Parkinson's Disease (Yvonne Mbaki)

Question 1

What is the definition of Parkinsons?

Answer 1

Neurodegenerative; death of dopamine containing cells of the substantia nigra

Question 2

What is the substantia nigra?

Answer 2

The origin of dopaminergic afferents implicated in Parkinson’s disease

Question 3

What is the pathophysiology associated with Parkinson’s disease?

Answer 3

Domaine neurons in the substantia nigra in normal cells compared to the loss of noradrenergic and serotonergic neurons.

Question 4

How do Lewy bodies form?

Answer 4

Aggregation of protein deposits in substantia nigra, locus coeruleus and other brain regions
Alpha-synuclein aggregation.

Question 5

How is Parkinson’s disease linked to genetics?

Answer 5

The earlier the age of onset, the greater the familial occurrence
Odds of inheritance are increased if parent or sibling has PD

Question 6

Which specific genes are the causative agents of PD?

Answer 6

1. a-synuclein (autosomal dominant)
   Major constituent of Lewy bodies
   In familial Parkinson’s, too much or abnormal amounts of a-synuclein are produces.
   It is thought that it inhibits neurotransmitter release
2. LRRK2 (autosomal dominant)
   Leucine-rich repeat kinase 2
   High prevalence in North African Arabs / Central/Eastern European Jews.
3. Parkin (autosomal recessive)
   Juvenile parkinsonism - onset <30 yrs
   Acts as a ubiquitin-protein ligase; labels dead / damaged neurons to be cleared up

Question 7

How can rural living increase risk of PD?

Answer 7

Some pesticides are known to be potent mitochondrial inhibitors
Mitochondrial complex 1 extracts energy from NADH; this complex is deficient in patients that have died from PD.
Infusion of insecticide rotenone in rats caused dopamingergic cell death, Lewy body formation and motor defecit.

Question 8

How does mitochodrial inhibition cause PD?

Answer 8

Mitochondrial complex 1 extracts energy from NADH; this complex is deficient in patients that have died from PD.

Question 9

Which insecticide has shown to cause PD effect in rats?

Answer 9

Rotenone

Dopaminergic cell death, Lewy body formation and motor defecit

Question 10

Which two environmental factors can cause PD?

Answer 10

Pesticides that lead to mitochodrial inhibition

MPTP

Question 11

What is MPTP?

Answer 11

MPTP (1- methyl - 4-phenyl - 1, 2, 3, 6 - tetrahydropyridine)

Question 12

How was MPTP discovered?

Answer 12

By accident when synthetic heroin was the target
A student accidentally manufactured a neurotoxin MPTP
The student developed Parkinson’s disease smptoms but was responsive to treatment.
Autopsy showed destruction of substantia nigra but not Lewy body formation

Question 13

What does increased prevalence of Parkinson’s Disease suggest?

Answer 13

Age is a factor associated with development of PD.
Loss of striatal dopamine (dopamine from the striatum) and dopamine cells in the substantia nigra
The precise role of aging is still unclear.

Question 14

What are the motor symptoms associated with PD?

Answer 14

Bradykinesia: slowness of movement
Resting tremor: Shaking that disappears during active use of the affected body part
Rigidity: Increased resistance to passive movement
Postural instability: instability when standing, or impaired balance / coordination.

Question 15

What other motor symptoms are included in PD?

Answer 15

Drooling 
Fatigue 
Loss of facial expressions 
Speech problems 
Dysphagia

Question 16

What are the non-motor symptoms / autonomic symptoms of PD?

Answer 16

GI dysfunction 
Genitourinary dysfunction 
Cardiovascular dysfunction 
Cognitive dysfunction 
Sleep disorders 
Mood disorders
Pain

Question 17

What GI dysfunction is associated with PD?

Parasympathetic NS

Answer 17

Constipation

Incomplete bowel evacuation / bowel incontinence

Question 18

What genitourinary dysfunction is associated with PD?

Answer 18

Urinary urgency, frequency and incontinence

Sexual dysfunction presents in erectile dysfunction in men

Question 19

What cardiovascular dysfunction is associated with PD?

