessments should be considered depending on driving history and deficits noted on examination.

Laboratory studies

Genetic testing is not routinely recommended at this time. For those under 40 years old, serum ceruloplasmin should be obtained as a screening test for Wilson disease. Vitamin B12 and other vitamin insufficiencies should be considered particularly with exam findings of neuropathy or cognitive impairment.  Skin biopsies which detect skin alpha-synuclein deposits have been found to be potentially useful in differentiating PD from other causes of Parkinsonism, but larger studies are needed to determine the role and utility of this test.19

Imaging

Brain imaging may be unremarkable in PD but is used to evaluate for vascular parkinsonism or to exclude specific structural abnormalities, as well as to identify other disease states associated with parkinsonism features. Evidence of PD on magnetic resonance imaging (MRI) can include narrowing of the substantia nigra pars compacta on T2 weighted images. Advanced MRI and Dopamine transporter (DAT) single photon emission computerized tomography (DAT-SPECT) scans may help exclude atypical causes of parkinsonism. This imaging modality uses a radioactive tracer to bind to dopamine transporters in the basal ganglia; in Parkinson disease and parkinsonisms, the uptake of the tracer is typically reduced and the scan is positive.1

Transcranial ultrasound showing evidence of hyperechogenicity of the substantia nigra is a diagnostic tool undergoing investigation. Positron emission tomography can show an inverse relation between striatal uptake (especially in the posterior putamen) and the severity of motor symptoms.

Supplemental assessment tools

  • The Berg Balance Scale can be used to evaluate balance deficits and postural stability.
  • Video fluoroscopic swallow studies can determine the presence and type of dysphagia, aspiration risk, and intervention strategies.
  • The Montreal Cognitive Assessment (MoCA) is useful for cognitive screening.
  • Neuropsychological testing evaluates cognitive impairment and disease-associated subcortical dementia, including psychomotor retardation, memory retrieval, executive dysfunction, and visuospatial misperception.
  • REM behavior disorder and periodic limb movements with sleep are assessed through sleep studies.
  • Assessments such as the Timed-Get Up and Go can be performed with and without cognitive tasks to assess safety with dual tasks.

Early prediction of outcomes

Tremor predominant disease is associated with slower progression and decreased cognitive impairment.16 Axial symptoms such as postural instability are less responsive to dopaminergic treatment and are a major component of disease-associated disability.7 Older age is associated with greater risk of dementia.7  Fatigue and anxiety also contribute to decreased health-related quality of life in PD patients.18

Environmental

Home assessment can optimize patient’s environmental safety and accessibility.

Social role and social support system

As the disease progresses, availability of caregivers greatly improves the chances of maintaining safety and home independence.

Professional issues

Patient values guide goal setting, especially at later states of the disease. Decisions regarding potentially life-prolonging measures, such as feeding tube placement, are likely to be difficult for the patient, his or her family, and the provider.

Rehabilitation Management and Treatments

See Parkinson Disease: Part Two

Cutting Edge/Emerging and Unique Concepts and Practice

See Parkinson Disease: Part Two

Gaps in the Evidence-Based Knowledge

See Parkinson Disease: Part Two

References

  1. Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548-560.
  2. Camargos ST, Dornas LO, Momeni P, et al. Familial Parkinsonism and early onset Parkinson’s disease in a Brazilian movement disorders clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations. Mov Disord. 2009;24(5):662-666.
  3. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56(1):33-39.
  4. Lesage S, Brice A. Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009;18(R1):R48-59.
  5. Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci. 1999;22:123-144.
  6. Bandres-Ciga S, Diez-Fairen M, Kim JJ, Singleton AB. Genetics of Parkinson’s disease: An introspection of its journey towards precision medicine. Neurobiol Dis. 2020;137:104782.
  7. Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet. 2009;373(9680):2055-2066.
  8. Tan EK, Chao YX, West A, Chan LL, Poewe W, Jankovic J. Parkinson disease and the immune system – associations, mechanisms and therapeutics. Nat Rev Neurol. 2020.
  9. Macleod AD, Taylor KS, Counsell CE. Mortality in Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2014;29(13):1615-1622.
  10. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. 1967;17(5):427-442.
  11. Greenland JC, Barker RA. The Differential Diagnosis of Parkinson’s Disease. In: Stoker TB, Greenland JC, eds. Parkinson’s Disease: Pathogenesis and Clinical Aspects. Brisbane (AU)2018.
  12. Valkovic P, Minar M, Singliarova H, et al. Pain in Parkinson’s Disease: A Cross-Sectional Study of Its Prevalence, Types, and Relationship to Depression and Quality of Life. PLoS One. 2015;10(8):e0136541.
  13. Comi C, Magistrelli L, Oggioni GD, et al. Peripheral nervous system involvement in Parkinson’s disease: evidence and controversies. Parkinsonism Relat Disord. 2014;20(12):1329-1334.
  14. Mancini F, Comi C, Oggioni GD, et al. Prevalence and features of peripheral neuropathy in Parkinson’s disease patients under different therapeutic regimens. Parkinsonism Relat Disord. 2014;20(1):27-31.
  15. Karadi K, Lucza T, Aschermann Z, et al. Visuospatial impairment in Parkinson’s disease: the role of laterality. Laterality. 2015;20(1):112-127.
  16. Rajput AH, Voll A, Rajput ML, Robinson CA, Rajput A. Course in Parkinson disease subtypes: A 39-year clinicopathologic study. Neurology. 2009;73(3):206-212.
  17. Thaler A, Alcalay RN. Diagnosis and Medical Management of Parkinson Disease. Continuum (Minneap Minn). 2022 Oct 1;28(5):1281-1300.
  18. Kuhlman GD, Flanigan JL, Sperling SA, Barrett MJ. Predictors of health-related quality of life in Parkinson’s disease. Parkinsonism Relat Disord. 2019 Aug;65:86-90
  19. Giannoccaro, MP et al. Presence of Skin alpha-synuclein deposits discriminates Parkinson’s Disease from Progressive Supranuclear Palsy and Corticobasal Syndrome. Journal of Parkinson’s Disease, 2022. 12(2) 585-591.

Original Version of the Topic

Christina Marciniak, MD, Rachel Kermen, MD, Priya Mhatre, MD. Idiopathic Parkinson Disease.11/10/2011.

Previous Version(s) of the topic

Christina Marciniak, MD, Rachel Kermen, MD, Priya Mhatre, MD. Idiopathic Parkinson Disease. 9/18/2015

Christina Marciniak, MD, Priya Mhatre, MD, Rachel Kermen, MD, Kathyrn Altonji, MD, Lauren Woo, MD. Parkinson Disease Part One: Disease/Disorder, Essentials of Assessment. 9/1/2020

Author Disclosures

Priya Mhatre, MD
Nothing to Disclose

Lauren Woo, MD
Nothing to Disclose

Kathyrn Altonji, MD
Nothing to Disclose