Diagnosis and Initiation of Treatment in Parkinson's Disease

ABSTRACT

Parkinson's disease (PD) is the most common cause of parkinsonism, yet the diagnosis and management can be a challenge. The United Kingdom Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria and dopamine transporter/single-photon emission computed tomography (DaT-SPECT) are diagnostic aids that can improve diagnostic accuracy. Even though PD is a progressive disease, for years, physicians and patients have delayed treatment until functional disability occurs. However, studies of monoamine oxidase-type B (MAO-B) inhibitors, dopamine agonists, and levodopa, all of which can be used as initial therapy, have demonstrated that PD patients receiving treatment do better than those who do not receive treatment, and some studies have shown that those receiving treatment earlier do better long term. Therefore, the management strategy for PD has moved toward earlier initiation of treatment. Although treatment for each patient should be individualized and based on their specific symptoms, severity, and lifestyle, in general MAO-B inhibitors may be used initially to treat mild symptoms, adding a dopamine agonist in younger patients or levodopa in older patients, as symptoms become more severe.

KEYWORDS: :

• diagnostic criteria
• differential diagnosis
• early treatment
• treatment initiation

INTRODUCTION

Parkinson's disease (PD) is the most common cause of parkinsonism and affects over one million persons in the United States and over five million persons worldwide [1]. The cardinal motor symptoms of PD are bradykinesia, rigidity, and rest tremor with postural instability occurring as the disease advances. Nonmotor symptoms are also common throughout the course of PD and include neuropsychiatric symptoms such as anxiety, depression, dementia, and executive dysfunction; autonomic dysfunction such as constipation and other gastrointestinal disturbances, increased urinary frequency and urgency, and sexual dysfunction; sleep disturbances; olfactory dysfunction; and visual disturbances which can lead to significant disability [1–3].

The diagnosis of PD can be challenging as other than autopsy, there are no tests available to make a definitive diagnosis. Therefore, the experience and expertise of the clinician is critical, as the diagnosis is primarily based on patient history, clinical signs and symptoms, and response to medications. There are several initial treatment options including monoamine oxidase-type B (MAO-B) inhibitors, dopamine agonists, and levodopa as well as amantadine and anticholinergics which are used less commonly. The decision to initiate treatment is based on the type and severity of symptoms as well as the lifestyle of the individual. This review will briefly discuss diagnostic criteria for PD and the most common differential diagnoses. It will then focus on treatment options for early PD and factors influencing the initiation of treatment.

DIAGNOSIS OF PARKINSON'S DISEASE

The basic diagnostic criteria for PD are the presence of two of the three cardinal features of rest tremor, bradykinesia, and rigidity as well as an improvement of symptoms with levodopa. However these criteria often result in a large number of patients with atypical parkinsonism being incorrectly diagnosed as PD [4]. The United Kingdom Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria (UK PD Brain Bank criteria) are more specific and are generally considered the gold standard diagnostic criteria for PD [5]. These criteria involve a three-step process (see Table 1). The first step involves identifying signs and symptoms necessary to make a diagnosis of parkinsonism. The second step involves identifying signs and symptoms to exclude a diagnosis of PD. The third step involves identifying supportive criteria for the diagnosis of PD.

TABLE 1.  United Kingdom Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria for PD [5]

Step 1: Diagnosis of parkinsonian syndrome	• Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions)
	• AND one of the following
	• Muscular rigidity
	• 4–6 Hz rest tremor
	• Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction
Step 2: Exclusion criteria for PD	• History of repeated strokes with stepwise progression of parkinsonian features
	• History of repeated head injury
	• History of definite encephalitis
	• Oculogyric crises
	• Neuroleptic treatment at onset of symptoms
	• More than one affected relative
	• Sustained remission
	• Strictly unilateral features after 3 years
	• Supranuclear gaze palsy
	• Cerebellar signs
	• Early severe autonomic involvement
	• Early severe dementia with disturbances of memory, language, and praxis
	• Babinski sign
	• Presence of cerebral tumor or communicating hydrocephalus on CT scan
	• Negative response to large doses of levodopa (if malabsorption excluded)
	• MPTP exposure
Step 3: Supportive prospective positive criteria for PD	• Unilateral onset
	• Rest tremor present
	• Progressive disorder
	• Persistent asymmetry affecting side of onset most
	• Excellent response (70%–100%) to levodopa
	• Severe levodopa-induced chorea
	• Levodopa response for 5 years or more
	• Clinical course of 10 years or more

