Contents
Summary
Epidemiology
- Mean age of onset between 45-60
- Prevalence is 0.5-1% of the over 60’s in the UK
- 2nd most common neurodegenerative disease (after Alzheimer’s)
Aetiology
Parkinsonism is most commonly caused by ideopathic Parkinson’s disease. There are rare genetic syndromes that also cause the condition, and several drugs have also been implicated. See differential diagnoses (below) for other conditions that can cause similar clinical features.
Pathology
Results from the loss of dopaminergic neruons in the basal ganglia, most notably the substantia nigra. Surviving neurons contain aggregations of protein (mostly α-synuclein), called Lewy bodies. In some cases, the Lewy bodies are seen throughout the brain – in such instances there is often co-existing dementia.
Symptoms of PD are only seen once levels of dopamine are 20-40% that of normal. The degree of cell loss and akinesia is strongly correlated.
There is no obvious cause for this loss of neurons.
The disease is slowly progressive, without remission.
Clinical features
Parkinsonsim is often described as a triad of tremor, rigidity and bradykinesia. Signs are usually bilateral, although the initial presentation may be unilateral, and then progress.
- Tremor – usually of the hands @ 4-7Hz. Disappears with deliberate activity.
- Bradykinesia – slow movements. Fine motor movements are particularly badly affected
- Rigidity – increased resistance to passive movement. Sometimes called ‘lead pipe rigidity’. Rigidity is equal throughout the range of movement (unlike spasticity – which is velocity dependent ). Rigidity is also equal in both extensors and flexors – unlike spasticity.
- Sometimes called cogwheel rigidity – as the rigidity temporarily gives in certain ranges of movement – as if you are moving a cog (the result of tremor plus rigidity).
- Note that power remains normal, and there is no sensory loss.
- Posture and Gait – slow shuffling steps gait. Often stooped, with reduced arm swinging. Narrow based.
- Speech – may be slow and monotonous. In late stage disease may be slurred, or even lost.
- Plain face / facial stare. This effect is exaggerated by a reduced blinking rate.
- Depression – many Parkinson’s patients also suffer from depression. If this is present in the early stages, then the plain face symptom of Parkinson’s may be confused with a withdrawn emotional state often seen in depression.
- Dementia – is also often associated with PD – probably because in many cases, the degeneration seen in the basal ganglia is also found in other areas of the brain.
- Hallucinations are common, and are thought to be a combination of both the disease and the drugs used to treat it. Often they are not unpleasant.
Differentials and other causes of Parkinsonism
- Alzheimers
- Multi-infarct dementia
- Repeated head injury e.g. in boxers
- The VODKA signs:
- V – vascular events – e.g. stroke, MI
- O – orthostatic hypotension with atonic bladder – can be caused by multi-system strophy (MSA)
- D – Dementia with vertical gaze paralysis – could be a supranuclear palsy.
- K – Kayser-Fleisher rings – Wilson’s disease (causes cerebellar dysfunction)
- A – apraxic gait – communicating hydrocephalus
Cause | Age Onset | Presentation | Treatment | Info |
Idiopathic Parkinson’s Disease | 45-60 | Bradykinesia, rigidity, tremor. | L-Dopa – symptoms should improve | Caused by loss of dopaminergic neurons in the basal ganglai (substanita nigra) |
Drugs (usually dopamine antagonsists)–e.g. prochlorperazine, metoclopramide (antiemetics) phenozanthines, butyrophenones (neuroleptics) | ———- | General signs of Parkinsonism | Stop drugs | ———– |
Progressive Supranuclear Palsy | 60-65 | Falls, balance problems, paralysis of vertical gaze, parkinsonism, cognitive impairment, progressive, varying course, average 7 year survival | Responds poorly to L-Dopa – thus can be differentiated for idiopathic PD | Also known as Steel-Richardson-Olszewski syndrome |
Multi-system Atrophy | Parkinsonism, cerebellar problems, autonomic problems (particularly Postural hypotension), akinesia, rigidity. | Responds poorly to L-Dopa – thus can be differentiated for idiopathic PD | Degenerative neurological disorder | |
Wilson’s Disease | 6-20 | Parkinsonism, liver failure, renal failure, wide neuological problems; parkinsonism, chorea, akinesia, tremors, rigidity. Personality and behavioural problems, cognitive impariment. | Penicillamine – treat early, and it is very well controlled. | Autosomal-recessive, causing problems with copper metabolism. Copper is deposited in the liver, basal ganglia, cornea, and kidneys |
Sometimes, conditions that cause Parkinsonism are referred to Parkinson-plus syndromes.