Answer 19

Cardiac sympathetic denervation = loss of nerve supply
Responsible for light headedness and hypotension.
More commonly, postural hypotension related to medication for PD.

Question 20

What cognitive dysfunction is associated with PD?

Answer 20

Slowness of thought and executive dysfunction

Parkinson’s Disease Dementia

Question 21

What sleep disorders are associated with PD?

Answer 21

Rapid eye movement disorder
Restless legs syndrome 
Periodic limb movement of sleep 
Insomnia 
Excessive daytime sleepiness

Question 22

What are the mood disorders associated with PDD?

Answer 22

Depression
Psychosis (potentially due to too much dopamine as a result of Tx)
Anxiety - GAD, agoraphobia, panic disorder, social phobia

Question 23

What are the pain symptoms associated with PD?

Answer 23

Muscoskeletal pain; cramping aching deformities
Radicular neuropathic pain; radiates into the lower extremity directly along the course of a spinal nerve root
Dystonic pain; pain in the neck muscles (effect of medication)
Centra/primary pain; stabbing burning scalding pain

Question 24

What is the management strategy for treating PD?

Answer 24

Treat symptoms by replenishing dopamine

Prevent, delay, reverse neurodegeneration

Question 25

What is the first line therapy for PD?

Answer 25

First line therapy is Levodopa

Question 26

How does Levodopa treat PD?

Answer 26

Treats bradykinesia and rigidity | Mechanism of action - levodopa is converted to dopamine via DOPA-decarboxylase.

Question 27

What is often concomittantly given with Levodopa and why?

Answer 27

Dopa-decarboxylase inhibitor such as carbidopa (Sinemet) or benserazide (Madopar) Given in order to reduce peripheral side effects such as nausea, vomiting, cardiovascular

Question 28

What is the first line treatment in younger patients?

Answer 28

Dopamine agonists such as Ropinirole, Pramipexole, Rotigotine

Question 29

What is the factor that means young people have a different first line treatment?

Answer 29

They have fewer motor complications

Question 30

Which drugs are dopamine agonists?

Answer 30

Ropinirole, Pramipexole, Rotigone

Question 31

How do dopamine agonists work?

Answer 31

Agonists selective for D2 and D3 post synaptic receptors

Question 32

What can dopamine agonists be given in combination with?

Answer 32

Levodopa for effective treatment

Question 33

What are the side effects associated with dopamine agonists?

Answer 33

Nausea, sleepiness, dizziness, hallucinations and psychiatric disorders due to increased dopamine

Question 34

How do monoamine oxidase-B inhibitors treat PD?

Answer 34

Prevents the degradation of dopamine

Question 35

Which drugs are MAOi's?

Answer 35

Selegiline, Rasagaline

Question 36

What are the side effects associated with MAOi's?

Answer 36

Selegilline; excitement, anxiety or insomnia | Generally well tolerated

Question 37

What is the mechanism of action of amantadine?

Answer 37

Mechanism is unclear but has mixed dopaminergic and anti-glutamatergic effects Initially used as an anti-viral

Question 38

Which drugs are COMT inhibitors?

Answer 38

Entacapone

Question 39

What is the mechanism of action of COMT inhibitors?

Answer 39

Prevents degradation of dopamine

Question 40

How can PD medication compliance be improved?

Answer 40

Levodopa + Carbidopa + Entacapone Stalevo

Question 41

How can the cognitive function of PD be treated?

Answer 41

Rivastigmine for demention | Acetylcholinesterase inhibitor ; treats hallucinations more than amnesia

Question 42

How can mood orders be treated in PD?

Answer 42

Dopamine agonist - pramipexole | TCA SSRi

Question 43

How can pyschosis in PD patients be treated?

Answer 43

Atypical neuroleptics i.e clozapine (needs close monitoring due to bone marrow suppression).

Question 44

How can the cognitive function of PD be treated?

Answer 44

Rivastigmine for dementia | Acetylcholinesterase inhibitor ; treats hallucinations more than amnesia

Question 45

How can PD be managed surgically?

