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Parkinson Disease !p@r-kun-sunz-di-!zEz

by Hector A. Gonzalez-Usigli, MD, Alberto Espay, MD

Parkinson disease is a slowly progressive degenerative disorder of the central nervous system (brain and spinal cord). It is characterized by tremor when muscles are at rest (resting tremor), increased muscle tone (stiffness, or rigidity), slowness of voluntary movements, and difficulty maintaining balance (postural instability). In many people, thinking becomes impaired, or dementia develops.

  • Parkinson disease results from degeneration in the part of the brain that helps coordinate movements.

  • Often, the most obvious symptom is tremors that occur when muscles are relaxed.

  • Muscles become stiff, movements become slow and uncoordinated, and balance is easily lost.

  • Doctors base the diagnosis on symptoms.

  • Changes in lifestyle, drugs (such as levodopa plus carbidopa), and sometimes surgery help lessen symptoms, but the disease is progressive, eventually causing severe disability and immobility.

Parkinson disease is the second most common degenerative disorder of the central nervous system after Alzheimer disease. It affects about 1 of 250 people older than 40, about 1 of 100 people older than 65, and about 1 of 10 people older than 80. It commonly begins between the ages of 50 and 79. Rarely, Parkinson disease occurs in children or adolescents.

When the brain initiates an impulse to move a muscle (for example, to lift an arm), the impulse passes through the basal ganglia (collections of nerve cells located deep within the brain). The basal ganglia help smooth out muscle movements and coordinate changes in posture. Like all nerve cells, those in the basal ganglia release chemical messengers (neurotransmitters) that trigger the next nerve cell in the pathway to send an impulse. A key neurotransmitter in the basal ganglia is dopamine . Its overall effect is to increase nerve impulses to muscles. In Parkinson disease, nerve cells in part of the basal ganglia (called the substantia nigra) degenerate, reducing the production of dopamine and the number of connections between nerve cells in the basal ganglia. As a result, the basal ganglia cannot smooth out movements as they normally do, leading to tremor, loss of coordination, slow movement (bradykinesia), a tendency to move less (hypokinesia), and problems with posture and walking.

What causes Parkinson disease is unclear. According to one theory, Parkinson disease may result from abnormal deposits of synuclein (a protein in the brain that helps nerve cells communicate). These deposits, called Lewy bodies, can accumulate in several regions of the brain, particularly in the substantia nigra (deep within the cerebrum) and interfere with brain function. Lewy bodies often accumulate in other parts of the brain and nervous system, suggesting that they may be involved in other disorders. In Lewy body dementia, Lewy bodies form throughout the outer layer of the brain (cerebral cortex). Lewy bodies may also be involved in Alzheimer disease, possibly explaining why about one third of people with Parkinson disease have symptoms of Alzheimer disease.

About 15 to 20% of people with Parkinson disease have relatives who have or have had the disease. Thus, genetics may play a role.

Parkinsonism causes the same symptoms as Parkinson disease but is caused by various other conditions, such as multiple system atrophy, progressive supranuclear palsy, stroke, head injury, or certain drugs (see Parkinsonism).

Did You Know...

  • Many other disorders and drugs can cause symptoms similar to those of Parkinson disease.

  • Parkinson disease is sometimes hard to diagnose in older people because aging causes some of the same symptoms.

Symptoms

Usually, Parkinson disease begins subtly and progresses gradually. In about two thirds of people, tremors are the first symptom. In others, the first symptom is usually problems with movement or a reduced sense of smell.

Parkinson disease typically causes the following symptoms:

  • Tremors: Tremors are coarse and rhythmic. They usually occur in one hand while the hand is at rest (a resting tremor). The tremor is called a pill-rolling tremor because the hand moves as if it is rolling small objects around. The tremor decreases when the hand is moving purposefully and disappears completely during sleep. Emotional stress or fatigue may worsen the tremor. The tremor may eventually progress to the other hand, the arms, and the legs. A tremor may also affect the jaws, tongue, forehead, and eyelids, but not the voice. In some people, a tremor never develops.

  • Stiffness (rigidity): Muscles become stiff, making movement difficult. When a doctor tries to bend the person's forearm back or straighten it out, the arm resists being moved and, when it moves, moves it starts and stops, as it is being ratcheted (called cogwheel rigidity).

  • Slowed movements: Movements become slow and difficult to initiate, and people tend to move less. When they move less, moving becomes more difficult because joints become stiff and muscles weaken.

