Parkinson's Disease

Question 1

Define Parkinson’s disease.

Answer 1

Parkinson’s is a progressive, neurodegenerative disorder characterised by muscle rigidity, akinesia/dyskinesia (caused by difficulties in initiating movement), resting involuntary tremor (characteristic pill rolling of the thumb and forefinger), and a slow shuffling gait.

Question 2

What are the symptoms of Parkinson’s disease?

Answer 2

muscle rigidity, akinesia/dyskinesia (caused by difficulties in initiating movement), resting involuntary tremor (characteristic pill rolling of the thumb and forefinger), and a slow shuffling gait. Progression can be followed by the patients writing getting smaller as the disease progresses. Progression of the condition can be associated with dementia (PDD/DLB).

Question 3

What percentage of the total population suffers from Parkinson’s disease?

Answer 3

0.1%.

Question 4

After the age of 50, what percentage of people suffer from Parkinson’s disease?

Answer 4

1%.

Question 5

What is the mean survival time after diagnosis of Parkinson’s disease?

Answer 5

10 Years.

Question 6

Do patients die of Parkinson’s disease?

Answer 6

Patients don’t die of Parkinson’s, they die of complications related.

Question 7

What changes occur in the brain when one develops Parkinson’s disease?

Answer 7

Physiologically, Parkinson’s disease is a specific loss of the dopaminergic cells in the substantia nigra pars compacta which in turn leads to the loss of the dopaminergic nigrostriatal pathway.

Question 8

How can the brain slices of Parkinson’s patients be identified?

Answer 8

This can be seen, in brain slices, as a loss of the dark dopaminergic cells; these cells are dark because they contain melanin and as the cells die, the melanin goes with them.

Question 9

What can cause Parkinson’s disease?

Answer 9

Idiopathic, stroke, viral infection, genetics, environmental causes.

Question 10

What does the term Parkinsonism refer to?

Answer 10

The term Parkinsonism refers to drug-induced Parkinsonian symptoms; this can be caused by drugs such as amphetamines or neuroleptics.

Question 11

When and how was MPTP discovered?

Answer 11

It was discovered in California in the 1980s when heroin addicts were being found ‘frozen’ after using designer drugs which they thought were heroin.

Question 12

How does MPTP act to cause Parkinsonian symptoms?

Answer 12

MPTP is metabolised into MPP+ by MAO B and is taken up by specific DA transporter systems. It inhibits mitochondrial oxidation reactions, putting the neurones under oxidative stress eventually killing them.

Question 13

Despite its dangerous effects, how has MPTP been used usefully?

Answer 13

This has been a useful experimental tool for inducing Parkinsonism in laboratory animals.

Question 14

In early-onset Parkinson’s (<40 years), what is the main cause?

Answer 14

A genetic factor. This mutation leads to the presence of Lewy bodies which contain α-synuclein.

Question 15

What are the specific genes related to early onset Parkinson’s?

Answer 15

Parkin, Ubiquitin, LRRK2, PINK.

Question 16

What nuclei make up the basal ganglia?

Answer 16

Striatum, external globus pallides, internal globus pallides, subthalamic nucleus, substantia nigra pars compactum, substantia nigra pars reticulara.

Question 17

What is the function of the basal ganglia?

Answer 17

The basal ganglia integrate motor and sensory information from the cortex before relaying it back to the cortex via the thalamus.

Question 18

What controls output from the basal ganglia?

Answer 18

The output from the basal ganglia are controlled by two parallel but opposing pathways which are modulated by dopamine.

Question 19

How does motor impairment arise in Parkinson’s?

Answer 19

Motor dysfunction arises through an imbalance between the direct and indirect pathways. In Parkinson’s the loss of the nigrostriatal dopaminergic pathway leads to excessive inhibition of the thalamocortical pathway.

Question 20

What methods of assessment are there for assessing ones Parkinson’s?

Answer 20

UPDRS III, the unified Parkinson’s disease rating scale, is a 5-section system of evaluation of a person’s Parkinson’s. There are also carer assessments and ADL (activities of daily living (self-reported)) rating systems.

Question 21

Why is the UPDRS III Parkinson’s rating scale not very good?

Answer 21

Due to its subjectivity.

Question 22

What surgical interventions are available for the treatment of Parkinson’s?

Answer 22

Pallidotomy, Subthalmotomy (Thalamotomy), Deep Brain Stimulation.

Question 23

What is a pallidotomy/thalamotomy?

Answer 23

This involves the insertion of electrodes into the sub-thalamic nuclei and the use of electricity to kill the cells here. The aim was to prevent the massive inhibition of the thalamocortical motor loop.

