What is Parkinson's Disease?
PD is a neurodegenerative disease. It occurs when certain nerve cells, or neurons, die or become impaired. This degeneration takes place in an area of the brain called the substantia nigra, located in the brainstem, which is one of the centers that control movement (also called the basal ganglia). Normally, these neurons produce a chemical known as dopamine, which is responsible for transmitting signals across the nerve pathways to produce smooth, purposeful movements. Loss of dopamine causes nerve cells to fire abnormally. This leaves people living with PD with difficulty directing or controlling their movements in a natural manner. People living with PD have usually lost 80% or more of dopamine-producing cells in the substantia nigra by the time symptoms are visually apparent. In addition, there is also neuronal cell loss and related pathology in other brain regions, responsible for other non-motor symptoms.
The main reason why these cells die or become impaired is still a mystery. Most scientists believe that both genetic and environmental factors are contributing causes. However, how they lead to PD is still unclear.
Genetics Factors of Parkinson’s Disease
While Parkinson’s disease is not usually inherited, familial forms exist and first-degree relatives of people living with PD are at slightly higher risk for the condition. When a genetic vulnerability is combined with exposure to some –yet unknown- environmental trigger, the changes for developing the disease increase. This genetic contribution appears to be stronger for those cases of early-onset PD.
The study of families in which PD appears to be inherited has resulted in the discovery of several genes associated with PD. There are two types of genes associated with disease. There are “causal genes” in which the causal gene alone, without the influence of other genes of environmental factors, guarantees that a person who inherits will very likely develop PD. This type of genetic PD is very rare. The second type, “associated genes”, do not cause PD on their own, but increase the risk of developing it. These genes usually need to be combined with other genes and environmental factors to cause PD.
At the present time, mutations in at least five genes have been firmly associated with PD: alpha-synuclein (SNCA or PARK1), parkin (PRKN or PARK2), DJ-1 (or PARK7), PTEN-induced putative kinase 1 (PINK1 or PARK6) and leucine-rich repeat kinase 2 (LRRK2 or PARK8). The identification of genes associated with PD has allowed scientists to better understand the disease. At the present time, genetic PD is treated in the same way as non-genetic or sporadic PD and clinical genetic testing is not usually performed. Because of the complexity associated with the genes associated with PD, genetic counseling is always recommended when performing genetic testing.
The cardinal motor symptoms of Parkinson’s Disease are listed below:
- Slowness of movement (also known as Bradykinesia): This is typically an early sign and affects almost all people living with PD. It can be disabling because it interferes with normal daily activities. Bradykinesia includes difficulties with voluntary movement planning and execution. It is established by a decrease in speed, amplitude, dexterity and fluidity of movements. This includes decreased arm swing, changes in hand writing or micrographia, and shuffling gait. Other symptoms may include loss of facial expression, soft speech and difficulty swallowing.
- Tremor: The tremor or involuntary shaking in PD can be seen in the hands, arms, legs, jaw or face. Typically, it starts on one side of the body, and it is visible when the affected body part is at rest or not in motion. Tremors that are present only with movement of the limb are usually due to other conditions. While it is present in many patients, approximately 25% of people living with PD never develop a tremor.
- Rigidity: Rigidity or muscle stiffness may impair the full range of limb motion and interfere with normal activities. It may cause pain and a stooped posture.
- Postural instability: The loss of balance reflexes known as postural instability usually begins later in the course of the disease. It can lead to falls and contributes greatly to the disability associated with PD.
PD can also cause a variety of other symptoms outside the realm of the motor system, known collectively as non-motor symptoms. The non-motor symptoms include diminished sense of smell, memory loss, sleep disturbances, depression, constipation, urinary frequency/urgency and erectile dysfunction among others.
Please visit our FAQs page if you have any questions regarding the symptoms of Parkinson’s disease.
Currently, there is no specific test or marker for PD. Diagnosis is made by a neurologist following an examination. An MRI of the brain may be ordered to exclude other brain diseases. However, there are no clear changes on the MRI that can conclusively tell that a person has PD.
While not everyone will develop all four cardinal symptoms, at least two are required for diagnosis, in the absence of an alternative cause (for example, exposure to certain medications or history of strokes). When symptoms first appear and signs are subtle, a precise diagnosis may be difficult.
