[Editor's note: This article is from 2007. Some newer treatments, statistics, and risk factors may not be listed here. See further information on BrainWeb]
sections include: what causes Parkinson's disease?, diagnosing Parkinson's disease, treating Parkinson's disease
Parkinson's disease (PD) is a progressive neurological disorder that most commonly develops between the ages of 55 and 65. First described in England in 1817 by James Parkinson, PD today afflicts around 1 million individuals in the United States and approximately 1 percent of those over 55; approximately 50,000 new cases are reported annually. The disorder’s cardinal features are difficulty in initiating movement (akinesia), slowness of movement (bradykinesia), muscular stiffness (rigidity), unstable posture, and tremors at a rate of four to five per second. As the disease progresses and these symptoms become more pronounced, people who suffer from it may have difficulty walking, talking, and writing.
The onset of PD, which is typically subtle and gradual, is most often unilateral, affecting only one side of the body, with tremors the most common symptom. In its earliest stages, doctors may miss the diagnosis if a person does not have the characteristic resting hand tremor. Some of the other common earliest symptoms are decreased eye blinking, reduced facial expression, and shrinking handwriting (micrographia). This early period might last one to two years before more pronounced symptoms appear. Tremor, slowness of movement, and stiffness usually cause a person to seek medical help.
Doctors describe the tremor as “pill rolling,” meaning the motion one makes in rolling a pill across the tips of the fingers with one’s thumb; it is present at rest and is frequently a source of embarrassment. The tremor typically disappears with movement; driving is not affected early on. Other difficulties are slowness, clumsiness, and increasing fatigue in carrying out normal activities, as well as stiffness, or increased muscle tone (rigidity). A person with Parkinson’s disease typically develops a flexed posture, bending forward at the waist, with the arm on the affected side slightly flexed.
In addition to motor problems, people with PD commonly suffer from depression and anxiety. Depression affects as many as half of the patients. It may occur at any stage of the illness but is often missed because the decreased blinking and reduced facial expressions that are characteristic of the disease can mask depression. Or it may go untreated because of the inappropriate expectation by both patients and physicians that patients with Parkinson’s should be depressed because of their condition.
Up to 30 percent of people with PD suffer some degree of cognitive impairment—memory loss, impaired judgment, or poor planning—usually with advanced illness, and sometimes proceeding to dementia. But people with PD can develop similar problems from other causes: depression, drug side effects and unrelated conditions, such as Alzheimer’s disease. Doctors must therefore rule out those other causes before assuming that a person’s difficulties in thinking are related to PD.
Sleep disturbances are common in PD at any stage, with many people getting fewer hours of sleep or sleeping poorly. These individuals are often significantly less alert during the day, compounding their other challenges. Many factors may play a role in these sleep disturbances, including side effects of drugs, difficulty turning in bed, restless legs, vivid dreaming, and sleep apnea (the repeated obstruction of breathing). Correct diagnosis and treatment of sleep disturbances can greatly improve daytime functioning.
Other symptoms of PD include sexual, urinary, and bowel dysfunction. These, too, often respond to appropriate drug therapy. Speech becomes low-pitched and indistinct; the skin may develop seborrhea.
The course of PD varies considerably. Those who have tremor as their major symptom may do exceedingly well for a decade, while others may progress rapidly to more disability over several years. Most people respond excellently to drug treatment for the first three to five years, but thereafter enjoy less benefit because of drug-related complications, especially involuntary movements (dyskinesias) and “wearing off” of drug effects.
As the disease progresses, patients have increasingly frequent and severe difficulties with gait and balance. One hallmark of PD is the episodic “freezing” of gait: a patient will be walking and will suddenly be unable to take another step. Postural instability is one of the most disabling and difficult-to-treat features of PD, as well as a major factor contributing to falls, injuries, and dependence.
PD is not generally fatal by itself, but people with the disease do tend to have shorter life expectancies than normal. Especially in later stages of the disease, risks include choking, pneumonia, and severe and fatal falls.
What Causes Parkinson's Disease?