Investigations and Diagnosis
Usually completely clinical. MRI will usually be normal, and Dopamine transporter imaging is a fancy new technique, that is unreliable and expensive.
Treatment
Exercise and physiotherapy can improve mobility.
Drugs
L-DOPA
This is the main treatment. Dopamine cannot cross the BBB, but its precursor L-DOPA can, and once it has, it is converted to dopamine. Increases levels of free dopamine in the brain. Short half-life. Usually given with other agents (e.g. carbidopa, entacapone, benserazide) to prolong its half-life and increase efficacy.
Unwanted effects
- Efficacy decreases over time
- ‘On-off effect’ at the end of the dose
- Nausea / GI Upset
- Dyskinesias
- Psychosis
- Compulsive behaviours – often related to gambling, money or sexual behaviour.
Pramipexole and Ropinirole
Newer than L-DOPA, gaining popularity, selective D3 agonists. Often used as adjuncts to L-DOPA, and useful in younger patients, that you don’t want to start on L-DOPA yet (due to its decreased efficacy over time).
Fewer side effects than L-DOPA, but still:
- Nausea
- Hallucinations
- Drowsiness
Bromocriptine
A selective dopamine D2 agonist. Has a long HL, so does not need to be given as often as L-DOPA.
Side effects include: hallucinations, hypotension, nausea / vomiting, fibrosis (rare), drowsiness
Drugs that release dopamine e.g. amantadine
Often used as an adjunct to L-DOPA. Mechanisms is not well known, thought to be increased dopamine release. Is less effective than L-DOPA and bromocriptine, but also has fewer side effects.
MAO-B inhibitors e.g. Selegilene
Inhibits MAO-B selectively. MAO-B metabolises dopamine. Thus this helps increase the level of dopamine in the brain. Used widely as an adjunct to L-DOPA, helps to reduce the dose of L-DOPA, which in turn reduces the side-effects, and increases the long-term effectiveness of L-DOPA.
Side effects
Can be serious and very limiting:
- Postural hypotension
- AF
Other treatments
Surgery
Not very widely used, but on the increase. Interventions often involve the thalamus, either with lesions (provide temporary relief) or in the form of thalamus stimulation.
Tissue transplant
It is possible in the future that dopaminergic stem cells might be transplanted, but this is a long way off yet.
More Information
Parkinson’s disease is a progressive disease of neuronal degeneration, that usually presents in the elderly. In recent years, management has improved, and overall life-expectancy is not really affected, however, quality of life is likely to be vastly decreased in the later stages of the disease. Co-existing dementia and depression are common.
Epidemiology
- Usual onset between the age of 45 and 60
- Affects 0.5-1% of the population over the age of 60.
Aetiology
The cause of Parkinson’s disease is basically unknown. There are some rare genetic syndromes that have been described, with certain mutations, e.g. synuclein and parkin.
Some drugs can also cause parkinsonism
Pathology
PD results from a substantial loss of pigmented dopaminergic neurons from the substania nigra (and other brainstem nuclei). Surviving neurons often contain Lewy bodies. These are collections of proteins within the cell – usually containing large amounts of the protein α-synuclein.
- Lewy bodies are occasionally widespread throughout the brain – in which case they are associated with dementia – diffuse Lewy body disease.
In post mortem studies, the level of dopamine in the brains of those with PD is often <10% that of normal. This suggests there has to be huge neuronal loss before the signs of PD are seen. Symptoms of PD are only seen when dopamine levels reach 20-40% of normal. The degree of cell loss and akinesia is strongly correlated.