  • Difficulty maintaining balance and posture: Posture becomes stooped, and balance is difficult to maintain. Thus, people tend to topple forward or backward. Because movements are slow, people often cannot move their hands quickly enough to break a fall.

Walking becomes difficult, especially taking the first step. Once started, people often shuffle, taking short steps, keeping their arms bent at the waist, and swinging their arms little or not at all. While walking, some people have difficulty stopping or turning. When the disease is advanced, some people suddenly stop walking because they feel as if their feet are glued to the ground (called freezing). Other people unintentionally and gradually quicken their steps, breaking into a stumbling run to avoid falling. This symptom is called festination.

Stiffness and decreased mobility can contribute to muscle ache and fatigue. Having stiff muscles interferes with many movements: turning over in bed, getting in or out of a car, and standing up from a deep chair. Usual daily tasks (such as dressing, combing the hair, eating, and brushing the teeth) take longer. Because people often have difficulty controlling the small muscles of the hands, daily tasks, such as buttoning a shirt and tying shoelaces, become increasingly difficult. Most people with Parkinson disease have shaky, tiny handwriting (micrographia) because initiating and sustaining each stroke of the pen is difficult. People may mistakenly think of these symptoms as weakness. However, strength and sensation are usually normal.

The face becomes less expressive (masklike) because the facial muscles that control expression do not move. This lack of expression may be mistaken for depression, or it may cause depression to be overlooked. (Depression is common among people with Parkinson disease.) Eventually, the face can take on a blank stare with the mouth open, and the eyes may not blink often. Often, people drool or choke because the muscles in the face and throat are stiff, making swallowing difficult. People often speak softly in a monotone and may stutter because they have difficulty articulating words.

Parkinson disease also causes other symptoms:

  • Insomnia is common, often because people need to urinate frequently or because symptoms worsen during the night, making turning over in bed difficult. Rapid-eye-movement (REM) sleep behavior disorder commonly develops. In this disorder, the limbs, which normally do not move in REM sleep, may move suddenly and violently, sometimes injuring a bed partner. Lack of sleep may contribute to depression and drowsiness during the day.

  • Urination may be difficult to start and to maintain (called urinary hesitancy).

  • Constipation can develop because the intestine may move its contents more slowly. Inactivity and levodopa, the main drug used to treat Parkinson disease, can worsen constipation.

  • A sudden, excessive decrease in blood pressure may occur when a person stands up (orthostatic hypotension).

  • Scales (seborrheic dermatitis) develop often on the scalp and face and occasionally in other areas.

  • Loss of smell (anosmia) is common, but people may not notice it.

  • Dementia develops in about one third of people with Parkinson disease. In many others, thinking is impaired, but people may not recognize it.

Diagnosis

The diagnosis is likely if people have fewer, slow movements and either the characteristic tremor or muscle rigidity. Mild, early disease may be difficult for doctors to diagnose because it usually begins subtly. Diagnosis is especially difficult in older people because aging can cause some of the same problems as Parkinson disease, such as loss of balance, slow movements, muscle stiffness, and stooped posture. Sometimes essential tremor is misdiagnosed as Parkinson disease.

To exclude other causes of the symptoms, doctors ask about previous disorders, exposure to toxins, and use of drugs that could cause parkinsonism.

During the physical examination, doctors ask people to do certain movements, which can help confirm the diagnosis. For example, in people with Parkinson disease, the tremor disappears or lessens when doctors ask them to touch their nose with their finger. Also, people with the disease have difficulty performing rapidly alternating movements, such as placing their hands on their thighs, then rapidly turning their hands over back and forth several times.

No tests or imaging procedures can directly confirm the diagnosis. However, computed tomography (CT) and magnetic resonance imaging (MRI) may be done to look for a structural disorder that may be causing the symptoms. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) can detect brain abnormalities typical of the disease. However, SPECT and PET are currently used only in research facilities and do not distinguish Parkinson disease from other disorders that cause the same symptoms (parkinsonism).

If the diagnosis is unclear, doctors may give the person levodopa, a drug used to treat Parkinson disease. If levodopa results in clear improvement, Parkinson disease is likely.

Treatment

General measures used to treat Parkinson disease can help people function better. Many drugs (such as levodopa plus carbidopa) can make movement easier and enable people to function effectively for many years. But no drug can cure the disease. Two or more drugs may be needed. For older people, doses are often reduced. Drugs that cause or worsen symptoms, particularly antipsychotic drugs, are avoided.

