Parkinson's disease
Highlights
What Is Parkinson’s Disease?
Parkinson’s disease is a neurological disorder that affects movement, muscle control, and balance. Parkinson’s disease usually affects people 55 - 75 years old, but it can develop in younger people as well. The disease is progressive, with symptoms becoming more severe over time.
Symptoms of Parkinson’s Disease
Parkinson’s disease is difficult to diagnose in its early stages. The disease is diagnosed mostly through symptoms, which may include:
- Tremors (shaking) in the hands, arms, legs, and face
- Slowness of movement, especially when initiating motion
- Muscle rigidity
- Difficulty with walking, balance, and coordination
- Difficulty eating and swallowing
- Digestive problems
- Speech problems
- Depression and difficulties with memory and thought processes
Treatment
There is no cure for Parkinson’s disease. Treatments focus on controlling symptoms and improving quality of life.
- Medications. Because Parkinson’s disease symptoms are due to a lack of the brain chemical dopamine, the main drug treatments help increase dopamine levels in the brain. Levadopa, usually combined with carbidopa, is the standard drug treatment. For patients who do not respond to levadopa, dopamine agonist drugs may be prescribed. Other types of medication may also be used. Unfortunately, many of these drugs can cause side effects and lose effectiveness over time.
- Physical Therapy. Physical therapy is an important part of Parkinson’s treatment. Rehabilitation can help patients improve their mobility, speech, and functional abilities.
- Surgery. In some cases of advanced-stage Parkinson’s disease, surgery may help to control motor problems. Deep brain stimulation is currently the preferred surgical method.
Drug Recall
In 2008, the manufacturers of transdermal rotigotine (Neupro) recalled all batches of the skin patch because of formulation problems. It is not known if the product will return to the market.
Introduction
Parkinson's disease (PD) is a slowly progressive disorder that affects movement, muscle control, and balance. Parkinson's disease is referred to as idiopathic, which means that the cause is unknown. This term distinguishes the primary disease from parkinsonism, which are the symptoms occurring from a known cause. In addition to its effects on motor control, Parkinson's disease is now recognized as a broader condition that can include cognitive and behavioral disturbances, sleep disorders, speech difficulties, and other problems.
Parkinson's disease occurs from the following process in the brain:
- PD develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra.
- Nerve cells in the substantia nigra send out fibers to the corpus stratia, gray and white bands of tissue located in both sides of the brain.
- There the cells release dopamine, an essential neurotransmitter (a chemical messenger in the brain). Loss of dopamine in the corpus stratia is the primary defect in Parkinson's disease.
Dopamine. Dopamine deficiency is the hallmark feature in PD. It is one of three major neurotransmitters known as catecholamines, which help the body respond to stress and prepare it for the fight-or-flight response. Loss of dopamine negatively affects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease. Dopamine also appears to be important for efficient information processing, and deficiencies may also be responsible for problems in memory and concentration that occur in many patients.
Although it is clear that dopamine deficiency is the primary defect in Parkinson's disease, it is not clear what causes dopamine loss. The culprit is less likely to be a single cause than a combination of genetic and biologic factors, which are triggered by some environmental assault.
Other Changes. The PD disease process also appears to impair nerve endings in the heart, causing dysautonomia-- changes in the autonomic (also called sympathetic) nervous system. Such changes may impair the release of norepinephrine, a hormone that regulates blood pressure, pulse rate, perspiration, and other automatic responses to stress. Evidence suggests this may be responsible for the abrupt drops in blood pressure when standing that occur in PD. Further research is underway to determine if the loss of nerve terminals is confined to the heart or if it affects other organs as well.
Click the icon to see an animation about Parkinson's disease.
Research suggests that three molecules are critical in the development of inherited PD: alpha synuclein, parkin, and ubiquitin, which all interact in the normal brain. Normally, parkin and ubiquitin, are involved in the natural process of programmed cell death called apoptosis. If this process goes awry, for instance, with a defective parkin gene, cell death fails to occur. If synuclein is not eliminated in these cells, it builds up and becomes toxic to dopamine. In such cases, synuclein accumulates in Lewy bodies, the deposits of fibrous tissue found in all patients with PD.
Lewy bodies are the hallmark signs of Parkinson's disease. They are found in the substantia nigra, the place in the brain where dopamine is first released. These substances are also present in other diseases that cause dementia, such as Alzheimer's, and can occur in people without neurologic symptoms.
Another protein, beta amyloid, also increases the build-up of synuclein. Beta amyloid is a known factor in Alzheimer's disease, and may help explain the co-existence between Alzheimer's and Parkinson's disease in many patients.
Other biologic factors that may play a role in Parkinson's disease are also being investigated.
Specific genetic factors appear to play a strong role in early-onset Parkinson's disease, an uncommon form of the disease. Recent research suggests that multiple genetic factors may also be involved in some cases of late-onset Parkinson’s disease.
Environmental toxins, infections, and other triggers can provoke excessive production in the body of oxygen free-radicals, damaging particles that may play a major role in the deterioration of nerve cells that lead to Parkinson's.
Infectious Organisms. Some research has identified immune factors that suggest a viral presence in the Lewy bodies and swollen nerve pathways of Parkinson's brains. Influenza and other potent viruses have long been known to be a cause of parkinsonism. In one well-known example, a major flu epidemic causing encephalitis in the early twentieth century left many of its victims with parkinsonism.
Environmental and Industrial Chemicals. Intense exposure to certain environmental and industrial chemicals is also being studied.
- Pesticides and Herbicides. Some evidence implicates pesticides and herbicides as important factors in many cases of Parkinson's disease. A higher incidence of parkinsonism has long been noted in people who live in rural areas, particularly those who drink private well water or are agricultural workers.
- Other Chemicals. Intense exposure to other industrial chemicals and metals (manganese, copper, lead, iron, mercury, zinc, aluminum, and others) has also been linked with parkinsonism, a cause that is often reversible. The role of long-term exposure in the development of Parkinson's disease is unclear. High levels of iron content observed in critical parts of the brain in PD are under particular scrutiny.