There is no obvious cause for this loss of neurons.
The neurons of the substantia nigra actually synthesise dopamine, which usually acts as an inhibitory neurotransmitter at projection sites in the corpus striatum.
The disease is slowly progressive, and remissions are not possible
- In rare circumstances, often times of great emotion, patients report that their symptoms disappear for a very short time – for a few seconds or minutes.
The usual course of the disease is over 10-15 years. The main cause of death is bronchopneumonia, most commonly the result of dysphagia.
Many of the clinical features of Parkinson’s are the result of reduced output of the basal ganglia. The basal ganglai are involved in modifying motor cortex activity, and in normal function can both inhibit and amplifiy signals. However, in PD, there is overall inhibition.
- Bradykinesia – this sign of PD is directly related to the lack of dopamine
- Other signs of PD – e.g. tremor and rigidity – these are more complex, and complex mechanisms involving other NTs are involved. For example, neurons in the corpus striatum release ACh, whose release is normally inhibited by dopamine. In PD, there is not this inhibition, so these neurons release too much ACh.
Mechanism of cell damage
As in other nerodegenerative conditions, the mechanisms of cell death involve excitotoxicity, oxidative stress, and apoptosis.
Clinical features
- Tremor
- Usually most and first apparent in the hands. Usually rolling tremor of about 4-7Hz. Disappears with activity. Most apparent as the thumb rolls over the forefinger (pill rolling tremor)
- Bradykinesia
- Rapid, fine motor movements (e.g. picking up/using tools, playing the piano) are particularly badly affected.
- Rigidity
- Increased resistance to passive movement. Sometimes called lead pipe. Rigidity is equal throughout the range of movement (unlike spasticity – which is velocity dependent ). Rigidity is also equal in both extensors and flexors – unlike spasticity.
- Sometimes called cogwheel rigidity – as the rigidity temporarily gives in certain ranges of movement – as if you are moving a cog.
- Note that power remains normal, and there is no sensory loss.
- Posture and gait:
- Shuffling gait
- Stoop
- Reduced arm swigning
- Narrow base
- Often the signs are unilateral initially, but as the disease progresses, will become bilateral.
- Speech – normal tone is lost. Becomes monotonous, and may lose normal scanning quality. Later in the disease, there may be slurring, and even complete loss of speech.
- Plain face / facial stare. This effect is exaggerated by a reduced blinking rate.
- Skin – may become greasy and sweaty
- GI problems – heartburn, dribbling, dysphagia, weight loss and constipation.
- Depression – many Parkinson’s patients also suffer from depression. If this is present in the early stages, then the plain face symptom of Parkinson’s may be confused with a withdrawn emotional state often seen in depression.
- Dementia – is also often associated with PD – probably because in many cases, the degeneration seen in the basal ganglia is also found in other areas of the brain.
- Hallucinations are common, and are thought to be a combination of both the disease and the drugs used to treat it. Often they are not unpleasant.
Questions to ask in the history
- General lethargy and tiredness
- Problems using tools
- General problems with dexterity
- ‘Freezing’ – often whilst walking the patient may suddenly stop. This is particularly apparent at times when hesitation is normal, e.g. when turning, or when going through a doorway
- Difficulty rolling over in bed
- Ask them about their handwriting
- Typically it becomes smaller, and more spidery (micrographia). You may want to ask them to write their name and address to show you their writing, or draw a spiral. Keep in the notes to compare at future visits.
- Anosmia – start by asking if they have noticed any changes in their sense of smell. See below for how to examine
- Violent dreams – patients with PD may act out their dreams whilst laid in bed – particularly violent ones. This may involve arm swinging and legs kicking (REM behaviour disorder). Often their partner will sleep in a different bed.
- Visual hallucinations – usually these are not distressing, and many patients find them intriguing. For example, may involve seeing animals walking around the room, or seeing a hat stand, and thinking it is a person.
