Idiopathic Parkinson Disease

Author(s): Christina Marciniak, MD, Rachel Kermen, MD, Priya Mhatre, MD

Originally published:11/10/2011

Last updated:09/18/2015

1. DISEASE/DISORDER:

Definition

Parkinson disease (PD) is a progressive neurodegenerative movement disorder, distinguished by loss of dopaminergic neurons from the substantia nigra of the basal ganglia.1

Cardinal motor signs of the disorder are bradykinesia, rigidity, tremor, and postural instability.2

Etiology

Etiology of idiopathic PD is unknown, with a sporadic disorder occurrence in most patients.1,3 However, at least 10 genetic mutations have been implicated so far in the development of familial parkinsonism.

Toxin exposure such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine and postencephalitic syndromes can produce symptoms similar to idiopathic PD.1

Epidemiology including risk factors and primary prevention

  1. The incidence of PD increases with age, with 90% of individuals being older than 45 years of age.
  2. In 2009, the prevalence of PD was estimated at 1 in 800, with a lifetime risk of 1.5% for developing the disease.1
  3. Men are approximately 1.5 times more likely than women to be affected, although this relationship has not been found in non-Western populations.1
  4. The disease is not specific to race.
  5. There are weak associations between PD development and environmental toxins (pesticides, rural living).
  6. Smoking and caffeine are associated with decreased risk.1

Patho-anatomy/physiology

  1. Key findings include degeneration of dopamine-producing neurons from the pars compacta of the substantia nigra, and cell loss in other brain structures.1
  2. Oxidative stress, excitotoxicity, mitochondrial dysfunction and immune modulators are thought to potentially contribute to cell death.3
  3. A majority of patients develop Lewy bodies: an abnormal aggregation of the protein α-synuclein within neurons.1,3
  4. The loss of dopamine in the substantia nigra results in imbalance between dopaminergic and cholinergic activity in the basal ganglia, which leads to disturbance of motor activity.

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

  1. Though previously viewed as a motor disorder, it is now evident that nonmotor manifestations may present years before motor symptoms.
  2. PD symptoms begin insidiously and often unilaterally, with diminished fine motor control, tremor, foot dystonia, or decreased arm swing.1,2
  3. Symptoms advance to bilateral with cardinal motor signs more evident, with progressive loss of motor function.
  4. Individuals may develop loss of smell and rapid eye movement (REM) sleep disorders.1
  5. In late stages, individuals demonstrate an expressionless face (hypomimia), hypophonia, stooped posture, and freezing of gait.
  6. Disease duration averages 15 years from diagnosis to death.1

Differential diagnosis includes:

  1. essential tremor
  2. progressive supranuclear palsy
  3. multiple system atrophy
  4. corticobasal degeneration
  5. diffuse Lewy body dementia
  6. Alzheimer’s disease
  7. drug-induced parkinsonism (neuroleptics, anti-psychotics)
  8. vascular parkinsonism

Specific secondary or associated conditions and complications

  1. high risk for falls with possible fractures
  2. urge urinary incontinence
  3. dysphagia
  4. aspiration pneumonia
  5. constipation
  6. anxiety disorder
  7. cognitive impairment
  8. pain syndromes

2. ESSENTIALS OF ASSESSMENT

History

Earlier symptoms include constipation, urinary incontinence, postural dizziness, sleep dysfunction, loss of smell and depression, and often precede motor symptoms.

Sexual dysfunction, sweating and abnormal thermoregulation may also be reported.

Tremor is the most common presenting motor symptom. Others include bradykinesia, hypophonia, “fatigue,” and rigidity reported as “stiffness.”1

Problems with balance and falls typically occur later in the disease course.2

Physical examination

Resting “pill-rolling” tremor is 3-7 Hertz (Hz) initially seen in the hand, unilaterally and distally.2 Tremors may also include the legs, lips, jaw and tongue, and are exacerbated by stress and excitement.

Rapid-alternating movements have decreased speed and amplitude with abnormal rhythm.