Most Parkinson's victims are elderly. Some studies indicate that the very elderly are not susceptible to the disease, indicating that the aging process itself is not the major player in the disease. Aging does appear to reduce the concentration of dopamine in structures called dopamine transporters, which carry the neurotransmitter back and forth between nerve cells. Some researchers posit that any excessive stress on these transporters might trigger Parkinson's disease in the aging, and more vulnerable, brain.
Symptoms
Parkinson's disease (PD) symptoms often start with tremor, which may occur in the following ways:
- Tremors may first be only occasional, starting in one finger and spreading over time to involve the whole arm. The tremor is often rhythmic, 4 - 5 cycles per second, and frequently causes an action of the thumb and fingers known as pill rolling.
- Tremors can occur when the limb is at rest or when it is held up in a stiff unsupported position. They usually disappear briefly during movement and do not occur during sleep.
- Tremors can also eventually occur in the head, lips, tongue, and feet. Symptoms can occur on one or both sides of the body.
In younger patients tremor is usually predominant and often suggests a less aggressive form of the disease. Some evidence suggests that tremor in PD may occur from mechanisms in the brain that are different from those that cause other PD symptoms.
A number of PD symptoms involve motor impairment caused by the abnormalities in the brain that regulate movement:
- Slowness of motion, particularly when initiating any movement (a condition called akinesia or bradykinesia), is one of the classic symptoms of Parkinson's disease.
- Patients may eventually develop a stooped posture and a slow, shuffling walk. The gait can be erratic and unsteady. After a number of years, muscles may freeze up or stall, usually when a patient is making a turn or passing through narrow spaces, such as a doorway. Patients' posture can be unstable and there is an increased risk for falls.
- Intestinal motility (the ability to swallow, digest, and eliminate) may slow down, causing eating problems and constipation.
- Muscles may become rigid. This symptom often begins in the legs and neck. Muscle rigidity in the face can produce a mask-like, staring appearance.
- Motor abnormalities that limit action in the hand may develop in late stages. Handwriting, for instance, often becomes diminutive.
- Normally spontaneous muscle movements, such as blinking, may need to be done consciously.
The traditional view of Parkinson's disease is shifting to reflect growing awareness that it is much more than a motor disease. Many non-motor components and their treatments are now under study. The following symptoms should be carefully monitored by doctors and caregivers:
- Depression is the most common psychiatric problem associated with PD, affecting about 40% of patients. Because depression is a common problem in older people, it is likely not to be recognized as a symptom.
- Anxiety affects about 30% of patients.
- Dementia and paranoia are more common than previously understood.
- Orthostatic hypotension -- some patients have a sudden drop in blood pressure when they stand. This can cause dizziness and fainting.
- Changes in sensations of temperature, hot flashes, and excessive sweating.
- Daytime sleepiness and other sleep disorders are common.
Risk Factors
Parkinson's disease affects about 3% of Americans over 65 years old. With an increasingly aging population, this percentage may grow. The symptoms of parkinsonism (tremor, gait disturbance, bradykinesia, and rigidity) occur in even more people, estimated to be 8 million over age 65. In a study that included very mild symptoms, parkinsonism occurred in about 15% of people 65 - 74 years of age, about 30% in those 75 - 84, and over half of people older than age 85.
The average age of onset of Parkinson's disease is 55. About 10% of Parkinson's cases are in people younger than 40 years old. Older adults are at higher risk for both parkinsonism and Parkinson's disease. There is some evidence, however, that the risk declines significantly after age 75 and that the very elderly are at low risk.
Some research indicates that men may face up to twice the risk as women. Estrogen may offer some protection for women up until menopause. A 2001 study, for example, reported a higher rate of Parkinson's disease in women who had undergone hysterectomy. Other studies suggest that the disease also progresses more rapidly in men than women. Older women seem to be more at risk for gait disturbance and men for rigidity and tremor.
People with siblings or parents who developed Parkinson's at a younger age are at higher risk for Parkinson's disease, but relatives of those who were elderly when they had the disease appear to have an average risk.
African- and Asian-Americans appear to have a lower risk than Caucasians.
Both smoking and coffee drinking have been associated with lower risk for PD. Researchers are trying to determine why these substances seem to protect against PD.
Smoking and Nicotine Replacement. Cigarette smokers appear to have a 40% lower risk for Parkinson's disease, indicating some protection by nicotine. This finding, of course, is no excuse to smoke, but such protection may help researchers develop new therapies. Studies on nicotine replacement have been few and have not provided any strong evidence that nicotine therapy provides benefits.
Coffee Consumption. Studies have indicated that the risk for PD in coffee drinkers is about 30% lower than for non-coffee drinkers. In a 30-year study of Japanese-American men, coffee consumption was associated with a lower risk for Parkinson's disease, and the more coffee they drank, the lower their risk became.
Complications
Parkinson's disease (PD) is not fatal, but it can reduce longevity. The disease progresses more quickly in older patients, and may lead to severe incapacity within 10 - 20 years. Older patients also tend to have freezing and greater declines in mental function and daily functioning than younger people. If PD starts without signs of tremor, it is likely to be more severe than if tremor had been present. Having other family members with PD does not appear to have any effect on the severity of the disease.
Parkinson's disease can seriously impair the quality of life in any age group. The physical and emotional impact on the family should not be underestimated as the patient becomes increasingly dependent on their support.
Treatment advances are increasingly effective in alleviating symptoms and even slowing progression of the disease. Taking many of the medications over time, however, can produce significant side effects. Newer drugs may help reduce these occurrences.
The negative effect of overall motor and muscle impairment on daily life can be considerable. Some motor complications can be life threatening.
- Disturbed gait and unstable posture are common and serious problems in elderly patients, since they increase the risk for falling and injury. Some studies have suggested that the appearance of these symptoms early in the course of the disease predict a faster decline than having tremor as the predominant symptom.
- Swallowing problems (dysphagia). The presence of dysphagia is associated with shorter survival time. Motor impairment of the muscles in the throat not only impairs swallowing (leading to malnourishment) but also poses a risk for aspiration pneumonia.
- Constipation is a major problem and occurs both as a result of the disease and a side effect of its treatment. Laxatives, stool softeners, and other medications may be prescribed.
