Parkinson’s Disease (PD)

Definition

Idiopathic progressive, neurodegenerative disorder characterized by resting Tremor, Rigidity, Akinesia/bradykinesia, and Postural instability (‘TRAP’). Symptoms usually manifest when ~80% of dopamine-producing cells within substantia nigra (SN) becomes non-functional resulting in dopamine depletion.

Etiology

Proposed Classification Scheme for Parkinsonism. (Ref: Galpern WR, Lang, AE Ann Neurol 2006; 59:449-458)

Classical Parkinsonism

• Sporadic
  • Idiopathic Parkinson’s disease
• Genetic
  • LRRK2 mutations
  • SNCA mutations, duplications
  • Parkin mutations
  • PINK1 mutations
  • DJ-1 mutations
  • GBA mutations
  • Others (e.g. SCA2)

Atypical Parkinsonism

• Sporadic
  • Dementia with Lewy bodies
  • Multiple system atrophy
  • Progressive supranuclear palsy
  • Corticobasal degeneration
  • Others
• Genetic
  • Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17)
  • Others
    • Wilsons disease
    • Huntington’s disease

Secondary Parkinsonism

• Drug-induced
• Toxin-induced
• Vascular/infection

Environmental risk factors for idiopathic PD

• Unknown, but the following have been suggested as associated with increased risk:
  • Environmental toxins
  • Pesticides/herbicides
  • Head trauma
• Environmental factors that have been suggested to have a protective effect
  • Smoking
  • Caffeine
  • Elevated urates
  • Use of non-steroidal anti-inflammatory drugs

Epidemiology

Canada:

• Prevalence: Approx. 160 per 100,000
• Incidence: 10 to 20/100,000/year

Both prevalence and incidence increase with age.

• 85% diagnosed are above the age 65 years
  • Approx. 100,000 Canadians affected
  • Approx. 6.3 million worldwide

Pathophysiology

• Disease probably begins in the olfactory tract and brain stem (early loss of sense of smell) and spreads rostrally and caudally to substantia nigra and eventually to cortical regions
• Loss of dopaminergic neurons in the substantia nigra leads to dopamine depletion within the basal ganglia. Multiple neurotransmitter abnormalities occur in the basal ganglia circuitry resulting in motor symptoms of PD
• Non-motor symptoms of PD, such as neuropsychiatric, autonomic, sleep and pain likely result from degeneration of cortical and other brainstem regions
• Observed pathological abnormalities in patients with PD include:
  • Degeneration of neurons in (SN)
  • Presence of Lewy bodies correlates with symptoms
• Exact mechanisms of neurodegeneration are unknown, likely involves genetic and environmental factors
• Mitochondrial dysfunction and oxidative stress as well as misfolding and aggregation of proteins (alpha synuclein) appears to underlie the neurodegenerative process
• There is growing evidence to suggest a potential link along the gut-brain axis in the pathogenesis of Parkinson’s Disease, whereby disturbances in the gut biome facilitates neuronal toxicity that contribute to increased  aberrant alpha synuclein production and subsequent injury to central neurons and co-ordinated cell death involving the brain stem, nigrostriatal and other pathways that manifest the clinical symptoms of Parkinson’s Disease

Clinical Presentation

1. Motor Symptoms

Tremor

“Pill-rolling”, resting tremor

• Usually begins unilaterally in the hand, less often the leg. May spread over several years
• Tremor can also involve the legs, lips, jaw, and tongue, Rarely involves the head
• Anxiety, emotional excitement, or stressful situations exacerbate the tremors
• Not all patients with PD develop tremor

Rigidity

• May begin unilaterally and spread to involve contralateral side
• Cogwheel rigidity due to overlay of tremor
• Lead pipe rigidity is the increased tone that is present throughout the range of movement
• Will increase with activation (ask subject to open and close opposite hand)

Akinesia / Bradykinesia

• Slow movements
• Masked facies (expressionless), decreased blink
• Speech may be hypophonic, stuttering or dysarthria
• Ability to initiate voluntary movement is decreased
• Affects routine tasks (buttoning, writing (micrographia), typing, tying knots, difficulty rising from seated position)