Gait is characterized by decreased walking speed, short shuffling steps, wide “en-bloc” turns, decreased arm swing, mild arm flexion at the elbow and Simian posture.1

Delayed movement initiation (freezing) is common.

Rigidity includes velocity and direction-independent increased resistance to passive movement. Cogwheeling includes “ratcheting” of the limb with movement.

Sensory impairment including decreased body and spatial awareness can be evident.

Other findings include hyposmia, infrequent blinking, hypophonia, hypokinetic dysarthria, monotonous speech quality, micrographia, bradyphrenia, apathy, abulia, palilalia, sialorrhea, seborrhea, and camptocormia.1

Clinical Functional assessment

  1. Reduced manual dexterity may impair buttoning clothes, tying shoelaces, and computer use.
  2. Mobility deficits include difficulty with transitional movements such as car transfers; gait impairment can impair postural stability.
  3. Other issues include swallow dysfunction, impaired cognition with forgetfulness, psychosis with hallucinations, sexual dysfunction, poor driving safety, excessive sweating, and pain.1

Laboratory studies

  1. Genetic testing is not routinely recommended at this time.
  2. For those under 40 years old, serum ceruloplasmin should be obtained as a screening test for Wilson disease.

Imaging

Brain imaging may be unremarkable in PD, but can be used to evaluate for vascular parkinsonism.

Evidence of disease may appear on T2-weighted magnetic resonance imaging, including narrowing of substantia nigra pars compacta.2

Dopamine transporter (DAT) single photon emission computerized tomography (DAT-SPECT) scans show presynaptic dopamine dysfunction and may help differentiate nigrostriatral degenerative diseases (idiopathic PD) from other causes of parkinsonism.

Positron emission tomography with flurodopa F18 and SPECT with iodine-123-beta-carbomethoxy-3 beta-(4-iodophenyltropane) (B-CIT) or iodine-123 fluoropropyl (FP-CIT) can show an inverse relation between striatal uptake (especially in the posterior putamen) and the severity of motor symptoms.

Supplemental assessment tools

  1. Sleep studies evaluate REM disorder and periodic limb movements during sleep.
  2. Videographic swallowing study can determine severity of dysphagia and aspiration risk.
  3. Berg Balance Scale can evaluate balance deficits and postural stability.
  4. Neuropsychogical testing evaluates cognitive impairment and disease-associated subcortical dementia, including psychomotor retardation, memory retrieval, executive dysfunction, and visuospatial misperception.

Early predictions of outcomes

  1. Tremor predominant disease is associated with slower progression and decreased cognitive impairment.4
  2. Axial symptoms such as postural instability are less responsive to dopaminergic treatment and are a major component of disease-associated disability.1
  3. Older age is associated with greater risk of developing dementia.1

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.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Practice parameters that outline treatment in PD have been published by the American Academy of Neurology 5,6

The European Federation of Neurological Societies and the Movement Disorder Society have issued treatment guidelines for early and late stage PD.7,8

Evidence-based reviews or guidelines highlighting the role of exercise to treat PD related impairments have also been published.9,10

At different disease stages

Early PD Treatment

Pharmacologic intervention in early PD is dependent on the level of functional impairment

Levodopa with carbidopa is the most effective drug for akinetic symptoms. Improvement with levodopa supports the diagnosis of PD. Levodopa-induced motor fluctuation and dyskinesias are associated with higher cumulative doses.1

Some experts recommend dopa-agonists (bromocriptine, pramipexole or ropinirole) as initial therapy in younger-onset patients, though recent studies do not support this concept.1

Anticholinergic agents, (eg, trihexyphenidyl hydrochloride) are used with impairing tremor.1

Amantadine may be useful for akinesia and rigidity with mild disease.4

Balance training and lower limb strengthening are recommended for balance impairment. Dance, Tai Chi and video gaming have also been demonstrated to improve balance. 11 Tai Chi has demonstrated efficacy in fall reduction in PD 12,

Stretching programs and consistent aerobic activity should be encouraged.

