21st June 2023

Parkinson’s Disease

Aetiology

Parkinson’s Disease (PD) is a neurodegenerative disease characterised by two features:

1. Lewy bodies (LBs) – intracellular eosinophilic inclusions of α-synuclein.
2. Subsequent loss of dopaminergic neurons in the substantia nigra of the midbrain in the basal ganglia.

Diagnosis

PD is difficult to distinguish from other causes of parkinsonism. PD is a clinical diagnosis. It is important to distinguish between PD and parkinsonism, as PD responds well to antiparkinsonian drugs, but parkinsonism does not.

There are some prodromal non-motor symptoms:

• Anosmia
• Rapid eye movement (REM) sleep disorder – unwanted, violent motor behaviour during dreaming due to lack of normal muscle atonia during REM sleep.
• Constipation

The classic triad is:

1. Resting tremor – 3-5Hz, pill rolling action of thumb over fingers
2. Bradykinesia – slow to initiate movements
3. Rigidity – lead pipe rigidity refers to a hypertonic state throughout the movement of a joint; cogwheel rigidity refers to lead-pipe rigidity with superimposed tremor.

Other features of PD are:

• Slow, shuffling gait
• Hypophonic speech
• Micrographia
• Expressionless facies
• Urinary frequency
• Depression
• Autonomic dysfunction
• Immobility
• Falls

The only diagnostic test, according to NICE, is a DaTscan. A DaTScan is a scan using 23I-FP-CIT single photon emission tomography (SPECT) imaging to look for the presence of dopamine transporters. It distinguishes PD from essential tremor or drug-induced parkinsonism that cannot be determined clinically.

In the end stages of PD, 20% develop Lewy Body dementia, characterised by fluctuating cognitive impairment, hallucinations and parkinsonism.

Treatment

Levodopa

Levodopa is the first-line treatment for early PD with motor features that are impacting their quality of life.

The first line treatment when motor symptoms do not impact their quality of life is either non-ergot-derived dopamine agonists, levodopa, or monoamine oxidase B (MAO-B) inhibitors.

Several motor fluctuations can occur after being on levodopa for <10 years:

• Dyskinesia
• “On” time – PD symptoms well controlled
• Wearing-off symptoms – parkinsonian symptoms reoccur
• Freezing

Sudden dose reduction or withdrawal of levodopa can cause neuroleptic malignant syndrome (NMS).

Dopa-decarboxylase inhibitors

Levodopa is commonly prescribed in combination with peripheral dopa-decarboxylase inhibitors such as carbidopa and benserazide to prevent conversion to dopamine peripherally and therefore decrease the side effects of peripheral dopaminergic action. It causes a 4-5-fold reduction in levodopa dose due to increased levels crossing the blood brain barrier.

Dopamine-receptor agonists

Dopamine-receptor agonists (DAs) stimulate D2 and D3 receptors. DAs are split into older ergot-derived DAs and newer non-ergot-derived DAs. Safety advice has been released by the Medicines and Healthcare product Regulatory Agency on ergot-derived DAs:

• Echo on initiation – cardiac valvopathy and fibrosis
• Examine for pulmonary fibrosis and pleural effusion

Rotigotine and apomorphine are the only PD drugs that aren’t given orally. This is particularly important when a patient is nil-by-mouth. It is key to ensure that no doses of PD medications are missed. Rotigotine can be used in this case and is a transdermal patch. Apomorphine is given by subcutaneous injection and can be used in the end stages of PD.

In chronic use, DAs can cause:

• Choreiform and dystonic movements
• Psychosis
• Impulse control disorders, e.g. hypersexuality, excessive gambling, and obsessive hobbying

Dopamine toxicity:

• Dyskinesia
• Dystonia
• Hypotension
• Dysrhythmias

Monoamine oxidase-B (MAO-B) inhibitors

MAO-B inhibitors, such as rasagiline and selegiline, inhibit the breakdown of monoamines, such as dopamine.

One of the classic interactions of MAO-B inhibitors is with tyramine-rich foods, including cheese, cured meats, yeast extract, and pickled fish, which can lead to a hypertensive crisis, sometimes referred to as “the cheese effect”. Tyramine is a monoamine, and therefore the MAO-B inhibitors prevent its breakdown.

Catechol-O-methyl transferase inhibitors

Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone and tolcapone, prevent the breakdown of levodopa in the periphery, which increases its effects in the brain. COMT inhibitors are particularly used to increase the “on” time and decrease the “off” time of levodopa.

One severe side effect of COMT inhibitors is hepatic dysfunction and liver toxicity. COMT inhibitors should not be given to patients with liver impairment. LFTs should be monitored closely, as tolcapone can increase AST and ALT by 2-3 times.

Amantadine

The mechanism of action of amantadine is not fully understood, but it is an NMDA receptor antagonist, which increases dopamine release. NICE recommends amantadine in dyskinesia.

Serious adverse effects:

• Neuromalignant syndrome
• CNS depression
• Suicidal ideation
• Psychosis

Treatment of non-motor features

Levodopa and DAs can increase the risk of daytime sleepiness or sudden onset of sleep. The Driver and Vehicle Licensing Agency (DVLA) recommends that the patient cannot drive and to consider occupational hazards. This can be managed with modafinil.

Drooling:

• Glycopyrronium bromide
• Refractory – botulinum toxin A into parotids and submandibular glands

Orthostatic hypertension:

• Midodrine or fludrocortisone

Lewy Body Dementia:

• Rivastigmine – cholinesterase inhibitor