Parkinson's Disease Flashcards
What is Parkinson’s disease?
Progressive neurodegenerative disease (CNS disorder), due to the loss of dopaminergic neurons in the substantia nigra (80% loss => clinical symptoms)
Majority are idiopathic
May also be familial
What is Parkinsonism?
Manifestation of symptoms of Parkinson’s, but not itself PD
E.g., can be drug-induced, toxin-induced, vascular
Incidence and prevalence of PD
- 2nd most common neurodegenerative disease after dementia
- Increases with age (average age of onset: early to mid 60s)
- Slight male preponderance (1.35 : 1)
- VS young-onset PD: age 21-40y
- VS juvenile-onset PD: <20y, mostly genetically inherited
What are the symptoms of PD?
Extrapyramidal motor symptoms (due to striatal dopaminergic deficiency): TRAP
- Tremors at rest (pill-rolling)
- Muscular rigidity (cogwheeling)
- Bradykinesia (slowness of movement)
- Postural instability, gait imbalance
Non-motor symptoms due to involvement of other neurotransmitters: POCAS
- Cognitive impairment
- Dementia
- Confusion
- Psychiatric symptoms
- Depression
- Psychosis
- Mood changes
- Sleep disorders
- REM sleep behavior disorder (dream-enactment behaviors)
- Sleep disturbances
- Autonomic dysfunction
- Constipation
- GI motility (e.g., difficulty swallowing, food movement)
- Orthostatic hypotension (labile BP, in later stages may drop out of nowhere)
- Sialorrhea
- Others:
- Fatigue
- Suboptimal nutrition (due to GI problems)
- Lose sense of smell
How is PD diagnosed?
Based on clinical signs, physical examination, and history
2 of the 3 cardinal signs must be present:
- Tremor at rest
- disappears with movement, increases with stress
- e.g., pill-rolling
- Rigidity
- ‘rachet’ like stiffness, cogwheel rigidity, leadpipe rigidity
- Akinesia/Bradykinesia
- Sense of weakness
- Loss of dexterity
- Loss of facial expression
- difficulty getting out of bed/chair
- Difficulty turning while walking
- Slowness of movement
Common clinical presentation of a PD patient:
- Stooped posture
- Rigidity in movement
- Flexed elbows and wrists
- Forward tilt of trunk
- Masked facial expression
- Reduced arm swing
- Micrographia - handwriting become small and cramped
- Loss of smell
Features of idiopathic PD at initial presentation:
- Asymmetric
- Positive response to levodopa or apomorphine
- Less rapid progression at early stages
Not present at time of diagnosis, in early stage:
- Postural instability (and falls)
- Autonomic dysfunction
Limited role for neuroimaging in early stage
Impaired olfaction (smell) is controversial
Idiopathic PD disease progression (toward later stages)
- Unable to perform basic ADLs (include mobility, continence, toileting)
- Choking (due to involvement of GIT, difficulty swallowing)
- Pneumonia (choking => aspiration risk => pneumonia)
- Freezing and Falls
Increasingly dependent in ADL, more motor fluctuations, dyskinesia, and non-motor symptoms
Describe the features of young-onset PD:
- Age 21-40
- Slower disease progression
- Features: less cognitive decline, earlier motor complication, dystonia common in initial presentation (VS freezing and falls which are more common in late-osnet)
- Prefer to use dopamine agonist rather than Levodopa in young-onset PD
Factors that may contribute to PD
Genetics:
- predisposition to toxins/insults
- genetic abnormalities
Increasing age:
- age-related loss of neurons (?)