Resistive exercises have been shown to ameliorate PD motor progression on the UPDRS for up to 2 years, and growing evidence shows that more intense forms of specific exercise leads to better outcomes. 13,14

Subacute

  1. Secondary prevention and disease management strategies
    • Monoamine oxidase B inhibitors have been studied for neuroprotection effects. Selegiline provides mild symptomatic benefit but neuroprotection has neither been confirmed nor disproven; it may be added when there is insufficient or decreased levodopa response.
    • The Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial compared two doses of rasagiline, with the 1-mg dose meeting criteria for a disease modifying effect while the 2-mg dose did not.15
  2. Symptom relief
    • Reassessment of dosing (frequency, use of long-acting formulations and timing) should be done throughout the disease course.
    • Pain is common, often correlating with medication fluctuations.
  3. Rehabilitation strategies to optimize function
    • Axial rigidity can be addressed with flexibility training.
    • Cardiovascular conditioning, lower limb strengthening and training with external cues, cognitive movement strategies, rhythm and body-weight supported treadmill training may assist with maintaining activity and improving ambulation.
    • Visual spatial deficits, micrographia, and memory impairment may require rehabilitation interventions.

Chronic/stable

  1. Secondary prevention
    • Patients on dopa-agonists should be monitored for impulse control disorders and sleep attacks (sudden unexpected sleep with activities such as driving).
  2. Palliative strategies
    • The catechol-O-methyl transferase inhibitors (tolcapone and entacapone) may be added to extend levodopa effect to combat on/off fluctuations.
    • Injectable apomorphine is available for sudden akinesia.
    • Recently approved are a long-acting dopamine formulation and continuous enteric dopamine infusion for those with frequent on/off fluctuations with oral dopamine.
  3. Symptom relief
    • Deep brain stimulation of the subthalamic nucleus or globus pallidus is used with recalcitrant dyskinesias or motor fluctuation. 16
    • Thalamic stimulation may assist with medication-resistant tremors.16
  4. Rehabilitation strategies
    • Patients with poor balance may benefit from specialized wheeled walkers with brakes and a stabilizing base.
    • Visual and auditory cueing strategies such as laser lights and portable metronomic devices may assist gait initiation and gait speed, respectively.
    • Patients should be trained in strategies to help with freezing.

Pre-terminal or end of life care

  1. Evaluation for paranoid psychoses and visual hallucinations includes re-evaluation of PD treatments, particularly anticholinergics. The atypical neuroleptics, clozapine and quetiapine, may help these psychiatric symptoms.
  2. Gastrostomy tubes may be required with severe dysphagia.

Coordination of care

A team approach including neurology, physiatry, speech-language pathology, physical therapy, occupational therapy and social work is recommended for continual reassessment of disease status and interventions. Interdisciplinary inpatient rehabilitation reduces functional impairment in selected patients, despite the progressive disease process.13

Patient & family education

  1. With advanced disease, caring for patients with dementia and psychoses is particularly challenging.
  2. Identification of supplemental caregiver assistance, and support groups, may reduce caregiver stress.
  3. Patients/caregivers should receive education regarding medications, disease fluctuation, progression, exercise and rehabilitation strategies.

Emerging/unique Interventions

Measurement of Treatment Outcomes

The Hoehn and Yahr Scale assesses clinical disease severity:

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 17

Measurement of patient outcomes

The Unified Parkinson Disease Rating Scale is useful to follow the longitudinal course of PD.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Functional clinical measures include the Timed Get-up-and-Go test, 5 times sit to stand and the 2-minute Walk Test.

Performance decrement may be found during dual tasking and should be incorporated into training and safety recommendations.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

  1. Virtual reality training using visual cues can improve gait. 18
  2. Lee Silverman Voice Treatment focuses on vocal loudness in therapy to promote distributed benefits including improvements in speech intelligibility, hypophonia, hoarseness, facial expression and swallowing.
  3. The “Think Big” training features repetition and self-cueing for large-amplitude movements such as arm swing or step. 19
  4. Rhythmic Auditory Stimulation strategies utilizing music or metronome-based cues improve gait performance and modulate variability.
  5. Forced exercise paradigms, such as tandem bicycle training, can improve motor function and bimanual dexterity. 20
  6. Animal studies demonstrate that exercise of sufficient intensity and duration prevents or reverses PD motor impairments. Limited human research indicates similar effects.
  7. MRI-guided focused ultrasound transcranial thermal ablation is being studied for the treatment of dyskinesias.

