Parkinson’s Disease

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability. Parkinson disease is diagnosed clinically on the basis of characteristic signs and symptoms. The postmortem finding of Lewy bodies in the brain is the only confirmation for the disease. Treatment includes supportive physical and emotional care plus medications such as levodopa/carbidopa, monoamine oxidase type B inhibitors, and dopamine agonists.

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Overview

Definition

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder affecting the CNS with cardinal features of resting tremor, rigidity, bradykinesia, and postural instability.

Epidemiology

  • One of the most common neurodegenerative disorders
  • Annual incidence: 4.5–21 cases per 100,000 population
  • Mean age at onset: approximately 60 years
  • Lifetime risk: approximately 2% for men and 1.3% for women

Etiology

The etiology of PD is unclear but depends on various genetic and environmental factors. 

Risk factors

  • Environmental and nongenetic risk factors: 
    • Exposure to pesticides
    • Exposure to nitrogen dioxide
    • History of traumatic brain injury
    • Exposure to hydrocarbon solvents
    • Living in a rural environment
    • Living in proximity to industrial plants or quarries
    • Drinking well water
    • Use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to cause irreversible parkinsonism.
    • Excess body weight
    • Type 2 diabetes
  • Gene mutations associated with PD:
    • Alpha-synuclein (SNCA) gene
    • Leucine-rich repeat kinase 2 (LRRK2) gene loci
    • Parkin (PARK2) gene mutations
    • Phosphatase and tensin homolog (PTEN)–induced putative kinase 1 (PINK1) gene loci

Pathophysiology

Compensatory mechanisms in the brain may temporarily decrease the effects of dopamine depletion until these mechanisms are overpowered by the progression of PD.

  • Depletion of dopaminergic neurons in the substantia nigra pars compacta → depletion of dopamine in the nigrostriatal pathway → development of motor symptoms
  • Overactivity of the indirect pathway functionally disables functioning of the substantia nigra. 
  • Lewy bodies: the pathologic hallmark of PD:
    • Round, eosinophilic, intracytoplasmic neuronal inclusions
    • Contain abnormal alpha-synuclein proteins 
    • Seen in:
      • Substantia nigra
      • Locus coeruleus
      • Cerebral cortex
      • Sympathetic ganglia
  • The pathologic changes in PD start in the olfactory bulb → progress over many years to the cerebral cortex in 6 stages, called Braak staging:
    • Presymptomatic stages 1 and 2: pathologic changes are found in:
      • Olfactory bulb
      • Medulla oblongata 
    • Stages 3 and 4: symptoms start appearing as the pathology migrates to:
      • Substantia nigra pars compacta 
      • Structures of the midbrain
    • Stages 5 and 6: pathologic process reaches:
      • Temporal lobe
      • Frontal lobe

Clinical Presentation

The signs of PD are progressive and gradually appear over a long period of years to decades.

Cardinal motor manifestations

  • Bradykinesia = slowness of movements:
    • Seen in about 80% of individuals with PD
    • Decreased manual dexterity of the fingers 
    • Progresses proximally
    • Difficulty in completing simple tasks such as tying shoelaces, buttoning clothes, and picking up small objects. 
    • Short shuffling gait 
    • Loss of coordination of movements as the disease progresses
    • Advanced stages: Freezing of movements may occur.
  • Tremor: 
    • Resting tremor described as a “pill-rolling” tremor
    • Intermittent in the early stages
    • Decreases with voluntary action
    • Can involve the hands, legs, lips, jaw, and tongue
    • Exacerbated by anxiety, emotional excitement, and stressful situations
    • Initially unilateral involvement → progresses to bilateral
  • Rigidity:
    • Seen in 70%–90% of individuals with PD
    • Described as increased resistance to passive movement
    • Begins unilaterally → progresses to the contralateral side; remains asymmetrical throughout the course of the disease.
    • Cogwheel rigidity = a pattern of resistance and relaxation in passive movement
    • “Lead pipe” rigidity may also be seen in a few individuals = tonic resistance that is smooth in passive movement 
  • Rigidity affecting the face: characteristic “masked” expression
  • Postural instability = impairment of postural reflexes resulting in a feeling of imbalance and a tendency to fall: 
    • Usually occurs in advanced stages of PD 
    • In the “pull test,” the examiner stands behind the individual and pulls the individual by their shoulders; those with PD are likely to take a few steps back or fall.

