Neal Hermanowicz, MD

The ideal medication for Parkinson disease (PD) would reduce disability and halt or slow disease progression without intolerable adverse effects. Although such an agent is not yet available, current treatments offer significant symptom control for most patients. The decision about when to start therapy is highly individual; however, delaying treatment because of fear of adverse effects may not be in the patient's best interest.

Options for initial treatment of motor symptoms include levodopa, dopamine agonists, anticholinergic agents,  amantadine, and selective monoamine oxidase B (MAO-B) inhibitors (Table). 

Since 1959, when brain dopamine deficiency was identified as a key factor in PD, medical treatment has centered on methods to enhance dopamine transmission. Dopamine agonists currently available in the United States include ropinirole (Requip), pramipexole (Mirapex), pergolide (Permax), and bromocriptine (Parlodel). Another, rotigotine (marketed as Neupro in Europe), will likely be available soon in the form of a daily skin patch. Ropinirole and pramipexole are the 2 most widely prescribed dopamine agonists. Pergolide and bromocriptine are used less because, as ergot derivatives, they have been associated with rare instances of fibrosis of the heart valves, lungs, and retroperitoneum.

Levodopa and the dopamine agonists remain the mainstays of PD treatment. However, soon after these agents went into widespread use, reports of adverse events began to appear, including short duration of benefit and involuntary choreic movements (dyskinesia) with levodopa and abnormal psychiatric states with bromocriptine. As awareness of the adverse effects of these and other medications that were introduced later grew, it became evident that physician familiarity with the use of levodopa and 1 or 2 dopamine agonists was crucial to satisfactory patient outcomes.

Levodopa and dopamine agonists complement one another and are often used together to maximize efficacy and minimize adverse effects. Probably because of its short half-life, levodopa is more likely to produce dyskinesia and other motor complications when used as monotherapy. The dopamine agonists have long half-lives and are less likely to produce these effects; however, they are not as effective as levodopa. Dopamine agonists must be introduced more slowly; they are more likely to cause adverse effects such as drowsiness, hypotension, hallucinations, and compulsive behavior.

Two large-scale studies that compared initial therapy with levodopa and initial therapy with a dopamine agonist established that initial treatment with a dopamine agonist reduces or delays the appearance of motor complications-specifically dyskinesia-and end-of-dose wearing off.

 However, in both studies, most patients eventually received levodopa in conjunction with the dopamine agonist. Unfortunately, these results were misinterpreted by some clinicians to mean that levodopa is to be avoided, a phenomenon dubbed levodopa phobia.

 Clinicians who fail to prescribe levodopa withhold from their patients the single most effective agent for symptomatic treatment.

According to the practice parameters of the American Academy of Neurology, treatment may be started with either levodopa or a dopamine agonist.

 To minimize the risk of motor complications, many movement disorder specialists suggest that it may be preferable to start therapy with a nonergot dopamine agonist for patients aged 65 years or younger and to add levodopa later as necessary to optimize mobility. For patients older than 75 years, levodopa may be used first and, in many cases, as monotherapy. Younger patients appear to be at greater risk for dyskinesia, and motor complications may take years to develop.

In patients aged 65 to 75 years, the choice depends on the patient. Determine whether the patient is likely to comply with the dosing changes involved in the titration of a dopamine agonist, which requires 3 to 8 weeks, or whether prompt relief of symptoms is needed. In the latter case, levodopa would be the appropriate choice.

Anticholinergic medications, such as trihexyphenidyl (Artane) and benztropine (Cogentin), were the mainstays of therapy before levodopa became available. However, these agents are not superior for tremor and are often associated with distressing adverse effects, such as dry mouth, blurred vision, and exacerbation of constipation and cognitive dysfunction.

This agent is thought by some experts to be effective for patients with mild symptoms who do not yet require levodopa or a dopamine agonist. However, amantadine does not effectively reduce symptoms in many patients, and it has been associated with hallucinations and peripheral edema, as well as with livedo reticularis, a benign skin discoloration. Amantadine is the only medication that effectively relieves dyskinesia.

