2 parkinson disease

8/7/2019 2 Parkinson Disease

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Introduction

Parkinson's disease (PD) was first described in 1817 by James Parkinson, in "An Essay on theShaking Palsy." It is a neurodegenerative disease, meaning it is caused by degeneration

(dysfunction and death) of neurons within the brain. PD causes motor (movement) and nonmotor

symptoms.

PD is believed to affect approximately one million people in the United States. Misdiagnosis of

PD is common, however, so this figure is not precise. The likelihood of developing PD increases

with age. PD typically begins in a person's 50s or 60s, and slowly progresses with increasing age.The average age of onset is 62.4 years. Onset before age 30 is rare, but up to 10% of cases begin

by age 40.

While no treatments have yet been shown conclusively to slow the disease, a large number of

drugs are available to treat symptoms, as well as several forms of surgery and numerousnonpharmacological (non-drug) approaches.

Symptoms

The cardinal motor symptoms are slowed movements (called bradykinesia), resting tremor

(shaking in an arm or leg when it is not being moved), muscle rigidity (stiffness), and posturalinstability. Other symptoms are listed in the Box below. Symptoms typically begin on one side

of the body (unilateral) and progress to include both sides.

Symptoms of Parkinson's Disease

(Not all people with PD develop all these symptoms.)

Motor Symptomso Tremoro Bradykinesiao Rigidity and freezing in placeo Stooped, shuffling gaito Decreased arm swing when walkingo Difficulty arising from a chairo Micrographia (small handwriting)o Lack of facial expressiono Slowed activities of daily livingo Postural instabilityo Difficulty turning in bed


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Nonmotor Symptomso Diminished sense of smello Low voice volumeo Painful foot crampso Sleep disturbanceo Depressiono Constipationo Droolingo Increased sweatingo Urinary frequency/urgencyo Male erectile dysfunction

The Substantia Nigra in PD

The substantia nigra (literally meaning "black substance") is a small region in the brain stem, justabove the spinal cord. It is one of the centers that help control movements. Cells within the

substantia nigra (SN) produce and release a chemical called dopamine. Dopamine is aneurotransmitter that controls movement and balance and is essential to the proper functioning of

the central nervous system (CNS). Dopamine assists in the effective communication

(transmission) of electrochemical signals from one nerve cell (neuron) to another. Dopaminereleased by SN neurons lands on the surface of neurons in other brain centers, controlling their

activities or "firing" and thus regulating movement. The main target regions of dopamine release

from the substantia nigra are called the caudate and the putamen.

In PD, cells of the SN degenerate, and therefore can no longer produce adequate dopamine.

When this occurs, neurons elsewhere in the brain are no longer well regulated and do not behavein a normal manner. This results in a loss of control of movements, leading to slowed

movements, tremor, and rigidity.

A principal aim of PD therapy is to replace the brain's supply of dopamine with the drug

levodopa, which the brain uses to make more dopamine. Alternatively, drugs called dopamine

agonists can mimic dopamine's effects on its target cells (in the caudate and the putamen).

Risk Factors and Protective Factors

The single biggest risk factor for PD is advancing age. Men have a slightly higher risk compared

to women. Family history is also an important risk factor. Individuals with an affected first-

degree relative (parent or sibling) are estimated to have an approximately doubled risk fordeveloping PD. This increased risk is likely to be a combination of environmental and genetic

factors that close relations have on common.


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The single factor that has been most consistently associated with a reduced risk of PD is cigarette

smoking, which has been demonstrated in numerous studies. It is not known whether smokingconfers a genuine protective effect, or whether individuals who are prone to develop PD for other

reasons are also prone to avoid smoking. Nonetheless, the negative impact on general health

from smoking is enormous, far in excess of any slight reduction in risk for PD. Smoking cannot

be recommended as a strategy for avoiding PD.

Caffeine consumption is also associated with a reduced incidence of PD. In women, hormone

replacement therapy appears to be associated with a reduced incidence in women who consume

only small quantities of caffeine, but may be a risk factor in those who consume more than five

cups per day.

Environmental Causes of PD

The vast majority of cases of PD are thought to be due to the potential interactions of genes and

the environment. Environmental causes are presumed to be one or more widely present but weaktoxins. The effects of these toxins may build up over time and eventually lead to disease in

genetically predisposed individuals. The identity of these toxins is unknown, although several

environmental risk factors have been identified through epidemiological studies.

A strong and consistent finding is that the risk of PD is increased by rural living, exposure to

well water, and agricultural work, suggesting that pesticides or herbicides may cause or

contribute to PD. It should be pointed out, however, that these individual factors do not by anymeans guarantee the development of PD, nor does their absence protect against it; there are many

cases of individuals with none of these risk factors who develop PD, and many with them whodo not.

