Parkinson's disease

Definition:

Parkinson's disease (PD) is a slowly progressive neurological disorder that affects movement, muscle control, and balance.

Parkinson’s disease is part of a group of conditions called motor system disorders, which are associated with the loss of dopamine-producing brain cells.

These dopamine-associated motor disorders are referred to as parkinsonisms.

Parkinson's Disease and Dopamine Loss

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 tissue located in both sides of the brain.

• There the cells release essential neurotransmitters that help control movement and coordination.

• 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 deficiency is the hallmark feature in PD.

• Dopamine 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.

Causes The exact cause of Parkinson's disease is unknown. Scientists

think that Parkinson's is probably due to a combination of genetic and environmental factors.

• Genetic Factors 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 Factors Environmental factors alone are probably not a cause of

Parkinson's disease, but they may trigger the condition in people who are genetically susceptible.

Some evidence implicates pesticides and herbicides as possible factors in some cases of Parkinson's disease. A higher incidence of parkinsonism has long been observed in people who live in rural areas, particularly those who drink private well water or are agricultural workers.

Risk Factors• Age 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.

• Gender Parkinson’s disease is more common in men than in women.

• Family History 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.

• Race and Ethnicity African- and Asian-Americans appear to have a lower risk than

Caucasians.

Possible Protective Factors Both smoking and coffee drinking have been associated with a

lower risk for PD.

• Smoking and Nicotine Replacement. Cigarette smokers appear to have a 40% lower risk for Parkinson's disease, indicating possible protection by nicotine. This finding, of course, is no excuse to smoke. Studies on nicotine replacement as a treatment for Parkinson’s have been few and have not provided any strong evidence that nicotine therapy provides benefits.

• Coffee Consumption. Some 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 muscle 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.

Parkinson's disease can seriously impair the quality of life in any age group.

In addition to motor symptoms (motion difficulties, tremors) Parkinson’s can cause various non-motor problems that have physical and emotional impacts on patients and their families.

Swallowing Problems

Swallowing problems (dysphagia) are sometimes associated with shorter survival time.

Motor impairment of the muscles in the throat not only impairs chewing and swallowing, which can lead to malnourishment, but also poses a risk for aspiration pneumonia.

Emotional and Behavioral Problems

• Depression is very common in patients with Parkinson's.

• The disease process itself causes changes in chemicals in the brain that affect mood and well-being.

• Anxiety is also very common and may present along with depression.

• 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

Cognitive and Memory Problems

Impaired Thinking (Cognitive Impairment).

• Defects in thinking, language, and problem solving skills may occur early on or later in the course of the disease.

• These problems can occur from the disease process or from side effects of medications used to treat Parkinson’s.

• 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 occurs in about two-thirds of patients with Parkinson’s,

especially in those who developed Parkinson’s after age 60.

• Dementia is significant loss of cognitive functions such as memory, judgment, attention, and abstract thinking.

• 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 as a side effect of dopamine medication.) Unlike in Alzheimer's, language is not usually affected in Parkinson's-related dementia.

Sleep Disorder• Excessive daytime sleepiness, insomnia, and other

sleep disorders are common in PD, both from the disease itself and the drugs that treat it.

• Bladder problems can also contribute to sleep disturbances.

• Many patients also suffer from nighttime leg cramps and restless legs syndrome.

• Some of the medications used for Parkinson's may cause vivid dreams as well as waking hallucinations.

Sexual Dysfunction• Although Parkinson's disease and its treatments can cause

compulsive sexual behavior, the disease can also cause a loss of sexual desire in both men and women.

• For men, erectile dysfunction can be a complication of Parkinson’s.

Bowel and Bladder Complications• Constipation is a common complication of Parkinson’s

disease. • It is often caused by muscle weakness that can slow down

the action of the digestive system. • Weakness in pelvic floor muscles can also make it difficult to

defecate.• Patients with Parkinson’s disease frequently experience

urinary incontinence, including increased urge and frequency. • Parkinson’s can also cause urinary retention (incomplete

emptying of the bladder).

Sensory Problems

• Decreased Sense of Smell. Many patients experience an impaired sense of smell.

• Vision Problems. Vision may be affected, including impaired color perception and contrast sensitivity.

• Pain. Painful symptoms associated with Parkinson’s disease include muscle numbness, tingling, and aching.

• Pain in Parkinson’s is often a result of dystonia, involuntary muscle contractions and spasms that can cause twisting and jerking.

Symptoms

TremorsParkinson's disease (PD) symptoms often start with tremor,

which may occur in the following ways:

• Tremors may be only occasional at first, 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.

• About a quarter of patients with Parkinson’s do not develop tremor.

Motion and Motor ImpairmentA number of PD symptoms involve motor impairment caused by

the abnormalities in the brain nerves 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 small.

• Normally spontaneous muscle movements, such as blinking, may need to be done consciously.

• Patients may develop speech problems, including soft voice or slurred speech.

Other Symptoms of Parkinson's Disease• Parkinson’s disease also causes non-motor

symptoms including sleep problems, gastrointestinal and urinary disorders, sexual dysfunction, decreased sense of smell, and depression and anxiety.

• Sialorrhea (drooling) is a common and bothersome symptom for those with Parkinson's disease.

• It can cause chapped skin and lips around the mouth, dehydration, an unpleasant odor, and social embarrassment.

Diagnosis• Parkinson’s disease can be difficult to diagnose in its

early stages.

• Doctors base their diagnosis on the patient’s medical history and symptoms evaluated during a neurological exam.

• No laboratory or imaging tests can diagnose Parkinson’s, although brain scans such as computed tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomographic (PET) may be used to rule out other neurological disorders.

Medical History• A medical and personal history should include any relevant

symptoms as well as any medications taken, and information on other conditions the patient may have.

Neurological ExamIn a neurological exam, the doctor will ask the patient to sit, stand,

walk, and extend arms. The doctor will observe the patient’s balance and coordination. Parkinson's may be suspected in patients who have at least two of

the following four symptoms, especially if they are more obvious on one side of the body:

• Tremor (shaking) when the limb is at rest • Slowness of movement (bradykinesia) • Rigidity, stiffness, or increased resistance to movement in the

limbs or torso • Poor balance (postural instability)

Drug Challenge Test• A levodopa challenge test may confirm a diagnosis of

Parkinson's disease. • If patients' symptoms improve when they take levodopa, they

likely have Parkinson's, ruling out other neurological diseases.

Tests for Depression and Dementia• 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.

Ruling out Conditions that Mimic Parkinson's DiseaseParkinsonism Plus Syndromes. Parkinson’s disease is the most

common type of parkinsonism. Parkinsonism refers to a group of movement disorders that share similar symptoms with Parkinson’s disease, but also have unique symptoms of their own. About 15% of parkinsonism cases are due to conditions called Parkinson’s plus syndromes (PPS) or atypical parkinsonism. These syndromes include:

• Corticobasal degeneration. Marked by apraxia (inability to perform coordinated movements or use familiar objects), stiffness that is more severe than typical Parkinson’s disease, and twitching or jerking in the hand.

• Lewy body dementia. One of the most common types of progressive dementia. Symptoms include visual hallucinations and loss of spontaneous movement.

• Multiple system atrophy. Symptoms include fainting, constipation, erectile dysfunction, urinary retention, and loss of muscle coordination.

• Progressive supranuclear palsy. Marked by frequent falls, personality changes, and difficulty focusing the eyes.

• Patients with PPS often have earlier and more severe dementia than those with Parkinson’s disease.

• In addition, they do not usually respond to medications that are used to treat Parkinson’s disease.

• Other Neurologic Conditions. Many medical conditions may cause some symptoms of Parkinson's disease and parkinsonism. Hardening of the arteries (arteriosclerosis) in the brain can cause multiple small strokes, which can produce loss of motor control. Alzheimer’s disease can share similar symptoms with Parkinson’s and the conditions can exist together.

• Medications. A number of drugs, including antipsychotic and antiseizure medications, can cause Parkinson’s symptoms.

Treatment There is no cure for Parkinson’s disease but drugs, physical

therapy, and surgical interventions can help control symptoms and improve quality of life.

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 condition. 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 proven to change the course of the disease.

• For early disease with little or no impairment, drug therapy 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, • side effect profile,• loss of effectiveness over time,• and other considerations.

Treatments for Onset of Parkinson's DiseaseThe 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.

•These drugs include pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel).

Monoamine oxidase B (MAO-B) inhibitor

•Selegiline (Eldepryl) and Rasagiline (Azilect).• Selegiline is a monoamine oxidase B (MAO-B) inhibitor that may have some mild benefit as an initial therapy.

•Rasagiline (Azilect) is another MAO-B inhibitor used for treatment of Parkinson’s.

Treatments for Off Time 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.

The American Academy of Neurology (AAN) recommends the following drugs as best 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.

• Other dopamine agonists, such as ropinirole (Requip) and pramipexole (Mirapex), and the COMT inhibitor tolcapone (Tasmar) may also be helpful for treating off-time symptoms.

• Deep brain stimulation is a surgical treatment that may help improve motor fluctuations in some patients.

Treatments for Other Symptoms of Parkinson'sConditions associated with non-motor impairment

symptoms of Parkinson's disease may need a variety of treatments.

Depression. • 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 psychotic symptoms.

Dementia.

• The cholinesterase inhibitor drugs donepezil (Aricept) and rivastigmine (Exelon) are used to treat Alzheimer’s disease and are sometimes used for Parkinson’s.

• The benefit from these drugs is often small, and patients and their families may not notice much change.

Daytime Sleepiness and Fatigue.

• Modafinil (Provigil), a drug used to treat narcolepsy may be helpful for patients with sleepiness related to their disease.

• Methylphenidate (Ritalin) may be considered for patients who experience fatigue.

Erectile Dysfunction. • Sildenafil (Viagra) can be helpful for men with Parkinson's

disease who suffer from erectile dysfunction.

