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Parkinsons disease remains the second most common neurodegenerative disease after Alzheimers disease. It is often linked to ageing and therefore it is very likely that the number of PD cases will increase with the longevity of the population. Around one percent of the population over the age of 60 suffer from the disease, with the number rising to two percent for those over 80. It is estimated that the prevalence of the disease will double over the next 20 years. Although there have been some important advances in our understanding of the aetiology, the pathophysiology, investigation and management of the disease, there is still much knowledge to be sought. Parkinson's disease remains incurable to this day and the only pharmaceutical methods of managing the symptoms of the disease remain highly problematic. They also lack impact on the natural progression of the disease.
1. Circuitry of the basal ganglia
The basal ganglia are a group of nuclei found deep within the brain. They comprise of the caudate nucleus, the putamen and the globus pallidus (in the telecephalon), the subthalamic nucleus (in the diencephalon) and the substantia nigra (in the mesencephalon).
These nuclei are concerned with the initiation and maintenance of motor actions. Therefore, they are involved in the decision making process and control what we are going to do next. Together with the supplementary motor cortex they scale the strength of the response and organise the correct sequence of excitation of the primary motor cortex. In addition, they work with the cerebellum to modify movement.
The input nuclei are the caudate nucleus, the putamen, and the internal capsule which together are known are the striatum. The output nuclei are the globus pallidus, substantia nigra and the subthalamic nucleus. These nuclei project to the ventral lateral and the ventral anterior thalamic nuclei.
The globus pallidus can be split into two divisions: the internal and the external. It is the globus pallidus internal that is the major output nucleus from the basal ganglia to the thalamus.
The substantia nigra can also be split up into two parts.
The substantia nigra pars compacta - Cells within this structure produce dopamine which is important for normal movement. These cells degenerate in Parkinson's disease.
The substantia nigra pars reticulata - This also receives input from the striatum but sends it to control head and eye movements outside of the basal ganglia.
The basal ganglia circuitry consists of the direct and indirect pathway which consist of inhibitory or excitatory loops that regulate movement.
The striatum receives a huge glutamatergic excitatory input from the cortex via the corticostriatal pathway. The corticostriatal axons terminate on medium spiny neurones in the striatum. These neurons represent 95% of the neurones in the striatum and project gamma-aminobutyric acid GABA as their main neurotransmitter. The projection to the globus pallidus internal and substantia nigra pars reticulata forms the direct pathway. The striatal GABA release is localised with other peptides such as dynorphins and substance P. The globus pallidus internal and substantia nigra pars reticulata neurones are also GABAergic and project to the thalamus. The thalamic nucleus then projects to the cortex with glutamateric neurones thus closing the circuit.
On the other hand, the indirect pathway the GABAergic striatal neurons project to the globus pallidus external which then projects GABAergic neurons to the subthalamic nucleus. The subthalamic nucleus glutamatergic neurones then project to the globus pallidus internal and the substantia nigra pars reticulata.. The circuit is then completed in the same fashion as the direct pathway with a GABAergic nigrostriatal pathway and a glutamatergic thalamocortical pathway. (Miller, 2013) (Longmore, Wilkinson, & Davidson) (Kimura, 1995) (Steiner & Tseng, 2010)
These two pathways therefore work by either increasing (direct pathway) or decreasing (indirect) the thalamocortical projection.
The substantia nigra pars compacta contains dopaminergic neurons that project to the striatum and regulate the activity of the striatal projection. There are two main populations of spiny neurones in the striatum that make up two different receptors for dopamine. Both receive dopaminergic input from the substantia nigra pars compacta but their responses are differentially modulated. The D1 dopamine receptor is excitatory and projects to globus pallidus internal whereas the D2 dopamine receptor is inhibitory and projects to globus pallidus external. Therefore, in normal situations when movement is required, there is tonic activation and facilitation of the direct pathway by the substantia nigra pars compacta. There is a double inhibition that releases the thalamocortical cells from inhibition and allows changes in movement.
2. Pathophysiology of Parkinson's
Parkinson's disease is the second most common neurodegenerative disorder and leads to major disability and ultimately death. Its primary cause is still unknown and therefore a cure is yet to be discovered. However, its pathophysiology is well understood and symptoms can be treated effectively.
The main pathological feature of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta. This causes a decrease in the input to cells expressing D1 receptors and the release of inhibition of D2 expressing cells.
Loss of dopamine is thought to cause problems when trying to initiate a change in movement. This is because the direct pathway initiates change in movement, whilst the indirect pathway keep current movement programs running. There is often conflict between the two pathways. The loss of dopamine reduces the activity of the direct pathway and enhances the activity of the indirect pathway.
Thus, the indirect pathway is facilitated in PD and becomes dominant leading to inhibition of the thalamus and decreased activity in the thalamocortical projection. This suppresses any change in ongoing motor activity. The patient cannot stop the current motor program or start a new one.