Genetics

There are several genes that are known to cause PD, but they account for a very small minority

of cases. The most important is a gene called parkin. The parkin gene creates a protein, alsocalled parkin that helps to break down defective proteins inside brain cells (neurons). When the

parkin gene is altered, or mutated, this function is impaired. It is hypothesized that theaccumulation of defective proteins contributes to death of neurons. Two mutated copies of parkin

are needed to develop PD. This type of inheritance pattern is called "autosomal recessive." Onecopy of the defective gene is inherited from each parent. Parkin mutations cause young-onset

PD, with symptoms beginning usually in the 40s. Parkin mutations are the most common genetic

cause of PD, but still account for less than one percent of all cases.


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Other known genes for PD include alpha-synuclein, DJ-1, PINK-1, and UCHL-1, but altogether

these represent only a small number of PD cases.

Diagnosis

Since there is no specific test or marker for PD, diagnosis is by a physician and depends on thepresence of at least two of the three major signs: tremor at rest, rigidity, and bradykinesia, as wellas the absence of a secondary cause, such as antipsychotic medications or multiple small strokes

in the regions of the brain controlling movement. Patients tend to be most aware of tremor and

bradykinesia, and less so of rigidity.

To diagnose PD, the physician will perform a standard neurological examination, involving

various simple tests of reactions, reflexes, and movements.

Bradykinesia is tested by determining how quickly the person can tap the finger and thumbtogether, or tap the foot up and down.

Tremor is determined by simple inspection. The physician assesses rigidity by moving the neck, upper limbs, and lower limbs while the

patient relaxes, feeling for resistance to movement.

Postural instability is tested with the "pull test," in which the examiner stands behind thepatient and asks the patient to maintain their balance when pulled backwards. The examiner

pulls back briskly to assess the patient's ability to recover, being careful to prevent the patient

from falling.

The examination also involves recording a careful medical history, especially for exposure tomedications that can block dopamine function in the brain. Several drugs with similar propertiesare also used for other purposes, and the physician inquires about these other drugs. A list of

such medications is shown in the table below.

Generic (Trade Name)

Acetophenazine (Tindal)

Amoxapine (Asendin)

Chlorpromazine (Thorazine)

Fluphenazine (Permitil, Prolixin)

Haloperidol (Haldol)


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Loxapine (Loxitane, Daxolin)

Mesoridazine (Serentil)

Metaclopramide (Reglan)

Molindone (Lindone, Moban)

Perphenazine (Trilafon or Triavil)

Piperacetazine (Quide)

Prochlorperazine (Compazine, Combid)

Promazine (Sparine)

Promethazine (Phenergan)

Thiethylperazine (Torecan)

Thioridazine (Mellaril)

Thiothixene (Navane)

Trifluoperazine (Stelazine)

Triflupromazine (Vesprin)

Trimeprazine (Temaril)

Several other disorders have certain features that are similar to those of PD, and are sometimesmistaken for PD. These include:

Essential tremor, in which tremor is the only symptom Progressive supranuclear palsy, characterized by inability to look downward Multiple system atrophy, characterized by early and prominent autonomic symptoms Vascular (related to blood vessels) parkinsonism, caused by multiple small strokes Poisoning by carbon monoxide, manganese, or certain pesticides


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Treatments

Unlike for many other neurodegenerative diseases, there is effective treatment for the symptoms

of Parkinson's disease. For most patients, these treatments can provide several years of

satisfactory treatment. Unfortunately, no therapy has yet been conclusively shown to slow or

reverse the disease. Several candidates have been tested in this regard, and have shown intriguingresults. However, these studies will need to be repeated and expanded before these agents can be

widely recommended.

Several important factors influence decision-making in treatment of PD. These include:

Levodopa continues to be the most effective treatment for motor symptoms, and all patientseventually require it.

Long-term complications of levodopa therapy are a concern, and may influence whethertherapy begins with levodopa or a dopamine agonist.

Non-motor symptoms, especially depression, are increasingly being seen as important targets oftherapy.

Surgical treatment has become a mainstay of late-stage management, although not all patientscan afford it or are appropriate candidates.

Cell transplant therapies are still experimental, and their usefulness is currently lessened by thepossibility of unacceptable complications. Additional studies are needed to understand and

avoid these complications.

Non-pharmacological treatments remain an important part of the whole treatment program.Long-term Complications of Treatment

As PD progresses, it becomes increasingly difficult to adequately control symptoms with

medications. The most common problems that arise are motor complications, which includemotor fluctuations and dyskinesias.

Motor fluctuations refer to unanticipated loss of effect of a given dose of levodopainstead of a

smooth, predictable symptomatic benefit, the patient may lose benefit earlier than usual (termed

"wearing off") or may suddenly switch from "on" (symptoms controlled) to "off" (symptomsreturn). Dyskinesias are involuntary movements that occur when dopamine levels are too high.

Motor complications are discussed in more detail in the section "Complications of Treatment."