PD is one of the best understood neurodegenerative disorders. The pathological hallmarks of this disorder include the degeneration of a small group of dopamine-containing neurons in a part of the brain stem, in a structure called the substantia nigra. Dopamine is a chemical messenger that is released in portions of the basal ganglia involved in the control of movement. Loss of dopamine causes nerve cells to fire abnormally and excessively, which disrupts the functioning of other portions of the motor system that are directly responsible for movement, causing excess neuronal activity in some areas and diminished activity in others. Because these disruptions are so specific to movement, some scientists suggest thinking of PD as a “circuit disorder.” Loss of dopamine neurons in the substantia nigra occurs gradually over many years, and PD symptoms develop only when 50 percent to 80 percent of those cells have been lost and compensatory mechanisms fail.
Many researchers are intensely studying the causes of cell loss. For instance, “oxidative stress” caused by cell-damaging free radicals, possibly through abnormal breakdown of dopamine, is thought to be at least partly responsible for the deaths of nigral cells. Excessive accumulation of the protein alpha-synuclein, which is often found clumped in dying nigral cells, is also believed to play a role. Excess iron and other metals are also often found in affected brain regions. The synthetic opiate MPTP can cause Parkinson’s-like symptoms, and, after being accidentally discovered in drug users in the 1980s, became a chemical used to model the disease in experimental animals. Other toxins and pesticides have also been implicated in the origin of PD.
Scientists are also studying the role of extranigral changes in the brain, or those occurring outside the substantia nigra, particularly inflammation and neurodegeneration in the locus coeruleus, dorsal motor nucleus of the vagus, and nucleus basalis.
It is generally believed that the vast majority of PD cases result from an interaction between genetic and environmental factors, but the relative roles of heredity and environment are still uncertain. PD strikes men and women in almost equal numbers across social, economic, and geographic boundaries. Studies have shown that the disease risk is higher among those who live in rural areas, drink well water, or are exposed to pesticides. Recent research has uncovered specific genetic mutations in a small number of familial forms of PD. For instance, mutations in the alpha-synuclein gene can cause a rare inherited form, and chromosomal areas known as PARK3, PARK8, PARK9, PARK10, and PARK11 have also been linked to Parkinson’s susceptibility. While this provides new insight into the disease’s causes, it does not in itself explain the vast majority of cases—approximately 95 percent—that appear “spontaneously,” without obvious genetic triggers.
How the loss of dopamine in the brain leads to the symptoms of slowness, stiffness, tremor, and the other features of PD has received considerable study. This research has led to new medical and surgical treatments for the disease’s symptoms.
Diagnosing Parkinson's Disease
Parkinson’s disease is a clinical diagnosis; that is, there are no specific medical tests for the illness. Though generally not sensitive enough to directly observe Parkinson’s-related brain changes, neuroimaging with positron-emission tomography (PET) or single-photon-emission computed tomography (SPECT) may help rule out other conditions that clinically resemble PD. These syndromes are often difficult to distinguish from “atypical forms” of parkinsonism or “parkinsonism plus.” These conditions share some of the four primary symptoms described at the beginning of this section, but not all are the result of losing dopamine-producing brain cells. It is important to distinguish PD from other types of parkinsonism because treatment and prognosis differ significantly. Here are some indications that a person’s symptoms are not due to PD:
- The presence of clinical findings indicating other disorders.
- Gait and balance difficulties appear early rather than later.
- The symptoms do not respond satisfactorily to antiparkinson medications (levodopa or dopamine agonists).
- Imaging studies (magnetic resonance imaging, PET) show that structures other than the basal ganglia are involved in a person’s difficulties.
Scientists are now experimenting with radiotracers and PET to directly track changes in the nigral areas of the brain; many Parkinson’s patients show abnormalities on such scans. Recently, tensor diffusion imaging of the substantia nigra also showed promise. Some experts estimate that diagnosis levels remain very low, with as many as 20 undiagnosed people with Parkinson’s for every known case.