Please visit our FAQs page if you have any questions regarding the diagnosis process of Parkinson’s disease.
The treatment of PD may be challenging, but unlike other neurodegenerative diseases, there is effective symptomatic treatment. The treatment should be orchestrated by a neurologist with movement disorders training and tailored to the individual patient. While medical and surgical therapy can provide long-lasting benefits, the ultimate goal of therapeutics in PD is neuroprotection (the development of drugs that can halt or slow down the progression). To date, no medication has demonstrated definite neuroprotection. However, monoamino oxidase inhibitors (MAOB-I) like rasagiline (Azilect®) may have disease modifying effects. There are also several other agents that have shown sufficient promise to warrant larger trials (creatine). In addition, DaTSCAN was approved by the FDA and it can be used as a tool to monitor the dopamine system in Parkinson's disease.
There are a large number of drugs available to treat motor and non-motor aspects of PD. Symptoms can be controlled in numerous patients for many years.
Adjuvant therapy is paramount in PD. Regular daily exercise is a vital component to maintaining mobility, flexibility and balance. Research studies have shown that certain PD symptoms can be improved by aerobic exercises such as walking on a treadmill, dancing or biking, and by specific exercise modalities such as yoga, tai-chi or qi-gong. Improvement of mobility through exercise and physical therapy improves quality of life in PD. More so, studies in animal models of PD have shown that exercise may be neuroprotective, slowing the progression of disease, although more research is needed in this area.
For most people living with PD, maintaining a healthy lifestyle, proper diet and regular daily exercise are recommended for an improved quality of life. Support groups for both patients and carepartners are beneficial for psychological support, educational information and practical advice.
Drugs Used to Treat Parkinson's Disease
- Levodopa: also called L-dopa, is currently the single most effective drug for the treatment of PD. It is converted into dopamine in the brain, the neurotransmitter produced by cells in the substantia nigra. Levodopa helps control the main motor symptoms of PD. It is generally taken with another drug, carbidopa, to avoid its most common side effect, nausea. In the United States, this combination is commercialized under the name carbidopa-levodopa, Sinemet®, Sinemet® CR, or StaLevo®, a single pill containing carbidopa, levodopa and entacapone. There is controversy about how early in the disease levodopa therapy should be initiated.
- Dopamine agonists: are drugs that stimulate dopamine receptors directly in the brain, mimicking the effect of levodopa. These medications are used to treat the motor symptoms of PD, particularly early in the disease and in younger patients. They are not as potent as levodopa, but they delay the onset of motor complications associated with chronic levodopa use. Agonists currently available in the United States are pramipexole (Mirapex®), ropinirole (Requip®), and apomorphine (Apokyn®). The rotigotine patch (Neupro®) was withdrawn from the U.S. market in April 2008, but it is still available in other countries.
- COMT inhibitors: prevent the breakdown of dopamine in the brain. When taken with levodopa, the effect of a single dose is prolonged. The two COMT inhibitors available in United States are entacapone (Comtan®) and tolcapone (Tasmar®). A combination of levodopa, carbidopa and entacapone in a single tablet is available as StaLevo®.
- Monoaminooxidase inhibitors (MAOB-I): Selegiline (Eldepryl®, Zelapar®) and rasagiline (Azilect®), the two MAOB-I commercially available for the treatment of PD, also inhibit the breakdown of dopamine in the brain, prolonging its effect. Recent trials suggest that rasagiline may have disease-modifying effects (neuroprotection). An older study on selegiline indicated that the medication also slowed down the disease. The results were however inconclusive, as the benefit could have also been explained by its symptomatic effects.
- Anticholinergic medications: are drugs that block the effect of the chemical acetylcholine in the brain. Acetylcholine opposes the effect of dopamine. They are useful against tremor and stiffness. Their use is limited by their high rate of side effects. The most commonly used anticholinergic medications are trihexyphenidyl (Artane®) and benztropine (Cogentin®). Ethopropazine (Parsitan®) is available in Canada.