Drugs Used to Treat PD

Five classes of drugs are used to treat the motor symptoms of PD:

Dopaminergic Agents

Levodopa (precursor to dopamine)

Dopamine agonists


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Apomorphine (Apokyn)

Bromocriptine (Parlodel)

Cabergoline (Not approved in the US)

Lisuride (Not approved in the US)

Pergolide (Permax withdrawn from US market March 2007)

Pramipexole (Mirapex)Ropinirole (Requip)

COMT Inhibitors

Entacapone (Comtan)

Tolcapone (Tasmar)

MAO-B Inhibitors

Rasagiline as Azilect

Selegiline as Eldepryl and Zelapar (an orally disintegrating selegiline tablet)

AnticholinergicsTrihexyphenidyl (Artane)

Benztropine

Ethopropazine

Amantadine (Symmetrel)

Dopaminergic AgentsLevodopa

Levodopa is converted in the brain into dopamine, the same chemical created by substantia nigracells and used to control movement. Levodopa was introduced as a PD therapy in the 1960s, and

remains the most effective therapy for motor symptoms. It lessens and helps to control all themajor motor symptoms of PD, including bradykinesia, which is generally the most disabling

feature of the disease.

Carbidopa is included in the standard oral formulation to increase the effectiveness of a dose of

levodopa and minimize side effects such as nausea and vomiting.

Levodopa is a type of amino acid. Amino acids, which are contained in certain foods, are the

building blocks of proteins. These building blocks are transported into the blood stream throughthe wall of the intestines. In similar fashion, levodopa must be absorbed into the blood streamthrough the wall of the intestines. This requires the action of a specific "transporter" or amino

acid vehicle in the intestinal lining. Because this transporter can only work so fast, an excessive

amount of dietary protein can slow the transport of levodopa into the blood stream. If sufficientamounts of levodopa do not get into the blood stream and ultimately to the brain, then the dose

prescribed may not be effective in treating the symptoms of PD. Once levodopa is in the blood

stream, it must then cross into the brain, where it becomes active in controlling the symptoms of


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PD. However, the same "transport phenomenon" occurs when levodopa crosses from the

bloodstream into the brain. To avoid the competition of levodopa with other dietary amino acids,patients with more advanced PD may need to time their doses to avoid meals, or reduce the

protein content of certain meals.

Adverse effects

Nausea and vomiting are the most common side effects, and are due to accumulation of

dopamine in the bloodstream. Orthostatic hypotension (low blood pressure upon standing) alsooccurs. The risk of hallucinations and paranoia increases over time. Compulsive behavior,

including gambling and hypersexuality, is another risk.

Drowsiness is a common adverse effect of levodopa and other dopaminergic therapies, and

sudden sleep onset is possible. Patients may not experience any warning signs of sudden sleeponset. It is important to understand this possibility, especially when levodopa therapy begins,

when increasing doses, or switching agents.

The most troubling adverse effect from long-term levodopa use is dyskinesias. Dyskinesias are

uncontrolled movements, including writhing, twitching, and shaking. Dyskinesias result from the

combination of long-term levodopa use and continued neurodegeneration. They typically begin

to develop in milder forms after 3 to 5 years of treatment, but are more severe after 5 to 10 yearsof treatment.

As the disease progresses, the increasing dose of levodopa required for symptom control

approaches the dose at which intolerable dyskinesias occur. This limits the continuing usefulness

of levodopa. At this point, surgery may be the only effective option. Because of this potential,many physicians recommend starting a younger patient on a dopamine agonist instead of

levodopa, which delays the onset of dyskinesias.

Immediate-release levodopa/carbidopa is formulated in doses of 10/100, 25/100, and 25/250

milligram pills. Onset of effect is usually 20 to 40 minutes, and duration of benefit is 2 to 4 hours

in more advanced stages of PD.

Dissolving the tablets in orange juice is a possible strategy for speeding the onset of effect.

Patients must be sure to consult with their physician before trying this, as the duration of benefitis usually shorter as well.

Continuous infusion of levodopa into the intestine, through a feeding tube, is being studied as of

mid-2004. The hope is that continuous infusion may lessen the risk for developing dyskinesias.However, this treatment approach is logistically challenging, and is reserved for only a small

subset of patients with severe motor fluctuations or dyskinesias.


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Dopamine Agonists

Dopamine agonists are drugs that imitate or mimic the action of levodopa in the brain by directly

stimulating dopamine receptors, the same receptors that dopamine itself stimulates. While they

are not quite as effective as levodopa, they provide excellent relief of symptoms and delay the

onset of motor complications.

A variety of dopamine agonists are available that differ in their duration of action, chemical

makeup, method of delivery, and adverse effect profile. The currently available agonists are:

Dopamine Agonists (generic name followed by trade name):

Apomorphine (Apokyn) Bromocriptine (Parlodel) Pergolide (Permax) Pramipexole (Mirapex) Ropinirole (Requip)

Clinical trials of several of both pramipexole and ropinirole have shown their ability to delay

motor complications when used as monotherapy (the only drug given) early in the disease.

Agonists tend to produce more edema and psychosis than levodopa, effects which may be moresignificant than mild dyskinesias, especially in older patients. Hence, in patients who are younger

(less than age 70) and otherwise healthy, initiation of dopaminergic therapy with a dopamine

agonist may be indicated. Older PD patients (especially those with cognitive problems) areusually treated with levodopa alone.