- Bladder control and urinary incontinence are also important complications of PD.
- Speech problems occur in more than 70% of patients, by some estimates. Speech difficulty can be caused by rigidity of the facial muscles, loss of motor control, and impaired breath control. Tone can become monotonous, words may be repeated over and over, or the rate of speech may even be very fast.
Depression is extremely common, affecting up to 40% of patients with Parkinson's. PD poses multiple threats on the emotional health:
- The disease process itself causes changes in chemicals in the brain that affect mood and well-being.
- The complications of its symptoms have a profound impact on daily life that can be emotionally devastating without help and support.
- Some drug treatments (levodopa combined with a dopamine agonist) can cause compulsive behavior, such as gambling, shopping, and increased sexuality. Patients who have pre-existing tendencies to novelty-seeking behavior, or a family or personal history of alcohol abuse, may be more likely to develop compulsive gambling. Deep brain stimulus (DBS) surgery may also increase the risk for compulsive gambling in patients who have a history of gambling.
Impaired Thinking (Cognitive Impairment). Defects in thinking, memory, language, and problem solving skills may occur early on in untreated patients or late in the course of the disease. Medications may play a role in thinking problems. Patients with PD are slower in detecting associations, although (unlike in Alzheimer's disease) once they discover them they are able to apply this knowledge to other concepts.
Dementia. Dementia is three to six times more common in the elderly Parkinson patient than in the average older adult. It is most likely to occur in older patients who have had major depression. PD marked by muscle rigidity (akinesia), rather than tremor, and early hallucinations also increase the risk for dementia. (Visual hallucinations can also occur in about a third of patients from PD medication.) Unlike in Alzheimer's, language is not usually affected in Parkinson's related dementia.
A number of other problems associated with Parkinson's disease affect daily life.
Vision Problems. Vision is also affected, including impaired color perception and contrast sensitivity. These problems progress and can impair motor functioning.
Sleep Disorders. Excessive daytime sleepiness and other sleep disorders are common in PD, both from the disease itself and the drugs that treat it. In general, patients have a 25% higher risk for daytime sleepiness, including suddenly falling asleep, than patients with other neurologic diseases.
Restless legs syndrome, an irresistible urge to move the calves, which often occurs at night, affects many patients. However, Parkinson's disease itself does not seem to increase the risk for RLS. Nor does RLS early in life predispose to Parkinson's later on. The common connection between RLS and Parkinson's disease may derive from iron deficiencies that can play a role in both conditions.
Many patients also suffer from nighttime leg cramps. And, some of the medications cause vivid dreams as well as waking hallucinations.
Impaired Sexuality. Although Parkinson's disease and its treatments can cause compulsive sexual behavior, the disease can also affect patients' self-esteem and inhibit sexuality. This is an area not often studied but which is important for many patients' well-being. A 2000 study reported that not only did sexual dysfunction occur, but also affectionate touching and expression of feelings were reduced, even though both partners maintained a desire for intimacy.
Worsened Sense of Smell. The sense of smell is impaired in about 70% of patients.
Osteoporosis. Parkinson’s disease may increase the risk for low bone density and osteoporosis. Both men and women are at risk. Experts recommend that patients with Parkinson’s disease get tested for osteoporosis, especially if they have problems with walking.
Diagnosis
It is difficult to diagnose Parkinson's in early stages. The disease is primarily diagnosed by its symptoms, and studies indicate that doctors make an incorrect initial diagnosis of Parkinson's disease in 8 - 35% of cases. Even neurologists have difficulties in correctly identifying the disease.
A medical and personal history should include any relevant symptoms as well as any medications taken, and information on exposure to environmental toxins.
Early Symptoms. Early symptoms are often mild, so Parkinson's disease can be missed, particularly in young adults. Repeated assessment of symptoms over time is important for improving the accuracy of diagnosis. Too often a younger person with Parkinson's may be diagnosed with mental illness, because the doctor associates the disease only with older people.
Parkinson's may be suspected in patients with the following symptoms:
- Slowness and difficulty of movement. These are usually the first symptoms. The patient will be asked to walk and to get out of a chair, preferably a deep one. Early gait disturbance, however, often indicates a disease other than Parkinson's disease.
- A tremor when their limb is relaxed. (As many as 25% of patients, however, will not have a tremor.)
- Symptoms on one side of the body.
Later Symptoms. In later stages of Parkinson's disease, the symptoms are usually unmistakable, and the problem can often be diagnosed using simple physical tests and a medical and personal history.
The loss of smell is associated with loss of dopamine receptors in the brain. “Scratch and sniff” smell tests can help a doctor diagnose Parkinson’s disease. Smell tests can help differentiate Parkinson’s disease from other conditions with similar symptoms. Some patients with a very similar condition called multiple system atrophy will have a good initial response to levodopa, but it is not usually sustained.
Levodopa and apomorphine can confirm a diagnosis of Parkinson’s disease. If patients’ symptoms improve when they take these drugs, they likely have Parkinson’s, ruling out other neurological diseases.
There is not enough evidence to recommend for or against the use of imaging techniques such as computerized tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomographic (PET) to diagnose PD.
When symptoms resemble Parkinson's disease but have an identifiable cause, the syndrome is known as parkinsonism. People who have parkinsonism, but not Parkinson's disease, often have additional neurologic symptoms. A number of conditions can also have similar or some of these symptoms.
Other Neurologic Conditions. Many medical conditions may cause some symptoms of Parkinson's disease:
- Hardening of the arteries (arteriosclerosis) in the brain can cause multiple small strokes, which can produce loss of motor control.
Click the icon to see an image of plaque in an artery.
- Alzheimer's disease can be very similar. The two diseases often coexist, and research suggests that Alzheimer's and Parkinson's disease may sometimes share a common biologic origin, the accumulation of the protein alpha synuclein and Lewy bodies in the brain.
- Lewy bodies variant (LBV), also called dementia with Lewy bodies, is a separate disease from both Alzheimer's and Parkinson's disease. It has similar symptoms to both but is marked by early dementia.
- Encephalitis caused by influenza has been known to cause parkinsonism.