Other motor manifestations

  • Speech impairment
  • Laryngeal dysfunction and dysphagia
  • Blurred vision
  • Micrographia
  • Stooped posture
  • Myoclonus
  • Gait abnormalities:
    • Shuffling, short-stepped gait
    • Freezing in gait
    • Festinating gait = pattern described as small, increasingly quick steps

Nonmotor symptoms

  • Autonomic dysfunction presenting as:
    • Orthostasis
    • Constipation
    • Diaphoresis
    • Urinary difficulties
    • Sexual dysfunction
  • Olfactory dysfunction: anosmia
  • Mood disorders, including depression and anxiety
  • Pain and sensory disturbances
  • Cognitive dysfunction and dementia
    • Psychosis 
    • Hallucinations
  • Sleep disturbances:
    • Insomnia
    • Daytime sleepiness
    • REM sleep behavior disorder (RBD)

Diagnosis

The diagnosis of PD is made by clinical history and neurologic examination.

Diagnosis requires 4 things:

  1. Motor parkinsonism
  2. No absolute exclusion criteria
  3. At least 2 supportive criteria
  4. No red flags

Motor parkinsonism, an essential criterion of PD, requires bradykinesia and at least 1 of the following:

  • Resting tremor
  • Rigidity
  • Postural instability

Absolute exclusion criteria (incompatible with a diagnosis of PD):

  • Cerebellar abnormalities such as cerebellar gait or limb ataxia
  • Downward vertical supranuclear gaze palsy or selective slowing of downward vertical saccades
  • Diagnosis of frontotemporal dementia within the 1st 5 years after disease onset
  • Parkinsonian features restricted to the lower limbs for > 3 years
  • Treatment in the past year with a dopamine receptor blocker that may be associated with drug-induced parkinsonism
  • Absence of observable response to high-dose levodopa with moderate severity of disease
  • Unequivocal cortical sensory loss (agraphesthesia, astereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia
  • Normal functional neuroimaging of the presynaptic dopaminergic system

Supportive criteria:

  • Dramatic improvement of symptoms with dopaminergic drugs
  • Levodopa-induced dyskinesia
  • Resting tremor of a limb (unilateral or bilateral)
  • Either olfactory loss or cardiac sympathetic denervation on nuclear medicine imaging

Red flags (signs of alternative pathology that point toward another diagnosis):

  • Rapid progression of gait impairment requiring the use of a wheelchair
  • Absence of progression of motor symptoms or signs > 5 years
  • Early bulbar dysfunction: severe dysphonia or dysarthria or severe dysphagia within the 1st 5 years after onset
  • Inspiratory stridor or dyspnea
  • Severe autonomic failure (e.g., orthostatic dysfunction, severe urinary retention) in the 1st 5 years after disease onset
  • Recurrent falls due to impaired balance within 3 years after onset
  • Involuntary flexion of the neck or contractures of hand or feet 
  • Absence of the common nonmotor symptoms in the 1st 5 years after disease onset
  • Unexplained pyramidal tract signs: pyramidal weakness or clear pathologic hyperreflexia
  • Bilateral symmetric parkinsonism

There are no physiologic, radiologic, or blood tests to confirm the clinical diagnosis of PD:

  • Imaging may be needed to rule out other causes of parkinsonism (e.g., stroke):
    • MRI
    • DaTscan: a type of SPECT that can visualize brain dopamine transporter levels
  • Olfactory and nuclear medicine tests for autonomic testing for cardiac sympathetic denervation are helpful in distinguishing PD from other causes of parkinsonism (supportive criteria as above).

Parkinson disease is confirmed with the finding of Lewy bodies on postmortem analysis.

Lewy bodies confirming Parkinson's disease

Lewy bodies as seen in a Parkinson’s disease specimen

Image: “Staining of multiple Lewy bodies” by Division of Neurology, William Beaumont Hospital Research Institute, Royal Oak, MI 48073, USA. License: CC BY 2.0

Management

The goal of management is to treat the symptomatic motor and nonmotor features of the disorder to improve quality of life.