Adverse Effects

Drowsiness is a common adverse effect of dopamine agonists and levodopa, and sudden sleeponset is possible. Patients may not experience any warning signs of sudden sleep onset. It isimportant to understand this possibility, which is especially likely at the commencement of

therapy, when increasing doses, or switching to a different dopamine agonist.

Other significant adverse effects of dopamine agonists include nausea and vomiting, orthostatic

hypotension, edema, and psychosis.

Fibrosis is a risk from the ergot-derived dopamine agonists, which are pergolide, bromocriptine,

cabergoline, and lisuride. Pulmonary and retroperitoneal fibrosis are rare, while recent studiessuggest fibrosis of the heart valves may be common enough to warrant monitoring of all patients

on ergot-derived agonists, and switching to a non-ergot agonist when possible. Pergolide waswithdrawn from the US market in March 2007 over concern for this effect.


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Apomorphine

Apomorphine (Apokyn) is the dopamine agonist whose symptomatic effect is most like that of

dopamine. However, it cannot be taken in pill form, and must be delivered by injection beneath

the skin (subcutaneously). Its duration of effect is also shorter than levodopa's.

Subcutaneously injected apomorphine is used as a "rescue" therapy for patients with "off"episodes. Its onset of effect is approximately 10 minutes, and lasts approximately 90 minutes. It

can be used whenever a patient feels an off episode approaching before the next dose of

levodopa takes effect, such as early in the morning, or during that day when wearing off occurs.It can be used up to 10 times per day. If a patient needs more treatment than that, alternative

therapies should be considered. Injection-site reactions may occur, but are generally not a

problem.

Nausea and vomiting are the principal adverse effects. An antiemetic is required at the beginning

of apomorphine therapy. Trimethobenzamide is the agent usually prescribed. Many patients are

able to stop taking it after several weeks of therapy.

COMT Inhibitors

COMT inhibitors prolong the effectiveness of a dose of levodopa by preventing its breakdown.Two agents are approved in the United States, entacapone (Comtan) and tolcapone (Tasmar).Both have been shown to decrease the duration of "off" time (the period of time when PD

symptoms are present) in patients with significant off time. Tolcapone is more effective than

entacapone, reducing off time in clinical trials by 2-3 hours, versus 1 to 2 hours for entacapone.Both treatments usually allow reduction of levodopa dose, in the range of 20% to 25%.

Entacapone is dosed at 200 mg with each levodopa dose. Diarrhea is the most common sideeffect, which may require stopping treatment, but it occurs in severe form in only about 5% of

patients.

Tolcapone is dosed at 100 or 200 mg, three times per day. Side effects include diarrhea, which

may eliminate this as a treatment option in up to 15% of patients. Four cases of severe liver

disease (acute fulminant hepatic necrosis), with three deaths, were reported in 1998, and led theFDA to issue a "black box" warning on tolcapone. This warning recommends that physicians

only prescribe tolcapone for patients whose symptoms cannot be adequately controlled withoutit. Frequent liver function monitoring is required for patients commencing therapy. This requiresa blood test every 2-4 weeks for the first 6 months, to be sure that certain critical liver function

values are not rising. After that, blood tests are recommended at intervals deemed clinically

relevant. Treatment should be discontinued if the ALT/AST levels rise above twice the upper

limit of normal.


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A combination of levodopa, carbidopa, and entacapone in a single tablet (Stalevo) is also

available, with a similar side effect profile to the agents used alone.

MAO-B Inhibitors

MAO-B inhibitors slow the breakdown of dopamine in the brain. There are two MAO-Binhibitors, in three formulations, approved for use in PD in the United States.

Rasagiline (Azilect)

Rasagiline in an oral tablet is approved for the treatment of signs and symptoms of Parkinson'sdisease as initial monotherapy and as adjunct therapy to levodopa.

Selegiline swallowed tablets (Eldepryl, generics)

Selegiline in tablet form is approved as an adjunct in the management of parkinsonian patientsbeing treated with levodopa/carbidopa who exhibit deterioration in the quality of their responseto this therapy.

Selegiline orally dissolving tablet (Zelapar)

An orally dissolving form of selegiline is available for patients who have difficulty swallowing,or prefer not to take pills. It is approved as an adjunct in the management of patients with

Parkinson's disease being treated with levodopa/carbidopa who exhibit deterioration in the

quality of their response to this therapy.

Side effects of MAO-B inhibitor therapy include insomnia, hallucinations, and orthostatichypotension. Patients who are also taking certain types of antidepressants may not be eligible to

take MAO-B inhibitors, since these drugs may interact to dangerously raise blood pressure

(called the serotonin syndrome). Patients are also cautioned to avoid certain types of foods thatare high in tyramine, a dietary amino acid. These foods include certain kinds of aged cheeses,

fermented meats, and fermented soy products.

Selegiline

Selegiline offers mild symptomatic benefit, primarily for patients with early disease. The dose is5 mg twice each day. Side effects include insomnia, hallucinations, and orthostatic hypotension.Patients who are also taking certain types of antidepressants may not be eligible to take

selegiline, since these drugs may interact to dangerously raise blood pressure (called the

serotonin syndrome).