Note: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

DIFFERENTIAL DIAGNOSIS OF PARKINSON'S DISEASE

There are multiple neurological disorders that may have various signs and symptoms of parkinsonism that can make the diagnosis and accurate differential diagnosis of PD a challenge. The American Academy of Neurology (AAN) practice parameter on the diagnosis of PD [6] indicates that early falling, poor response to levodopa, symmetry of symptoms, rapid disease progression, lack of tremor, and early autonomic dysfunction are suggestive of a diagnosis other than PD. Table 2 lists the most common differential diagnoses for PD and the key features to help differentiate these disorders from PD. These include the atypical forms of parkinsonism such as corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP); secondary forms of parkinsonism such as drug-induced parkinsonism (DIP), vascular parkinsonism, and psychogenic parkinsonism; as well as other neurological disorders such as essential tremor (ET) and Alzheimer's disease (AD).

TABLE 2.  Key defining features of common differential diagnoses of PD

Atypical Parkinsonism
Corticobasal degeneration	Alien limb phenomenon, apraxia, cortical sensory loss, dystonia, myoclonus
Dementia with Lewy bodies	Dementia within 1 year of parkinsonism; early hallucinations
Multiple system atrophy	Early autonomic problems, ataxia, cerebellar signs, early speech dysfunction, early falling, response to levodopa minimal or poor and typically not sustained
Progressive supranuclear palsy	Early postural instability and falling, gaze palsy, symmetric onset, rapid progression, minimal to poor response to levodopa
Secondary parkinsonism
Drug-induced	Recent exposure to neuroleptics or other dopamine blocking drugs, resolves with drug discontinuation, symmetric onset, acute onset
Psychogenic	Inconsistent symptoms, distractibility, entrainment
Trauma/tumor	Abnormalities on neuroimaging
Vascular	Abnormal neuroimaging, cardiovascular risk factors, often affects lower limbs more severely, sudden onset, stepwise progression; often a poor response to levodopa
Alzheimer's disease	Primary symptom is dementia, parkinsonism occurs years after dementia
Essential tremor	Bilateral action tremor, alcohol responsive tremor, head or voice tremor, family history of tremor, no other parkinsonian signs
Normal pressure hydrocephalus	Abnormal neuroimaging, confusion, gait abnormality, urinary incontinence

In one study, when using the UK PD Brain Bank criteria, diagnostic accuracy of neurologists for 100 autopsied cases was increased from 76% to 82% [5]. Similarly, in another study, specialists applied the UK PD Brain Bank criteria to cases diagnosed with parkinsonism in the community and 15% of the patients diagnosed with PD did not have PD while 19% with another diagnosis were actually PD [4]. When the UK PD Brain Bank criteria were applied to 402 patients with parkinsonism diagnosed by general practitioners, it was determined that 47% of the patients were misdiagnosed [7]. Therefore, the UK PD Brain Bank criteria improve the accuracy of differentiating PD from other forms of parkinsonism as well as other neurological disorders such ET and AD.

Dopamine transporter/single-photon emission computed tomography (DaT-SPECT; ioflupane I-123 injection) is a radiopharmaceutical used with single-photon emission computed tomography (SPECT) to measure dopamine transporter (DAT) density [8]. It is approved as a diagnostic tool to aid in the differentiation of ET and tremor due to parkinsonism with dopaminergic dysfunction such as PD, PSP, and MSA; however, it is not able to differentiate between these forms of parkinsonism. Studies have shown that ET and PD are differentiated with a sensitivity of 87%–98% and a specificity of 80%–100%. PD patients have a decrease in DAT density, whereas images for ET patients are normal [9–12]. Studies have also shown that patients with DIP [13, 14], vascular parkinsonism [15, 16], and psychogenic parkinsonism [17, 18] have normal images and could therefore be differentiated from the abnormal images of those affected by parkinsonism related to dopaminergic dysfunction. Therefore, DaT-SPECT is a diagnostic aid to assist the physician in the diagnosis of uncertain or difficult cases and is not recommended as a routine test in cases of straightforward parkinsonism or ET.

INITIAL TREATMENT OPTIONS FOR PARKINSON'S DISEASE

The goal of treatment for PD is to use as little medication as needed to control symptoms without causing adverse events. There are many factors that need to be considered when determining whether to initiate treatment and which treatment option to use. These include age, cognitive and psychiatric issues, comorbidities, employment, life style, and symptom severity. After review of two large, randomized, placebo-controlled studies of PD patients not yet starting treatment, it was determined that the two strongest predictors of need for dopaminergic medication were symptom severity as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) score at the start of the study and full-time employment [19]. However, given that dopamine depletion is 60%–80% by the time of the emergence of motor symptoms, it is becoming more common to initiate treatment earlier rather than waiting for symptoms to cause functional impairment [20, 21]. Initial treatment considerations include nonpharmacologic options, carbidopa/levodopa, MAO-B inhibitors, dopamine agonists, and less commonly anticholinergics and amantadine. Table 3 provides medication options for the initiation of therapy in PD as well as the recommended titration schedules. Table 4 provides the recommendations of the American Academy of Neurology (AAN) [22], Movement Disorder Society (MDS) [23], European Federation of Neurological Societies (EFNS) [24], National Institute for Health and Clinical Excellence (NICE) [25], and the Scottish Intercollegiate Guidelines Network (SIGN) [26] on the initiation of treatment for PD.

TABLE 3.  Initial treatment options for Parkinson's disease

Medication	Initiation and titration*
Carbidopa/levodopa (Sinemet, Parcopa, generics)	Start with ½ of a 25/100 tablet three times daily and increase as needed up to 2,000 mg/day
MAO-B inhibitors
Rasagiline (Azilect)	Start with 1 mg once daily, no titration
Selegiline (Eldepryl, generic)	Start with 5 mg in the morning and 5 mg in the afternoon, no titration
Dopamine agonists
Pramipexole (Mirapex, generic)	Start with 0.125 mg three times daily and increase weekly to 0.25, 0.5, 0.75, 1.0, 1.25, and 1.5 mg three times daily as needed
Pramipexole extended-release (Mirapex ER)	Start with 0.375 once daily and increase in a week to 0.75 mg once daily and then by 0.75 mg/d every week as need to a maximum of 4.5 mg/d
Ropinirole (Requip, generic)	Start with 0.25 mg three times a day and increase weekly to 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, and 3 mg three times a day; continue to increase slowly as needed to a maximum of 8 mg three times a day
Ropinirole prolonged-release (Requip XL)	Start with 2 mg once a day and increase every 1–2 weeks to 4, 6, and 8 mg daily; continue to slowly increase to a maximum of 24 mg once daily
Anticholinergics
Benztropine (Cogentin, generic)	Start with a single dose at bedtime of 0.5 or 0.5 bid; slowly increase by 0.5 mg every 5–6 days to a maximum of 6 mg/d
Trihexyphenidyl (Artane, generic)	Start with 1 mg/d and increase by 2 mg as needed every 3–5 days; may increase more slowly in those over 60 years
Other
Amantadine	Start with 100 mg once daily and after at least one week increase to 100 mg twice daily if needed; can slowly increase to 400 mg in divided doses if needed

*Taken from package inserts and slightly modified on the basis of clinical experience.

TABLE 4.  Guidelines for the initiation of treatment in Parkinson's disease patients

	MAO-B inhibitors	Dopamine agonists	Levodopa	Other
AAN (2002) [22]	Rasagiline-–no data Selegiline-–mild benefit	Effective but less so than levodopa; more frequent adverse events but fewer motor complications than levodopa	Most effective, risk of motor complications	Anticholinergics mild effect mainly on tremor; Amantadine modest effect, low adverse effect profile
MDS (2005) [23]	Efficacious, clinically useful	Efficacious, clinically useful	Efficacious, clinically useful	Anticholinergics likely efficacious, clinically useful; Amantadine likely efficacious, clinically useful
EFNS (2006) [24]	Effective but more modest than levodopa; easy to use	Effective but less so than levodopa; more frequent adverse events but fewer motor complications than levodopa	Most effective, early use in elderly, related to development of motor complications	Anticholinergics small effect, poorly tolerated in elderly; Amantadine induces symptomatic improvement
NICE (2006) [25]	First choice option; moderate symptom control	First choice option; moderate symptom control	First choice option; good symptom control; use lowest dose possible to maintain good function and reduce motor complications	Anticholinergics not a first choice option; Amantadine not a first choice option
SIGN (2010) [26]	May be considered	May be considered but warn about impulse control disorders and excessive daytime sleepiness	May be considered; use lowest effective dose to minimize adverse effects	Anticholinergics should not be used as first line; Amantadine not mentioned

Note: AAN: American Academy of Neurology; MDS: Movement Disorder Society; EFNS: European Federation of Neurological Societies; NICE: National Institute for Health and Clinical Excellence; SIGN: Scottish Intercollegiate Guidelines Network.

Nonpharmacologic Treatments

There is increasing evidence in animal and human studies that targeted exercise and physical therapy early in the disease process can provide benefit and may be neuroprotective [27]. Therefore, it is important that all PD patients adopt a regular exercise routine or consult a physical therapist to develop an exercise plan. Similarly, targeted exercise for speech and swallowing problems has also been shown to have beneficial effects and can be initiated well before significant problems occur [28]. In addition, it is important that patients and their families receive credible educational materials, have an adequate support system that may be family and friends or a local PD support group, maintain a healthy diet, and practice good sleep habits.

Carbidopa/Levodopa

Carbidopa/levodopa is the most effective treatment for PD, and at some point in the disease course, it is required by nearly all patients. However, at higher doses and with continued use, carbidopa/levodopa often results in motor fluctuations and dyskinesia [29]. The ELLDOPA (Earlier Versus Later Levodopa Therapy in Parkinson's Disease) study compared levodopa at daily dosages of 150 mg, 300 mg, and 600 mg and placebo in drug-naïve PD patients diagnosed for less than 2 years [30]. Study subjects received treatment for 40 weeks followed by a 2-week washout period. At 24 weeks, there was a significant improvement in UPDRS motor scores compared with baseline for all levodopa doses and no change for placebo [31]. There was a dose dependent improvement of 3 points with 150 mg, 5.9 points with 300 mg, and 7.1 points with 600 mg of levodopa. At 42 weeks, after washout of the study drug, the total UPDRS improved in a dose-dependent fashion compared with placebo with a worsening of 7.8 points with placebo, 1.9 points with both 150 and 300 mg of levodopa, and an improvement of 1.4 points with 600 mg of levodopa. However, with 600 mg of levodopa, there was a significant increase in dyskinesia affecting 16.5% of the subjects compared with the other groups for which only 2%–3% were affected. Wearing off occurred in nearly 30% of the subjects in the levodopa 600 mg group compared with 18% or less of the subjects in the other groups. On the basis of these results, it is generally recommended that if levodopa is the initial treatment, daily dosages should be kept below 600 mg adding an additional medication to levodopa when needed. Alternatively, initiation could begin with an alternate treatment option, adding levodopa later as needed.

The most common side effects of carbidopa/levodopa include nausea, vomiting, dizziness, and orthostatic hypotension as well as motor fluctuations and dyskinesia. Older patients (>70 years) are often initiated with levodopa to avoid side effects more common with other PD medications primarily psychiatric symptoms such as confusion and hallucinations. Similarly, patients with cognitive issues, psychiatric problems, or significant comorbidities are often initiated with levodopa in an attempt to minimize side effects. Younger patients are generally not started with carbidopa/levodopa, as they tend to be more likely to develop motor fluctuations and dyskinesia [32]. However, if the patient is employed and job performance is in question, low-dose carbidopa/levodopa may be the initial treatment of choice.

A 5-year, randomized, double-blind study compared carbidopa/levodopa immediate release with the extended release formulation in PD patients not previously exposed to dopaminergic treatments to determine if the extended release preparation would result in fewer motor complications [33]. At 5 years, the average daily dose of immediate release carbidopa/levodopa was 426 mg compared with the bioavailable dose of 510 mg for the extended release group. There were no differences between the two formulations in terms of UPDRS motor scores and adverse events including motor complications that were about 20% for each group. Consequently, at the present time, there are no advantages of using the extended release formulation as initial treatment.

Carbidopa/levodopa/entacapone has been examined as an initial treatment for PD. In the FIRST-STEP study [34], PD patients not taking dopaminergic therapies were randomized to carbidopa/levodopa/entacapone or carbidopa/levodopa to compare the safety and efficacy of the two compounds. After 39 weeks, there was a significant improvement in total UPDRS scores of 10 points with carbidopa/levodopa/entacapone compared with 8.5 points with carbidopa/levodopa. There were no differences in motor complications between the two groups. Nausea, diarrhea, and chromaturia were more common in the carbidopa/levodopa/entacapone group. In the STRIDE-PD study [35], PD patients not taking levodopa were randomized to carbidopa/levodopa or carbidopa/levodopa/entacapone to determine if the triple combination drug could delay the development of dyskinesia. In contrast, dyskinesia developed more quickly and they were significantly more common with carbidopa/levodopa/entacapone (42%) compared with carbidopa/levodopa (32%). In conclusion, carbidopa/levodopa/entacapone is not recommended nor approved as an initial treatment for PD.

MAO-B Inhibitors

MAO-B inhibitors block MAO-B and allow more dopamine to reach the brain. Selegiline and rasagiline are currently available for the treatment of PD. Both medications have been shown to have a mild effect as monotherapy with selegiline demonstrating an improvement of approximately 2–3 points in the total UPDRS score compared with placebo [36, 37] and rasagiline demonstrating an improvement of 3–4 points on the total UPDRS compared with placebo [38, 39].

In the DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) study, PD patients not currently treated were randomized to either selegiline or placebo [36]. At 3 months, there was a 1.5 point improvement with selegiline and a 1.6 point worsening with placebo. At approximately 1 year, 24% of selegiline patients compared with 44% of the placebo group required rescue therapy with levodopa. In a 7-year study, de novo patients were randomized to either selegiline or placebo and received levodopa when clinically necessary. At 3 months, there was a 1.7 point improvement in total UPDRS scores compared with a 1.0 point worsening with placebo. In addition, the need for levodopa was significantly delayed with selegiline (12.7 months) compared with placebo (8.6 months) [37]. Furthermore, there was an improvement in total UPDRS scores at 1 year (2.9 points), 3 years (7.7 points), and 5 years (9.9 points) in the selegiline plus levodopa group compared with the placebo plus levodopa group and levodopa dose was 19% higher in the placebo group, as were motor complications [40].

In the TEMPO (Rasagiline Mesylate (TVP-1012) in Early Monotherapy for Parkinson's Disease Outpatients) study [38], PD patients not needing dopaminergic therapy were randomized to either rasagiline (1 mg or 2 mg) or placebo. At 26 weeks, there was an improvement of 4.2 points in total UPDRS scores with 1 mg rasagiline and 3.6 points with 2 mg rasagiline compared with placebo. An additional analysis after 1 year indicated that subjects receiving rasagiline (1 or 2 mg) for 1 year compared with those who received placebo for 6 months followed by 2 mg rasagiline for 6 months had significantly less decline in total UPDRS scores. The degree of improvement compared with the group that initially received placebo was 1.8 points for the 1 mg rasagiline group and 2.3 points for the 2 mg group [41]. Finally, after 6.5 years, those initiated with rasagiline compared with those initiated with placebo had significantly less worsening in UPDRS total scores of 2.5 points [42].

In the ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) study, PD subjects not taking PD medication were randomized to either rasagiline or placebo for 36 weeks [39]. For the following 36 weeks, the rasagiline group maintained the same daily dose and the placebo group was randomized to either 1 or 2 mg rasagiline. The rasagiline 1 and 2 mg groups both had a significant improvement of approximately 3 points at 36 weeks compared with placebo. At 72 weeks, the 1 mg early-start rasagiline group had an improvement in total UPDRS of 1.7 points compared with the delayed-start group. There was no significant difference between the early- and delayed-start rasagiline 2 mg groups. However, in an additional analysis, when only those rasagiline patients in the highest quartile of baseline UPDRS total scores (>25.5 points) were examined, there was an improvement of 6.4 points with rasagiline compared with placebo. These findings suggest that rasagiline may have a mild effect in very early disease; however, as PD severity increases, rasagiline has a more robust improvement in PD signs and symptoms.

MAO-B inhibitors are contraindicated with meperidine, tramadol, methadone, propoxyphene, dextromethorphan, St. John's wort, and cyclobenzaprine. Selegiline has amphetamine metabolites that can result in insomnia, hallucinations, and confusion. In contrast, rasagiline is metabolized to aminoindan and does not have amphetamine metabolites and is generally well tolerated [21]. MAO-B inhibitors are often initiated in patients with mild symptoms, adding a dopamine agonist or levodopa as symptoms become more severe.

Dopamine Agonists

Dopamine agonists stimulate post-synaptic dopamine receptors. The dopamine agonists currently available in the United States are pramipexole and ropinirole as well as once daily, extended release formulations of each. Pramipexole immediate release has been shown to improve UPDRS total scores by 4–5 points compared with placebo [43, 44]. In a study comparing initiation of treatment with pramipexole immediate and extended release formulations, total UPDRS scores were improved by 4.8 points with immediate release and 4.7 points with extended release compared with placebo [45]. In a study of immediate release ropinirole, UPDRS motor scores were improved by 4.5 points compared with placebo [46]. There are no studies comparing ropinirole prolonged-release to placebo, but it has been shown to be comparable to the immediate release formulation [47].

Studies have compared the initiation of pramipexole and ropinirole to initiation with levodopa to determine if delaying the use of levodopa results in fewer motor complications. In a 4-year study, subjects were initiated with either pramipexole or levodopa and supplemental levodopa was allowed in both groups as necessary [48]. UPDRS motor scores were significantly improved with levodopa by 3.4 points compared with a worsening of 1.3 points with pramipexole. However, in the pramipexole group, dyskinesia occurred in 25% of the subjects compared with 54% in the levodopa group. Similarly, wearing off occurred in 47% of the pramipexole group and 63% of the levodopa group. Therefore, although there was significantly greater efficacy with the initiation of levodopa, there was also a significant increase in dyskinesia and wearing off compared with initiation with pramipexole.

In a 5-year study, subjects were initiated with either ropinirole or levodopa and additional levodopa was allowed as needed [49]. There was a significant difference in UPDRS motor scores with the levodopa group having an improvement of 4.8 points compared with an improvement of only 0.8 points with ropinirole. In the ropinirole group, 20% developed dyskinesia of which 8% had disabling dyskinesia compared with the development of dyskinesia in 45% of the levodopa group with 23% of these subjects reporting disabling dyskinesia. Wearing off occurred in 23% of the ropinirole group and 34% of the levodopa group. Similar to the results of the pramipexole study, this study indicated that initial treatment with levodopa not only provides significantly greater efficacy, but also results in significantly more patients developing motor complications compared with initiation with ropinirole.

A randomized, double-blind study compared the addition of either ropinirole prolonged-release or additional levodopa in patients taking less than 600 mg/d of levodopa for up to 3 years with suboptimal symptom control to determine if the addition of ropinirole prolonged-release would result in comparable efficacy and decrease the incidence of dyskinesia compared with additional levodopa [50]. In this study, dyskinesia occurred in 17% of the additional levodopa group and only 3% of the ropinirole prolonged-release group. In addition, there were no differences in UPDRS activities of daily living or motor scores between the two groups. This study, in combination with the studies comparing initiation of treatment with pramipexole or ropinirole versus levodopa, suggests that regardless of whether initial treatment is with a dopamine agonist or levodopa, combining these two treatments while keeping the levodopa dose below 600 mg/d results in fewer motor complications.

