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This case is about a headmaster, Mr Boddy, who was experiencing a variety of problems that increased in severity and had an ever-increasing impact on his life. The symptoms were becoming increasingly obvious to both Mr Boddy and his children which lead to him going to see his GP who referred him to a specialist. The specialist started him on a course of drug but decided to change it within less than a year. From the symptoms described in the case, it is obvious that Mr Boddy has Parkinson’s Disease. The issues presented in this case were discussed and learning objectives were produced which will be explored in this essay.
Anatomy and function of the basal ganglia
The basal ganglia are a group of deep nuclei that are located at the base of the forebrain and are linked to the thalamus. The deep nuclei that make up the basal ganglia are the caudate nucleus, the putamen, the globus pallidus, the substantia nigra and the subthalamic nucleus. (Michael-Titus, et al., 2010)The main function of the basal ganglia is to start and maintain motor actions and they play a vital role in the decision-making processes in the brain by processing cognitive and emotional information from the environment. They also communicate with the supplementary motor cortex to organise the correct excitation of the primary motor cortex as well as scaling the strength of the response. Another function is that they adjust movement on a minute by minute basis by communicating with the cerebellum. (Buot & Yelnik, 2012)
The nuclei of the basal ganglia can be classified as either input nuclei or output nuclei. The input nuclei are made up of the caudate and the putamen and as they are functionally similar they are known together as the striatum. They can be seen in Figure 1 where they are coloured purple. Most of its input comes from the cerebral cortex, however it also receives some input from the other basal ganglia nuclei. (Rolls, 1994) The output nuclei are the globus pallidus, substantia nigra and subthalamic nuclei. They can also be seen in Figure 1 and are in very close proximity to the striatum. The substantia nigra is split into two parts, the pars compacta(SNpc) and the pars reticulata (SNpr). The SNpc are the cells that produce dopamine and are damaged in parkinsons which is what happened to Mr Boddy. The SNpr receives input from the striatum and sends it to the ventral anterior, ventral lateral, and mediodorsal thalamic nuclei to control head and eye movements as well as carry out other functions. The globus pallidus is split into the internal (GPi) and external (GPe). The function of internal part of the nucleus is to send outputs to the thalamus. However, the function of the external portion of the nucleus is not fully understood but it appears to regulate and focus activity in the rest of the basal ganglia. (Hanna, et al., 2011) Damage to the basal ganglia is what caused Mr Boddy’s Parkinsons disease.
Neurological pathway of dopamine and neurotransmitters involved in basal ganglia pathway
One of the main effects of Parkinson’s is on movement and this is true with Mr Boddy as he developed a lot of movement problems. Thus, there must be a problem with the basal ganglia’s modulation of movement. The normal modulation of movement can be explained in terms of a “brake theory”. In essence, to start one movement the brakes must be applied to other movements. So damage to the basal ganglia will result in an inability to stop current movements as well as difficulty initiating movement. (Rhoades & Bell, 2009)
The initiation of a motor programme and the maintenance of a motor programme are respectively controlled by the dopaminergic direct and indirect pathways. Whether a motor programme is going to start or be maintained is determined by the interaction of the two pathways. So damage to the substantia nigra pars reticulata which produces dopamine has adverse effects on these two pathways and alters their function thus altering their combined effect which manifests as the symptoms of Parkinsons. The direct pathway is excitatory and the indirect pathway is inhibitory. (Lenglet, et al., 2012)
The direct pathway is activated via excitatory glutamatergic neurones from the cortex. This combined with the dopamine being released from the substantia nigra pars compacta causes inhibition, via GABAergic neurones, of the internal globus pallidus which then causes the net reduction of the inhibition, via GABAergic neurones, of the thalamus. This ultimately results in the increased excitation of the cortex via glutamatergic neurones which then causes increased excitatory output from the cortex to the muscle fibres via the lateral corticospinal tract. The excitatory direct pathway can be seen in Figure 2. The indirect pathway is very similar to the direct pathway. Once stimulated by the cortex, the neurones from the striatum project onto the external globus pallidus nuclei which causes inhibition. This inhibition results in the net reduction in the inhibition of the subthalamic nucleus. This results in the subthalamic nucleus’ projection of excitatory, glutamatergic, inputs into the internal globus pallidus which causes inhibition of the thalamus and this decreases stimulation of the motor cortex. Which then results in reduced muscle activity. As with the direct pathway, the indirect pathway is illustrated in Figure 2. The reason why dopamine released from the substantia nigra can have both excitatory and inhibitory affects is because of the dopamine receptors. The dopamine receptors D1 and D5 are found in the internal globus pallidus and are excitatory. The dopamine receptors D2-D4 are found in the external globus pallidus and are inhibitory. (Lenglet, et al., 2012)
In Parkinson’s disease substantia nigra pars compacta have degenerated and thus are producing less dopamine. This affects the D1-D5 receptors which results in less stimulation of the direct pathway and release of the inhibition of the indirect pathway. This means that the indirect pathway becomes the dominant one which inhibits the thalamus and thus will reduce motor activity in the motor cortex. This results in the characteristic symptoms of parkinsons. A diagram of the changes can be seen in Figure 3.These changes are what caused the problems that Mr Boddy was experiencing and the increasing severity of his symptoms was most likely caused by the continuing degeneration of his substantia nigra pars compacta cells. (Wu, et al., 2012)
Symptoms of Parkinson’s
The symptoms that Mr Boddy experienced are mainly caused by the lack of dopamine resulting in the dominance of the indirect pathway. The first symptom that he developed was sleeping problems and this was most probably caused because the body has trouble initiating a sleep cycle. So once he wakes up in the middle of the night to go to the toilet for example, then he will not be able to go back to sleep because of the under activity of the direct pathway. The loss of the sense of humour and the tremors are also caused by Mr Boddy becoming stuck in a motor programme. The pill-rolling tremor is characteristic of Parkinson’s. The clumsiness and falling over occur because the basal ganglia damage means that it cannot communicate normally with the cerebellum.