Postural instability and gait dysfunction

• Usually appears later in the disease course, but may occur early in some
• Tendency to fall forward (propulsion) or backward (retropulsion)
• Loss of postural reflexes
• Stooped posture
• Difficulty in starting to walk, turning, and stopping
• Shuffling gait with short, quick steps (festinating gait)
• Decreased arm swing
• Freezing may occur which is sudden inhibition of movements

OTHER SYMPTOMS

Motor fluctuations

• On/Off phenomenon:
  • May occur with advancing disease due to disease progression and chronic levodopa treatment
  • Periods of satisfactory or good control (on effect) is followed by periods of near immobility (off effect)
  • Symptoms of wearing off are apparent when the duration of levodopa effect subsides
• Dyskinesia:
  • Over time many patients with PD may develop medication-induced dyskinesia some of which can be disabling
  • Many PD patients may be either unaware of dyskinesia or not have any functional disability with the involuntary movements

Musculoskeletal problems

• Camptocormia (bent-spine)
• Head drop (less common)
• Kyphosis

2. Non-Motor Symptoms

Dementia

• Dementia can occur later in the course of disease in 10-15% patients
• Short-term memory and visuoperceptual functions may be affected

Psychosis

• Sense of presence: Well formed visual and less commonly auditory and tactile hallucinations
• Paranoid delusions: May be associated with cognitive impairment; Can be triggered by dopaminergic drugs; always rule out other causes of delirium e.g. infection

Mood disorders

• Depression
• Anxiety
• Apathy
• All very common in PD. Maybe ‘premotor’ features i.e. occur years before the onset of PD

Sleep disorders

• Excessive daytime sleepiness
• Insomnia
• REM sleep behaviour disorder (maybe a ‘premotor’ feature)
• Sleep disorders are very common and are often drug-induced

Autonomic dysfunction

• Urinary frequency and nocturia
• Constipation
• Postural hypotension

Pain

• Can be multifactorial due to rigidity or dystonia or ‘central’
• Sensory symptoms-Numbness/tingling

Differential Diagnosis

Essential tremors

• Bilateral, no rest component in tremors in the early stage of disease
• Positive family history in 50%
• Alcohol-responsive in >50%

Lacunar stroke

• Multiple strokes leading to steady decline in cortical function, and associated gait instability (apraxic gait), rigidity, dysarthria
• Usually no resting tremors and bilateral symptoms with upper motor neuron signs (sometimes called ‘Lower body Parkinson’s disease)

Normal pressure hydrocephalus

• Dementia, apraxic gait (wide-based small steps, normal arm swing), urinary incontinence (needs CT/MRI brain scan)

Wilson’s disease

• Derangement in Copper metabolism
• ‘Odd’ tremors e.g. ‘wing flapping’ tremor and dystonia in face and limbs
• Check for corneal Keiser-Fleischer rings and 24h urinary copper excretion

Multiple system atrophy (MSA)

• May present with parkinsonism but early onset of dysautonomia, cerebellar involvement (gait ataxia), and pyramidal signs
• Loss of levodopa response over time
• May have abnormal brain MRI with basal ganglia and cerebellar atrophy (e.g. ‘Hot cross bun’ sign)

Progressive supranuclear palsy

• Older age, gaze abnormalities, early unexplained falls, dysarthria, dysphagia, and dementia

Cortical-basal ganglionic degeneration

• Asymmetrical bradykinesia, rigidity, dystonia, myoclonus, central loss of sensory function and apraxia

Alzheimer disease

• Symptoms of parkinsonism may develop in the late stage of Alzheimer

Investigation and Workup

Diagnosis of PD is based upon clinical evaluation

• Thorough history of presenting complaints
• Family and occupational history
• Neurological exam
• Response to dopaminergic therapy
• Neuroimaging-CT/ MRI brain: Rule out structural abnormalities such as hydrocephalus, tumour, or lacunar infarcts

Treatment

Clinical Trials

• Levodopa and the Progression of Parkinson’s Disease
• A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson’s Disease
• A Five-Year Study of the Incidence of Dyskinesia in Patients with Early Parkinson’s Disease Who Were Treated with Ropinirole or Levodopa
• Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial)
• Rivastigmine for Dementia Associated with Parkinson’s Disease
• Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease (CALM-PD)

Pipeline Agents

• Gene delivery of AAV2-neurturin for Parkinson’s disease
• Preladenant in patients with Parkinson’s disease and motor fluctuations
• Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease

Physician Resources

1. Tips for patient care

General management:

• Medication may not be indicated in early stages
• Encourage exercise and a healthy lifestyle
• Communication with patients and families is paramount. Both oral and written communication may be helpful throughout the course of the disease, as patient with PD may develop cognitive impairment, a communication deficit and/or depression
• Depression is very common in all stages of PD and is often missed due to the clinical features of the disease. Anxiety is also common; the patient who is frequently calling the office is likely anxious. Treatment of anxiety and depression through counselling, or appropriate medications is often beneficial
• Inform patients and families about potential sleeping problems such as insomnia or REM sleep behaviour disorder
• Patients with PD who have sudden onset of sleep (usually medication induced) should be cautioned and advised not to drive. Document sleep disturbances using the Epworth Sleepiness Scale (http://epworthsleepinessscale.com)
• As the disease progresses patients and families need to be aware of:
  • Fall risk-encourage the use of canes and walkers where appropriate
  • Remove rugs and avoid uneven floors
  • Nearing end-stage be aware of
    • – Aspiration risk and ensuing pneumonia
    • – Bedsores (due to immobility)
• Suggest high fluid intake and a high-fiber diet to prevent or treat constipation
• Patients should be encouraged to keep follow-up visit with a Neurologist

Medications:

• Most drug therapy is required when symptoms interfere with everyday life
• Use lower starting doses in elderly and debilitated patients
• Treatment should be titrated slowly to avoid unnecessary side effects
• Advise patient to establish prescribed routine for pill-taking
• Evaluate cost and affordability and insurance coverage for patients
• Consider concurrent risk factors and disease states with the prescribed therapy
• Monitor patient regularly to adjust medications as required
• The management of depression in people with PD should be individualized, and needs to take into account their co-existing therapy
• Be aware of impulse control disorder (ICD) (abnormal behaviours, such as hypersexuality, pathological gambling, compulsive eating (usually sweets) that can occur in up to 15% of patients treated with a dopamine agonist. People at risk are younger, male, often with preexisting or family history of addiction. Always ask about ICD as patients and family members may not volunteer this information
• Adherence to treatment should be assessed at each visit
• Psychosis is due to the disease itself and may be exacerbated by drugs but remember to exclude reversible causes such as intercurrent infections etc.

Social and Stress factors:

• Ensure patient and family are well informed about disease and its treatment
• Include family or social support in lifestyle modification
• Patient and family should be made aware of local support groups as well as online information

Activities (Physical, Mental, others):

• Stress the importance of staying active and having a regular exercise routine
• Occupational therapy should be available for people with PD
• Speech therapy indicated and helpful in dysarthria or hypoarthria
• Advise patients to keep themselves mentally active

2. Scales and Tables:

• Parkinson’s disease-pathophysiology
• Distinguishing features: Essential vs Parkinson’s tremor

References

Core Resources:

• Brust JCM (2007) Current Diagnosis and Treatment (Neurology) (2nd ed.) New York: McGraw Hill
• Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist Association. Toronto: Webcom Inc. 2012
• Day RA, Paul P, Williams B, et al (eds). Brunner & Suddarth’s Textbook of Canadian Medical-Surgical Nursing. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
• Foster C, Mistry NF, Peddi PF, Sharma S, eds. The Washington Manual of Medical Therapeutics. 33rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010
• Gray J, ed. Therapeutic Choices. Canadian Pharmacists Association. 6th ed. Toronto: Webcom Inc. 2011
• Grimes D, Gordon J, Snelgrove B. et al. Canadian Guidelines on Parkinson’s Disease. Can J Neurol Sci. 2012;39: S1-S30
• Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11th ed. New York: McGraw-Hill; 2009
• Longo D, Fauci A, Kasper D, et al (eds). Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2011
• McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York: McGraw-Hill; 2010
• Pagana KD, Pagana TJ eds. Mosby’s Diagnostic and Laboratory Test Reference. 9th ed. St. Louis: Elsevier-Mosby; 2009
• Rowland LP et al. (2010) Merritt’s Neurology (9th ed.) Philadelphia: Lippincott Williams and Wilkins
• Skidmore-Roth L. ed. Mosby’s drug guide for nurses. 9th ed. St. Louis: Elsevier-Mosby; 2011
• Skidmore-Roth L, ed. Mosby’s nursing drug reference. 24th ed. St. Louis: Elsevier-Mosby; 2011
• National Collaborating Centre for Chronic Conditions. Parkinson’s disease: national clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians, 2006

