Updates in the medical management of Parkinson disease

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More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
Rigidity, which is felt by the examiner rather than seen by an observer.
Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Although the archetypical patient is an elderly man with shaking, masked facies, and slow gait, these features are only the tip of the iceberg of the syndrome, and nonmotor features are often more disabling (Table 1).

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

10 to 20 years: juvenile-onset
21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
Strokes in the basal ganglia
Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

Progressive supranuclear palsy
Multiple system atrophy
Corticobasal degeneration
Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

MANAGING PARKINSON DISEASE

Most general neurologists follow an algorithm for treating Parkinson disease (Figure 1).

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

References

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Stocchi F, Barbato L, Nordera G, Bolner A, Caraceni T. Entacapone improves the pharmacokinetic and therapeutic response of controlled release levodopa/carbidopa in Parkinson’s patients. J Neural Transm 2004; 111:173–180.
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Poewe WH, Deuschl G, Gordin A, Kultalahti ER, Leinonen M; Celomen Study Group. Efficacy and safety of entacapone in Parkinson’s disease patients with soboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand 2002; 105:245–255.
Rinne UK, Larsen JP, Siden A, Worm-Petersen J. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998; 51:1309–1314.
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Metman LV, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999; 56:1383–1386.
Snow BJ, Macdonald L, Mcauley D, Wallis W. The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 2000; 23:82–85.
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Hubert H. Fernandez, MD, FAAN, FANA
Head, Section of Movement Disorders, Center for Neurological Restoration, Neurological Institute, Cleveland Clinic

Address: Hubert Fernandez, MD, FAAN, FANA, Center for Neurological Restoration, S31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail fernanH@ccf.org

Dr. Fernandez has received research support from Abbott, Acadia, Biotic Therapeutics, EMD-Serono, Huntington Study Group, Ipsen, Merz Pharmaceuticals, Michael J. Fox Foundation, Movement Disorders Society, National Parkinson Foundation, NIH/NINDS, Novartis, Parkinson Study Group, and Teva. He has received honoraria from USF CME, Cleveland Clinic CME, Medical Communications Media, Health Professions Conferencing, Ipsen, Merz Pharmaceutcials, and US World Meds. He has received royalty payments from Demos Publishing, Manson Publishing, and Springer Publishing for serving as a book author. He is a consultant for Merz Pharmaceuticals, Ipsen Pharmaceuticals, and United Biosource Corporation. Also, Cleveland Clinic has contracts with EMD Serono, Abbott, and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for Safinamide and LCIG studies and head principal investigator for the Zeomin Registry Study, but he does not receive any personal compensation for these roles. He has received a stipend from the Movement Disorders Society for serving as medical editor of its Web site.

Medical Grand Rounds articles are based on edited transcripts of Medical Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

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Hubert H. Fernandez, MD, FAAN, FANA
Head, Section of Movement Disorders, Center for Neurological Restoration, Neurological Institute, Cleveland Clinic

Address: Hubert Fernandez, MD, FAAN, FANA, Center for Neurological Restoration, S31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail fernanH@ccf.org

Dr. Fernandez has received research support from Abbott, Acadia, Biotic Therapeutics, EMD-Serono, Huntington Study Group, Ipsen, Merz Pharmaceuticals, Michael J. Fox Foundation, Movement Disorders Society, National Parkinson Foundation, NIH/NINDS, Novartis, Parkinson Study Group, and Teva. He has received honoraria from USF CME, Cleveland Clinic CME, Medical Communications Media, Health Professions Conferencing, Ipsen, Merz Pharmaceutcials, and US World Meds. He has received royalty payments from Demos Publishing, Manson Publishing, and Springer Publishing for serving as a book author. He is a consultant for Merz Pharmaceuticals, Ipsen Pharmaceuticals, and United Biosource Corporation. Also, Cleveland Clinic has contracts with EMD Serono, Abbott, and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for Safinamide and LCIG studies and head principal investigator for the Zeomin Registry Study, but he does not receive any personal compensation for these roles. He has received a stipend from the Movement Disorders Society for serving as medical editor of its Web site.