Surgery is considered if people have advanced disease but no dementia nor psychiatric symptoms and drugs are ineffective or have severe side effects.

General measures

Various simple measures can help people with Parkinson disease maintain mobility and independence:

  • Continuing to do as many daily activities as possible

  • Following a program of regular exercise

  • Simplifying daily tasks—for example, having buttons on clothing replaced with Velcro fasteners or buying shoes with Velcro fasteners

  • Using assistive devices, such as zipper pulls and button hooks

Physical therapists (see Physical Therapy (PT)) and occupational therapists (see Occupational Therapy (OT)) can help people learn how to incorporate these measures into their daily activities, as well as recommend exercises to improve muscle tone and maintain range of motion. Therapists may also recommend mechanical aids, such as wheeled walkers, to help people maintain independence.

Simple changes around the home can make it safer for people with Parkinson disease:

  • Removing throw rugs to prevent tripping

  • Installing grab bars in bathrooms and railings in hallways and other locations to reduce the risk of falling

For constipation, the following can help:

  • Consuming a high-fiber diet, including such foods as prunes and fruit juices

  • Exercising

  • Drinking plenty of fluids

  • Using stool softeners (such as senna concentrate), supplements (such as psyllium), or stimulant laxatives (such as bisacodyl taken by mouth) to keep bowel movements regular

Difficulty swallowing may limit food intake, so the diet must be nutritious. Making an effort to sniff more deeply may improve the ability to smell, enhancing the appetite.

Levodopa/carbidopa

Traditionally, levodopa, which is given with carbidopa, is the first drug used. These drugs, taken by mouth, are the mainstay of treatment for Parkinson disease. But when taken for a long time, levodopa may have side effects and become less effective. So some experts have suggested that using other drugs first and delaying use of levodopa might help. However, evidence now indicates that the side effects and reduced effectiveness after long-term use probably occur because Parkinson disease is worsening and are not related to when the drug was begun. Still, because levodopa may become less effective after several years of use, doctors may prescribe another drug for people under 60, who will be taking drugs to treat the disease for a long time. Other drugs that may be used include amantadine and dopamine agonists (drugs that act like dopamine, stimulating the same receptors on brain cells). Such drugs are used because production of dopamine is decreased in Parkinson disease.

Levodopa reduces muscle stiffness, improves movement, and substantially reduces tremor. Taking levodopa produces dramatic improvement in people with Parkinson disease. The drug enables many people with mild disease to return to a nearly normal level of activity and enables some people who are confined to bed to walk again. Levodopa rarely helps people who have other disorders that can cause symptoms similar to those of Parkinson disease (parkinsonism), such as multiple system atrophy and progressive supranuclear palsy.

Levodopa is a dopamine precursor. That is, it is converted into dopamine in the body. Conversion occurs in the basal ganglia, where levodopa helps compensate for the decrease in dopamine due to the disease. However, some of the drug is converted to dopamine by an enzyme in the blood before it reaches the brain. Having dopamine in the blood increases the risk of side effects such as nausea and flushing. Carbidopa is given with levodopa to prevent levodopa from being converted to dopamine in the blood. When levodopa and carbidopa are given together, a lower dose of levodopa can be used, and nausea and flushing occur less often and are less severe.

To determine the best dose of levodopa for a particular person, doctors must balance control of the disease with the development of side effects, which may limit the amount of levodopa the person can tolerate. These side effects include involuntary movements (of the mouth, face, and limbs) called dyskinesias, as well as nightmares, hallucinations, and changes in blood pressure.

After taking levodopa for 5 or more years, more than half the people begin to alternate rapidly between a good response to the drug and no response—called on-off effects. Within seconds, they may change from being fairly mobile to being severely impaired and immobile. The periods of mobility after each dose become shorter, and symptoms may occur before the next scheduled dose—the off effects. Also, symptoms may be accompanied by involuntary movements due to levodopa use, including writhing or hyperactivity. Taking lower, more frequent doses controls these effects for a while. Other options are switching to a form of levodopa that is released more gradually into the blood (a controlled-release formulation) or adding a dopamine agonist or amantadine. However, after 15 to 20 years, these effects become hard to suppress. Surgery is then considered.

Other drugs

Other drugs are generally less effective than levodopa, but they may benefit some people, particularly if levodopa is not tolerated or is insufficient.