Differentials
Parkinson’s disease is the most common cause of parkinsonism – but bear in mind that another cause may be present. Other possible causes of Parkinsonism include:
- Alzheimers
- Multi-infarct dementia
- Repeated head injury e.g. in boxers
- Drugs
- Neuroleptic drugs – haloperidol, chloropromazine – these drugs block dopamine receptors.
- Dopamine reducing drugs – e.g. reserpine
- The VODKA signs:
- V – vascular events – e.g. stroke, MI
- O – orthostatic hypotension with atonic bladder – can be caused by multi-system strophy (MSA)
- D – Dementia with vertical gaze paralysis – could be a supranuclear palsy.
- K – Kayser-Fleisher rings – Wilson’s disease (causes cerebellar dysfunction)
- A – apraxic gait – communicating hydrocephalus
Investigations
There are no laboratory investigations. Diagnosis is made clinically.
- MRI – is usually normal
- Dopamine transporter imaging – is a fancy new test (not available in many places) is not very useful
Treatment
As usual, the best care is from an MDT. Particularly in this case, you need to make sure that care arrangement and home modifications (e.g. stair lift, hand rails etc) are all catered for (refer to occupational therapist).
Many patients will require carers (either family members or professionals), and respite care in hospitals or other organisations can be beneficial to both patient and carer.
Exercise and phsyiotherapy can help to improve mobility.
Assessing function regularly – both physical and mental is very important to ensure the correct treatment is given.
Drug treatments
Dopamine and dopamine agonists – e.g. L-dopa (levodopa)
These are traditionally the first line treatments for PD, although newer agents (see below) are becoming popular.
Mechanism
Dopamine itself is not able to cross the BBB, but L-dopa can, and once it has, it is converted to dopamine, by DOPA carboylase. It is also converted to dopamine once inside the PNS, and it is thought that this may be responsible for some of the side effects of the drug.
It is thought that the dopamine essentially floods the synapses, and this, combined with the reduced amount of endogenous dopamine is enough to reduce the clinical consequences of Parkinsons
It increases the amount of free dopamine (or its agonists) in the brain, and compensate for the usual loss of dopamine. The main problem is that their efficacy tends to decrease over time, thus you should only give them when you feel the PD is adversely affecting life to great enough extent. Usually this is 10-12 months after diagnosis. Explain these issues to patients, and involve them in the decision making.
You should use the lowest dose possible to give symptoms releif to help prolong the duration for which you can use the drug.
Dosage
- L-Dopa is naturally very short acting
- Take with food to avoid nausea vomiting
- Usual dose is around 800mg/24hr in divided doses, but get up to this level gradually
- Usually, L-Dopa is given with carbidopa (cobeneldopa), entacapone or benserazide. These are agents that decrease L-dopa metabolism and thus prolong the half-life of L-dopa.
- These also reduce the dose needed by about 90%!
Side effects
- Nausea /GI upset / diarrhoea
- Unwanted movements – dyskinesias
- These usually occur in the face and limbs, and occur at the peak therapeutic effect, thus the line between therapeutic and high dose is fine.
- Hypotension
- Arrhythmia
- Psychosis and other psychological effects. These are a direct result of increased dopamine levels in the brain. More common psychological effects include:
- Confusion
- Disorientation
- Insomnia
- Nightmares
- Compulsive behvaiour
- Gambling
- Spending
- Inappropriate sexual behaviour
- On-off effect – related to the fluctuating plasma concentration of L-Dopa. The effect is seen more often the longer the drug has been used. It is also seen in untreated patients. This leads to occasions where the drug is effective, and periods where it is not effective at all, and the symptoms of PD dramatically return. This usually occurs at the ‘end of dose’ – i.e. in the hours as the drug is wearing off, but before it is time to take the next dose. You can try to reduce the on-off effect with slow release L-dopa (poor evidence). Often the on-off effect can never be eliminated once it has occurred.
Ropinirole and pramipexole
These are newer drugs, and are selective D3 dopamine agonists. They have fewer side effects than L-dopa, and the dosing regimen is simpler. Particularly, they have decreased risk of dyskinesias, and they appear not to exhibit the long-term diminished effectiveness, seen in L-dopa. As such, they may be used as 1st line treatment in younger patients.
