Irwin M. Arias, M.D.
Parkinson's disease (PD) is characterized by an insidious onset with slowing of emotional and voluntary movement, muscular rigidity, postural abnormality and tremor. Parkinson's disease was first described in 1817 by James Parkinson in a paper entitled "An Essay on the Shaking Palsy" (photos courtesy of the National Library of Medicine). It is a common neurological disorder with a prevalence of 1-2 per 1000 overall. However the incidence rises after the age of 50, such that 1-2% of the elderly in the UK are affected. The disease is due to the striatal deficiency of dopamine following neuronal degeneration within the substantia nigra.
The diagnosis of Parkinson's disease is generally a clinical one, however modern imaging techniques may have a role in the future in differentiating different Parkinsonian syndromes or in the pre-clinical diagnosis of Parkinson's disease. For example, by using fluoro-dopa PET imaging, one can clearly see in the Parkinsonian patient the markedly impaired fluoro-dopa uptake in the region of the caudate and putamen.
The cause is unknown, but a number of conditions can cause an akinetic-rigid syndrome in adults:
- Pure Parkinsonism
- Parkinsonism with other features
- Parkinson's disease
- Progressive supranuclear palsy
- Essential Tremor
- Drug-induced parkinsonism
- Multiple system atrophy
- Vascular (or arteriosclerotic) pseudoparkinsonism
- Postencephalitic parkinsonism
- Basal ganglia calcification
- MPTP parkinsonism
- Repetitive head trauma
- Cerebral anoxia
The predominant lesion in PD is cell degeneration and loss of pigmented neurones in the pars compacta of the substantia nigra as shown in this transverse section through the midbrain, where one can see quite marked macroscopic depigmentation compared to normal brain tissue. Microscopically, there is gliosis and pigment granules may be found extracellularly, leading to uptake within macrophages. Other neurones contain cytoplasmic inclusion bodies called Lewy bodies. Their precise origin is uncertain, but they are characterised by an eosinophilic core surrounded by a clear halo. They contain accumulations of normal neurofilament and stain positively with ubiquitin, a protein involved in proteolysis. However, Lewy bodies are found in other parts of the brain, including the substantia innominata, the intermediolateral cell column of the spinal cord, the locus coeruleus, the dorsal motor nucleus of the vagus nerve, and the cerebral cortex. Although believed to be highly sensitive markers for PD, they are not fully specific, e.g. diffuse cortical (Lewy-body) disease with dementia. Approximately 60 per cent of nigral neurones have to be lost, with an 80 per cent depletion of striatal dopamine, before the symptoms of PD develop.
The onset is insidious and common presenting symptoms include tremor, stiffness, or clumsiness, usually involving one side. Other presentations include difficulty walking, fatigue, depression, dysarthria, or limb discomfort. The disease is generally asymmetrical at presentation.
The typical signs include a blank, mask-like facial expression, a reduction in the spontaneous blink rate, and a soft monotonous voice. The gait is characterized by difficulty initiating walking, walking with small slow shuffling steps or rapid small steps (festination). 'Freezing' occurs on turning or changing direction. Voluntary movements are slow (bradykinetic) and of reduced amplitude (hypokinetic). Due to the impaired postural reflexes, falls may become a feature with disease progression.
The resting tremor of Parkinson's is present in 70-80% of cases (Quick Time movie). It is worsened by stress, and generally decreases or disappears with action. One may note a 'pill-rolling' tremor of the opposed thumb and fingers.
The rigidity of Parkinson's produces a resistance to passive movement which is equal in all muscle groups and does not alter throughout the range of the passive movement. If there is coexisting tremor, the smooth plastic nature of rigidity may be broken up by rhythmic catches (cogwheel phenomenon).
Clearly, the successful treatment of Parkinson's disease involves much more than just the use of drugs. It is vital that management is considered as part of a multidisciplinary approach with the involvement of nursing, occupational and physiotherapy, speech therapy, dieticians etc. Indeed, with recent advances in neurosurgery, on occasion, a number of surgical procedures need to be considered as one of the treatment options. Nonetheless, with these issues considered, for many patients, drugs play a very important part of their management, and it is for this reason I include some brief notes on some of the common drugs.