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

  1. Non-motor symptoms (eg anosmia, depression) in PD are common, but the pathophysiology of involved underlying neuronal pathways and the relationship with motor symptoms are not well understood.
  2. Well-designed evidence-based studies to treat non-motor symptoms, including pain, are lacking.
  3. Isradipine is currently being evaluated as a neuroprotective agent in clinical trials.

REFERENCES

  1. Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009;373:2055-66.
  2. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Archives of neurology 1999;56:33-9.
  3. Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson’s disease. Annual review of neuroscience 1999;22:123-44.
  4. Rajput AH, Voll A, Rajput ML, Robinson CA, Rajput A. Course in Parkinson disease subtypes: A 39-year clinicopathologic study. Neurology 2009;73:206-12.
  5. Pahwa R, Factor SA, Lyons KE, et al. Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983-95.
  6. Zesiewicz TA, Sullivan KL, Arnulf I, et al. Practice Parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2010;74:924-31.
  7. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES). Part II: late (complicated) Parkinson’s disease. Eur J Neurol 2006;13:1186-202.
  8. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006;13:1170-85.
  9. Keus S, Munneke M, Graziano M, et a. European union physiotherapy guideline for Parkinson’s Disease 2014.
  10. Salgado S, Williams N, Kotian R, Salgado M. An evidence-based exercise regimen for patients with mild to moderate Parkinson’s disease. Brain sciences 2013;3:87-100.
  11. Mhatre PV, Vilares I, Stibb SM, et al. Wii Fit balance board playing improves balance and gait in Parkinson disease. PM&R: the journal of injury, function, and rehabilitation 2013;5:769-77.
  12. Li F, Harmer P, Fitzgerald K, et al. Tai chi and postural stability in patients with Parkinson’s disease. The New England journal of medicine 2012;366:511-9.
  13. David FJ, Rafferty MR, Robichaud JA, et al. Progressive resistance exercise and Parkinson’s disease: a review of potential mechanisms. Parkinson’s disease 2012;2012:124527.
  14. Schenkman M, Hall DA, Baron AE, Schwartz RS, Mettler P, Kohrt WM. Exercise for people in early- or mid-stage Parkinson disease: a 16-month randomized controlled trial. Physical therapy 2012;92:1395-410.
  15. Toulouse A, Sullivan AM. Progress in Parkinson’s disease-where do we stand? Progress in neurobiology 2008;85:376-92.
  16. Okun MS. Deep-brain stimulation for Parkinson’s disease. The New England journal of medicine 2012;367:1529-38.
  17. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427-42.
  18. Mirelman A, Maidan I, Herman T, Deutsch JE, Giladi N, Hausdorff JM. Virtual reality for gait training: can it induce motor learning to enhance complex walking and reduce fall risk in patients with Parkinson’s disease? The journals of gerontology Series A, Biological sciences and medical sciences 2011;66:234-40.
  19. Ebersbach G, Ebersbach A, Edler D, et al. Comparing exercise in Parkinson’s disease–the Berlin LSVT(R)BIG study. Mov Disord 2010;25:1902-8.
  20. Ridgel AL, Vitek JL, Alberts JL. Forced, not voluntary, exercise improves motor function in Parkinson’s disease patients. Neurorehabilitation and neural repair 2009;23:600-8.

Author Disclosures

Christina Marciniak, MD
Received a research grant from Takeda Pharmaceuticals and Allergan, Inc. Paid consultant for Ipsen and Allergan, Inc.

Rachel Kermen, MD
Author indicated he/she has no relevant financial relationships to disclose.

Priya Mhatre, MD
Author indicated he/she has no relevant financial relationships to disclose.

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