Answer 45

Deep brain stimulation

Question 46

What criteria must be met in order for deep brain stimulation to be suitable for patients?

Answer 46

Excellent response to levodopa Younger age No / mild cognitive impairment Absence / well controlled psychiatric disease

Question 47

How does deep brain stimulation work?

Answer 47

Permanent implantation of leads into the subthalamic nucleus (basal ganglia) or globus pallidus Leads deliver high frequency electrical impulses contolled by stimulator Shown to alleviate motor problems Presents opportunity to reduce levodopa dose

Question 48

What is cell replacement therapy?

Answer 48

No therapies currently available but current research focusses on embryonic, mesenchymal, neural, pluripotent stem cells +long stability of grafted cells +long lasting function recovery + effective restoration of dopamine release in vivo

Question 49

What lifestyle factor can help in management of PD?

Answer 49

Dance, martial arts are considered useful as an adjunct to medication.

Question 50

What vitamin is associated with the non-pharmacological treatment of PD?

Answer 50

``` Vitamin D Low in patients with PD Related to bone health in PD Appears related to severity of symptoms Neuroprotective role in animal studies ```

Question 51

What are the complication in treating PD with levodopa?

Answer 51

Dyskinesia Fluctuations in clinical state Nausea

Question 52

What is dyskinesia (complication of levodopa)? | How can it be treated?

Answer 52

Involuntary writhing which develops in most patients | Amantadine or clozapine to treat

Question 53

What are fluctuations in clinical state (complications in levodopa)? How can it be treated?

Answer 53

Hypokinesia (reduced body movement) and rigidity worseding for a few minutes/hour then improving Levodopa-SR or levodopa and COMT combined Tx

Question 54

How can nausea (induced by levodopa) be managed?

Answer 54

Administer levodopa with food; combination with carbidopa/benserazide Domperidone anti-emetic (peripheral dopamine antagonist).

Question 55

What are the complications with treating PD with dopamine agonists?

Answer 55

Impulsive compulsive behaviour - exacerbated in a patient with a history of OCD, impulsive personality or addictive behaviour

Question 56

What action is taken when impulsive compulsive behaviour arises in people taking dopamine agonist medication for PD?

Answer 56

Reduce / discontinue dopamine agonists | Anti-convulsant zonisamide; reduces impulsive behaviour

Question 57

What are the benefits that arise in patients treating PD with clozapine?

Answer 57

Observed to improve psychosis

Question 58

What needs to be monitored in patients taking clozapine and why?

Answer 58

Agranulocytosis (lowered WBC count) | Blood monitoring is needed

Question 59

What are the co-morbities associated with Parkinson's disease?

Answer 59

Depression, cognitive impairment, orthostatic hypotension

Question 60

How can PD related depression be treated?

Answer 60

SSRi and TCA

Question 61

How does depression present as a co-morbidity in PD?

Answer 61

Widespread in patients with early onset of PD | Abnormalities of serotenergic, noradrenerfic and dopaminergic function

Question 62

Why is it hard to diagnose depression in PD?

Answer 62

Challenging diagnosis due to symptoms overlapping e.g. weight loss and insomnia

Question 63

How does cognitive impairment arise in PD?

Answer 63

Cholinergic dysfunction observed in patients over time

Question 64

How can cognitive impairment be treated as a PD comorbitiy?

Answer 64

Clinical trials; acetylcholinesterase inhibitor (rivastigmine, donepezil)

Question 65

How does orthostatic hypertension manifest in PD patients?

Answer 65

Exists as manifestation of autonomic dysfunction or adverse effect of dopaminergic medication

Question 66

What medications are in clinical trials for PD related postural hypotension?

Answer 66

Corticosteroid; fludrocortisone Cholinesterase inhibitor; pyridostigmine NSAID; indomethacin Domperidone

Question 67

What non-pharmacological advice can help alleviate orthostatic hypotension in PD?

Answer 67

Increase intake of fluid and salt --> Monitor for hypotension