Online Pharmacological Resources:

• e-Therapeutics
• Lexicomp
• RxList
• Epocrates

Journals/Clinical Trials:

• Angot E, Steiner JA, Hansen c. et al.  Are synucleinopathies prion-like disorders? Lancet Neurol 2010; 9: 1128–38
• Block, G, Liss, C, Reines, S, et al. Comparison of immediate-release and controlled-release carbidopa/levodopa in Parkinson’s disease: A multicenter 5-year study. Eur Neurol 1997; 37:23
• Cruz MP,  Xadago (Safinamide): A Monoamine Oxidase B Inhibitor for the Adjunct Treatment of Motor Symptoms in Parkinson’s Disease Pharmacy and Therapeutics  2017 Oct; 42(10): 622-624,637
• Emre M, Aarsland D, Albanese A, Rivastigmine for Dementia Associated with Parkinson’s Disease N Engl J Med 2004; 351:2509-2518
• Fahn, S, Bressman, SB. Should levodopa therapy for Parkinsonism be started early or late? Evidence against early treatment. Can J Neurol Sci 1984; 11:200
• Galpern WR, Lang, AE Interface between tauopathies and synucleinopathies: A tale of two proteins. Ann Neurol 2006; 59:449-458
• Goedert, M., Spillantini, M. G., Del Tredici, K. & Braak, H. 100 years of Lewy pathology. Nature Rev. Neurol 2012; 9, 13–24
• Hauser RA, Cantillon M, Pourcher E et al. Preladenant in patients with Parkinson’s disease and motor fluctuations The Lancet Neurology 2011; 10: 221-229
• Hauser, RA, McDermott, MP, Messing, S. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch Neurol 2006; 63:1756
• Irwin DJ, Lee VM, Trojanowski JQ. Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci. 2013;14(9):626-636. doi:10.1038/nrn3549
• Kumar, N, Van Gerpen, JA, Bower, JH, Ahlskog, JE. Levodopa-dyskinesia incidence by age of Parkinson’s disease onset. Mov Disord 2005; 20:342
• Lyons KE, Pahwa R. Outcomes of rotigotine clinical trials: effects on motor and nonmotor symptoms of Parkinson’s disease. Neurol Clin. 2013;31(3 Suppl): S51-9
• Marks MJ, Bartus RT, Siffert J, et al. Gene delivery of AAV2-neurturin for Parkinson’s disease The Lancet Neurology 2010; 9: 1164-1172
• Mizuno Y, Hasegawa K, Kondo T et al. Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease Mov Disord. 2010; 25:1437-43
• Olanow C W, Rascol O, Hauser R, et al, A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson’s Disease ADAGIO Study Investigators N Engl J Med 2009; 361:1268-1278
• Postuma, RB, Lang, AE. Homocysteine and levodopa: should Parkinson disease patients receive preventative therapy? Neurology 2004; 63:886
• Rascol O, Brooks DJ, Korczyn AD, et al, A Five-Year Study of the Incidence of Dyskinesia in Patients with Early Parkinson’s Disease Who Were Treated with Ropinirole or Levodopa. 056 Study Group.N Engl J Med 2000; 342:1484-1491
• Sampson TR, Debelius JW, Thron T, et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell. 2016;167(6):1469-1480.e12. doi:10.1016/j.cell.2016.11.018
• Shrivastava A The hot cross bun sign Radiology 2007, 245: 606-607
• The Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease Arch Neurol 2009; 66:563-70
• The Parkinson Study Group  A Controlled Trial of Rotigotine Monotherapy in Early Parkinson’s Disease. Arch Neurol. 2003;60 (12):1721-1728
• The Parkinson Study Group. Levodopa and the Progression of Parkinson’s Disease N Engl J Med 2004; 351:2498-2508
• The Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol 1996; 39:37-45
• Williams A, Gill S, Varma T, et al, for the PD SURG Collaborative Group Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial) The Lancet Neurology 2010; 9:581-591