- Primary progressive freezing gait is a progression condition, in which freezing gait occurs at the onset. Other Parkinson-like features, such as slow movement, often develop. Although very similar to PD, this condition does not respond to L-dopa or other PD medications.
- Essential tremor, unlike the tremor of Parkinson's disease, often occurs in the head and voice and is usually worse during motion, as opposed to rest.
- Progressive supranuclear palsy has similar symptoms, but involves less tremor and earlier rigidity, and it tends to affect both sides of the body symmetrically. Magnetic resonance imaging scans that measure parts of the midbrain may be a reliable method for distinguishing between PD and progressive supranuclear palsy.
- Multiple system atrophy (previously called Shy-Drager syndrome) is a degenerative nerve disease that also affects movement and blood pressure and has many of the symptoms of Parkinson's disease. Some research suggests that a trial using the drug apomorphine may help differentiate between the two.
- Other problems that may mimic Parkinson's disease include Wilson's disease, thyroid abnormalities, hydrocephalus, tumors, having the fragile X trait (but not the full disorder), and a number of degenerative neurologic diseases.
Drugs. Certain drugs or medications account for about 4% of all cases of parkinsonism. According to some studies, patients with drug-induced parkinsonism may actually be at an increased risk of developing Parkinson's disease later in life. A number of drugs can cause these symptoms, including antipsychotic and antiseizure drugs. Anyone with parkinsonism should discuss their medications with their doctor.
The American Academy of Neurology (AAN) recommends the Beck Depression Inventory or the Hamilton Depression Rating Scale to screen for depression in patients with Parkinson’s disease. The AAN recommends the Mini Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG) tests to screen for dementia. During these tests, the patient answers a series of questions.
Treatment
Drugs, physical therapy, and surgical interventions can manage Parkinson's disease. The goals of treatment for Parkinson's disease are to:
- Relieve disabilities
- Balance the problems of the disease with the side effects of the medications
Treatment is very individualized for this complicated disease. Patients must work closely with doctors and therapists throughout the course of the disease to customize a program suitable for their particular and changing needs. Patients should never change their medications without consulting their doctor, and they should never stop taking their medications abruptly.
No treatment method has been shown to change the course of the disease. For early disease with little or no impairment, active treatment with medications may not be necessary.
A number of issues must be considered in choosing medication treatment. These include how effective a specific drug group is in treating symptoms, which symptoms are predominant, side effect profile, loss of effectiveness over time, and other considerations.
The American Academy of Neurology recommends the following therapies for the initial treatment of Parkinson’s disease:
Levodopa (L-dopa). Levodopa, or L-dopa, has been used for years and is the gold standard for treating Parkinson's disease. L-dopa increases brain levels of dopamine. It is probably the most effective drug for controlling symptoms and is used in nearly all phases of the disease. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, a drug that slows the breakdown of levodopa. Levodopa is better at improving motor problems than dopamine agonists but increases the risk of involuntary movements (dyskinesia). Effectiveness tends to decrease after 4 - 5 years of usage.
Dopamine Agonists. Dopamine agonist drugs mimic dopamine to stimulate the dopamine system in the brain. They may be considered as a first choice for treating female patients 65 years and older. These drugs include pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). The Food and Drug Administration (FDA) pulled the dopamine agonist pergolide (Permax) from the market in March 2007 over safety concerns that included potentially fatal heart valve damage. In 2008, a skin patch dopamine agonist, transdermal rotigotine (Neupro), was recalled from the market.
Selegiline (Eldepryl) and rasagiline (Azilect). Selegiline is a monoamine oxidase B (MAO-B) inhibitor that may have some mild benefit as an initial therapy. However, unlike levodopa, it does not slow the progression of Parkinson’s disease. Another MAO-B inhibitor, rasagiline (Azilect), was approved in May 2006. Unlike selegiline, which needs to be taken by mouth twice a day, rasagiline needs to be taken only once a day.
Drug treatments for Parkinson disease do not consistently control symptoms. At certain points during the day, the beneficial effects of drugs wear off, and symptoms can return, including uncontrolled muscular motor function, difficulty walking, and loss of energy. In 2006, the American Academy of Neurology (AAN) reviewed evidence for the various drugs used to treat “off time.” The AAN found that the following drugs had the strongest evidence for controlling off time symptoms:
- Entacapone (Comtan) belongs to a class of drugs called catechol-o-methyl transferase (COMT) inhibitors. COMT inhibitors help prolong the effects of levodopa by blocking an enzyme that breaks down dopamine.
- Rasagiline (Azilect) belongs to a class of drugs called monoamine oxidase (MAO) inhibitors. These drugs slow the breakdown of dopamine that occurs naturally in the brain and dopamine produced from levodopa.
The AAN also found good evidence for the dopamine agonists ropinirole (Requip) and pramipexole (Mirapex), and the COMT inhibitor tolcapone (Tasmar). Deep brain stimulation is a surgical treatment that may help improve motor fluctuations in some patients.
Both levodopa and dopamine agonists can cause involuntary movements (dyskinesia). The AAN has not found any strong evidence to recommend any specific drug for treating dyskinesia. However, weak evidence suggests that the antiviral drug amantadine (Symmetrel) may help reduce stiffness and improve dyskinesia. There is also weak evidence that deep brain stimulation of the subthalamus area may be helpful.
Conditions associated with motor impairment and other symptoms of Parkinson's disease may need a variety of treatments.
Depression. Although depression is very common in PD, there have been surprisingly few controlled studies. Antidepressants used for PD include tricyclics, particularly amitriptyline (Elavil). Some studies have found that selective serotonin-reuptake inhibitors (SSRIs) -- which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) -- may worsen symptoms of Parkinson's. Doctors should monitor patients taking SSRIs.
Psychotic Side Effects. Studies indicate that clozapine (Clozaril) and quetiapine (Seroquel), antipsychotic drugs used to treat schizophrenia, may be the best drugs for treating psychosis in patients with Parkinson's disease. A similar drug, olanzapine (Zyprexa), should not be used for patients with PD because it can worsen their psychotic symptoms.
Dementia. The cholinesterase inhibitor drugs donepezil (Aricept) and rivastigmine (Exelon) are used to treat Alzheimer’s disease. Studies suggest that these drugs may also help treat dementia associated with Parkinson’s disease. However, the actual clinical improvement is very modest at best.