Medical Grand Rounds articles are based on edited transcripts of Medical Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

Author and Disclosure Information

Hubert H. Fernandez, MD, FAAN, FANA
Head, Section of Movement Disorders, Center for Neurological Restoration, Neurological Institute, Cleveland Clinic

Address: Hubert Fernandez, MD, FAAN, FANA, Center for Neurological Restoration, S31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail fernanH@ccf.org

Dr. Fernandez has received research support from Abbott, Acadia, Biotic Therapeutics, EMD-Serono, Huntington Study Group, Ipsen, Merz Pharmaceuticals, Michael J. Fox Foundation, Movement Disorders Society, National Parkinson Foundation, NIH/NINDS, Novartis, Parkinson Study Group, and Teva. He has received honoraria from USF CME, Cleveland Clinic CME, Medical Communications Media, Health Professions Conferencing, Ipsen, Merz Pharmaceutcials, and US World Meds. He has received royalty payments from Demos Publishing, Manson Publishing, and Springer Publishing for serving as a book author. He is a consultant for Merz Pharmaceuticals, Ipsen Pharmaceuticals, and United Biosource Corporation. Also, Cleveland Clinic has contracts with EMD Serono, Abbott, and Merz Pharmaceuticals for Dr. Fernandez’s role as a member of the Global Steering Committee for Safinamide and LCIG studies and head principal investigator for the Zeomin Registry Study, but he does not receive any personal compensation for these roles. He has received a stipend from the Movement Disorders Society for serving as medical editor of its Web site.

Medical Grand Rounds articles are based on edited transcripts of Medical Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

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More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
Rigidity, which is felt by the examiner rather than seen by an observer.
Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Although the archetypical patient is an elderly man with shaking, masked facies, and slow gait, these features are only the tip of the iceberg of the syndrome, and nonmotor features are often more disabling (Table 1).

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

10 to 20 years: juvenile-onset
21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
Strokes in the basal ganglia
Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

Progressive supranuclear palsy
Multiple system atrophy
Corticobasal degeneration
Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

MANAGING PARKINSON DISEASE

Most general neurologists follow an algorithm for treating Parkinson disease (Figure 1).

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
Rigidity, which is felt by the examiner rather than seen by an observer.
Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Although the archetypical patient is an elderly man with shaking, masked facies, and slow gait, these features are only the tip of the iceberg of the syndrome, and nonmotor features are often more disabling (Table 1).

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

10 to 20 years: juvenile-onset
21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
Strokes in the basal ganglia
Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

Progressive supranuclear palsy
Multiple system atrophy
Corticobasal degeneration
Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

MANAGING PARKINSON DISEASE

Most general neurologists follow an algorithm for treating Parkinson disease (Figure 1).

