Motor symptoms; Parkinson's Disease Flashcards
1
Q
What is Parkinson’s Disease? 22:12
A
Neurodegenerative; death/depletion of DA-containing cells of the substantia nigra.
2
Q
What is the substantia nigra?
A
- Origin of dopaminergic afferents (neurones) implicated in Parkinson’s
- DA neurones stretch from the substantia nigra to the higher centres of the brain; but information is compromised a result in Parkinson’s
3
Q
What is the pathophysiology of Parkinson’s?
A
- DA neuron loss in the substantia nigra (primarily)
- But also loss of NA (locus coeruleus) and serotonergic (5-HT) neurons (Raphe nuclei)
4
Q
What is a Lewy body, and its significance?
A
- Accumulation of protein deposits (abnormal) in substantia nigra, locus coeruleus and other brain regions
- Disrupt brain’s normal functioning; deplete DA
= Parkinson’s (and Lewy-Dementia)
5
Q
What is the genetic influence of Parkinson’s aetiology?
A
- The earlier the age of onset, the greater the familial occurrence
- About 15-25% of people w/Parkinson’s disease have a relative w/the disease
»> Odds greatly increased if relative is parent or sibling.
6
Q
What is the aetiology of Parkinson’s in regards to specific genes?
A
- α-Synuclein; autosomal dominant
- LRRK2 - autosomal dominant
- Parkn - autosomal recessive
7
Q
What is α-Synuclein, and its significance in Parkinson’s?
A
Key in aetiology of of Parkinson’s (genes):
- Autosomal dominant
- Major constituent of Lewy bodies (contains the protein α-5ynuclein)
- Too much or abnormal α-Synuclein produced in familial Parkinson’s
- Inhibits NT release (DA)
8
Q
What is LRRK2, and its significance in Parkinson’s?
A
Key in aetiology of of Parkinson’s (genes):
- Autosomal dominant
- leucine-rich repeat kinase 2
- High prevalence in North African Arabs and Ashkenazi Jews (Central/Eastern Europe)
- Responsible for 2% of PD in Western populations
9
Q
What is Parkin, and its significance in Parkinson’s?
A
Key in aetiology of of Parkinson’s (genes):
- Autosomal recessive
- Also known as Juvenile Parkinsonism; onset age < 30 years
- Acts as a ubiquitin-protein ligase; labels neurones for degradation (normally dead/damaged); mopped up by microglia afterwards
»> Wrongly labelled neurons w/mutation
- Portrayal of a protective role
10
Q
What is meant by an autosomal dominant gene vs. an autosomal recessive one?
A
- Autosomal dominant; only need contribution from one parent for Parkinson’s mutation
- Autosomal recessive; need copies from both genes to result in mutated gene (Parkin)
11
Q
What is the aetiology of Parkinson’s WRT the environment?
A
- Rural living
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
- Ageing
12
Q
How is rural living implicated in the aetiology of Parkinson’s? Evidence?
A
Some pesticides known to be potent mitochondrial inhibitors:
- Mitochondrial complex 1
• Extracts energy from NADH
• Complex is deficient in patients who have died from Parkinson’s; pesticides inhibit mitochondrial complex 1, hence deficiency.
Additional evidence:
- Infusion of insecticide ROTENONE in rats caused dopaminergic cell death, Lewy body formation and motor deficit
»> Direct link w/pesticides
13
Q
How is MPTP implicated in the aetiology of Parkinson’s?
A
- Student tried to manufacture synthetic heroin, MPPP
- However manufacture MPTP instead
- Developed symptoms of PD, but responsive to treatment
- Autopsy following death revealed:
• Destruction in substantia nigra (hence Parkinson’s symptoms)
• But lacking in Lewy bodies
14
Q
How is ageing implicated in the aetiology of Parkinson’s?
A
- Increased prevalence of PD at older ages
»> Loss of striatal DA and DA cells (neurones) in the substantia nigra
(Though precise role in pathogenesis still unclear)
15
Q
What are the characteristic motor symptoms associated w/PD?
A
- Bradykinesia; slowness of movement, ‘shuffling’, stooped posture
- Resting tremor; shaking that disappears during active use of the affected body part (basal ganglia normally filter unwanted movement)
- Rigidity; increased resistance to passive movement
- Postural instability; instability when standing, or impaired balance and coordination
16
Q
What other symptoms are characteristic of PD?
A
- Drooling
- Fatigue
- Loss of facial expression (effect on motor cortex)
- Speech problems (talking = lots of muscles)
- Dysphagia; problems swalling
17
Q
What are the characteristic non-motor (autonomic) symptoms of PD?