- They are also now often used as adjuncts to L-DOPA in patients of any age.
Side effects
Much less than L-Dopa, may still include:
- Drowsiness
- Hallucinations
- Nausea
Bromocriptine
A selective dopamine D2 agonist. Has a long HL, so does not need to be given as often as L-DOPA.
Side effects
- Hallucinations
- Hypotension
- Nausea / vomiting
- Fibrosis (rare)
- Drowsiness
MAO-B inhibitors e.g. Selegilene
Inhibits MAO-B selectively. MAO-B metabolises dopamine. Thus this helps increase the level of dopamine in the brain.
- In the early stages of PD it may help to slow the progression of the disease (controversial). If given at diagnosis, the mean time at which patients start L-DOPA is 18 months (normal 10-12). Long-term outcome is not altered.
- Used widely as an adjunct to L-DOPA, helps to reduce the dose of L-DOPA, which in turn reduces the side-effects, and increases the long-term effectiveness of L-DOPA.
- As it is selective for MAO-B, it lacks many of the side effects seen in the MAO inhibitors used to treat depression. It does not cause the ‘cheese-effect’ or cause many drug interactions.
Side effects
Can be serious and very limiting:
- Postural hypotension
- AF
Drugs that release dopamine e.g. amantadine
Often used as an adjunct to L-DOPA. Mechanisms is not weel known, thought to be increased dopamine release.
Is less effective than L-DOPA and bromocriptine, but also has fewer side effects.
Anticholinergics e.g. orphenadrine, atropine
Many of the motor symptoms of PD are the result of over-activity of ACh releasing neurons, because their dopamine inhibition has been lost. Anticholinergics can reduce this overactivity, and thus reduce the motor signs seen in PD.
They are rarely used – but are useful in patient on anti-psychotics – because antipsychotics are dopamine antagonists – and greatly reduce the effect of L-DOPA.
Contraindicitions
Side effects
- Dry mouth
- Dizziness
- Urinary retention
- Anxiety
- Confusion
- Tachycardia
- Hallucinations
- Insomnia
- Memory problems
Many of these will resolve after the first few days of use.
Other treatments
Surgery
Not very widely used, but on the increase. Interventions often involve the thalamus, either with lesions (provide temporary relief) or in the form of thalamus stimulation.
Tissue transplant
It is possible in the future that dopaminergic stem cells can be transplanted, but this is a long way off yet.
Other causes of Parkinsonism
Cause | Age Onset | Presentation | Treatment | Info |
Idiopathic Parkinson’s Disease | 45-60 | Bradykinesia, rigidity, tremor | L-Dopa – symptoms should improve | Caused by loss of dopaminergic neurons in the basal ganglai (substanita nigra) |
Dopamine antagonists –e.g. prochlorperazine, metoclopramide (antiemetics) phenozanthines, butyrophenones (neuroleptics) | ———- | General signs of Parkinsonism | Stop drugs | ———– |
Progressive Supranuclear Palsy | 60-65 | Falls, balance problems, paralysis of vertical gaze, parkinsonism, cognitive impairment, progressive, varying course, average 7 year survival | Responds poorly to L-Dopa – thus can be differentiated for idiopathic PD | Also known as Steel-Richardson-Olszewski syndrome |
Multi-system Atrophy | Parkinsonism, cerebellar problems, autonomic problems (particularly postural hypotension), akinesia, rigidity. | Responds poorly to L-Dopa – thus can be differentiated for idiopathic PD | Degenerative neurological disorder | |
Wilson’s Disease | 6-20 | Parkinsonism, liver failure, renal failure, wide neuological problems; parkinsonism, chorea, akinesia, tremors, rigidity. Personality and behavioural problems, cognitive impariment. | Penicillamine – treat early, and it is very well controlled. | Autosomal-recessive, causing problems with copper metabolism. Copper is deposited in the liver, basal ganglia, cornea, and kidneys |
Sometimes, conditions that cause Parkinsonism are referred to Parkinson-plus syndromes.
Flashcard
References
- Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
- Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
- Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy