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

References

Adler CH, Ahlskog JE. Parkinson’s Disease and Movement Disorders: Diagnosis and Treatment Guidelines for The Practicing Physician. Totowa, NJ: Humana Press; 2000.
Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med 2005; 353:1021–1027.
Litvan I, Bhatia KP, Burn DJ, et al; Movement Disorders Society Scientific Issues Committee. Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003; 18:467–486.
Wenning GK, Ben-Shlomo Y, Hughes A, Daniel SE, Lees A, Quinn NP. What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000; 68:434–440.
Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001; 16:448–458.
Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Parkinson Study Group. JAMA 2000; 284:1931–1938.
Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342:1484–1491.
Oertel WH, Wolters E, Sampaio C, et al. Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: The PELMOPET study. Mov Disord 2006; 21:343–353.
Lees AJ, Katzenschlager R, Head J, Ben-Shlomo Y. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology 2001; 57:1687–1694.
Fowler JS, Volkow ND, Logan J, et al. Slow recovery of human brain MAO B after L-deprenyl (selegeline) withdrawal. Synapse 1994; 18:86–93.
Elmer LW, Bertoni JM. The increasing role of monoamine oxidase type B inhibitors in Parkinson’s disease therapy. Expert Opin Pharmacother 2008; 9:2759–2772.
Olanow CW, Rascol O, Hauser R, et al; ADAGIO Study Investigators. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:1268–1278. Erratum in: N Engl J Med 2011; 364:1882.
Stocchi F, Barbato L, Nordera G, Bolner A, Caraceni T. Entacapone improves the pharmacokinetic and therapeutic response of controlled release levodopa/carbidopa in Parkinson’s patients. J Neural Transm 2004; 111:173–180.
Brooks DJ, Sagar HUK-Irish Entacapone Study Group. Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s disease: a randomised, placebo controlled, double blind six month study. J Neurol Neurosurg Psychiatry 2003; 74:1071–1079.
Poewe WH, Deuschl G, Gordin A, Kultalahti ER, Leinonen M; Celomen Study Group. Efficacy and safety of entacapone in Parkinson’s disease patients with soboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand 2002; 105:245–255.
Rinne UK, Larsen JP, Siden A, Worm-Petersen J. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998; 51:1309–1314.
Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Parkinson Study Group. Ann Neurol 1997; 42:747–755.
Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005; 62:241–248.
Rascol O, Brooks DJ, Melamed E, et al; LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365:947–954.
Metman LV, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999; 56:1383–1386.
Snow BJ, Macdonald L, Mcauley D, Wallis W. The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 2000; 23:82–85.
Almaraz AC, Driver-Dunckley ED, Woodruff BK, et al. Efficacy of rivastigmine for cognitive symptoms in Parkinson disease with dementia. Neurologist 2009; 15:234–237.
Fénelon G, Mahieux F, Huon R, Ziégler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 2000; 123:733–745.
Fernandez HH, Donnelly EM, Friedman JH. Long-term outcome of clozapine use for psychosis in parkinsonian patients. Mov Disord 2004; 19:831–833.
Goetz CG, Wuu J, Curgian LM, Leurgans S. Hallucinations and sleep disorders in PD: six-year prospective longitudinal study. Neurology 2005; 64:81–86.
Tollefson GD, Dellva MA, Mattler CA, Kane JM, Wirshing DA, Kinon BJ. Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. The Collaborative Crossover Study Group. J Clin Psychopharmacol 1999; 19:435–443.
Fernandez HH, Trieschmann ME, Okun MS. Rebound psychosis: effect of discontinuation of antipsychotics in Parkinson’s disease. Mov Disord 2005; 20:104–105.
McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry 2003; 54:363–375.
Devos D, Dujardin K, Poirot I, et al. Comparison of desipramine and citalopram treatments for depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Mov Disord 2008; 23:850–857.
Menza M, Dobkin RD, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009; 72:886–892.
Voon V, Sohr M, Lang AE, et al. Impulse control disorders in Parkinson disease: a multicenter case-control study. Ann Neurol 2011; 69:986–996. .

References

Adler CH, Ahlskog JE. Parkinson’s Disease and Movement Disorders: Diagnosis and Treatment Guidelines for The Practicing Physician. Totowa, NJ: Humana Press; 2000.
Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med 2005; 353:1021–1027.
Litvan I, Bhatia KP, Burn DJ, et al; Movement Disorders Society Scientific Issues Committee. Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003; 18:467–486.
Wenning GK, Ben-Shlomo Y, Hughes A, Daniel SE, Lees A, Quinn NP. What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000; 68:434–440.
Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001; 16:448–458.
Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Parkinson Study Group. JAMA 2000; 284:1931–1938.
Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342:1484–1491.
Oertel WH, Wolters E, Sampaio C, et al. Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: The PELMOPET study. Mov Disord 2006; 21:343–353.
Lees AJ, Katzenschlager R, Head J, Ben-Shlomo Y. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Neurology 2001; 57:1687–1694.
Fowler JS, Volkow ND, Logan J, et al. Slow recovery of human brain MAO B after L-deprenyl (selegeline) withdrawal. Synapse 1994; 18:86–93.
Elmer LW, Bertoni JM. The increasing role of monoamine oxidase type B inhibitors in Parkinson’s disease therapy. Expert Opin Pharmacother 2008; 9:2759–2772.
Olanow CW, Rascol O, Hauser R, et al; ADAGIO Study Investigators. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361:1268–1278. Erratum in: N Engl J Med 2011; 364:1882.
Stocchi F, Barbato L, Nordera G, Bolner A, Caraceni T. Entacapone improves the pharmacokinetic and therapeutic response of controlled release levodopa/carbidopa in Parkinson’s patients. J Neural Transm 2004; 111:173–180.
Brooks DJ, Sagar HUK-Irish Entacapone Study Group. Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s disease: a randomised, placebo controlled, double blind six month study. J Neurol Neurosurg Psychiatry 2003; 74:1071–1079.
Poewe WH, Deuschl G, Gordin A, Kultalahti ER, Leinonen M; Celomen Study Group. Efficacy and safety of entacapone in Parkinson’s disease patients with soboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand 2002; 105:245–255.
Rinne UK, Larsen JP, Siden A, Worm-Petersen J. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998; 51:1309–1314.
Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Parkinson Study Group. Ann Neurol 1997; 42:747–755.
Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005; 62:241–248.
Rascol O, Brooks DJ, Melamed E, et al; LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365:947–954.
Metman LV, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999; 56:1383–1386.
Snow BJ, Macdonald L, Mcauley D, Wallis W. The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 2000; 23:82–85.
Almaraz AC, Driver-Dunckley ED, Woodruff BK, et al. Efficacy of rivastigmine for cognitive symptoms in Parkinson disease with dementia. Neurologist 2009; 15:234–237.
Fénelon G, Mahieux F, Huon R, Ziégler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 2000; 123:733–745.
Fernandez HH, Donnelly EM, Friedman JH. Long-term outcome of clozapine use for psychosis in parkinsonian patients. Mov Disord 2004; 19:831–833.
Goetz CG, Wuu J, Curgian LM, Leurgans S. Hallucinations and sleep disorders in PD: six-year prospective longitudinal study. Neurology 2005; 64:81–86.
Tollefson GD, Dellva MA, Mattler CA, Kane JM, Wirshing DA, Kinon BJ. Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. The Collaborative Crossover Study Group. J Clin Psychopharmacol 1999; 19:435–443.
Fernandez HH, Trieschmann ME, Okun MS. Rebound psychosis: effect of discontinuation of antipsychotics in Parkinson’s disease. Mov Disord 2005; 20:104–105.
McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry 2003; 54:363–375.
Devos D, Dujardin K, Poirot I, et al. Comparison of desipramine and citalopram treatments for depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled study. Mov Disord 2008; 23:850–857.
Menza M, Dobkin RD, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009; 72:886–892.
Voon V, Sohr M, Lang AE, et al. Impulse control disorders in Parkinson disease: a multicenter case-control study. Ann Neurol 2011; 69:986–996. .