MAO-B inhibitors and neuroprotection


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Neuroprotection refers to the ability to prevent or slow the death of neurons. Selegiline was thesubject of a major neuroprotective trial in PD, the DATATOP trial. While the initial analysis ofthe results appeared to indicate that selegiline slowed disease, more detailed study indicated that

the benefit seen could also be explained by its symptomatic effects. Thus, the results of this trial

were inconclusive.

In 2004, a preliminary trial of rasagiline with a different trial design suggested that rasagilinemay have disease-modifying properties. This study will need to be repeated and expanded before

firm conclusions can be drawn.

Anticholinergics

Anticholinergics have a limited role in PD. They are primarily effective against tremor and

rigidity, and their side effects may be significant, especially in elderly patients. Typical doses forcommon anticholinergics are:

Trihexyphenidyl (Artane): 2 to 15 mg/day Benztropine: 1.0 to 4.5 mg/day Ethopropazine: 10 to 200 mg/day

Common side effects are memory loss, dry mouth, urinary retention, constipation, sedation,

delirium, and hallucinations.

Amantadine

Amantadine (Symmetrel) has a mild symptomatic effect on the motor symptoms of PD, but amore significant effect on the reduction of dyskinesias. The usual dose is 100 mg 2 to 4 times

each day. Side effects include hallucinations, difficulty falling asleep or staying asleep(insomnia), agitation, and difficulty concentrating; dry mouth, ankle swelling, and skin mottling

(uneven color tones) may also be present. Amantadine may be ineffective for dyskinesias in up

to one-third of patients.

Treatment Decision-MakingEarly Disease

The central questions in commencing treatment of PD are when to begin, and with what agent(s).


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Potential NeuroprotectionIf and when clearly neuroprotective agents are identified, they will obviously become the firsttreatments offered, and will be started as early as possible. As of mid-2007, no agent has been

definitively shown to offer neuroprotection. The MAO-B inhibitors selegiline and rasagiline

offer a mild symptomatic benefit, and are often used early for this in combination with their

proposed (and much debated) effects on slowing disease progression. Coenzyme Q10, availableover the counter, is also used early. Its use is based on a single trial whose results suggested a

possibly mild neuroprotective effect. Most PD experts believe the results of this trial are toopreliminary and not compelling enough to change early treatment practices without repeating the

study and duplicating the results.

Commencing Symptomatic TherapyThe decision of when to begin symptomatic therapy is an individual one made between patient

and physician. Factors include:

Degree of functional impairment Effect of symptoms on employment Patient attitudes towards medications

A patient who is fully educated regarding the benefits and limitations of therapy can be a fullpartner in the decision-making process. This obvious benefit is especially important in PD

treatment, since treatment must be reevaluated and adjusted so often during the course of the

disease, based on the changing condition of the patient and the response to previous therapy. It isin the interest of both patient and physician to develop such a partnership from the very

beginning.

Initial Treatment OptionsThe choice of initial treatment is strongly influenced by patient age and condition. Levodopa is

the usual treatment of choice in the elderly patient, because of its lower risk for psychiatriccomplications compared to dopamine agonists. A dopamine agonist may be preferable in the

younger patient, who is likely to be more tolerant of its side effects, and for whom delaying

motor complications is an important goal, given the longer treatment horizon. Selegiline,rasagiline, amantadine, or an anticholinergic drug may also be appropriate initial treatment for

mild symptoms, provided the side effects can be tolerated.

Depression and anxiety may also be early debilitating symptoms, and therefore may become the

object of initial therapy.

Complications of Treatment

Many PD patients have several years of trouble-free treatment following diagnosis. Theremaining neurons of the substantia nigra are believed to be sufficiently active to smooth out

changes in the levels of levodopa, thus providing a relatively constant amount of dopamine. As


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the disease progresses, this "honeymoon" gradually diminishes, and a majority of patients begin

to develop motor complications after five or more years. At this stage, adjustment of medicationsbecomes a frequent and increasingly complex task for physician and patient. Nonmotor

complications of disease can also be debilitating, and are important objects of treatment.

Motor complications

Motor complications include motor fluctuations ("wearing off"), dyskinesias, off-perioddystonia, freezing, and falls.

Motor fluctuations refer to:

Wearing off, or premature loss of benefit from a given dose of levodopa On-off, or sudden and unpredictable switch to off (usually seen in very advanced PD) Dose failure (failure to turn on from a dose)

Dyskinesias are unwanted involuntary movements that typically occur during the peak effect of a

dose of levodopa.

Off-period dystonia may also occur as a motor complication, especially in the morning before

the first dose of medication. Medication adjustments may be used to try to minimize each of

these complications.

Freezing is a type of motor block or hesitation that may appear at the beginning of a movement,

when passing through doorways, or while turning. This type of motor block does not alwaysrespond to medication. Sensory cues, such as auditory, visual, or proprioceptive (touch) triggers,

are employed to overcome the block.

Frequent falling, usually seen in advanced PD only, may require an evaluation for physical

therapy as well as use of a cane, scooter, or wheelchair.

Nonmotor complicationsWhile PD is classified as a movement disorder, there are many nonmotor aspects of the disease.

These may be as disabling as or more disabling than the motor symptoms, and treating them canimprove the quality of life for both patient and family/caregiver. Recognizing that a symptom is

part of the disease is an important step toward effective treatment.

Depression is reported to affect up to 50% or even more of PD patients. Treatments are usuallyvery effective, although complete resolution is rare. Treatments include certain antidepressant

medications, usually a class of drugs known as selective serotonin reuptake inhibitors (SSRIs)

including Prozac, Paxil, Luvox, Zoloft, or others. Another class of drugs, known as tricyclic

antidepressants, may be used including Elavil, Endep, and others. With modern techniques

and anesthesia, electroconvulsive therapy (also called electroshock therapy or ECT) may be

effective for relieving depression in PD. It may also improve motor symptoms of the disease,

although it is not prescribed for this reason alone.


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Anxiety and restlessness are common. When severe, these symptoms may be treated withbenzodiazepines; however, the potential for addiction should be factored into the decision to

use them. Since symptoms are often worse during periods of low levodopa levels, some

adjustment in dosing frequency may be effective as well.

Sleep disorders are very common in PD, ranging from insomnia to excessive sleepiness to vividdreaming. A careful history and reduction of unnecessary or offending medications may be

helpful. Treatment of depression may improve sleep.

Mild orthostatic hypotension is frequently seen in patients with PD. Strategies for treatmentincludes reducing antihypertension medications, increasing salt intake, and use of compressive

stockings. Fludrocortisone or midodrine may be indicated as well.

Psychosis may be a side effect of antiparkinsonian medications, as well as a feature of diseaseprogression. Initial features may include vivid dreaming and nightmares, which may progress to

delusions, paranoia, disorientation, and hallucinations. Reducing unnecessary medications is the

first line of treatment, with anticholinergics the first to go. Atypical neuroleptics are valuable for

patients with continued symptoms. Clozapine (Clozaril) is the most effective, but requires

frequent blood monitoring for the rare occurrence of serious blood disorder (agranulocytosis).

Quetiapine (Seroquel) and olanzapine (Zyprexa) may also be useful.

Surgery

Brain surgery is an option for advanced PD patients whose symptoms can no longer be

adequately managed with medications. The best surgical candidate is someone who:

Responds well to dopaminergic therapy Has motor complications (off periods and dyskinesias) that are limiting factors Is otherwise healthy and a good surgical risk.

Advanced age is not necessarily a barrier to surgery, but impaired cognition, including

forgetfulness, diminished decision-making ability, and language difficulties, along with gradual

loss of brain matter (brain atrophy or shrinkage), make the surgery more risky and decreases the

likelihood of an optimal outcome.


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Depending on the patient, procedure, and skill of the operating team, cognition may be mildly

impaired or largely unaffected by the surgery itself. The most commonly reported adversecognitive effects are reduced decision-making abilities and language impairments.

It is impossible to predict the benefit any individual patient can expect from surgery. The general

rule of thumb is that the maximum benefit is equal to the best response from a dose of levodopa(minus the effect on dyskinesias). Therefore, if a patient's symptoms are 50% better at the peakof a levodopa dose, the surgery is not likely to improve the patient's symptoms more than that

amount. Importantly though, improvements from surgery are most dramatic during the times the

patient is not experiencing the effects of medications ("off" time). Therefore, surgery may greatly

improve the amount of the day during which symptoms are reduced.

Types of Surgery

There are two surgical procedureslesioning and deep brain stimulationand three target

locations in PD surgery: thalamus, globus pallidum internus (GPi), and subthalamic nucleus(STN). Other surgery-based procedurescell transplants, gene therapy, and neurotrophic factor

deliveryremain experimental procedures for the treatment of PD.

Lesion procedures (i.e., pallidotomy, thalamotomy) deliver radio-frequency energy to heat andablate (destroy) a pea-sized region within the target, where there is abnormal activity related to

the movement problems.

Deep brain stimulation (DBS) uses implanted electrodes to stimulate one or another of these

same regions. The electrical stimulation interferes with the abnormal activity, creating the sameeffect as a lesion. The effect lasts as long as the stimulation continues, but ceases when it is shut

off.

During needle-guided (stereotaxic) brain surgery, the patient remains awake. This is for two

reasons. The first is that the brain itself has no pain sensors, and once the initial incision is made

(using a local anesthetic like Novocain), there is no pain. The second is that patients must be ableto respond to the surgical team's questions about what they are experiencing during the surgical

procedure. The pathway to the target lies close to several other important structures in the brain

that may be inadvertently stimulated during the procedure. This may cause unusual sensationssuch as flashing lights, tingling, or experience of emotions. Patients then report these sensations

to the surgeon during the procedure. Avoiding these areas is crucial for successful surgery.

Because surgery requires very precise placement of surgical instruments, a three-dimensional

frame is attached to the patient's head to guide the surgeon. The frame may be uncomfortable and

local anesthetic is used to ease the discomfort. Before surgery, patients will also undergo severalimaging procedures, in order to identify the target and other landmarks within the brain.

Depending on the center, the procedures may include magnetic resonance imaging (MRI) scans,

computerized tomography (CT), or ventriculography.


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Pallidotomy

Until the late 1990s, pallidotomy was the most common type of PD surgery; deep brainstimulation or DBS is now being performed more often. A pallidotomy involves destruction ofpart of the globus pallidus (GPi), a region of the brain involved with the control of movement.

Destroying part of the GPi may help to restore the balance in that area of brain, which normal

movement requires. Pallidotomy is performed by insertion of a wire probe into the GPi. Once its

placement has been confirmed by electrical tests, the probe heats surrounding tissue by emissionof radio waves. The heat destroys nearby tissue. Effects of the surgery are apparent almost

immediately. Improvements from pallidotomy range from 70% to 90% reduction of dyskinesias

and dystonia, and 25% to 50% for tremor, rigidity, bradykinesia, and gait disturbance. Levodopadose may be reduced after the surgery, and dyskinesia improvement is based partly on this

reduction.

Pallidotomy may be unilateral (one-sided) or bilateral (two-sided). Following a unilateral

pallidotomy, improvements are primarily to the side of the body opposite to the lesioned side of

the brain. Bilateral surgery is possible and improves dyskinesias further, but greatly increases therisk for worsening effects on cognition, swallowing, and speech; hence, it is done very rarely if

at all.

Adverse effects of pallidotomy may include hemorrhage, weakness, visual deficits, speech

deficits, and confusion, but the risk of these is relatively low in centers with an experienced

surgical team. Weight gain is very common following surgery.

Thalamotomy

Thalamotomy is primarily effective for tremor, and is therefore used mainly in patients for whom

tremor is the only disabling symptom. During a thalamotomy, a selected portion of the thalamus

is surgically destroyed (ablated). The thalamus is a paired structure deep within the brain that isinvolved in the control of movement. In this procedure, neurosurgeons use specialized

equipment, enabling them to use three-dimensional coordinates to precisely locate an area of the

thalamus. Bilateral (both sides of the brain) procedures are poorly tolerated because of increased

complication risks, including vision and speech problems. The procedure is gradually beingreplaced by subthalamic deep brain stimulation (DBS), since this procedure can improve tremor

and other symptoms of PD.


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Deep Brain Stimulation

Unlike lesion procedures, DBS leaves electrodes in place in the brain to deliver continuous

stimulation. The electrodes are powered by a programmable stimulator (like a pacemaker), which

is implanted in the chest wall. The stimulator is connected to the electrodes by thin wires (leads)

that are tunneled under the skin in the neck and scalp. The stimulator can be turned on and off bya magnet waved over the surface. Many patients turn the stimulator off at night or during periods

of prolonged activity, to prolong battery life. Batteries can be replaced as needed, generally after5 years. Since the battery is in the chest wall, brain surgery is not required to replace them.

Adjusting the stimulator and medications after electrode implantation is a major time

commitment on the part of the neurological team and patient. The maximum effect of the

procedure is achieved once that adjustment occurs, which may be weeks or even months after the

procedure itself.

Risks for DBS procedures include surgical risks (hemorrhage, infection) as well as hardware

complications. These include leads breaking, electrode malfunction, stimulator failure andbattery failure.

Thalamic DBS

Like thalamotomy, thalamic DBS is primarily effective against tremor. Bilateral procedures are

possible, but with a higher risk of adverse effects. Compared to thalamotomy, thalamic DBS hasa lower risk of severe side effects.

GPi DBSEffects of GPi DBS tend to mimic those of pallidotomy. Dyskinesia improvement is a major

effect, along with some improvement in tremor, rigidity, and bradykinesia, primarily in the off-

medication state. Bilateral DBS is better tolerated than bilateral pallidotomy.

Subthalamic Deep Brain Stimulation (DBS)

The subthalamic nucleus has become a major target for deep brain stimulation (DBS), with manyteams considering it the target of choice for control of PD. It leads to improvement of all major

motor features of PD, with improvement of motor scores of 40% to 60% in the off condition, and

10% in the on condition. Levodopa dosage reduction is typically around 30%, with resultingimprovement in dyskinesias. Bilateral procedures appear to be superior to unilateral, with only a

slightly increased risk of complications.

As DBS has become more common, rare but serious neuropsychiatric adverse events have been

increasingly reported. Onset or worsening of depression occurs post-operatively in a smallpercentage of patients, often in those who were at increased risk before the procedure. Suicide, awell-known risk in depressed patients, has been reported in a small handful of patients. Pre-

operative neuropsychiatric evaluation and post-operative follow-up is a critical part of patient

care.


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Experimental Therapies

Cell Transplant Therapy

Transplant of fetal substantia nigra cells has been performed in several hundred patients to date

in multiple centers throughout the world. While results have been encouraging in some

individual patients, two recent double-blind placebo-controlled studies showed that consistentbenefit was only seen in young PD patients (age 60 or below), and side effects in some patients

were significant. In particular, some patients developed off-medication dyskinesias (uncontrolledmovements) even without any levodopa or other dopaminergic medication. The lack of

consistently good results and the significant side effects encountered have been interpreted by

the scientific and medical community to indicate that further research in animal models of PD isneeded to improve upon what has been observed to date before more studies in PD patients are

undertaken.

Another cell transplant technique that shows some promise is the use of retinal pigment epithelial

cells. These cells are derived from tissue at the back of the eye, and they produce and release

dopamine. An open-label trial in six advanced PD patients has shown promise, and as of mid-2004, a double-blind trial is underway.

Gene TherapyAs of 2004, gene therapy has been tried in only a few PD patients, and is still highly

experimental. While experiments in animal models of PD have shown promise, further research

is needed. The only publicized trial is of delivery of the gene for glutamic acid decarboxylase(GAD) to the subthalamic nucleus or STN. GAD is a key enzyme in the production of the

inhibitory neurotransmitter GABA. Gene therapy with GAD is meant to increase GABA

production, reducing STN activity in the manner of STN DBS. Monitoring is still in progress.

Growth Factor DeliveryGlial cell-derived neurotrophic factor (GDNF) stimulates sprouting of dopamine neurons inanimal models. Direct delivery of GDNF to the brain has produced promising results in an open-

label trial in a small number of patients, but by mid-2004 a larger, double-blind trial failed to

show efficacy. Further research is needed, especially regarding how to improve delivery ofgrowth factors to the correct targets in the brain.

Nonpharmacologic Treatments

A wide variety of problems in PD may respond to nonpharmacological treatments. These

include:

Motor, balance, posture, gait, and mobility Difficulties with activities of daily living Speech and swallowing Inadequate nutrition


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Sleep disturbance Pain Constipation Sexual dysfunction Depression

In all cases, an individualized approach is needed to identify the problems and determine atreatment plan. Multiple members of the treatment teamphysical therapists, occupational

therapists, speech-language pathologists, gerontologists, neurologists, psychologists, and

othersmay be involved. Effective treatment may reduce the need for medications and improvequality of life.

Physical therapyGoals of physical therapy include maintaining or increasing activity levels, decreasing rigidity

and bradykinesia, optimizing gait, and improving balance and motor coordination. Features of

the PT program may include:

Regular exercise, such as walking (1+ miles/day), swimming, golf, or dancing, depending on thepatient's preferences and abilities

Stretching and strengthening Exaggerated or patterned movements, such as high stepping and weight shifting Mobility aids, orthotics (such as braces or splints) Training in transfer techniques Training in techniques to improve posture and walking

Occupational therapyGoals of occupational therapy include maximizing fine motor coordination, especially of theupper extremities, reducing energy expenditure, increasing safety and independence, and

improved efficiency of activities of daily living. Features of the OT program may include:

Use of orthoses and adaptive equipment Home and workplace modification, improving accessibility, and removing obstructions Adaptation and simplification of utensils, toileting articles, beds, etc

Speech and swallowingLow voice volume (hypophonia) often occurs in PD. Several PD-specific voice training

programs have been developed, which share an emphasis on consciously increasing voice

volume as a key strategy. Other features may include modification of speech patterns such as use

of shorter sentences, breathing exercises, and range-of-motion exercises for the muscles of

speech.

Drooling (sialorrhea) can be a common feature of advanced PD. The origin of the problem is not

in increased saliva production, but reduced spontaneity of swallowing. Awareness of the

problem, and consciously swallowing more often, may be effective. If not, treatments may

include a small dose of an anticholinergic medication under the tongue, or injection of botulinumtoxin into the salivary glands to temporarily paralyze them. Both of these reduce saliva

production.


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Management of swallowing difficulties may include instruction to take smaller bites, to

completely empty the mouth before taking the next bite, and eating softer foods.

SexualitySexual dysfunction affects a large proportion of patients with PD and their spouses. Difficulties

include erectile dysfunction in males, vaginal dryness, and loss of libido. Hypersexuality fromlevodopa and dopamine agonists also occurs. Many PD patients are reluctant to talk about theseissues with their doctor, and may not connect the symptom to the disease at all. There are useful

treatments, both medical and nonmedical, for many of these problems. Patients should always

have a thorough urological or gynecological evaluation to rule out non-PD related problems.

Sildenafil (Viagra) has been shown to be safe and effective in men in PD to treat erectiledysfunction.

DrivingPD patients tend to do worse than controls on tests of driving safety, because of increased

reaction times and movement times caused by PD. Vehicular control skills are generally well

preserved, but attention to safety landmarks declines. Decline in performance seems to be relatedto a worsening of motor abilities. Patients tend not to be good judges of their loss of driving

safety, and family members may need to intervene. A good way to determine driving capability

is to have the patient undergo a driving examination at a rehabilitation facility.

ConstipationA good bowel regimen can greatly reduce constipation. Increased fluid intake, a diet rich invegetables and fruits, use of stool softeners, and increased dietary and/or supplemental fiber are

just some interventions that can help. Working with one's physician and/or a gastroenterologist is

the approach to take.

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