- Amantadine: also known as Symmetrel® can relieve the motor symptoms of PD, particularly tremor. It has a more significant effect in reducing the abnormal movements (dyskinesias) caused by chronic dopaminergic treatment.
- Other agents: medications to treat depression and anxiety, constipation, urinary and erectile dysfunction, and sleep disturbances may be necessary to optimize quality of life for people living with PD.
Complications of Drug Treatment
Most people living with PD have many years of uncomplicated treatment after the diagnosis. However, as the disease progresses over time, a significant proportion can develop treatment complications. Medication adjustments may be required to minimize them.
Motor Complications of Treatment
Motor fluctuations: refers to as “wearing-off”, “on-off” and “dose failure”. “Wearing-off” is the shortening of the benefit period of a single medication dose. An “on-off” period is a sudden and unpredictable loss of the effect of a drug and “dose failure” is the lack of any benefit from one particular medication dose.
- Dyskinesias: are uncontrollable, abnormal dance-like movements that may occur in people living with PD after years of treatment with Levodopa. These movements usually occur at the peak effect of a dose of Levodopa. Amantadine may ameliorate this complication, as well as deep brain stimulation.
- “Off” Dystonia: is manifested by abnormal twisting movements, particularly of the fingers and toes. It typically occurs in the mornings before the first dose of medication.
- Freezing: occurs when there is a sudden inability or hesitation to move (motor block). It may appear at the beginning of a movement, when going through doorways or narrow passages or when turning. It may lead to falls. Freezing does not always respond to medications.
Non-motor complications of treatment:
- Psychosis: may result from side effects of antiparkinsonian medications. It includes hallucinations, delusions and disorientation. It may also be a feature of disease progression. Reducing and eliminating some medications can be helpful. The use of atypical antipsychotic medications, such as quetiapine (Seroquel®) or clozapine (Clozaril®), may be necessary in some cases.
- Orthostatic hypotension: occurs when there is a drop in blood pressure upon standing. It may cause dizziness, lightheadedness and even fainting in some cases.
When symptoms are inadequately treated with medications, brain surgery is an option. Not every person living with PD is a good candidate for surgery. An ideal candidate is an otherwise healthy person with PD who responds well to the medication but has developed severe motor complications.
There are two surgical procedures for PD: lesioning and deep brain stimulation (DBS). Lesion procedures (also known as pallidotomy or thalamotomy) deliver energy to heat and destroy a small part of the brain. These procedures are gradually being replaced by DBS, as the latter is a reversible and programmable therapy. DBS therapy uses a medical device, similar to a pacemaker, implanted in the chest wall, and a thin, flexible wire, called a lead. The lead is located deep in the brain, in three possible areas that control movement. The device sends mild electrical signals to the lead that block some of the brain messages that cause the motor symptoms. When used in an adequate candidate, DBS can lead to improvement of all motor features of PD, and many patients are able to decrease their medications. Risks of DBS include surgical risks (hemorrhage or infection) as well as hardware complications (leads breaking, electrode malfunction or battery failure). Side effects may include language impairment and walking difficulties. Please visit our FAQs page to learn more about surgical treatments like DBS for Parkinson’s disease.
Remarkable progress has occurred in the study of PD in the last few years. To date, however, there is no known cure for the disease. For most people living with PD, symptoms can be controlled for many years, and life expectancy is not significantly reduced.
Dystonia and Parkinson's Disease (PD) are movement disorders that are closely related. First, both conditions can occur together in certain diseases. People living with PD may experience dystonia as an early symptom or as a motor complication of treatment. Dopa-Responsive Dystonia and Rapid-Onset-Dystonia-Parkinsonism are hereditary forms of dystonia in which PD is often also present. Other neurodegenerative disorders, such as Wilson’s disease, may have both dystonia and PD, in conjunction to other clinical features. Second, dystonia and PD share common treatments. Anticholinergic medications and levodopa may ameliorate both conditions, and DBS is a surgical alternative for both, although the final brain target may vary. Lastly, PD and dystonia are thought to result from dysfunction of the basal ganglia and their output, although the ultimate cause of the disorders is not known. Further research is necessary to determine the various underlying genetic, environmental, or other underlying mechanisms that may play a role in causing these two related disorders.
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