An Introduction to Parkinson’s Disease

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Parkinson’s disease belongs to a group of conditions called motor system (movement) disorders, which are the result of the loss of dopamine-producing brain cells. It is a condition affecting the neurolgical system, characterized by symptoms such as tremor, muscle rigidity, slowing of physical movement (bradykinesia), and in extreme cases, loss of physical movement (akinesia). An abnormal protein called alpha syneuclein, which accumulates in the neurons in the nervous system is thought to be responsible for these changes. These symptoms are the results of insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain.

How do Symptoms of Parkinson’s Develop?

The condition starts six to seven years prior to the development of any physical motor symptoms but inevitably continues to invade more and more neurons. This causes an accumulation of symptoms over a person’s lifespan. The protein is first seen in part of on of the cranial nerves (the vagus nerve) and the olfactory bulb (part of the brain involved in detecting odours). It then slowly spreads up the brainstem to eventually involve the basal ganglia – a region in the brain involved with functions such as motor control, thinking, emotions and learning. It is at that stage that Parkinson symptoms appear (as described above). However non-Parkinson symptoms are common but not recognizable in the early stages. Some of these symptoms include loss of the ability to smell (anosmia), constipation, abnormalities in the heart and sleep disturbance. As more abnormal proteins accumulate, Lewy bodies develop in some neurons. These Lewy bodies are diagnostic of Parkinson’s disease.

Parkinson’s Disease Treatment

The development of motor symptoms is usually followed by a gradual decline in the individual patient’s ability to function, resulting in the use of symptomatic treatment. Currently no cure exists and the pathological process underlying the disease cannot be stopped. Treatment involves maximizing the function of dopamine (L-dopa therapy) or the use of artificial dopamine to replace low levels of dopamine (Dopamine agonists). Unfortunately, although dopamine agonists (especially agonists with a long half life) are better agents to provide more stable control of motor symptoms, they are generally much less potent than L-dopa. Therefore, most people become dependant on L-dopa for long term management. As the disease progresses, there is increasing loss of neurons in the part of the brain that produces dopamine – the substantia nigra. This gradual loss leads to a shortening of the duration of action of each dose of L-dopa, as it heralds the reduced capacity of remaining neurons to store dopamine and to provide a long duration response. Eventually the motor response will only be of one to two hours duration – this represents the half life of L dopa in the blood and represents the total delivery time to the brain. In addition to the shortened duration of response, difficulties in performing normal movements (dyskinesia) develops. With cumulative treatment, a narrow range of L dopa (2-5mg) needed to stimulate movement (i.e. the window of benefit between immobility and dyskinesia) can develop. This is also dependent on the age of onset. The reason for the development of the narrow window is unclear, but may be related to the pulsatile effect of L-dopa on certain neurons. Long half life (>60 hours) dopamine agonists like cabergoline, which act on the receptors to increase dopamine levels are quite effective in eliminating or reducing dyskinesia. Different approaches to manage advanced Parkinson symptoms include the use of liquid L-dopa, apomorphine infusion through the skin (subcutaneously) and concentrated L dopa pumped into part of the small intestine called the duodenum.

Parkinson’s and Deep Brain Stimulation

In younger people with advanced Parkinson’s symptoms an alternate approach has been the use of deep brain stimulation (DBS). DBS uses a surgically implanted device called a neurostimulator. The mechanism of action of DBS is unclear but may relate to delivering electrical stimulation to targeted areas in the brain that control movement, blocking the abnormal nerve signals that cause the symptoms of Parkinson’s disease. The benefits of DBS are the same as L dopa except that the benefit is provided constantly 24 hours a day. Consequently DBS leads to a reduction of L dopa usage and in some fortunate individuals L dopa can be eliminated completely. The amount of L dopa reduction cannot be predicted prior to surgery and appears to be an individual response, dependent upon many factors. These include: placement of the electrode, the way a person’s body is organised and the amount of current that can be used without causing side effects. The decision to proceed to DBS surgery has no evidence base as no comparison has taken place of best medical management compared to DBS outcomes. The decision has to also include the costs of the procedure ($A40,000 – $A60,000) as well as the side effects which can be quite high ( 5 – 10% major morbidity & 15 – 20% minor morbidity).

A recent report on DBS has partly addressed the best approach to managing advanced Parkinson motor fluctuations. This randomized controlled trial was carried out across multiple centres in Germany and Austria, and compared best medical management with DBS. Participants were enrolled in pairs and then randomized to either treatment with medication or surgery. End points were changes in the quality of life scale (PDQ39) and the unified Parkinson disease rating scale motor component (UPDRS III) at 6 months after the intervention was performed. 120 subjects were available for final analysis (60 pairs). A significant difference was found in favour of surgery in 50 pairs for the quality of life scale and in 55 pairs for the Parkinsons disease rating scale. A 4% death rate and 13% serious morbidity occurred in the surgery group compared to 1% death rate and 4% serious morbidity in the non-surgical group. Although this report is welcome, there are a number of questions which are unanswered, making the interpretation of the results difficult. The trial was not blinded (ie patients and people administering the treatment were not made unaware of what treatment was being administered). Best medical management was not defined. Although quality of life is important, it is a consequence of better motor control. One factor which is the primary determinant of quality of life is L dopa reduction and elimination. In this regard, surgery fell short of improving quality of life, as no subjects discontinued their medications post surgery.

Medical management was better in 25% of patient pairs. Unfortunately for the individual patient contemplating surgery, the decision is still difficult. Is the risk of surgery, with a combined death and major morbidity of 17% worth the 24% improvement in quality of life (the primary outcome measure).The real decision should balance the probability of elimination of L dopa or its maximal reduction with the morbidity and mortality rate of the surgical team. Uncertainty, unpredictability and chance still play major roles in decision making for management of severe motor fluctuations in Parkinson’s. Whether DBS is better than best medical treatment is yet to be established.

(Article kindly contributed by Professor Robert Iansek Ph.D FRACP, Director of the Geriatric Research Unit and Geriatric Neurology Service, Kingston Centre and Editorial Advisory Board member of the Virtual Neuro Centre.)

References

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