 Agents that selectively inhibit MAO-B are far less likely to cause the adverse drug and food interactions associated with nonselective (type A) monoamine oxidase inhibitors. Selegiline, available since 1989, has been reformulated in a new freeze-dried orally disintegrating form (Zelapar), which dissolves rapidly and is absorbed directly through the buccal mucosa.

 This allows once-daily administration with a lower dose than the older tablet or capsule form. Selegiline is approved as an adjunct to carbidopa/levodopa for patients who experience a loss of effectiveness with the latter therapy.

Rasagiline (Azilect) has recently been approved as monotherapy for mild PD and as an adjunct to levodopa for patients who are experiencing symptom fluctuations.

 This once-daily formulation is currently being investigated as a possible disease progression-slowing agent.

Both selegiline and rasagiline may interact with other medications. Concomitant use of either drug with antidepressants may be problematic or dangerous. Neither drug should be used within 14 days of administration of meperidine, tramadol, methadone, or dextromethorphan; neither drug should be used concomitantly with over-the-counter (OTC) cold and allergy remedies. Although the "cheese effect" of tyramine-containing foods is less likely to occur with MAO-B inhibitors, rasagiline carries a warning about this effect.

 Attempts to address the short half-life of levodopa include concurrent administration of COMT inhibitors, which inhibit a degradative pathway of levodopa. The COMT inhibitors entacapone (Comtan) and tolcapone (Tasmar) increase the effective plasma half-life of levodopa, allow enhanced delivery to the CNS, and prolong the efficacy of levodopa. Entacapone has been combined with levodopa and carbidopa in one tablet that is marketed as Stalevo. 

 Patients with cognitive impairment may benefit from ChEIs. A review of data on ChEI therapy for cognitive impairment in PD concluded that rivastigmine (Exelon) and donepezil (Aricept) are modestly beneficial.

 However, of the ChEIs, only rivastigmine has been examined in a large trial of patients with PD and dementia.

 Although it was modestly effective in some patients, it was also associated with nausea, vomiting, and increased tremor. It was recently approved for the treatment of mild to moderate dementia in patients with PD. A new patch form of rivastigmine that may cause fewer adverse effects will soon be available.

 Many patients inquire about CoQ10, an OTC supplement that has received a great deal of attention based on the results of one well-designed but small study.

 The study demonstrated apparent slower progression of early PD in patients who were otherwise untreated for 16 months. The outcome reached statistical significance only at the highest dosage studied (400 mg/tid). The results of this study require corroboration. A larger trial that has been organized and is being funded by the NIH has not yet begun. Pending additional results, we neither encourage nor discourage the use of this agent by our patients.

Traditionally, medical treatment for PD has not been started until the patient and clinician have judged that the symptoms are sufficiently troublesome to warrant therapy despite potential adverse effects. This strategy remains reasonable and is widely practiced. However, 2 recent studies of levodopa

 have led to a reexamination of this practice. In the former study, participants with early PD were assigned to placebo or levodopa, 150, 300, or 600 mg/d, divided into a thrice-daily regimen.

 They were observed for 9 months and reexamined after the medication had been discontinued for 2 weeks. Even after the discontinuation, patients in the levodopa group scored significantly higher on the Unified Parkinson's Disease Rating Scale than those in the placebo group. In the rasagiline study, participants originally assigned to placebo were switched to rasagiline after 6 months, but they did not improve to the same extent as patients who started in the rasagiline group.

These 2 studies of medications with different mechanisms of action, as well as some earlier evidence,

 raise the concern that a delay in treatment because of a patient's fears about adverse effects or desire to wait until the patient deems that his or her symptoms are intolerable may not be an optimal strategy and may even be deleterious.

The question of when to start therapy is not easily answered. We suggest that potential benefits and adverse effects of medication be discussed with patients in a realistic way. In our practice, we also explore the concerns of patients who are already taking medication for dyslipidemia, hypertension, or diabetes and are reluctant to begin another drug regimen.

Among the many adverse effects associated with PD medications, several warrant special emphasis.