Treatment

General measures:

  • Physical therapy
  • Occupational therapy 
  • Emotional support

Medical therapy:

  • Levodopa is the drug of choice in individuals of any age with moderate or severe symptoms:
    • A dopamine precursor converted into dopamine after crossing the blood–brain barrier 
    • Normally combined with carbidopa, which enhances CNS bioavailability 
  • Monoamine oxidase type B (MAO-B) inhibitors: selegiline, rasagiline, safinamide: 
    • Inhibit the enzyme MAO from breaking down dopamine, serotonin, norepinephrine, and tyramine in the brain 
    • Effective as an early symptomatic treatment for PD
    • Monotherapy or in combination with levodopa/carbidopa
  • Non-ergot dopamine agonists: pramipexole, ropinirole, apomorphine:
    • Indicated in younger individuals to postpone use of levodopa/carbidopa and avoid long-term side effects 
    • Monotherapy or in conjunction with levodopa/carbidopa
    • Should not be stopped abruptly

Deep brain stimulation:

  • Neurosurgical implantation of stimulating electrodes in the substantia nigra
  • Exact mechanism of action is unknown. 
  • Best candidates are individuals who:
    • Are younger
    • Have a short course of illness
    • Have a good response to levodopa 
  • Not recommended for those with atypical parkinsonism

Side effects of dopamine therapy

  • Nausea
  • Orthostasis: worsened by dopaminergic therapy 
    • May need to stop antihypertensive medication 
    • May need to taper dopamine agonists and MAO-B inhibitors 
  • Drug-induced dyskinesia (abnormal involuntary movements can occur with long-term use of levodopa)
  • Confusion and hallucinations
  • Impulse control disorders → dopamine agonist therapy must be reduced
  • Dopamine dysregulation syndrome: 
    • Cyclical mood disorder characterized by hypomania or manic psychosis 
    • Prevention of the excessive use of dopaminergic drugs is imperative.

Differential Diagnosis

  • Essential tremor: most common neurologic cause of action tremor. Essential tremor usually affects both hands and arms and is apparent when the arms are held outstretched or when they are engaged in activities. Essential tremor is most often symmetrical.
  • Dementia with Lewy bodies: characterized clinically by dementia with visual hallucinations, fluctuating cognition, RBD, and parkinsonism. Dementia occurs before the development of signs of parkinsonism. Cholinesterase inhibitors, atypical antipsychotics, and regular exercise are used for treatment. 
  • Corticobasal degeneration: distinctive form of parkinsonism that is a progressive asymmetric movement disorder. Cognitive features of corticobasal degeneration include aphasia, apraxia, behavioral changes, loss of executive function, and visuospatial dysfunction. Asymmetrical cortical atrophy is seen on imaging. 
  • Progressive supranuclear palsy: clinically presents as postural instability with a history of multiple falls. Progressive supranuclear palsy is the most common degenerative form of parkinsonism. The disorder includes dysarthria, dysphagia, rigidity, and cognitive symptoms. MRI shows the “hummingbird sign” or prominent midbrain atrophy without pontine atrophy. Management is supportive, with both pharmacologic and nonpharmacologic measures.
  • Multiple system atrophy (MSA): group of rare, fatal neurodegenerative symptoms. Multiple system atrophy presents with akinetic rigid parkinsonism, autonomic and urogenital dysfunction, cerebellar ataxia, and pyramidal signs. Lack of response to levodopa can help distinguish MSA from PD, and MSA progresses more rapidly than PD. Diagnosis is clinical and management is symptomatic, as there are no disease-modifying treatments available.

References

  1. Warren, C.O., Klein C., Schapira, A. H. V. (2018). Parkinson’s disease. In: Jameson J. L., et al. (Eds.). Harrison’s Principles of Internal Medicine, 20th ed., vol. 2, pp. 3120–3132. 
  2. Jankovic, J. (2021). Etiology and pathogenesis of Parkinson disease. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/etiology-and-pathogenesis-of-parkinson-disease
  3. Chou. K. L. (2021). Clinical manifestations of Parkinson disease. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-parkinson-disease
  4. Chou, K. L. (2021). Diagnosis and differential diagnosis of Parkinson disease. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/diagnosis-and-differential-diagnosis-of-parkinson-disease
  5. Splinder, M. A. (2021). Initial pharmacologic treatment of Parkinson disease. UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/initial-pharmacologic-treatment-of-parkinson-disease
  6. Hauser R. A. (2020). Parkinson disease. Medscape. Retrieved July 14, 2021, from https://emedicine.medscape.com/article/1831191
  7. Massano, J., Bhatia, K. P. (2012). Clinical approach to Parkinson’s disease: Features, diagnosis, and principles of management. Retrieved July 14, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367535/
  8. Kouli, A., Torsney, K. M., Kuan, W. (2018). Parkinson’s disease: etiology, neuropathology, and pathogenesis. Retrieved July 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK536722/
  9. Zafar, S., Yaddanapudi, S.S. (2020). Parkinson disease. StatPearls. Retrieved July 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK470193/

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