A common degenerative disease of dopaminergic neurones characterised by tremor, bradykinesia, rigidity and postural instability.
1 in 1000 adults and 1 in 200 over the age of 65.
Prevalence increases sharply with age.
M slightly > F
There is little known about the aetiology
Nicotine: Some epidemiological evidence suggests a decreased risk in smokers, but that may be due to younger death in this group.
There are some familial forms, particularly earlyonset Parkinson’s.
The substantia nigra is one of the nuclei of the basal ganglia. In Parkinson’s disease there is progressive cell loss and the appearance of eosinophilic inclusion bodies (Lewy bodies) in the dopamine-rich part of the sub-stantia nigra (called the pars compacta). Biochemically there is a loss of dopamine and melanin in the striatum which correlates with the degree of akinesia. Degeneration also occurs in other brain stem nuclei. The basal ganglia project via a dopaminergic pathway to the thalamus and then to the cerebral cortex, where it integrates with the pyramidal pathway to control movement. Hence it is sometimes called the extrapyramidal system.
The features are asymmetrical.
· The tremor is slow 4–6 Hz, typically pillrolling and may involve the whole limb, legs and trunk. It is increased by emotion and decreased on action.
· Increased tone and tremor together cause a cog wheeling rigidity. Increased tone alone may cause lead-pipe rigidity.
· The movement disorder consists of bradykinesia (slowness of movement) and hypokinesia (reduced size of movement). For example, tapping one hand on the other is slow, of reduced amplitude and frequency.
· The gait is characteristic, with difficulty initiating movement (hesitancy), then difficulty in stopping (festination), slowness or freezing when asked to turn. When walking there may be a reduced arm swing and increased pill-rolling tremor. The posture is usually stooped, flexed and the person has difficulty in keeping balance (postural instability), falling whilst standing or walking. There is a loss of postural reflexes.
· Other features include facial masking, dribbling of saliva, dysphagia, dysphonia and dysarthria – quiet monotonous speech with a tendency to peter out with continued effort. There is an increased incidence of dementia in Parkinson’s disease.
Loss of pigment from the substantia nigra due to the death of melanin-containing dopaminergic neurones. Surviving cells contain spherical inclusions called Lewy bodies – hyaline centres with a pale halo.
Clinical diagnosis, but other parkinsonian syndromes should be considered.
This includes a multidisciplinary approach for this chronic disease, including education, support, physio-therapy and physical aids.
Levodopa, a dopamine precursor, is the most important agent used. It is given with an peripheral dopadecarboxylase inhibitor (such as carbidopa or benserazide) to prevent the conversion of l-dopa to dopamine peripherally, and so to reduce side-effects of dopamine such as nausea and hypotension. Lev-odopa exerts most effect on bradykinesia and rigidity (less on tremor).
i. After several years of treatment, patients develop ‘on’ periods when they have a good response to the medication, lasting a few hours, then an ‘off ’ period, when they freeze. They may also have involuntary movements called dyskinesias, or painful dystonias (abnormal posturing – which may be an early feature). These appear to be due to the progressive degeneration of the neuronal terminals, such that dopamine is not taken up properly. It is speculated that they may be prevented by using other drugs to treat mild symptoms, and using drugs which may have a ‘neuroprotective’ action, e.g. by blocking free radicals, and preserve neuronal function.
ii. ‘On/off ’ phenomenon may be treated by increasing the frequency of doses, or using catechol-O-methyl transferase (COMT) inhibitors such as entacapone which inhibit the peripheral and central metabolism of l-dopa and dopamine, so giving a more stable level.
Dopamine agonists (such as bromocriptine, prami-pexole, cabergolide and apomorphine) act directly on dopamine receptors, and are useful in patients who responded to l-dopa, but have developed l-dopa related dyskinesias. These may be considered first-line treatment in young patients. They have a neuroprotective effect in vitro.
Anticholinergic agents may improve symptoms. In PD there is a relative overstimulation at the basal ganglia by cholinergics compared to dopamine. This can be redressed by anticholinergic drugs such as benztropine and procyclidine. They tend only to be used in mild tremor, and they do not help with akinesia or gait.
Selegiline is a monoamine oxidase B inhibitor which slows the catabolism of dopamine. It is useful in early Parkinson’s.
Amantadine is an antiviral agent, which is thought to act by increasing dopamine release and having NMDA receptor antagonist properties. It may be of value in mild early cases and has the advantage of few side-effects.
Depression is common, difficult to treat and makes Parkinson’s disease worse. Hallucinations due to medication and insomnia also occur frequently.
Surgery: These procedures are reserved for advanced cases.
Stereotactic placement of small lesions in the ventro-lateral nucleus of the thalamus can help tremor, but does not help bradykinesia. Unilateral pallidotomy (removal of or lesions made in the globus pallidus) can help tremor, rigidity, bradykinesia and postural instability. However surgery carries the risk of haem-orrhage or infarction in 4%, with a 1% mortality.
High frequency deep brain stimulation suppresses neuronal activity. Bilateral subthalamic nucleus stimulation or globus pallidus stimulation is most useful in those with difficulty with the on-off phenomenon, as it can improve motor function whilst off medication and dyskinesias whilst on medication. There is a risk of infection from the equipment.
The course of Parkinson’s disease is very variable. The average survival is ∼10 years from onset of symptoms. Drugs appear not to prolong life but levodopa has greatly improved quality of life.
With initial treatment: ∼1/3 improve markedly;
1/3 show some improvement;
1/3 show no significant improvement, which should prompt the search for another cause of the symptoms, as other causes of parkinsonism do not usually respond to the treatment for idiopathic Parkinson’s disease.