Treating Parkinson's Disease
Although there is no cure for Parkinson’s, people can be treated effectively for many years with medication, physical exercise, and conditioning. Surgical approaches provide new hope for patients for whom drugs no longer control symptoms adequately. The goal of these treatments is to maintain active functioning and quality of life.
Advancing the medical treatment of PD is one of the major accomplishments of modern medicine. Until the mid-sixties, the drug treatment of PD consisted mainly of anticholinergic drugs. These medications are still occasionally used to treat tremors, but they cause considerable side effects: memory impairment, visual blurring, and urinary difficulties. The discovery that people with PD have less dopamine in their brains led to the use of the dopamine precursor, levodopa. On entering the brain, this substance is chemically transformed into dopamine, which acts on the dopamine receptors in the basal ganglia. Levodopa therapy has become a mainstay of treatment. It vastly improves the quality of life of people with PD and has led to a nearly normal life span.
Soon after its introduction, however, it became evident that levodopa does not arrest progression of the disease. Even more problematic, it can lead to drug-induced motor impairment (dyskinesias) and cognitive complications. The introduction of alternative drugs has helped lessen and delay these complications. Levodopa is now given together with a drug called carbidopa, which prevents the metabolism of levodopa in the body. This reduces the side effects of nausea and vomiting and maximizes the amount of levodopa that enters the brain. Newer drugs that directly activate the brain’s dopamine receptors (called dopamine agonists) are now prescribed before levodopa because they appear to delay and mitigate drug-related complications. Amantadine is quite effective at reducing the severity of drug-induced dyskinesias.
Attempts are under way to find so-called neuroprotective treatments that will delay or arrest the progression of PD. Approaches that use substances known as growth factors and antioxidants are in this group. Studies using experimental models of PD have shown that destroying the part of the basal ganglia called the subthalamic nucleus can immediately reduce stiffness and tremor and improve mobility in the limbs on the opposite side of the body. This discovery renewed interest in surgical approaches to treating PD. To control tremor and rigidity, doctors can also perform a thalamotomy, in which a small section of the thalamus, a part of the brain that relays signals coordinating movement, is destroyed.
Another surgical procedure, pallidotomy, targets the globus pallidus, a part of the basal ganglia whose output leads directly to the symptoms of PD. All these surgeries carry some risk of damage to adjacent brain structures, but recent studies have found that they can be highly effective in alleviating symptoms and reducing side effects. It is as yet unknown how long the beneficial effects will persist.
Another procedure, which mimics the effect of lesions without actually destroying brain tissue, is deep brain stimulation (DBS). DBS, which has been approved by the Food & Drug Administration for treating PD, uses a device similar to a cardiac pacemaker. The surgeon, with imaging and physiological guidance, inserts an electrode into the subthalamic nucleus and the globus pallidus internal (GPi) that is connected to a small pulse generator placed under the skin. The pulse generator can be adjusted so that the optimal benefit is achieved by varying the voltage, frequency, and pulse duration, a process that usually takes several months. The advantages of this method over traditional surgery include the ability to adjust the generator or stop using it. DBS is generally employed only for those who do not or no longer respond to medication or who suffer from severe side effects. Studies have found that DBS is highly effective for treating PD, working better than standard drug therapy, but carries a higher risk of side effects, mostly of complications from the brain surgery. Interest in the treatment remains high, though, and more than 40,000 people have now undergone DBS surgery to treat tremor or PD.
People with PD should consider having surgery before the disease takes too great a toll on their independence, employment, and self confidence. Younger people with unilateral symptoms and intractable drug-induced dyskinesias are the best candidates for surgery, but there is no true age limit or lack of substantial benefit for older individuals. Patients who have developed dementia or have atypical parkinsonism are not suitable candidates. Before they consider surgery, or if they experience complications related to treatment, patients should consult a movement disorders specialist. All surgeries carry risk of severe side effects, including infection and bleeding in the brain, but brain surgeries also can cause neuropsychiatric side effects including depression, personality changes, and cognitive dysfunction.
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