A
- GI dysfunction
- Genitourinary dysfunction
- CV dysfunction
- Cognitive dysfunction
- Sleep disorders
- Mood disorders
- Pain
18
Q
Describe GI dysfunction as a symptom of PD.
A
- Autonomic, non-motor symptom:
• Constipation (most common)
• Incomplete bowel evacuation/bowel incontinence
(Parasympathetic NS)
19
Q
Describe the Genitourinary dysfunction that may arise as a result of PD.
A
- Autonomic, non-motor symptom:
• Urinary urgency/frequency/incontinence (M3 receptors)
• Sexual dysfunction (ED in men)
20
Q
Describe CV dysfunction as a symptom of PD.
A
- Autonomic, non-motor symptom:
• Cardiac sympathetic denervation; responsible for orthostatic (postural) light-headedness and hypotension (SUSCEPTIBLE to falling; blood doesn’t recalibrate)
• Though postural hypotension is more often related to dopaminergic medication
21
Q
Describe the degree of Cognitive dysfunction that may present in PD.
A
- Autonomic, non-motor symptom:
• Slowness of thought and executive dysfunction; Parkinson’s Disease Dementia
22
Q
Describe the sleep disorders that may present in PD.
A
- Autonomic, non-motor symptom:
• Rapid eye movement disorder (act out their dreams)
• Restless leg syndrome
• Periodic limb movement of sleep (flexing limbs every 20-30 seconds)
• Insomnia
• Excessive daytime sleepiness
23
Q
Describe how mood disorders may present in PD.
A
- Autonomic, non-motor symptom:
• Depression
• Psychosis
• Anxiety; GAD, agoraphobia, panic disorder, social phobia (as a result of motor symptoms)
24
Q
Describe how Pain may present as a symptom of PD?
A
- Autonomic, non-motor symptom:
• Musculoskeletal (not utilising all muscles); cramping, aching, skeletal deformities (from stooping) etc.
• Radicular neuropathic pain; radiates into the lower extremity directly along the course of a spinal nerve root
• Dystonic pain; in the neck muscles; due to effects from medication
• Central/primary pain; stabbing, burning, scalding pain
25
What is the pharmacological management strategy of PD?
- Treat symptoms; replenish DA
| - Prevent, delay or reverse neurogeneration
26
What are the recommended pharmacological agents to treat PD?
- Levodopa (first line)
- DA agonists
- MAO type-B inhibitors
- COMT inhibitors
- Other; anticholinergics, Glu antagonists
27
Describe Levodopa's use in PD. What is it effective against? Mechanism?
- First line therapy
- Effective against bradykinesia (slowness of movement) and rigidity
- Mechanism; levodopa (L-DOPA) is natural precursor to DA; converted to DA via DOPA-decarboxylase
28
How is Levodopa prescribed for PD?
- Prescribed with dopa-decarboxylase inhibitor; Carbidopa (Sinamet) or Benserazide (Madopar)
- Reduces peripheral S/Es; N&V, CV (prophylactic measure)
- Mainstay
>>> NOT used for younger patients; chronic use presents with complications later on.
29
Why is Levodopa prescribed with a dopa-decarboxylase inhibtor (as Carbidopa/Benserazide)?
- L-DOPA given in general instead of DA as peripherally administered DA cannot penetrate BBB; L-DOPA can, and is converted to DA by dopa-decarboxylase in the brain
- PO administration of Levodopa alone results in rapid peripheral conversion of L-DOPA to DA = GIT S/Es (N&V), decreases therapeutic effect
>>> Thus, as Carbidopa (w/DOPA-decarboxylase inhibitor), peripherally circling L-DOPA is not converted into DA (inhibits peripheral DOPA-decarboxylase), minising S/Es, improving therapeutics
30
When are DA agonists used for PD treatment? Give examples. Mechanism?
E.g. ropinirole, pramipexole, rotigotine
- First line in younger patients (< 30); reduced motor complications
- Combination therapy w/levodopa v. effective; give lower dose of levodopa in this instance
- Mechanism; DA agonists selective for D2 and D3 postsynaptic receptors
31
What are the S/Es associated with DA agonist therapy?
- Nausea
- Sleepiness
- Dizziness
- Hallucinations
- Psychiatric disorders
>>> Due to elevated DA throughout body
32
What is the mechanism for MAO inhibitors? Give examples. S/Es?
Mechanism:
Prevents degradation (metabolism) of DA; by inhibiting MAO.
- Selegiline; S/Es = excitement, anxiety, insomnia (central)
- Rasagaline (S/Es specific to Selegiline)
>>> Generally well tolerated; option for younger patients.
33
What is the mechanism for COMT inhibitors? Give an example. Advantages?
Catechol-O-methyltransferase inhibitors
E.g. entacapone
- Mechanism; prevents DA degradation
- Increased 'on time' in patients w/advanced PD
>>> On time = patient experience good response to medication
34
What is a potential method of improving compliance in PD treatment?