Issue

Cleveland Clinic Journal of Medicine - 79(1)

Issue

Cleveland Clinic Journal of Medicine - 79(1)

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28-35

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28-35

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Cleveland Clinic Journal of Medicine

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Cleveland Clinic Journal of Medicine

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Neurology

Drug Therapy

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Updates in the medical management of Parkinson disease

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Updates in the medical management of Parkinson disease

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KEY POINTS

Parkinson disease can usually be diagnosed on the basis of clinical features: slow movement, resting tremor, rigidity, and asymmetrical presentation, as well as alleviation of symptoms with dopaminergic therapy.
Early disease can be treated with levodopa, dopamine agonists, anticholinergics, and monoamine oxidase-B inhibitors.
Advanced Parkinson disease may require a catechol-O-methyltransferase (COMT) inhibitor, apomorphine, and amantadine (Symmetrel). Side effects include motor fluctuations, dyskinesias, and cognitive problems.

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Imaging useful in select patients

Check for Wilson disease or brain tumors in young or atypical cases

Consider secondary parkinsonism

Parkinson-plus syndromes

Levodopa: The most effective drug, until it wears off

Dopamine agonists may be best for younger patients in early stages

Anticholinergic drugs for tremor

Monoamine oxidase B inhibitors are well tolerated but less effective

Rasagiline: Protective effects still unknown

Managing dyskinesias

Dementia: One of the most limiting nonmotor features

Psychosis: Also very common

Mood disturbances

Imaging useful in select patients

Check for Wilson disease or brain tumors in young or atypical cases

Consider secondary parkinsonism

Parkinson-plus syndromes

Levodopa: The most effective drug, until it wears off

Dopamine agonists may be best for younger patients in early stages

Anticholinergic drugs for tremor

Monoamine oxidase B inhibitors are well tolerated but less effective

Rasagiline: Protective effects still unknown

Managing dyskinesias

Dementia: One of the most limiting nonmotor features

Psychosis: Also very common

Mood disturbances

Imaging useful in select patients

Check for Wilson disease or brain tumors in young or atypical cases

Consider secondary parkinsonism

Parkinson-plus syndromes

Levodopa: The most effective drug, until it wears off

Dopamine agonists may be best for younger patients in early stages

Anticholinergic drugs for tremor

Monoamine oxidase B inhibitors are well tolerated but less effective

Rasagiline: Protective effects still unknown

Managing dyskinesias

Dementia: One of the most limiting nonmotor features

Psychosis: Also very common

Mood disturbances