Daytime Sleepiness. Modafinil (Provigil), a drug used to treat narcolepsy, is proving to be very helpful for patients with sleepiness related to their disease.
Drooling. In search of a simple solution for the problem of drooling, scientists have reported that injections of very small amounts of botulinum toxin effectively reduce saliva production and drooling. In such small amounts, the toxin is safe. Speech therapy may also help in managing the secretions and reducing the risk of aspiration.
Voice Loss. A relatively simple procedure using collagen injections in the neck to augment the collagen in the vocal fold may be tried in patients who can still initiate speech. There is minimal evidence from controlled trials for this technique, however. Speech therapy is also an option.
Erectile Dysfunction. Sildenafil (Viagra) is proving to be very helpful for men with Parkinson's disease who suffer from impotence. However, the drug may worsen orthostatic hypotension, a side effect of some PD medications.
Eventually, symptoms such as stooped posture, freezing, and speech difficulties may not respond to drug treatment. (Total unresponsiveness is unlikely, however, even after 20 years of treatment.) The following approaches may be tried:
- Simply increasing the dose of levodopa or its frequency raises an unacceptable risk of the distressing side effects. Some doctors have tried hospitalizing patients, totally withdrawing the levodopa, and then re-administering it. Benefits were seen for only a few months, however, and there were some dangerous risks to the process of withdrawal, including pneumonia and blood clots in the lungs.
- Surgical treatments, including deep brain stimulation and pallidotomy, may help some patients.
- Research is ongoing to develop drugs and procedures that will manage advanced disease and possibly even reverse the process.
Levadopa (L-dopa)
Levodopa, also called L-dopa, which is converted to dopamine in the brain, remains the gold standard for treating Parkinson's disease. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Levodopa can also be combined with benserazide (Madopar) with similar results, but Sinemet is almost always used in America. Dosages vary, although the preparation is usually taken in three or four divided doses per day.
In general L-dopa has the following effects on Parkinson's disease:
- It is most effective against rigidity and slowness.
- It produces less benefit for tremor, balance, and gait.
In many patients, levodopa significantly improves the quality of life for many years. If symptoms do not improve after 2 - 3 months, one of the following reasons may account for the failure:
- Other neurologic problems may be causing the symptoms.
- Some patients have abnormalities in other brain sites that do not respond to L-dopa.
- Sometimes patients are so depressed they cannot tell if the drug is beneficial or not. Only a series of physical examinations by the doctor will indicate that the drug is actually helping.
Studies suggest that levodopa may help slow disease progression and protect against brain cell degeneration.
The toxic effects of levodopa with or without carbidopa are considerable.
Physical Side Effects. The physical side effects include:
- Low blood pressure. Low blood pressure is a common problem during the first few weeks, particularly if the initial dose is too high. The addition of extra supplements of carbidopa reduces this effect to some degree. The patient should drink lots of fluids and possibly increase salt intake to maintain normal blood pressure.
- Arrhythmia. In some cases the drug may cause abnormal heart rhythms.
- Gastrointestinal effects. Stomach and intestinal side effects are common even with carbidopa. Taking the drug with food can alleviate the nausea. However, proteins interfere with intestinal absorption of levodopa, and some doctors recommend not eating any protein until nighttime in order to avoid this interference. The drug can also cause gastrointestinal bleeding.
- Effects in the lung. Levodopa can cause disturbances in breathing function, although it may benefit patients who have upper airway obstruction.
- Hair loss.
Psychiatric and Mental Side Effects. The major adverse effects of the drug are psychiatric. Patients taking levodopa, especially in combination with other drugs, can experience:
- Confusion.
- Extreme emotional states, particularly anxiety.
- Vivid dreams.
- Visual and possibly auditory hallucinations. The drug may even unmask dementia that had not been previously noticed.
- Effects on learning. L-dopa appears to have mixed effects on learning. It may improve working memory. However, some evidence suggests that it impairs areas of the brain related to other learning functions and social behavior.
- Sleepiness and sleep attacks.
Levodopa causes fewer psychiatric side effects than other drugs used for Parkinson's disease, including anticholinergics, selegiline, amantadine, and dopamine agonists. Because psychiatric side effects often occur at night, if they are severe some doctors recommend reducing or stopping the evening dose.
Within 4 - 6 years of treatment with levodopa, the effects of the drug in many patients begin to last for shorter periods of time (called the wearing-off effect) and the following pattern may occur:
- Patients may first notice slowness (bradykinesia) or tremor in the morning before the next dose is due.
- Less commonly, some experience painful dystonia, muscle spasms that can cause sustained contortions of various parts of the body, particularly the neck, jaw, trunk, and eyes and possibly the feet.
- Patients must increase the frequency of levodopa doses. This puts them at risk for dyskinesia (the inability to control muscles), which usually occurs when the drug level peaks. Dyskinesia can take many forms, most often uncontrolled flailing of the arms and legs or chorea, rapid and repetitive motions that can affect the limbs, face, tongue, mouth, and neck. Dyskinesia is not painful, but it is very distressing.
- In some people, eventually L-dopa is effective only for 1 - 2 hours, and most patients start to have motor fluctuations. In about 15 - 20% of patients, such fluctuations become extreme, a phenomenon known as the on-off effect, which consists of unpredictable, alternating periods of dyskinesia and immobility. Sometimes the symptoms switch back in forth within minutes or even seconds. (The transition may follow such symptoms as intense anxiety, sweating, and rapid heartbeats.)
Reasons for the Wearing-Off Effect. Debate is ongoing about the cause of the wearing-off effect and dyskinesia. Some theories suggested for these effects are:
- The disease progresses beyond the ability of levodopa to control it.
- Some patients become tolerant to prolonged exposure to dopamine and, at the same time, the disease is progressing.
- The brain's own dopamine neurons become incapable of storing dopamine. When the levodopa wears off, little or no natural dopamine remains.
- Levodopa itself accelerates the disease by producing oxygen free radicals, unstable particles that increase injuries to the brain and dopamine degradation.