Question 24

What is the major risk associated with a pallidotomy/thalamotomy?

Answer 24

This had the chance of causing massive haemorrhage and death due to the nucleus’ close proximity to a major blood vessel.

Question 25

What is deep brain stimulation?

Answer 25

This is electrical stimulation of the subthalamic nucleus at a frequency of 130Hz. This is used to provide stimulation to override the dysfunction of the pathways here; providing optimal action of the thalamocortical motor loop.

Question 26

What other surgical interventions for treating Parkinson's disease have been proposed?

Answer 26

Direct, non-invasive stimulation of the motor cortex is the next aim for researchers however this has proved hard to achieve and as of yet hasn’t been developed to a point where it can be used.

Question 27

What is the primary aim of most drug therapies for Parkinson's disease?

Answer 27

Most therapies are aimed at replacing or replenishing dopaminergic neurotransmission or reducing ACh action at muscarinic receptors.

Question 28

What determines the choice of drug therapy for the treatment of Parkinson's disease?

Answer 28

The choice of therapy depends on the patients’ age, symptoms, cognitive impairment, and other illnesses.

Question 29

What antimuscarinics are used in the treatment of Parkinson's disease?

Answer 29

Benztropine, Biperiden.

Question 30

Why should antimuscarinics be avoided in elderly patients?

Answer 30

They have potentially troublesome side effects.

Question 31

How are antimuscarinics used in the treatment of Parkinson's disease?

Answer 31

These drugs are used in the early-mid stage of the disease and are helpful for the treatment of tremor, however, have no effect on hypokinesia or rigidity. They are useful in secondary Parkinsonism such as neuroleptic-induced Parkinsonism (D2 receptor antagonist-induced, can’t give L-DOPA as this exacerbates psychosis).

Question 32

What is the first line pharmacological treatment for Parkinson's disease?

Answer 32

L-DOPA.

Question 33

How does L-DOPA work to treat Parkinson's disease?

Answer 33

It is given orally and crosses the BBB to be metabolised into dopamine, replenishing the brain’s stores of the neurotransmitter.

Question 34

What is the dosage regimen for L-DOPA in Parkinson's disease?

Answer 34

It is given in doses of 250mg to 8g per day, split into 3 doses per day. So much is given so frequently as the drug has a short half-life of 1.5 hours and constant coverage is needed.

Question 35

What adjunct treatment is L-DOPA often given with?

Answer 35

The peripheral dopa decarboxylase inhibitor carbidopa; at a dose of 500mg-1g two or three times a day. Brands of this include Sinemet and Sinemet CR.

Question 36

How effective is L-DOPA treatment?

Answer 36

Initially, about 80% of patients show improvement with drug therapy and 20% become ‘normal’ although normal is subjective.

Question 37

What treatment is given to Parkinson's patients who are resistant to drug therapy?

Answer 37

Surgical interventions.

Question 38

What are the side effects of L-DOPA?

Answer 38

Dyskinesia, wearing off effects, progressive on-off swinging, neuropsychiatric effects, nausea and vomiting, anorexia, hypotension.

Question 39

One of the side effects of L-DOPA is progressive on-off swinging; define this.

Answer 39

On periods complicated by dyskinesias and off periods being seriously akinetic.

Question 40

One of the side effects of L-DOPA is neuropsychiatric effects; define this.

Answer 40

Schizophrenic symptoms i.e. hallucinations.

Question 41

What adjunct therapies is L-DOPA often given with?

Answer 41

DOPA-decarboxylase inhibitors, dopamine agonists, COMT inhibitors, MAO-B inhibitors, DA releasers, ACh antagonists.

Question 42

Give examples of DOPA-decarboxylase inhibitors.

Answer 42

Carbidopa, benserazide.

Question 43

Give examples of dopamine agonists.

Answer 43

Bromocriptine, pramipexole, apomorphine.

Question 44

Give examples of COMT inhibitors.

Answer 44

Entacapone.

Question 45

Give examples of DA releasers.

Answer 45

Amantadine.

Question 46

Give examples of MAO-B inhibitors.

Answer 46

Selegiline.

Question 47

Give examples of ACh antagonists.

Answer 47

Benzotropine.

Question 48

Apomorphine is a dopamine agonist used in the treatment of Parkinson's disease. How is it used?

Answer 48

This is a dopamine agonist that is administered by injection on a when required basis by the patient. It is used as a rescue treatment for sudden on/off periods and works within 5-15 minutes.