Dopamine agonists, which act like dopamine , may be useful at any stage of the disease. They include pramipexole and ropinirole (given by mouth), rotigotine (given through a skin patch), and apomorphine (injected under the skin). Because apomorphine is quick-acting, it is used to reverse the off effects of levodopa—when movement is difficult to initiate. Thus, this drug is called rescue therapy. It is usually used when people freeze in place, preventing them, for example, from walking. Affected people or another person (such as a family member) can inject the drug up to 5 times a day as needed.

Rasagiline and selegiline belong to a class of drugs called monoamine oxidase inhibitors (MAO inhibitors—see Table: Drugs Used to Treat Depression). They prevent the breakdown of dopamine , thereby prolonging dopamine ’s action in the body. Theoretically, if taken with certain foods (such as certain cheeses), beverages (such as red wine), or drugs, MAO inhibitors can have a serious side effect called hypertensive crisis (see Table: Some Drug-Food Interactions). However, this effect is unlikely when Parkinson disease is being treated because the doses used are low and the type of MAO inhibitor used (MAO type B inhibitors) is less likely to have this effect.

Catechol O -methyltransferase (COMT) inhibitors (entacapone and tolcapone) slow the breakdown of levodopa and dopamine , prolonging their effects, and therefore appear to be a useful supplement to levodopa. These drugs are used only with levodopa. Tolcapone is seldom used because rarely, it damages the liver. However, tolcapone is stronger than entacapone and may be more useful if off effects are severe or long-lasting.

Some drugs with anticholinergic effects (see Anticholinergic: What Does It Mean?), such as benztropine and trihexyphenidyl, are effective in reducing the severity of a tremor and can be used in the early stages of Parkinson disease. They are particularly useful for very young people whose most troublesome symptom is a tremor. These drugs can also be used in the later stages to supplement levodopa. They may reduce tremor because they block the action of acetylcholine, and tremor is thought to be caused by an imbalance of acetylcholine (too much) and dopamine (too little). Other drugs with anticholinergic effects, including some antihistamines and tricyclic antidepressants, are mildly effective and may be used to supplement levodopa. However, because these drugs are only mildly effective and because many anticholinergic effects are troublesome (especially in older people), these drugs, except for benztropine and trihexyphenidyl, are seldom used to treat Parkinson disease. These side effects include confusion, drowsiness, dry mouth, blurred vision, dizziness, constipation, difficulty urinating, and loss of bladder control.

Amantadine, a drug sometimes used to treat influenza, may be used alone to treat mild Parkinson disease or as a supplement to levodopa. Amantadine probably has many effects that make it work. For example, it stimulates nerve cells to release dopamine . It is used most often to help control the involuntary movements that are side effects of levodopa.

Propranolol, a beta-blocker, may be used to reduce the severity of a tremor if the tremor is worsened by holding a limb in a position that requires resisting the pull of gravity (for example, holding the arms outstretched).

Drugs Used to Treat Parkinson Disease

Drug

Some Side Effects

Comments

Dopamine precursor

Levodopa (given with carbidopa)

For levodopa: Involuntary movements (of the mouth, face, and limbs), nightmares, low blood pressure when a person stands up (orthostatic hypotension), constipation, nausea, drowsiness, confusion, hallucinations, palpitations, and flushing

If these drugs are suddenly stopped, neuroleptic malignant syndrome (with high fever, high blood pressure, muscle stiffness, muscle damage, and coma), which can be life threatening

This combination is the mainstay of treatment. Carbidopa helps increase the effectiveness of levodopa and reduce its side effects. After several years, the effectiveness of the combination may lessen.

Dopamine agonists

Pramipexole

Ropinirole

Drowsiness, nausea, orthostatic hypotension, involuntary movements, confusion, obsessive-compulsive behavior, new or increased urges (eg, gambling), and hallucinations

When these drugs are suddenly stopped, neuroleptic malignant syndrome

Early in the disease, these drugs may be used alone or with small doses of levodopa to possibly delay levodopa’s side effects. Later in the disease, dopamine agonists are useful when the on-off effects of levodopa make it less effective. These drugs are especially useful in people under 65.

Apomorphine

Severe nausea, vomiting, and lumps (nodules) under the skin at the injection site

This quick-acting drug is injected under the skin. It is used as rescue therapy to reverse the off effects of levodopa.

Rotigotine

Drowsiness, nausea, orthostatic hypotension, confusion, obsessive-compulsive behavior, new or increased urges (eg, gambling), hallucinations, weight gain (possibly due to fluid retention), and sometimes skin irritation where the patch is applied

This drug is available as a skin patch. It is used alone, early in the disease. The patch is worn continuously for 24 hours, then removed and replaced. The patch should be placed in different locations each day to reduce risk of skin irritation.