 Sleep disorders are common in PD, and daytime somnolence sometimes is a symptom of PD. However, PD medications, particularly the dopamine agonists, may induce sudden, severe drowsiness, and this raises concerns about motor vehicle safety. Patients who experience drowsiness should exercise at least the same level of caution when driving as they would with any medication that has this adverse effect. Although no formal guidelines exist, evidence suggests that patients with PD-other than those with the mildest symptoms-are at greater risk for automobile accidents than are unaffected age-matched peers.

. Visual hallucinations are relatively common; they are often benign initially but are likely to be disruptive within 2 or 3 years of onset.

 Patients may be untroubled if they see insects or small animals, but are likely to be agitated if they believe they are seeing burglars entering the house.

Similarly, dopaminergic and anticholinergic medications may produce delusions. Patients may begin to suspect spousal infidelity or become paranoid about personal safety and financial matters. These delusions are frightening, agitating, and disruptive for the entire household.

When hallucinations or delusions become disruptive, it is best to gradually lower medication dosage, especially that of dopamine agonists, and perhaps simultaneously add an antipsychotic agent, such as quetiapine (Seroquel) or clozapine. Abrupt discontinuation of any PD agent may result in sudden and dangerous worsening of rigidity. Patients who experience psychiatric adverse effects often do best with levodopa monotherapy.

 Amantadine and the dopamine agonists may cause leg edema. Entacapone and tolcapone can cause diarrhea as well as a benign change in urine color that may upset some patients if they are not forewarned. Dopamine agonists also can result in compulsive behavior that may be destructive.

 We have observed compulsive gambling, eating, and shopping in our patients with PD. We caution our patients about these phenomena and ask that they notify us if they occur. We have found that elimination of the responsible medication is required when compulsive behavior occurs; the substitution of one agent for another (eg, ropinirole for pramipexole) does not solve the problem.

Surgery has had a recrudescence in the treatment of PD. Surgical intervention has been practiced in some form since the accidental discovery in the 1950s that tremor could be reduced by partial infarction of the thalamus.

The most common current treatment, deep brain stimulation (DBS), entails permanent placement of an electrode in the subthalamic nucleus, usually on both sides of the brain. Application of an electrical current to this location reduces tremor, stiffness, and slowness of the contralateral limbs. This technique does not generally eliminate the need for medication (although a small number of patients are able to discontinue medication, at least temporarily) and is unlikely to be effective for patients who do not have any discernible response to levodopa.

DBS works best for carefully selected patients,

 such as those who respond well to dopaminergic agents but for too short a period (2 hours or less), those who have dyskinesia that causes functional impairment, and those who are in their 60s or younger (although advanced age alone is not a restricting factor).

The procedure carries a small risk of symptomatic stroke from a hemorrhage that may occur at the time of electrode placement.

 The devices sometimes break and require repair or become infected and need to be removed. Moreover, DBS will not ameliorate symptoms that do not improve with medications, such as impaired balance and freezing of gait. Some symptoms, such as those that involve speech and cognition, may be exacerbated by DBS.

 The technique also requires substantial commitment from the patient and physician alike for adjustment of the implanted stimulator settings and medications. For carefully chosen candidates, the procedure can be life-enhancing for years.

Although DBS clinics have sprung up in various parts of the country, the procedure requires careful consideration that should include an extensive evaluation by a neurosurgeon who regularly collaborates with specialists in the diagnosis and treatment of PD.

Although clinical data are sparse, it appears that physical activity, particularly aerobic exercise, helps patients maintain optimal mobility.

 Walking on a level surface, pedaling a stationary bicycle, and participating in pool aerobics are reasonable options for many. Exercises that require mild exertion, such as Tai Chi and qigong, also appear to be beneficial.

 Such activities as daily stretching, Pilates, and yoga are enjoyable and helpful for many patients. We routinely refer patients to physical therapists for assessment of balance, training to reduce the risk of falls, and development of a realistic exercise regimen. Group programs can help sustain patients' enthusiasm and adherence.

To address symptoms such as dysarthria and dysphagia that do not respond well to medication, we often refer patients to speech pathologists with experience in PD for recommendations and treatment. Rehabilitative therapies draw upon diverse expertise that allows for an optimal level of care that cannot be achieved by a single practitioner.