Slightly more common in male (1.35 : 1)
Environmental/Occupation factors:
- Pesticide use (environmental toxins: MPTP-MPP+, pesticides, herbicides)
- Heavy metal exposure
- Head injury
[FYI]
Diet:
- Smoking, alcohol, caffeine may decrease risk (but not encouraged)
Pharmacologic:
- non-aspirin NSAIDs, estrogens, statins, may dcr risk
Pathophysiology of PD
Impaired clearing of abnormal/damaged intracellular proteins by ubiquitin-proteasomal system
Causes accumulation of aggresomes (misfolded proteins) and apoptosis
Microscopy: Lewy bodies (aggresomes, containing a-synuclein and ubiquitin) - eosinophilic cytoplasmic inclusions
=> Degeneration of dopaminergic neurons with Lewy Body inclusions in substantia nigra, therefore causing dysfunction of the nigrostriatal pathway
Loss of substantial nigra => no release of inhibition => hypokinetic state
Hallmarks of PD
- Neuroinflammation
- Neurodegeneration for specific dopamine neurons
- Lewy bodies (misfolded a-synuclein proteins)
Measuring disease progression
- Hoehn and Yahr staging
Describes the symptom progression of PD, based on decreasing mobility/independence, and increasing disability
Stage 1: Unilateral, tremor, rigidity, akinesia
Stage 2: Bilateral
Stage 3: Poor balance, impaired postural reflexes
Stage 4: Falls, dependency, cognitive decline
Stage 5: Chair/bed bound, dementia
Note: rapid progression is defined by Hoehn and Yahr stage 3 within 3 years, typically would take 10y to reach stage 3, 20y to reach stage 5
Measuring disease progression
- Movement Disorder Society (MDS) Unified Parkinson’s Disease Rating Scale (UPDRS)
- Non-motor experiences in daily living (e.g., mood, cognition, sleep, autonomic dysfunction)
- Motor experiences in daily living (ADLs - speech, walking, dressing)
- Motor examination (e.g., facial expression, tremor at rest, gait imbalance)
- Motor complications of therapy (dyskinesia with Levodopa)
Goals of PD treatment
- Manage symptoms
- Maintain function and autonomy
No cure, no treatment has shown to be neuroprotective
Also note that there is no monitoring parameter in PD, monitor base on pt function and ability to engage in ADLs
Non-pharmacological management of PD
- Physiotherapy
- Stretching, transfers, posture, walking, overcome freezing
- Occupational therapy
- Mobility aids, home, workplace safety
- Speech and swallowing
- Impt for pharmacists to know which drugs can be crushed - NGT, percutaneous tube
- Surgery
- E.g., deep brain stimulation: implantation device called a neurostimulator sends electrical impulses to specific parts of the brain, help to relieve symptoms
Describe the synthesis of dopamine
Synthesis of dopamine occurs in the presynaptic membrane
L-tyrosine => (tyrosine hydroxylase) => L-dopa => (DOPA decarboxylase) => Dopamine
L-dopa VS Dopamine
- which passes the BBB?
L-dopa passes the BBB, dopamine does not
Describe the breakdown of dopamine
Breakdown of dopamine occurs in the presynaptic membrane
Dopamine => Homovanillic acid (HVA)
Via COMT and MAO-B enzymes in any sequence
Note that COMT and MAO-B can also breakdown L-dopa
Note that COMT and MAO-B are also found in the periphery, outside BBB
[Pharmacologicals in PD]
What are the dopaminergic approach drugs used in PD?
- Levodopa + DOPA carboxylase inhibitor
- Dopamine agonists
- MAO-B inhibitors
- COMT inhibitors
[Pharmacologicals in PD: Levodopa + DCI]
Efficacy
- Gold standard, most effective drug for treatment of symptoms: esp bradykinesia and rigidity
- Less effective for speech, postural reflex, and gait disturbances
[Pharmacologicals in PD: Levodopa + DCI]
Place in therapy
Gold standard, most efficacious for symptomatic management of both early and late PD
However, dose should be kept to the minimum necessary to achieve good motor function due to SEs
Subsequently should switch due to the risk of dyskinesia
[Pharmacologicals in PD: Levodopa + DCI]
Purpose of DOPA-decarboxylase inhibitor (DCI)
2 in 1 preparation with Carbidopa or Benserazide
=> Peripheral DOPA-decarboxylase inhibitors, do not cross the BBB, prevent breakdown of L-dopa to dopamine in the periphery
- Prevent systemic side effects due to excess Dopamine outside the brain
- Allows more L-dopa to cross the BBB and exert its action in the brain
[Pharmacologicals in PD: Levodopa + DCI]
Dosing ratios of Levodopa and DCI in formulations
75-100mg DCI daily required to saturate DOPA decarboxylase
Formulations (4:1 or 10:1)
- Madopar (100mg L-dopa + 25mg Benserazide); (200mg + 50mg)
- Sinemet (100mg L-dopa + 10mg Carbidopa); (250mg + 25mg)