• However, the drug may worsen orthostatic hypotension (lightheadedness or dizziness that occurs when suddenly standing up), a side effect of some PD medications.

Constipation. • Laxatives that contain macrogol (polyethylene glycol) may be

helpful for improving constipation..• Drooling. Glycopyrrolate, scopolamine, and botulinum toxin may

be used to relieve drooling symptoms.

Treating Advanced Disease• Advanced Parkinson’s disease poses challenges for both patients

and caregivers.

• Eventually, symptoms such as stooped posture, freezing, and speech difficulties may no longer respond to drug treatment.

• Surgery (deep brain stimulation) may be considered for some

patients.

• Patients become increasingly dependent on others for care and require assistance with daily tasks.

• Modifications (wheelchair ramps, grab bars and handrails) may need to be made in the home.

• Some patients may need to move to an assisted living facility or nursing home.

• The goal of treatment for advanced Parkinson’s disease should be on providing patients with safety, comfort, and quality of life.

• 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.

Dosages vary, although the preparation is usually taken in three or four divided doses per day

Indications of Early Treatment Success or FailuresIn 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

Side EffectsThe toxic effects of levodopa with or without carbidopa are

considerable.Physical Side Effects. The physical side effects include:• Dyskinesia. Dyskinesia (the inability to control muscles) is a very

distressing side effect of levodopa• hypotension. Low blood pressure is a common problem during the

first few weeks, particularly if the initial dose is too high. • 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.

The Wearing-Off Effect and Dyskinesia (Inability to Control Muscles)Within 4 - 6 years of treatment with levodopa, the effects of the drug in many patients

begin to last for shorter periods of time after a dose (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

• Patients must increase the frequency or the dose of levodopa. This puts them at risk for dyskinesia (the inability to control muscles), which usually occurs when the drug level peaks.

• In some people, L-dopa eventually becomes effective only for 1 - 2 hours, and 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.)

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 used 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) may control fluctuations for some patients.

Other MedicationsMonoamine Oxidase B (MAO-B) Inhibitors• 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.

• A newer MAO-B inhibitor, rasagiline (Azilect), 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.

Side 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 many antidepressants. 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. While taking selegiline or rasagiline, and for 2 weeks after stopping medication, patients should avoid foods such as aged cheeses, processed lunch meats, pickled herring, yeast extract, aged red wines, draft beers, 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 doctors 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• 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.

• 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 (difficulty controlling muscle movements) can also occur with dopamine agonists. There is debate about the value of dopamine agonists as initial therapy for Parkinson’s disease. Recent research suggests that early treatment with dopamine agonists may not provide any long-term advantages compared with starting treatment with L-dopa

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.

Other Dopamine Agonists.• Specific dopamine agonists that contain ergot alkaloids

include bromocriptine (Parodel), pergolide (Permax) and lisuride (Dopergin).

• Bromocriptine is the only ergot dopamine agonist approved for Parkinson's treatment in the United States.

• 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.

It is FDA-approved 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

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 may 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.

• The FDA is currently investigating whether Stavelo increases the risk of prostate cancer.

Anticholinergic Drugs

• Anticholinergics were the first drugs used for PD, but have largely been replaced by dopamine drugs.

• They are generally used only to control 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. • 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 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 with caution.

• Amantadine

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.

Side Effects. • Side effects are similar to those of anticholinergic

drugs and may include swollen ankles and mottled skin.

• Amantadine 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.

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.

Deep Brain Stimulation• 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.

• 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. These side effects include infection at the surgical site and nervous system, psychiatric, and heart disorders. Researchers are also studying whether DBS can benefit patients with earlier-stage Parkinson's disease.

Pallidotomy and Thalamotomy

• 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.

Stem Cell Implantation• 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.

• All of this research is still preliminary.

Lifestyle Changes• Dietary Factors• No special diets or natural foods have been shown to slow 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.

• 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.

• Dietary fiber is the part of food that is not affected by the digestive process in the body. Only a small amount of fiber is metabolized in the stomach and intestine, the rest is passed through the gastrointestinal tract and makes up a part of the stool. There are two types of dietary fiber, soluble and insoluble. Soluble fiber retains water and turns to gel during digestion. It also slows digestion and nutrient absorption from the stomach and intestine. Soluble fiber is found in foods such as oat bran, barley, nuts, seeds, beans, lentils, peas, and some fruits and vegetables. Insoluble fiber appears to speed the passage of foods through the stomach and intestines and adds bulk to the stool. It is found in foods such as wheat bran, vegetables, and whole grains. Fiber is very important to a healthy diet and can be a helpful aid in weight management. One of the best sources of fiber comes from legumes, the group of food containing dried peas and beans.

• 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, (found in products such as Metamucil), is an excellent soluble fiber supplement.

• Drinking lots of fluids is particularly important in preventing constipation.

Herbs and Supplements• 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 help some patients.

Rehabilitation Therapies• 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, and practice in normal activities.

• To date, no specific exercise approach has been proven to be better than others.