We also encourage intellectual exercise-crossword puzzles, card playing, socializing, participating in community activities, and keeping up with the news. Support groups can be quite helpful but are not suitable for all patients. Younger patients, in particular, feel that conventional support groups, most of whose members are older, do not address their needs. Patients in an earlier stage of disease may be unsettled by seeing those at a more advanced stage.

Researchers are investigating such promising areas as gene therapy, neurotrophic factors, and stem cell therapy.

 The ultimate "cure" may involve identifying persons at risk for PD and arresting the disease process before it becomes clinically evident. This strategy is currently being explored.    

 A version of this article was published in the October 2006 issue of 

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Examples of evidence-basedmedicine related to this articleinclude:

 Deuschl G, Schade-Brittinger C, KrackP, et al; German Parkinson Study Group,Neurostimulation Section. A randomizedtrial of deep-brain stimulation for Parkinson'sdisease [published correctionappears in N Engl J Med. 2006;355:1289].N Engl J Med. 2006;355:896-908.

 Goetz CG, Poewe W, Rascol O, SampaioC. Evidence-based medical reviewupdate: pharmacological and surgicaltreatments of Parkinson's disease: 2001to 2004. Mov Disord. 2005;20:523-539.

Articles

Clinical Pearls on the Management of Parkinson Disease

Parkinson disease (PD) is the second most common neurodegenerative disorder among elderly persons (after Alzheimer disease [AD]), and the incidence is expected to double in the next 15 to 20 years.

 About a million Americans have PD-which means that it is about 3 times as common as multiple sclerosis and half as common as epilepsy.

Most studies indicate that men are more often affected than women, although the reason is unknown. Coffee drinkers and smokers appear to be at reduced risk.

 Age is the only established risk factor for PD; average age at diagnosis is 55 to 60 years. PD is diagnosed in fewer than 5% of patients before the age of 40 years.

Because the manifestations of PD are protean and complex, the diagnosis can be difficult and treatment-challenging. However, an awareness of the key clinical features and familiarity with dopaminergic medications can facilitate management.


The diagnosis is established clinically and relies on a thorough history and physical examination. The lack of a reliable, affordable, and widely accessible test for PD-coupled with the variable clinical presentation-sometimes creates uncertainty about the diagnosis, even among the most experienced clinicians. Patients with a remarkable history and clinical findings of unilateral resting tremor, limb rigidity, and asymmetric slowness of movement meet the criteria for a PD diagnosis.

 MRI of the brain cannot detect the pathologic changes associated with PD. Generally, MRI is ordered only to rule out another condition, such as normal pressure hydrocephalus (NPH), that sometimes mimics PD and can be detected by imaging. In some centers, functional imaging such as [

I]b-CIT single photon emission computed tomography (SPECT) or fluorodopa positron emission tomography (PET) may provide information about dopamine metabolism in the brain, but these scans are not infallible and their accuracy depends on the experience of those performing and interpreting them. SPECT and PET are not considered standard for the diagnosis of PD; they are seldom covered by insurance plans and represent a substantial expense.

 Unilateral tremor-usually in a hand-that is often more prominent at rest, coupled with a change in handwriting (micrographia, marked by smaller letters and a decline in legibility) in a person aged 55 years or older strongly suggests PD. The changes in handwriting are often present even when the tremor does not affect the patient's dominant hand.

 Many patients (or their spouses) observe movement that is slow (bradykinesia), decreased (hypokinesia), or difficult to initiate (akinesia).

 Many patients (or their spouses) report that their voice has weakened (hypophonia) and that they are frequently asked to repeat themselves. Speech may become hoarse and monotonous.

 Gait is often affected fairly early, although the changes may be subtle. When asked specifically about walking, patients may observe that they drag a foot or shuffle. Although impaired balance is regarded as a central feature of PD, it is rarely evident early. Unsteadiness or falling in a patient with suspected PD suggests progressive supranuclear palsy.