MAO-B inhibitors

Rasagiline

Nausea, insomnia, drowsiness, and swelling due to fluid accumulation (edema)

Rasagiline can be used alone to postpone the use of levodopa but is often given as a supplement to levodopa. At best, rasagiline is modestly effective.

Selegiline

When given with levodopa, worsening of levodopa's side effects, including nausea, confusion, insomnia, and involuntary movements

Selegiline can be used alone to postpone the use of levodopa but is often given as a supplement to levodopa. At best, selegiline is modestly effective.

COMT inhibitors

Entacapone

Tolcapone

When given with levodopa, worsening of levodopa's side effects, including nausea, confusion, and involuntary movements

Diarrhea, back pain, and orange urine

With tolcapone, risk of liver damage

These drugs can be used to supplement levodopa late in the disease and to extend the interval between doses of levodopa. They are used only with levodopa.

When tolcapone is used, doctors periodically do blood tests to evaluate how well the liver is functioning and whether it is damaged (liver function tests)

Drugs with anticholinergic effects *

Benztropine

Trihexyphenidyl

Tricyclic antidepressants (such as amitriptyline), used if depression also needs to be treated

Some antihistamines (such as diphenhydramine)

Drowsiness, confusion, dry mouth, blurred vision, dizziness, constipation, difficulty urinating, loss of bladder control, and impaired regulation of body temperature

These drugs may be given alone in the early stages of the disease or as a supplement to levodopa in the later stages. They can reduce tremor but do not affect slow movements or relieve muscle stiffness.

Antiviral drug

Amantadine

Nausea, dizziness, insomnia, anxiety, confusion, edema, difficulty urinating, worsening of glaucoma, and mottled discoloration of the skin due to dilated blood vessels (livedo reticularis)

Rarely, when the drug is stopped or the dose is reduced, neuroleptic malignant syndrome

Amantadine is used alone in the early stages for mild disease but may become ineffective after several months. Later, it is used to supplement levodopa and to lessen involuntary movements due to levodopa.

Beta-blocker

Propranolol

Spasm of the airways (bronchospasm), an abnormally slow heart rate (bradycardia), heart failure, low blood pressure, increased blood sugar levels, impaired peripheral circulation, insomnia, fatigue, shortness of breath, depression, vivid dreams, hallucinations, and sexual dysfunction

Propranolol can be used to reduce the severity of tremors worsened by holding a limb in a position that requires resisting the pull of gravity (postural tremors).

If propranolol increases blood sugar levels, detecting low blood sugar levels after insulin injections may be difficult.

*Drugs with anticholinergic effects are seldom used to treat Parkinson disease because they are only mildly effective and have troublesome side effects.

MAO-B = monoamine oxidase type B; COMT = catechol O -methyltransferase.

Deep brain stimulation

People with involuntary movements due to long-term use of levodopa may benefit from deep brain stimulation. Tiny electrodes are surgically implanted in part of the basal ganglia. By stimulating this part, deep brain stimulation often greatly reduces involuntary movements and tremors and shortens the off part of the on-off effects.

Stem cells

Transplantation of stem cells into the brain, once thought to be a possible treatment for Parkinson disease, has been shown to be ineffective and to have troublesome side effects.

Caregiver and end-of-life issues

Because Parkinson disease is progressive, people eventually need help with normal daily activities, such as eating, bathing, dressing, and toileting. Caregivers can benefit from learning about the physical and psychologic effects of Parkinson disease and about ways to enable people to function as well as possible. Because such care is tiring and stressful, caregivers may benefit from support groups.

Eventually, most people with Parkinson disease become severely disabled and immobile. They may be unable to eat, even with assistance. Dementia develops in about one third of them. Because swallowing becomes increasingly difficult, death due to aspiration pneumonia (a lung infection due to inhaling fluids from the mouth or stomach) is a risk. For some people, a nursing home may be the best place for care. Before people with this disease are incapacitated, they should establish advance directives, indicating what kind of medical care they want at the end of life (see Advance Directives).

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Resources In This Article

Drugs Mentioned In This Article

  • Generic Name
    Select Brand Names
  • No US brand name
  • LODOSYN
  • DULCOLAX
  • COMTAN
  • INDERAL
  • MIRAPEX
  • COGENTIN
  • AZILECT
  • ELDEPRYL
  • NEUPRO
  • REQUIP
  • APOKYN