Preventing the Wearing-Off Effect. To reduce the effects of fluctuation and the wearing-off effect, it is important to maintain as consistent a level of dopamine as possible. Unfortunately, levodopa is poorly absorbed and may remain in the stomach a long time. A number of strategies are being developed to take care of these problems:
- Some patients take multiple small doses on an empty stomach, crushing the pills and mixing them with a lot of liquid.
- A liquid form of Sinemet may produce fewer fluctuations and a prolonged "on" time compared with the tablet.
- A prolonged release version of levodopa and carbidopa (Sinemet CR) is also available to control fluctuations for some people. (Some evidence suggests that there is no actual difference in symptom control between the sustained and immediate release forms, but patients on Sinemet CR tend to experience a better quality of life.)
Other Medications
Selegiline (Eldepryl, Movergan, Zelepar), also known as deprenyl, is an antioxidant drug that blocks monoamine oxidase B (MAO-B), an enzyme that degrades dopamine. Until recently, selegiline was commonly used in early-onset disease and in combination with levodopa for maintenance. Concerns over significant side effects have been raised, however.
Rasagiline (Azilect), another MAO-B inhibitor, was approved in May 2006 for the initial treatment of Parkinson’s disease. It is used alone during early-stage PD and in combination with L-dopa for moderate-to-advanced PD. Unlike selegiline, which is taken twice a day, rasagiline is taken once a day.
Other Adverse Effects. MAO-B inhibitors may have severe side effects:
- One of the most important side effects is orthostatic hypotension, particularly in people taking Sinemet plus selegiline. This condition is a sudden drop in blood pressure that causes dizziness and lightheadedness when a patient stands up. Orthostatic hypotension can also occur with other Parkinson's drugs.
- Can cause high blood pressure (hypertension) if combined with drugs that increase serotonin levels -- such drugs include nearly every major antidepressant. Patients suffering from depression and taking selegiline should discuss all treatment options with their doctor.
- Can also cause a dangerous increase in blood pressure if patients eat foods rich in the amino acid tyramine. Patients should avoid the following foods while taking selegiline or rasagiline and for 2 weeks after stopping medication: aged cheeses, air-dried meats, pickled herring, yeast extract, aged red wines, draft beers, sauerkraut, and soy sauce
Debate over Mortality Rates. Some major studies have reported higher mortality rates in patients with advanced PD. Such findings may be due to adverse effects on the heart and blood vessels. Although other studies have not reported lower survival rates, some experts believe that, given its modest effects, selegiline may be a poorer drug choice than others, particularly in patients with risk factors for heart disease.
Dopamine agonists stimulate dopamine receptors in the substantia nigra, the part of the brain in which Parkinson's is thought to originate. Dopamine agonists are effective in delaying motor complications during the first 1 or 2 years of treatment.
Newer Dopamine Agonists. The most commonly prescribed dopamine agonists are pramipexole (Mirapex) and ropinirole (Requip). They are used either alone or in combination with L-dopa. Pramipexole appears to work better and have fewer side effects than ropinirole.
Studies still report, however, that L-dopa is superior for improving motor function. In one study, motor function was no different in disease progression among all of the drugs by the third year of treatment. Recent research suggests that L-dopa is better at improving motor disability and dopamine agonists are better at reducing motor complications. L-dopa has a higher risk for dyskinesia side effects than dopamine agonists, but dyskinesia can also occur with dopamine agonists.
Side Effects. Side effects of pramipexole and ropinirole vary but can be severe and include:
- Gastrointestinal side effects (nausea and constipation). Nausea can be controlled by drugs, such as domperidone.
- Headache
- Orthostatic hypotension (sudden drop in blood pressure upon standing up)
- Nasal congestion
- Nightmares, hallucinations, and psychosis (more severe than with L-dopa for both drugs)
- Sudden sleep attacks. These can be very serious, particularly if patients are driving. (Sleep attacks may occur -- although less commonly -- with other PD drugs.)
Other Dopamine Agonists.
- Specific dopamine agonists that contain ergot alkaloids include bromocriptine (Parodel), pergolide (Permax), cabergoline (Dostinex), and lisuride (Dopergin). As of 2007, bromocriptine is the only ergot dopamine agonist approved for Parkinson’s treatment in the United States. However, pergolide and cabergoline have been found to be associated with heart valve damage. In March 2007, due to these safety concerns, the FDA withdrew pergolide from the U.S. market. Cabergoline and lisuride are not approved in the U.S. for Parkinson’s disease treatment but are used for this purpose in other countries. There have been no heart valve problems associated with bromocriptine or lisuride.
- Apomorphine is a dopamine agonist used as a "rescue" drug in people having on-off effects severe enough to require going off L-dopa for a few days. In 2004, the FDA approved apomorphine for treating off-time episodes of Parkinson’s disease. Apomorphine is given by injection. Because it causes severe nausea and vomiting, it must be taken with an anti-nausea drug.
Catechol-O-methyl transferase (COMT) inhibitors increase concentrations of existing dopamine in the brain. Entacapone (Comtan, Stalevo) is the current standard COMT inhibitor. (Stalevo combines entacapone and levodopa into a single pill.) It improves motor fluctuations related to the wearing-off effect and has shown good results in improving on time and reducing the requirements for L-dopa. If the patient does not respond to the drug within 3 weeks, it should be withdrawn. No one should withdraw abruptly from these drugs.
Side Effects. Side effects include:
- Involuntary muscle movements
- Mental confusion and hallucinations
- Cramps, nausea, and vomiting
- Insomnia
- Headache
- Urine discoloration (a harmless side effect but should be reported to the doctor)
- Diarrhea
- Less commonly, constipation, susceptibility to respiratory infection, sweating, dry mouth
Of major concern are reports of a few deaths from liver damage in patients taking the COMT inhibitor tolcapone (Tasmar). The drug has been taken off the market in many countries and is recommended in the U.S. only for patients who cannot tolerate other drugs. Entacapone does not appear to have the same effects on the liver and does not require monitoring. Still, patients should watch out for symptoms of liver damage, including jaundice (yellowish skin), fatigue, and loss of appetite.