 Inquire about activities of daily living as well as occupational and social functioning. Patients may report increasing difficulties. Some may be aware of slowness or awkwardness in certain activities, such as getting out of bed in the morning or fastening buttons. A spouse or other family member may have noticed a change in facial expressiveness-the so-called masked facies of PD. A full picture of daily functional status, in conjunction with the physical examination, helps in the selection or modification of the treatment plan.

 Have the patient sit with his hands supported by the armrests of the chair or in the lap. Engaging the patient in conversation allows for better assessment; moreover, with diversion, a subtle or significant tremor may emerge that might otherwise be missed. Conversation also allows for assessment of facial expressiveness (including diminished blinking) and speech.

When the patient is seated and asked to shrug his shoulders, the affected side will often show a slight lag. Check the tone in the patient's arms and legs by asking him to relax, go limp, and not help in moving the limbs. Subtle rigidity can be elicited by asking the patient to simultaneously move the contralateral arm while the practitioner moves his other arm or a leg.

Check for speed and excursion of index finger tapping, hand opening and closing, and alternating hand movements. Alternatively, the patient can be asked to rapidly tap the palm and then the back of his hand on his knee. Patients with PD demonstrate slowing and awkwardness in these movements.

Ask the patient to stand up from a seated position with arms folded on the chest; observe whether he is able to do so or whether he needs to push against the armrests to rise. Persons with PD may require more than 1 attempt to rise or will need to assist themselves with that push. Stand behind the patient and pull him backward with a forceful tug on the shoulders to check balance. Warn the patient beforehand, and demonstrate that he should take a step backward to steady himself if needed. Position larger patients so that their backs are near a wall. When pulled, a patient with early PD may need to take a few steps backward, beyond the normal 1 or 2. Frank falling-with the need to be caught by the examiner-is not typical of early PD and may suggest another diagnosis.

Finally, watch as the patient walks 30 feet in the corridor. Look for postural changes, such as leaning forward or asymmetric shoulder height, and for arm swing. Commonly, the arm on the affected side will swing less than the unaffected arm, or it may be held flexed at the elbow.


A number of diseases mimic PD. Essential tremor, a condition sometimes confused with early PD, is about 10 times more prevalent than PD. Distinguishing characteristics are listed in Table 1.

Other disorders that may mimic PD include NPH and neurodegenerative disorders, such as progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and diffuse Lewy body disease. Distinguishing among these diagnoses with certainty can be challenging-and sometimes impossible. However, a definitive diagnosis may have important ramifications for treatment; for example, NPH sometimes responds to neurosurgical intervention, whereas the other conditions often do not. Furthermore, other neurodegenerative diseases usually respond poorly to medications used to treat PD. Features that suggest neurodegenerative diseases other than PD include:

Symmetric findings at the time of presentation.

Early prominent gait disorder, falls, or cognitive impairment.

No improved mobility with levodopa treatment.

Drug-induced parkinsonism also must be ruled out in the diagnosis of PD. Dopamine antagonists, including metoclopramide and prochlorperazine, may produce symptoms and signs identical to those of PD. Other classes of drugs that may induce parkinsonism include older and newer antipsychotic agents, antiemetic drugs and, rarely, calcium channel blockers. Discontinuation of the offending medication reverses the symptoms, although this process may take many months or up to a year or more.


After the history taking and physical examination, observations should be discussed with the patient, including findings that are obvious to him and those that may not be, such as changes in tone or an asymmetric arm swing.

Patients often suspect the diagnosis, so it does not come as a complete shock, but confirmation of the suspicion may be unsettling-and sometimes devastating. Support and education are crucial (Table 2). The clinician should stress that PD, like most disorders, covers a broad spectrum of symptom severity. Although PD is a progressive disorder, a course of relentless decline is not inevitable. Many patients have long periods of clinical stability with little perceptible change. Emphasize that although the cause of PD remains unknown and a cure is not yet available, many of its symptoms are treatable.

It is important to inform patients that PD symptoms do not worsen abruptly. Sudden changes may occur with a medication mishap-for example, the addition of a dopamine antagonist to the medication regimen-or because of a concurrent acute condition, such as a urinary tract infection, pneumonia, or prolonged constipation.