3. Motor and non motor symptoms of the disease
It is foremost important to differentiate between Parkinsonism and Parkinson's disease. Parkinsonism is the clinical definition of a variety of symptoms including bradykinesia, tremor, rigidity or stiffness. There are a number of various disorders that can lead to the symptoms known as Parkinsonism; Parkinson's disease being just one of these.
The three main motor symptoms of Parkinson's disease are:
This can be either bilateral or unilateral and is normally present at rest in the extremities of the body. The tremor may begin in one area of the body and spread to others. Most commonly, the distal joints of the limbs are affected. In the hands a 'pill rolling' movement is often seen which involves the thumb and fingers rolling together. This tremor normally disappears when an intentional movement is initiated. The tremor is made worse by the patient feeling anxious.
Bradykinesia is slow movement whereas akinesia is the complete loss of movement. Akinesia is only seen in advanced stages of the disease whereas bradykinesia is more common. Patients show signs of reduced arm swinging whilst walking, blinks less frequently and finds it difficult to carry out complex motor tasks. Facial or expression may gradually be lost with poorly articulated speech also being present. Eating and swallowing may be difficult and can lead to sialorrhoea (drooling).
Patients usually show increased muscle tone and resistance to passive movement. It is caused by inappropriate sensitivity of muscles to stretch and the inability to obtain complete relaxation. The patient will have "leadpipe" rigidity in particular which is a form of rigidity in which the same level of resistance is found through the entire passive movement.
Other motor or non motor symptoms include:
Patients have a tendency to fall due to their state of rigidity and flexed posture. Failure to adjust their movement can also lead to falls such as inability to hold out the arms.
Patients begin to develop an abnormal gait in which small shuffling steps are made with slowness of movement. The patient finds it hard to initiate the walk and then finds it hard to stop.
PD can cause improper functioning of the autonomic nervous system. The Auerbach and Meissner plexuses found as a part of the enteric nervous system therefore function abnormally. This leads to poorly regulated smooth muscle contractions in the lumen of the gut thereby causing a decreased gastrointestinal motility.
Micrographia is the progressive decline in handwriting. Writing becomes progressively smaller and indecipherable.
DEMENTIA AND DEPRESSION
Memory impairment, confusion and disorientation are common features. Patients may also fall into depression.
This is mainly a result of bladder detrusor hyperreflexia.
4. Investigations and diagnosis including differential diagnosis
The diagnosis of Parkinson's disease is made entirely on the presentation of the patient's symptoms and rarely involves any invasive laboratory testing or imaging. However, reduction in dopamine production by the substantia nigra pars compacta can sometimes be seen by dopamine transporter imaging.
Brain scans can be used to rule out disorders with similar symptoms. Other causes that can secondarily lead to parkinsonian syndrome include Alzheimer's disease, multiple cerebral infarction and drug induced parkinsonism.
Parkinson plus syndromes are a group of neurodegenerative disorders that feature the classic symptoms of Parkinson's disease but also have some additional features that rule them out from simple idiopathic Parkinson's disease. These include progressive supranuclear palsy and multiply system atrophy.
Therefore, patients are diagnosed with Parkinson's disease by:
Showing at least two of the motor impairments from:
problems in posture
problems in gait
Responding positively to dopamine replacement medication by cessation of parkinsonian symptoms
Interestingly, the finding of Lewy bodies in the midbrain on autopsy confirms that a patient has suffered from Parkinson's disease. The Braak staging method is a method that can now be used to classify the degree of severity of Alzheimer's disease and Parkinson's disease on autopsy. The mechanisms by which cell death occurs in the brain can be varied. One method is by the abnormal accumulation of the alpha synuclein protein bound to ubiquitin in the damaged cells. These aggregations cause deposits of protein to form which are often called Lewy bodies. A genetic defect in the gene coding for alpha synuclein can lead to a patient developing Parkinson's disease.
5. Pharmacological and non pharmacological treatment
Pharmacological treatment for PD attempts to compensate for the degeneration of dopaminergic nigral cells and rectify the modulatory input to the striatum. The main method of controlling parkinsonian symptoms for the past 30 years has been through dopamine replacement therapy.
The most effective symptomatic relief for Parkinson's disease remains to be Levodopa, a precursor in the biosynthetic pathway of dopamine. As dopamine itself does not cross the blood brain barrier, it is ineffective in treating symptoms and is not prescribed. Levodopa, however, is taken orally and crosses the blood brain barrier where it is taken up by the remaining dopaminergic cells in the substantia nigra and converted into dopamine. The problem with levodopa is that it is also absorbed into the systemic circulation. DOPA decarboxylase is the enzyme that converts levodopa into dopamine. To prevent the conversion of levodopa outside the blood brain barrier a peripheral decarboxylase inhibitor such as carbidopa or benserazide is usually prescribed. This is to prevent adverse effects of nausea and vomiting by dopamine activating the vomiting centre. Other complications of L-Dopa use include postural hypotension, dizziness, nausea, hallucinations, paranoia, impulse disorders and hypersexuality. (The National Collaborating Centre for Chronic Conditions, 2006) (Longmore, Wilkinson, & Davidson)
Table 1 - Other drugs used in the treatment of Parkinson's disease
Class of drug
Mechanism of action
Protects residual dopamine from oxidation, thereby reducing its breakdown . Effective in early PD, and enables reduction in L-Dopa dosage in late PD.
Can lead to postural hypotension and atrial fibrillation. Selectivity for MaOB makes it less likely to produce side effects involving tyramine. However can interact with MaOA at high doses.
Compensates directly for dopamine by acting on D1 and D2 dopamine receptors within the striatum.
Associated with several side effects including dyskinesias, drowsiness, sweating and hypotension.
Adjuvant therapy often given alongsides L-Dopa. Shorten the 'off' period seen in long term L-Dopa use.
Adverse effects include dyskinesias, nausea, confusion, diarrhoea, abdominal pain and sleep disorders.
Dopamine loss leads to hyperactivity of cholinergic cells and this causes the symptoms of resting tremor. Anticholinergic drugs are therefore used to reduce tremor and rigidity but have little effect on bradykinesia
Can effect gut function and lead to constipation. Other side effects include dry mouth, impaired vision, inability to sweat, urinary retention and drowsiness.
Antiviral drug with antiparkinsonian properties
Potentiates dopaminergic function by modifying synthesis, release, or reuptake of dopamine.
Adverse effects are primary CNS including restlessness, depression, irritability, insomnia, agitation, hallucinations and confusion.
There is convincing evidence that PD is associated with increased oxidative stress and therefore Vitamin E is given and has shown neuroprotective effects. Reduces oxidative stress.
Pallidotomy or deep brain stimulation of the subthalamic nucleus can be used to alleviate symptoms of PD or to relieve L-DOPA induced side effects. However, these procedures are currently unavailable to patients on a large scale and are only able to undertake these procedures under specific circumstances. Depression or early signs or dementia class a patient unsuitable for treatment via deep brain stimulation. (Deiner, 2009)
Long term graft therapy
Pharmacological and surgical treatment both fail to actually prevent the natural progression of the disease and the loss of more and more dopaminergic nigral cells. Intrastriatal grafts of either embryonic nigral cells or genetically modified cells can be used to return the patient's ability to produce dopamine from nigral cells.
6. Prognosis and consequences of management
Although L-Dopa remains the most efficacious pharmaceutical therapy for the treatment of Parkinson's disease, 75% of the patients develop complications within 5 years of L-Dopa therapy. The motor fluctuations of long term therapy are particularly disabling and there cause for them remains unknown.
This is the dramatic fluctuations in motor performance. The patient will experience moments of normal mobility followed by periods of freezing where they cannot move.
end of dose deterioration
Patients who have been using L-Dopa for several years experience rapid wearing off of the clinical benefits. The half life seems to decrease with chronic usage.
delayed or no "on" responses
These are abnormal uncoordinated involuntary movements that can be divided into chorea like movements and dystonias (intense and sustained muscle contractions).
Non motor complications
These include tingling, pain, akathisia and autonomic dysfunction.
Normally associated with hallucinations, delirium, mood changes, hypersexuality, sleep fragmentation and nightmares.
How and when to start first line medication
There is much debate as to what medication to start patients on who present with Parkinsonian symptoms. The most effective treatment remains to be L-Dopa, however long term use leads to the motor complications described above. Thus is it often suggested that it may be better to start therapy with MaOB inhibitors and dopaminergic agonists in order to delay the introduction of L-Dopa until the symptoms become more severe and cannot be controlled effectively enough by milder forms of treatment.
Parkinson's disease is a progressive disease and motor function continues to decline throughout the course of L-Dopa therapy. However, disability is mainly related to non motor symptoms due to the use of therapies that improve motor function. Patients suffer from autonomic disturbances, sleep problems, mood alterations and cognitive decline. Ultimately, life expectancy is decreased with patients dying between 15-20 years after diagnosis.
Although the symptoms of Parkinson's disease can be treated, it still remains an incurable disease. The use of pharmacological therapy also has its long term complications. However these could potentially be reduced by combining levodopa with other adjuvant therapies to prevent the onset of these complications. In the future however, it is hoped that Parkinson's disease progression can be halted or at least slowed down through the use of human embryonic mesencephalic grafts. This technique would not only improve quality of life of the patients, but also increase their life expectancy.