Anticholinergics were the first drugs used for PD, but have largely been replaced by dopamine drugs. They are generally used only against tremor in the early stages. They are not as effective against bradykinesia and posture problems and may increase the risk for dementia in late stages. Among the many anticholinergics are trihexyphenidyl (Artane, Trihexy), benztropine (Cogentin), biperiden (Akineton), procyclidine (Kemadrin), and ethopropazine (Parisdol). Orphenadrine (Norflex) is a drug with anticholinergic properties, but is also a muscle relaxant and does not cause urinary retention.
Side effects of Anticholinergics. Anticholinergics commonly cause dryness of the mouth (which can actually be an advantage in some people who experience drooling). Other side effects are nausea, urinary retention, blurred vision, and constipation. These drugs can also increase heart rate and worsen constipation. Anticholinergics can sometimes cause significant mental problems, including memory loss, confusion, and even hallucinations. People with glaucoma should use these drugs cautiously.
Amantadine (Symadine, Symmetrel) stimulates the release of dopamine and may be used for patients with early mild symptoms. It has some benefit against muscle rigidity and slowness and may help some patients in advanced stages who are unresponsive to other drugs. It is less powerful than levodopa and may lose its effectiveness after 6 months. It may also reduce motor fluctuations brought on by levodopa, however, and these benefits appear to persist for at least a year. Large, well-conducted studies are still needed to determine its true benefits and safety.
Side Effects. Side effects are similar to those of anticholinergic drugs and also may include swollen ankles and mottled skin. It can also cause visual hallucinations. Overdose can cause serious and even life-threatening toxicity. Patients with Parkinson's should not withdraw from this drug abruptly. In rare instances, it can cause acute delirium or a life-threatening condition called neuroleptic malignant syndrome. Pregnant or nursing women should not use this drug.
Anticonvulsants. Zonisamide (Zonegran), a drug used to treat epilepsy, is showing promise in treating tremors, motor problems, and involuntary movements in patients with Parkinson’s disease.
Surgery
Surgical procedures are recommended for specific patients with advanced Parkinson’s disease who no longer respond to drug treatments. Surgical treatment cannot cure Parkinson's disease, but it may help control symptoms such as motor fluctuations and dyskinesia. Pallidotomy and thalamotomy are older procedures that destroy tissue in certain parts of the brain. Deep brain stimulation, the current standard surgical practice for Parkinson’s disease, has largely replaced the older operations.
In deep brain stimulation (DBS), also called neurostimulation, an electric pulse generator controls symptoms. The generator is similar to a heart pacemaker. It sends electrical pulses to specific regions of the brain. Candidates for surgery are generally patients who have responded well to levodopa drug treatment. Patients who have had PD for fewer than 16 years may experience greater benefit from DBS than patients who have had the disease longer.
Evidence indicates that DBS improves motor function and reduces dyskinesia best when the procedure targets the subthalamic nucleus (STN) of the brain. Many studies demonstrate the effectiveness of STN stimulation. Procedures that target the globus pallidus interna or ventral intermediate nucleus of the thalamus can also sometimes treat rigidity and tremors. However, there is not yet enough evidence to support stimulation of these parts of the brain.
The procedure is performed as follows:
- The surgeon implants a tiny pulse generator near the collarbone, which is connected to four electrodes that have been implanted in the target area in the brain.
- The generator delivers programmed pulses to this area, which the patient can turn on and off using a magnet held over the skin.
- When on, the pulses suppress symptoms. Complications occur in 2 - 4% of operations. The most serious ones are bleeding in the brain and infection. Depression is common.
When compared to drug therapy, many patients who receive DBS show better improvement in symptoms and quality of life. However, patients who receive neurostimulation may have more serious side effects than those who are treated only with medications. Researchers are also studying whether DBS can benefit patients with earlier-stage Parkinson’s disease.
Pallidotomy and thalamotomy are surgical procedures that destroy brain tissue in regions of the brain associated with Parkinson’s symptoms, such as dyskinesia, rigidity, and tremor. In these procedures, a surgeon drills a small hole in the patient’s skull and inserts an electrode to destroy brain tissue. Pallidotomy targets the global pallidus area. Thalamotomy targets the thalamus. Because these procedures permanently eliminate brain tissue, most experts now recommend deep brain stimulation instead of pallidotomy or thalamotomy.
Surgical complications may include behavioral or personality changes, trouble speaking and swallowing, facial paralysis, and vision problems. Weight gain after surgery is also common.
Scientists are investigating whether stem cells may eventually help treat Parkinson disease. Experimental surgery has shown promise using fetal brain cells rich in dopamine implanted in the substantia nigra area of the brain. Because the use of embryonic stem cells is controversial, researchers are studying alternative types of cells, including stem cells from adult brains and cells from human placentas or umbilical cords. Studies are also using gene therapies and other advanced treatments for transplanting dopamine-producing cells or nerve-protecting cells into the brain. All of this research is still preliminary.
Lifestyle Changes
No special diets or natural foods have been shown to slow down the progression of Parkinson's disease, but there are some dietary recommendations.
Protein. High levels of proteins may affect how much levodopa can reach the brain and may, therefore, reduce the drug's effectiveness. Avoiding protein altogether is not the solution, since malnutrition can result. Most doctors recommend trying to maintain a carbohydrate-to-protein ratio of 7:1 throughout the day. This may be difficult to calculate, and some doctors recommend simply keeping proteins to 12% of total daily calories.
As an aid in calculation, food labels indicate proteins in grams. One gram of protein equals four calories. Good control of protein intake may help minimize fluctuations and wearing-off and may allow some patients to reduce their daily levodopa dosage.
Fruits and Vegetables and Increasing Fiber. Eating whole grains, fresh fruits, and vegetables is the best approach for any healthy life. A diet rich in fruits and vegetables may help protect nerve cell function. Many of these foods are also often rich in fiber, which is particularly important for helping to prevent constipation.
People whose diets have been low in fiber should increase it gradually. It is best to obtain dietary fiber, soluble or insoluble, in the natural form of whole grains, nuts, legumes, fruits, and vegetables. If it proves difficult to do so, psyllium, a grain naturally found in India, is an excellent soluble fiber supplement (Metamucil, Fiberall, Perdiem Fiber). Fluids are particularly important in preventing constipation.
