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Parkinson's Disease

Parkinson’s disease is a progressive neurological disorder mainly of unknown aetiology. It is often seen to co-exist with dementia and depression.
-          Mean age of onset between 45-60
-          Prevalence is 0.5-1% of the over 60’s in the UK
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.
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 is equal throughout the range of movement (unlike spasticity – which is velocity dependent ). Rigidity is also equal in both extensors and flexors – unlike spasticity.
o   Sometimes called cogwheel rigidity – as the rigidity temporarily gives in certain ranges of movement – as if you are moving a cog.
o   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
-          Alzeihmers
-          Multi-infarct dementia
-          Repeated head injury e.g. in boxers
-          The VODKA signs:
o   V – vascular events – e.g. stroke, MI
o   O – orthostatic hypotension with atonic bladder – can be caused by multi-system strophy (MSA)
o   D – Dementia with vertical gaze paralysis – could be a supranuclear palsy.
o   K – Kayser-Fleisher ringsWilson’s disease (causes cerebellar dysfunction)
o   A – apraxic gait – communicating hydrocephalus
Age Onset
Idiopathic Parkinson’s Disease
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
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
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.
Exercise and physiotherapy can improve mobility.
This is the main treatment. Dopamine cannot cross the BBB, but 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
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
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.

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