There are also a number of other symptoms that present in patients with parkinsons disease. Even though everyone presents with Parkinson’s differently, there are a number of symptoms that are present in everyone. They are listed in Table 1.
Diagnosis of Parkinson’s
Diagnosis of Parkinson’s is made from a medical history and neurological examinations alone. This is because the only test for Parkinson’s at the present time can only be performed during a post mortem. After the neurological tests and the history have been taken the NICE guidelines (Table 2) have to be applied to the finding. In Mr Boddy’s case, he had two of the three criteria in Step 1 as well as four of the criteria that had to be met in Step 3 to make a definite diagnosis.
Lewy bodies can be found during a post-mortem of a patient with Parkinson’s. They appear as spherical masses which contain abnormal alpha synuclein protein deposits and are found on the brainstem. An example of a Lewy body can be seen in Figure 4.
Treatment of Parkinson’s
There are a number of treatments for Parkinson’s disease, each with their own side effects which means that their use must be strictly controlled and monitored.
The most effective class of drug at elevating the symptoms of Parkinson’s is L- dopa. L-dopa is the precursor for dopamine and it can cross the blood brain barrier where it is converted to dopamine by dopa decarboxylase to restore the dopamine levels in the brain to a normal level. Dopamine itself cannot be given as it cannot cross the blood brain barrier. However, if L-dopa is given on its own it will breakdown in the body and activate the vomiting centre in the brain and cause vomiting. So to counteract this problem, it is given with a dopa decarboxylase inhibitor which stops the conversion to dopamine in the body. As it cannot cross the blood brain barrier dopamine can still be produced in the brain. The main side effect is that after a long period of use side effects known as “on-off phenomenon” develop. Which is where there are periods of activity (on) followed by a state of being immobile (off). The patient can suddenly switch between these two states. Another side effect is dyskinesia. (Goetz, 2007)
To avoid the end of dose side effects of L-dopa other drugs that are less effective are given first to prolong the time before L-dopa has to be given and the “on-off effect” starts happening. One type is a dopamine agonist. They work by binding to the post-synaptic receptors in the brain and have similar effects to L-dopa. However possible side effects include nausea, vomiting and fatigue. An example is bromocriptine or rotigotine. Another class of drug that is used is Monoamine oxidase inhibitors. They work by preventing the breakdown of dopamine. Their side effects include; headache, joint pain and depression. Catechol-O-methyl transferase (COMT) inhibitor works by preventing the breakdown of L-Dopa and the adverse effects are nausea, vomiting, diahorrea and abdominal pain. An example of a COMT inhibitor is entacapone. Mr Boddy was given Rasagiline to start with which is a monoamine oxidase inhibitor. And then he was switched to L-Dopa which had a marked effect. (Longmore, 2007)
Deep brain stimulation is another option for the treatment of Parkinsons. It cannot cure Parkinson’s but by firing high frequency impulses into the brain it can reduce the symptoms of Parkinson’s as well as reducing the adverse effects of the drugs which improves the patients quality of life. It could be suggested to Mr Boddy that he tries this option when the “on-off effects” start happening. (Rodriguez-Oroz, et al., 2005)
Prognosis of Parkinson’s
If Parkinson’s isn’t treated then patients will be bedridden after 10 years of onset of the disease. The symptoms will advance rapidly. In people taking drugs the time taken for the disease to reach a stage where they are bed ridden is well over 15 years. (Poewe, 2006) However, the course of the disease is different in every individual with the disease progression being faster in people who are older. (Obeso, et al., 2010) Disability is linked to motor symptoms at the start of the disease but as it advances they are linked to motor symptoms that don’t respond to medicine. Life expectancy for people with PD is also reduced. (Poewe, 2006) The advice that can be given to Mr Boddy is that there is no way of knowing for certain how Parkinson’s will affect his future. However, the best case scenario is that he can carry on as normal for another 7 to 10 years before his symptoms greatly affect his job and family life.
In conclusion, this was a very interesting subject to look into and it made me realise how complex the disease is and how much of an impact it has on a person’s life. If I had more time I would like to look further into the genetic links behind Parkinson’s as well as looking into new methods of diagnosis that are being developed as I didn’t have the time to do so.
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