Vitamin E. Researchers have investigated antioxidant vitamins, especially vitamin E, for their effect on the brain. Some studies have reported slower mental decline and lower risk for Parkinson's and Alzheimer's disease in people who ate large amounts of foods rich in vitamin E. Such foods include vegetable oils (particularly wheat germ oil), sweet potatoes, turnip greens, mangos, avocados, nuts, sunflower seeds, and soybeans. Vitamin E supplements, however, do not appear to be helpful for slowing disease progression or improving symptoms.
Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.
The following dietary supplements are being studied for treatment of Parkinson's disease:
- Creatine. Creatine is a nutritional supplement that is sometimes used to improve exercise performance. In 2007, the U.S. National Institutes of Health launched a large-scale clinical trial to study whether creatine can slow the progression of Parkinson’s disease. The trial will enroll patients who have been diagnosed with PD within the last 5 years and who have received levodopa therapy for no more than 2 years.
- Coenzyme Q10 (Ubiquinone). Coenzyme Q10 (also called ubiquinone) is an antioxidant being studied for the treatment of Parkinson's disease. This enzyme is important for cellular energy, which may be impaired in PD. However, a high-quality study was unable to demonstrate a benefit for low dosages of this dietary supplement. Researchers are still investigating whether larger doses given over a long period of time may benefit some patients.
Exercise is an important component of rehabilitation. Physical therapy may help with physical function and quality of life. It usually includes active and passive exercise, gait training, practice in normal activities, and if needed, hot or cold treatments, water therapy, and electrical stimulation. Exercise is also essential for well-being and helps patients maintain productive years. To date, no specific approach has been proven to be better than others.
Exercise Programs. Exercise programs are defined as passive or active.
- Passive exercise, mostly stretching and manipulation of muscles by a physical therapist, is aimed at preventing muscles from shortening. A passive exercise program that begins with slow and gentle exercises and becomes progressively more intense may improve mobility in patients with early and mid-stage Parkinson's disease.
- Active exercises are used to help range-of-motion, coordination, and speed. Patients should continually make efforts to practice movement, even simple ones, such as marching in place, making circular arm movements, and raising the legs up and down while sitting. Patients who enjoy sports or the use of exercise equipment should continue with these activities even if their skills diminish, assuming there are no other medical conditions that would prevent participation.
Gait Training. Practicing new methods for standing, walking, and turning may help retain balance. The following tips may be helpful:
- Take large steps when walking forward, raising the toes at the forward step, and hitting the ground with the heel.
- Take small steps while turning.
- When walking or turning, have the legs 12 - 15 inches apart to provide a wide base.
- Do not wear rubber or crepe-soled shoes because they grip the floor and may cause the patient to fall forward.
- Using devices that keep a rhythmic beat, such a metronome (a simple device used by musicians to keep time), may be very effective, possibly more than music itself, in helping patients to walk faster and take longer steps. One study found that setting a metronome rhythm to about 10% faster than the patient's fastest gait offers significant improvement over walking to no rhythm at all or to a rhythm that matches their gait.
Reducing Muscle Freezing. The patient should practice regular daily activities that simplify actions and reduce the incidence of muscle freezing. Most often, freezing occurs when a patient begins to move or is presented with an obstacle. The following tips may be helpful:
- Rock from side to side.
- If the legs feel frozen, lift the toes. This simple action may free spasm in some cases.
- Hum marching tunes. In fact, music has been shown to help people move and to get out of bed in the morning. Some studies report that wearing a Walkman and turning music on in situations associated with freezing, such as crossing a street, is helpful.
- Divide actions into separate events, which may prevent freezing that occurs from trying to coordinate too many physical operations at one time. For instance, when going through a doorway, approach the door, stop at the door, open it, stop, and then walk through the doorway.
- A cane equipped with a laser pointer may be helpful, at least temporarily.
- Simply being touched by another person can sometimes release the patient (although a patient with PD should never be pulled or pushed).
Mental Tasks. Mental training may increase dopamine in the brain. Some studies indicate that being mentally fit may be as important for patients as being physically fit. Helpful approaches include:
- Select and learn new hobbies that require finger and hand mobility, such as sewing, carpentry, fishing, or playing cards.
- Practice deep breathing and relaxation exercises. These may help maintain proper speech control, control tremor, and reduce anxiety.
- Both the patient and any caregivers should consider psychological therapy and support for depression and loss of motivation. If psychological therapy is too costly, inexpensive support programs and groups are widely available and can be invaluable for the patient and the family.
Speech Therapy. Speech therapy may help those who develop a monotone voice and lose volume, particularly in combination with medications. Therapy is prescribed to help with speech and to evaluate and monitor swallowing.
There are no well-conducted studies comparing specific speech therapies, but the Lee Silverman Voice Treatment (LSVT) appears to be an example of an effective technique. It has five major components:
- Focus on the voice ("think loud/think shout")
- High effort (pushes patients to overcome limitations)
- Intensive treatment (16 sessions in 1 month)
- Calibration (learning to know and accept the amount of effort needed to produce normal sound so it becomes automatic)
- Quantification (continuous feedback to objectively document success)
LSVT may help swallowing as well as speech.
Equipment and Devices. A number of devices can be helpful for maintaining stability and preventing falls. Examples include:
- Rails installed where the patient needs support in getting up or down, such as along the bed and in the bathroom.
- Walkers with locking wheels. (Walkers do not appear to be helpful for freezing.)
- Chairs with straight backs, firm seats, and arm rests.
- Firm mattresses and satin sheets or less expensive sheets with high thread counts. (These are useful for helping patients slide out of bed.)
Resources
- www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
- www.aan.com -- American Academy of Neurology
- www.apdaparkinson.org -- American Parkinson's Disease Association
- www.pdf.org -- Parkinson's Disease Foundation
- www.parkinson.org -- National Parkinson Foundation
- www.michaeljfox.org -- Michael J. Fox Foundation for Parkinson's Research
- www.wemove.org -- Worldwide Education and Awareness for Movement Disorders
- www.parkinsonsaction.org -- Parkinson's Action Network
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Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
