Parkinson’s Disease

Question 1

Parkinson’s disease

Answer 1

Parkinson’s disease is a chronic, progressive neurodegenerative condition that occurs secondary to loss of dopaminergic neurones within the substantia nigra.

Question 2

Parkinson’s disease is the most common form of parkinsonism. Parkinsonism describes the presence of bradykinesia and at least one of the following:

Answer 2

Resting tremor
Rigidity
Postural instability

Question 3

The onset of Parkinson’s disease usually peaks between the ages …

Answer 3

The onset of Parkinson’s disease usually peaks between the ages of 55-65 years and generally has a slowly progressive onset.

Question 4

Aetiology
Parkinson’s disease

Answer 4

Parkinson’s disease is a condition of idiopathic aetiology.
It is thought that a small proportion (approx 2-3% ) of cases of Parkinson’s disease can be attributed to a monogenic cause (i.e. a single gene variant causing the disease).

In the majority of cases the aetiology is largely unknown and probably related to a complex interaction between a patients genetics and their environment.

Question 5

Pathophysiology
Parkinson’s disease

Answer 5

Parkinson’s disease may not be apparent until a substantial number of neurones (50-80%) have been lost within the substantia nigra.
The basal ganglia are essential for the modulation of pyramidal motor output to allow normal movement. This process of modulation is dependent on two pathways within the substantia nigra, the direct and indirect pathways.

Question 6

Direct pathway

Answer 6

The direct pathway is mostly a stimulatory pathway (‘on’ pathway) that is shorter, mostly off and predominantly associated with D1 receptors.

Activation of the direct pathway leads to a series of neural connections through the basal ganglia, which eventually leads to the initiation of movement. Dopamine that is released from the substantia nigra via dopaminergic neurones is able to activate the direct pathway via D1 receptors leading to the generation of movement.

Question 7

Indirect pathway

Answer 7

The indirect pathway is mostly an inhibitory pathway (‘off’ pathway) that is longer, mostly on and predominantly associated with D2 receptors.

Activation of the indirect pathway is essential in the inhibition of muscular tone to prevent unnecessary movement. Dopamine that is released from the substantia nigra via dopaminergic neurones is able to inhibit the indirect pathway via D2 receptors therefore leading to the generation of movement (i.e. inhibiting the inhibitor)

Question 8

The classic clinical features of Parkinson’s disease are bradykinesia, resting ‘…’ tremor and … rigidity.

Answer 8

The classic clinical features of Parkinson’s disease are bradykinesia, resting ‘pill-rolling’ tremor and cogwheel rigidity.

Question 9

Bradykinesia

Answer 9

A general slowing of voluntary movements
Reduced arm swing
Reduction in amplitude with repetitive movements

Question 10

Tremor - PD

Answer 10

Traditionally resting and described as ‘pill-rolling’
4-6 Hz in frequency
Can be induced by distraction

Question 11

Rigidity - PD

Answer 11

Increase resistance to passive movement
Cogwheel due to superimposed tremor

Question 12

Other signs in PD

Answer 12

Expressionless face (‘Parkinsonian mask’)
Micrographia - small writing
Soft voice
Drooling of saliva
Shuffling gait (festinating gait)
Glabellar tap - repeated tapping of forehead associated with persistent blinking (patient should stop blinking in the absence of pathology)
Depression
Bowel & bladder symptoms (urgency, incontinence, constipation)
Sleep disorder
Sexual dysfunction

Question 13

Step 1

Step 1 involves the identification of features of parkinsonian syndrome.

Bradykinesia and one of the following:

Answer 13

Muscular rigidity
Postural instability
Resting tremor (4-6 Hz)

Question 14

Step 2 identifies exclusion criteria for Parkinson’s disease.

Answer 14

Repeated strokes and stepwise progression.
History of trauma (head injury)
Definite encephalitis
> 1 relative affected
Sustained remission
Unilateral features after 3 years
Oculogyric crisis
Antipsychotic or dopamine-depleting drugs
Exposure to neurotoxin
Cerebral tumour or hydrocephalus
Other atypical neurological features
Negative response to levodopa

Question 15

Step 3 involves the identification of supportive criteria of Parkinson’s disease.

Three or more of the following:

Answer 15

Progressive disorder
Unilateral onset
Resting tremor
Persistent asymmetry
Excellent response to levodopa
Severe levodopa induced chorea
Levodopa response ≥ 5 years
Clinical course of ≥ 10 years

Question 16

More recently, the movement disorder society (MDS) have released a new diagnostic criteria that outperformed the UK brain bank criteria.

This diagnostic criteria follows a similar methodology to the UK brain bank criteria for reaching a diagnosis.

The diagnosis of clinically established PD is based on:

Answer 16

Confirmation of Parkinsonism: must be evidence of ‘motor’ parkinsonism (bradykinesia + tremor or rigidity)
No absolute exclusion criteria present: multiple exclusion criterias exist. Examples include unequivocal cerebellar abnormalities, vertical supranuclear gaze palsy, parkinsonism restricted to lower limbs ≥3 years, suspected frontotemporal dementia, others.
≥2 supportive criteria: dramatic response to dopaminergic drugs, levodopa-induced dyskinesia, rest tremor of limb (typically unilateral onset), others.
Absence of red flags: rapid development gait impairment, early bulbar dysfunction, non-progressive motor symptoms ≥ 5 years while not on treatment, respiratory dysfunction, early severe autonomic dysfunction, others.