Using combination therapy of levodopa + carbidopa + entacapone
>>> Stalevo (3 in 1)
35
What are the other options for the pharmacological management of PD? Mechanisms? S/Es?
- Amantadine
• Initially an anti-viral
• Mild anti-Parkinsonian effect ( short term use)
• Mechanism; unclear; mixed dopaminergic and glutamatergic actions
• S/Es: confusion, insomnia
- Antimuscarinics e.g. benzhexol
• Inhibits DA suppression
• Compensatory mechanism for decreasing DA
36
How are the non-motor symptoms of PD approached pharmacologically?
GI dysfunction
- Constipation; Macrogol (osmotic laxative)
Cognitive dysfunction
- Dementia; rivastigmine (AcetylCoE inhibitor; hallucinations >> amnesia)
```
Mood disorders
- Depression; DA agonist
• Pramipexole (w/efficacy against depression too)
• TCA (nortriptyline)
• SSRI
```
Psychosis
- Atypical neuroleptics (e.g. risperidone)
37
What is the requirement criteria for surgical management of PD?
- Excellent response to levodopa
- Younger age
- No/mild cognitive impairment
- Absent/well controlled psychiatric disease (e.g. depression)
38
What does surgical management of PD entail?
- Permanent implantation of leads into the subthalamic nucleus or globus pallidus (both part of basal ganglia)
- Leads deliver high frequency electrical impulses controlled by stimulator
- Alleviates motor symptoms
- Presents opportunity to decrease levodopa dose (preventing chronic use, or even stopping L-DOPA)
39
What are the non-pharmacological management options for PD?
- Cell replacement therapy
- Exercise/physiotherapy
- Vitamin D
40
What does Cell replacement therapy propose for PD management? Advantages?
Non-pharmacological management:
- No therapies currently availible
- Current research; embryonic, mesenchymal, neural, pluripotent stem cells
+ Long stability of the grafted cells (no rejection)
+ Long-lasting function recovery
+ Effective restoration of DA release in vivo
41
How does exercise/physiotherapy aid PD therapy? Evidence?
- Dance/martial arts: considered useful as an adjunct to pharmacological therapy
• Evidence; rat model of PD demonstrated decreased DA degeneration when 'forced' to use affected limb; >>> exercise protective in PD???
42
What does Vitamin D have to do with PD?
- Low in PD patients
- Related to bone health in PD
- Related to severity of PD symptoms
>>> NEUROPROTECTIVE role in animal studies
- Most exciting, but also challenging translating to humans
43
What complications (and their resulting modifications) arise in treating PD with Levodopa?
> Consider decreasing dose w/adjuncts; DA agonist, MAO and COMT inhibitors
Example S/Es
Dyskinesia:
- Involuntary writhing which develops in most patients
- Amantadine or clozapine effective
Fluctuations in clinical state
- Hypokinesia (decreased body movement) and rigidity worsening for a few minutes/hours, then improving
- Levodopa-SR or levodopa + COMT inhibitor (maintaining steady state to avoid troughs)
Nausea:
- Administer w/food; combination w/carbidopa/benserazide; domperidone (peripheral DA antagonist)
44
What complications (and their resulting modifications) arise in treating PD with DA agonists?
Impulsive compulsive behaviour:
- Exacerbated in a patient w/history of OCD, impulsive personality, addictive behaviour
Action:
• Reduce/discontinue DA agonists
• Anticonvulsant zonisamide; reduces impulsive behaviour
45
What complications (and their resulting modifications) arise in treating PD-induced psychosis with Clozapine?
Requires blood monitoring (weekly) due to agranulocytosis risk (neutropenia risk etc.)
46
What commodities are associated w/PD, and their treatments?
Depression
- Widespread in early-onset PD
- Challenging diagnosis due to symptom overlap; e.g. weight loss and insomnia
- Pathophysiology; abnormalities of serotonergic, noradrenergic and dopaminergic function
>>> Current recommended treatment (SSRIs)
Cognitive impairment
- Cholinergic dysfunction observed in patients over time
>>> Treatment (clinical trials); acetylcholinesterase inhibitor (rivastigmine, donepezil)
- 2 year treatment required (not 100% efficacious)
Orthostatic (postural) hypotension (common; due to meds)
- Due to autonomic dysfunction OR ADR of dopaminergic medication
>>> Treatment (clinical trials);
• Fludrocortisone (corticosteroid, increases blood volume, thus BP)
• Pyridostigmine (cholinesterase inhibitor)
• Indomethacin (NSAID)
• Domperidone
• Increase salt and fluid consumption BUT monitor for hypertension!!!