Finally, although the genetics of PD is an increasingly fruitful area of research, PD does not typically run in families in any identifiable Mendelian pattern. The risk of PD in the children of patients with the disease, although higher than that of a person without an affected first-degree relative, is still very low.


PD does not manifest solely as a neurologic disorder that produces tremor and impairment of mobility. The initial appearance of pathology in the brain may not be in areas that affect motor function but instead may affect olfactory pathways and brain stem structures involved in sleep regulation. The clinical consequences include impaired sense of smell and rapid eye movement (REM) sleep behavior disorder that may appear years before the more typical motor symptoms.

The microscopic pathology of PD also is found in the autonomic nervous system.

 This may explain symptoms of autonomic dysfunction, such as constipation, urinary urgency and frequency, abnormal sweating, erectile dysfunction, and blood pressure regulation problems. Constipation is thought to be a possible early symptom that precedes motor dysfunction.

Most patients with PD have both motor and nonmotor symptoms. Sleep disturbances and bladder and bowel difficulties are particularly common and trouble- some. Patients report a variety of sleep problems.

 Some fall asleep but awaken prematurely and have difficulty in getting back to sleep. Restless legs syndrome is common. Patients may be somnolent and doze irresistibly during the day and also fall asleep at meals or during conversation or sedentary activities. Their dreams are frequently intense, realistic, and unpleasant and may be associated with REM sleep behavior disturbance. Patients may fling their limbs and grab or strike their bed partner as they wrestle with imaginary characters or animals. Some yell loudly while dreaming.

Patients often report visual problems despite normal findings on ophthalmologic evaluation. Occasionally, patients have impaired eye movements that result in frank diplopia. The complaint of reduced acuity may be attributable to retinal changes that are detectable only with specialized testing, such as electroretinography for color contrast sensitivity.

 Some patients report dry eyes or increased tearing; these can contribute to altered acuity.

Patients sometimes complain of shortness of breath despite normal pulmonary and cardiac assessments. This may be a result of restriction of chest wall expansion when medication has worn off and symptoms are returning, irregular breathing as an adverse effect of therapy, or alterations of brain stem respiratory centers.

Fatigue, depression, and anxiety are also commonly reported. Suicide, although uncommon, is not unknown among patients with PD. Mood may sometimes correspond with medication: a decline in mood and an increase in anxiety may coincide with the last dose of medication wears off.

 Fatigue, the most troubling symptom for some patients, is poorly understood as a manifestation of PD and usually difficult to treat.

Many patients with a new diagnosis of PD fear cognitive loss, dementia, and dependence. Cognitive impairment in many patients takes the form of slowing of memory and difficulty with visual spatial tasks and executive function (multitasking and creating a plan and bringing it to completion). Reports of the incidence of dementia in PD vary, but frank dementia, such as in AD, is uncommon.

Of all the PD symptoms, those that affect motor function have been investigated most thoroughly. Many reports demonstrate that these symptoms respond to treatment, but not all of them respond equally, and some do not respond at all. Stiffness and slowness often improve with dopaminergic medication, for example, whereas tremor may improve less reliably. Thus, a more realistic treatment goal than tremor eradication is improved overall mobility.

 A version of this article was published in the October 2006 issue of Consultant.

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Examples of evidence-based medicine related to this article:

Nutt JG, Wooten CF. Diagnosis and initial management of Parkinson's disease. N Engl J Med. 2005;353:1021-1027.

Jain S, Lo SE, Louis ED. Common misdiagnosis of a common neurological disorder: how are we misdiagnosing essential tremor? Arch Neurol. 2006;63: 1100-1104.

Parkinson disease (PD) is the second most common neurodegenerative disorder among elderly persons (after Alzheimer disease [AD]), and the incidence is expected to double in the next 15 to 20 years. About a million Americans have PD which means that it is about 3 times as common as multiple sclerosis and half as common as epilepsy.

Author | Neal Hermanowicz, MD

Articles

Clinical Pearls on the Management of Parkinson Disease

Parkinson Disease: Essentials of Diagnosis