Question 17

The diagnosis of clinically probable PD is based on:

Answer 17

Confirmation of Parkinsonism
No absolute exclusion criteria
Presence of red flags, but counterbalanced by supportive criteria: no more than two red flags allowed.

Question 18

Multi-system atrophy (MSA)

Answer 18

MSA is an adult-onset, rapidly progressive disease that is characterised by profound autonomic dysfunction leading to severe postural hypotension, urogenital dysfunction and a plethora of other features including cerebellar and corticospinal features. There is a poor response to treatment.

Question 19

Progressive supranuclear palsy (PSP)

Answer 19

Progressive supranuclear palsy (PSP)

PSP is a neurodegenerative disorder that typically begins at age 50-60 years and is characterised by vertical gaze dysfunction, dysarthria and cognitive decline. Tremor is rare in this condition.

Question 20

Dementia with Lewy-body (DLB)

Answer 20

DLB is characterised by early onset dementia (< 1 year) with features of parkinsonism. Dementia is usually the proceeding feature prior to motor symptoms and it is characterised by visual hallucination and fluctuating consciousness

Question 21

Corticobasal degeneration (CBD)

Answer 21

CBD is a neurodegenerative disorder that is characterised by a progressive dementia, parkinsonism and limb apraxia. Apraxia refers to problems with motor planning (i.e. unable to wave hello).

In severe cases CBD may be associated with alien limb syndrome when there is a feeling that the limb is acting on its own.

Question 22

Investigations
Parkinson’s disease is largely a clinical diagnosis, however, some investigations may be required to rule out an underlying cause.

Answer 22

The important investigation that may be required is neuroimaging (CT/MRI), particularly where there is a strong suspicion of a secondary cause (e.g. cerebrovascular disease) or failed response to treatment.

Positron emission tomography (PET) scanning with fluorodopa is being increasingly use to help localise dopamine deficiency in the basal ganglia. Although it is predominantly reserved for research at present.

Striatal dopamine transporter imaging using 123I-FP-CIT single-photon emission computed tomography (DaTscan) may be used to differentiate Parkinsonism from essential tremor. It is unable to differentiate different causes of Parkinsonism.

Question 23

Initial therapy

Answer 23

The main options for the initial management of Parkinson’s disease include Levodopa, dopamine agonists, or monoamine oxidase B inhibitors (MAO-Bs).

Question 24

Levodopa

Answer 24

Levodopa is the most effective treatment for Parkinson’s disease, which generally gives good motor control fro 4-6 years.

Levodopa is converted into dopamine for use within the brain by DOPA decarboxylase once it crosses the blood brain barrier. Unfortunately, levodopa may be converted into dopamine peripherally as the enzyme is also found outside the brain. To combat this, levodopa is given in combination with a DOPA decarboxylase inhibitor (DDCI),

Levodopa provides the best relief of symptoms with fewest short-term side-effects, however, long-term significant motor complications can occur. This complications can be difficult to control. Consequently, younger patients are often given dopamine agonists in the early stages of treatment.

Question 25

Dopamine agonists - pd

Answer 25

Dopamine agonists (e.g. ropinirole, pramipexole) work by binding to post-synaptic dopamine receptors. They provide moderate relief of symptoms, can be used in early disease and have less long-term side-effects compared to levodopa. Dopamine agonists are themselves associated with side-effects and one particular issue is the development of impulse-control disorders.

Question 26

MAO-B inhibitors

Answer 26

MAO-B inhibitors can also be selected as initial therapy in the treatment of Parkinson’s disease. Rasagiline, a MAO-B inhibitor, works through inhibition of the enzyme monoamine oxidase, which is involved in the breakdown of monoamines, such as dopamine, within the in pre-synaptic neurone. This means more dopamine is available for ordinary function.

Question 27

R.., a MAO-B inhibitor

Answer 27

Rasagiline, a MAO-B inhibito

Question 28

COMT inhibitors - PD

Answer 28

COMT inhibitors (e.g. Entacapone) inhibit the peripheral breakdown of levodopa by the COMT enzyme allowing more levodopa to cross the blood brain barrier. Therefore, this is an adjuvant therapy in those on levodopa (combination drugs are available).

Question 29

Others - PD adjuvant

Answer 29

Anti-muscarinics (e.g. procyclidine) may be used although evidence is poor. Amantadine may be used as early monotherapy or late adjuvant to help with dyskinesia.

Apomorphine, which is a non-selective dopamine agonist, is generally reserved for advanced disease. It is given via subcutaneous injection/infusion, but can cause significant postural hypotension.

Question 30

Motor complications PD

Answer 30

Motor ‘on-off’ fluctuations - switch from dyskinesia to immobility in a few minutes
Dyskinesia - hyperkinetic movement due to dosing of medications
Freezing of gait - complete inability to move
‘Wearing off’ phenomenon - towards end of dose
Falls.

Question 31

Non-motor complications PD

Answer 31

Aspiration pneumonia
Nutritional deficiency, dysphagia & weight loss
Bladder, bowel & sexual dysfunction
Pressure sores
Sleep disorders
Dementia & depression
Postural hypotension
Impulse control disorders and psychosis.

Question 32

Medication for Parkinson’s

Answer 32

levodopa, ropinirole rivastigmine
SSRIs, quetiapine clonazepa

Question 33

REM sleep in PD?

Answer 33

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterised by complex motor enactment of dreams and is a potential prodromal marker of Parkinson’s disease (PD)