Question 49

What class of drugs may be an alternative to L-DOPA in young Parkinson's patients?

Answer 49

Dopamine agonists.

Question 50

How to COMT inhibitors act to help treat Parkinson's disease?

Answer 50

COMT inhibitors are used as an adjunct therapy and work to prolong the half-life of L-DOPA by blocking the metabolic action of COMT. They also reduce the plasma concentration fluctuations, which as shown above contribute to the dyskinesia associated with L-DOPA use.

Question 51

What are the side effects of COMT inhibitors?

Answer 51

The side effects associated with COMT inhibitor use are diarrhoea and discoloured urine.

Question 52

At what daily dose is the MAO-B inhibitor selegiline given?

Answer 52

5-10mg.

Question 53

What are the side effects of selegiline?

Answer 53

Hallucinations and confusion.

Question 54

What drugs should selegiline not be given with and why?

Answer 54

Opioids = fatal interactions. TCAs and SSRIs = selegiline is a mild antidepressant.

Question 55

How do dopamine releaser work in the treatment of Parkinson's?

Answer 55

They enhance dopamine release and block re-uptake.

Question 56

What is amantadine useful for treating in terms of Parkinson's?

Answer 56

Amantadine is useful in early treatment for rigidity and end-stage dyskinesia.

Question 57

What are the side effects of amantadine?

Answer 57

Confusion, lightheadedness, red spiders web mottling of the legs.

Question 58

How does amantadine impair a patients cognition?

Answer 58

It is antagonistic against NMDA receptors.

Question 59

What alternative therapies may be used to treat Parkinson's?

Answer 59

Foetal nigrostriatal transplantation, green tea, smoking, cannabis, ecstasy, use of stem cells, gene therapy.

Question 60

What is the most common Levodopa-induced side effect?

Answer 60

Vomiting and nausea.

Question 61

Is levodopa given alone?

Answer 61

No.

Question 62

What enzyme rapidly metabolises dopamine in the periphery?

Answer 62

Dopa decarboxylase.

Question 63

When titrating doses of antiparkinsonian medication, what form should be used and why?

Answer 63

Immediate release medications as modified release medications have less predictable release profiles and can lead to dose accumulation and the sudden emergence of levodopa-induced dyskinesias.

Question 64

Define dystonias.

Answer 64

Abnormal muscle contractions.

Question 65

One of the most common problems associated with levodopa therapy is the emergence of 'end of dose' tail off. What is this?

Answer 65

A phenomenon that after several years of therapy. Patients begin to notice re-emergence of motor symptoms before the next dose is due.

Question 66

What can the 'end of dose' tail off associated with levodopa therapy progress into?

Answer 66

It can ultimately progress into 'on-off' phenomenon; where patients switch between symptom control (on) and total freezing (off).

Question 67

When 'end of dose' tail off is seen in patients with Parkinson's disease, why is simply increasing the dose not necessarily the best solution?

Answer 67

Because it can lead to an increased likelihood of the patient developing dyskinesias during peak plasma levels.

Question 68

Compared to immediate release medications, what is the bioavailability of CR antiparkinsonian medications?

Answer 68

60-70%.

Question 69

What is the best solution for treating a patient who has Parkinson's disease and is experiencing 'end of dose' tail off (not including the use of CR formulations)?

Answer 69

Often the best solution is reducing the dosing interval but maintaining the same daily dose.

Question 70

The latency of CR antiparkinsonian medications is considerably longer than that of immediate release medications. What does this mean for the dosage regimen of a patient on such formulations?

Answer 70

It is sometimes necessary to 'kick start' a patient in the morning with a standard release preparation.

Question 71

How should a patient with early-stage Parkinsons be counselled to take their Levodopa in relation to food?

Answer 71

They should take their Levodopa with food to avoid nausea.

Question 72

How should a patient with late-stage Parkinson's be counselled to take their Levodopa in relation to food?

Answer 72

They should take their Levodopa 30 minutes before food as dietary proteins can critically interfere with absorption.

Question 73

What patient group is most likely to benefit from the use of Dopamine Agonists?

Answer 73

Patients with early-onset Parkinson's.

Question 74

What form can rivastigmine be given in to help with the administration to patients with swallowing difficulties?

Answer 74

A transdermal patch.

Question 75

What are the symptoms of impulse control disorder (also known as dopamine dysregulation disorder)?

Answer 75

Pathological gambling, hypersexuality, binge eating.

Question 76

What drug can be used to manage nausea and vomiting associated with dopamine agonist use?

Answer 76

Domperidone.