These drugs have a mild antiparkinsonian effect and are said to be more effective for tremor. These drugs should always be stopped slowly to avoid a rebound worsening of Parkinsonian symptoms.
Potential side effects:
This is a mild antiparkinsonian drug. The dose should be reduced with renal impairment.
Selegiline is a selective inhibitor of monoamine oxidase type B which metabolizes dopamine.
There was considerable interest in the use of Selegiline as a neuroprotective agent given the results of the DATATOP study (NEJM 1989;321:1364-1371). However, there has been considerable controversy over the interpretation of the results of this and other studies in that was Selegiline truly neuroprotective or does it have some kind of symptomatic effect. Most neurologists now tend to favour the latter.
Secondly, there has been some suggestion that the use of Selegiline is associated with increased mortality (BMJ 1995;311:1602-1607). This has been shown in one study, however, the causes of death are unknown at present. Nonetheless it would seem to lay to rest the neuroprotective argument for Selegiline. Since we do not have data from any other studies or details on the causes of death in the Selegiline group in the BMJ paper, at present we do not know whether the reported increased mortality in the BMJ paper is causally linked with Selegiline or not.
Example: Sinemet, Madopar
Since dopamine does not cross the blood brain barrier, but its precursor Levodopa does, L-Dopa is given in an effort to replace the striatal dopamine deficiency. However, since L-dopa has significant peripheral metabolism, resulting in untoward side effects (nausea and vomiting) and decreased brain delivery of L-dopa, it is combined with a peripheral decarboxylase inhibitor.
Examples: Bromocriptine; Pergolide; Lisuride.
These 3 drugs vary both in their duration of action and the degree to which they are D1 or D2 agonists. Thus:
- Lisuride — short duration of action, mainly a D2 agonist
- Pergolide — longest duration of action, acts on both D1 and D2 receptors.
There is evidence that patients who can tolerate monotherapy with a dopamine agonist for a prolonged time that the incidence of dyskinesias and motor fluctuations in the long term is reduced. The downside of this is that the dose needs to be gradually increased very slowly and side effects are more common than L-dopa.
These act directly on the dopamine D1 and D2 receptors. Since they also act in the periphery on the dopamine receptors of the vomiting centre, they can also cause nausea and vomiting.
Apomorphine is also a D1 and D2 agonist, but since it is given parentally via subcutaneous injection, its use is generally witheld until problems with motor fluctuations and 'on-off' fluctuations occur which are not being easily controlled via other drugs. As a result of this, initiation of therapy is best instituted in the context of a specialist Parkinson's clinic.
Examples: Tolcapone, Entacapone
These are relatively new drugs and Tolcapone is no longer licensed in the UK due to some deaths due to liver failure. They are COMT inhibitors (catechol-O-methyltransferase inhibitors) and as such slow down break down of L-dopa either in the periphery alone (Entacapone) or centrally as well (Tolcapone). Results from studies suggest that they have a role in reducing on-off fluctuations and dyskinesias. Trial have shown alterations in liver function tests (LFTs), the exact mechanism for this is unknown, but for the first 6 months, LFTs need to be checked. Some patients develop diarrhoea but this is reversible. The main problems with COMT inhibitors are worsening of peak-dose dyskinesias, but it is relatively easy to treat this by reducing the amount of L-dopa.
For further information about specific drugs, either ask YOUR doctor or search under the PharmInfoNet site.
Recent advances in neuroimaging and stereotactic surgery have led to a renaissance in neurosurgery for Parkinson's disease. This link includes some Quick Time and AVI files giving details of the surgery involved.
Can you help us? The Department of Neurology in Birmingham is actively trying to recruit people with a family history of Parkinson's disease for a research project looking at genetic factors in Parkinson's disease project. If you:
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