The most common side effects with dopamine agonists are somnolence, dizziness, hallucinations, nausea, vomiting, and pedal edema. Studies have shown that excessive daytime sleepiness occurs in 8%–21% of patients taking dopamine agonists [51] and sudden, unexpected onset of sleep occurs in approximately 1% [52]. Impulse control disorders are another potential side effect of dopamine agonists including gambling, excessive shopping or eating, and increased or abnormal sexual behavior. It has been estimated that these behaviors occur in up to 13.6% of PD patients, but when examined more closely they occurred in 17% taking dopamine agonists compared with 7% with other PD treatments [53]. In fact, in one study, the reduction or discontinuation of dopamine agonists resulted in 100% of patients reporting a reduction or complete resolution of impulse control disorders [54]. In another study, patients taking a dopamine agonist and experiencing either hallucinations, impulse control disorders, excessive daytime sleepiness, or pedal edema significantly reduced their dopamine agonist dose and added an MAO-B inhibitor [55]. Of those patients with excessive daytime sleepiness, 94% reported a reduction or complete resolution as did 86% with hallucinations, 84% with impulse control disorders, and 74% of those with pedal edema. There was also a significant improvement in UPDRS motor scores and patient-reported quality of life. The potential for these side effects should be monitored; however, they should not preclude the use of dopamine agonists. Due to the increased potential for side effects with dopamine agonists, they are often avoided in elderly patients.

Other

Amantadine is used less commonly in early disease, as it is more effective in the treatment of dyskinesia [21]. Multiple double-blind studies of amantadine in early disease demonstrated mild to moderate improvement in PD symptoms compared with placebo; however, the majority of these studies had a duration of only 2–4 weeks [56]. In one 20-week study, benefit was greatest at 2–3 months and declined thereafter [57]. The most common side effects of amantadine include dizziness, insomnia, nervousness, livedo reticularis, hallucinations, pedal edema, constipation, and confusion which also limit its use.

Anticholinergics are rarely used in the treatment of PD, as they have only a mild effect, primarily on tremor, and have a poor side-effect profile. The most common side effects include confusion, hallucinations, memory impairment, constipation, blurred vision, and urinary retention. They should be avoided in elderly patients due to these side effects.

CONCLUSIONS

Although the accurate diagnosis of PD can be difficult, a physician experienced in the treatment of PD, the use of the UK PD Brain Bank criteria, and the use of the diagnostic tool, DaT-SPECT for difficult cases, can significantly improve diagnostic accuracy. In recent years, the management strategy for PD has changed from withholding treatment until the development of functional disability to initiating both nonpharmacologic and pharmacologic therapy much earlier. All patients should be advised to begin a regular exercise program as early as possible. Regarding pharmacologic therapy, the choice of medications is based on the individual patient's type and severity of symptoms, cognitive and psychiatric issues, employment status, and other aspects of lifestyle. Early treatment options include MAO-B inhibitors, dopamine agonists, levodopa, and rarely amantadine and anticholinergics. Multiple placebo-controlled studies of selegiline, rasagiline, pramipexole, ropinirole, and levodopa have demonstrated that patients initiating treatment with one of these medications have better motor function compared with those taking placebo. In addition, studies of rasagiline and selegiline have shown that patients that received treatment earlier did better than those receiving treatment later, an effect that has been shown to be maintained for up to 6.5 years.

A proposed management plan (see Figure 1) is to initiate nonpharmacologic treatment at the time of diagnosis. If there is no significant functional disability, an MAO-B inhibitor should be initiated. Mild functional disability could be treated with amantadine. As symptoms progress, in a younger patient (<70 years), a dopamine agonist could be added, later adding levodopa as needed. In an older patient (>70 years), someone with cognitive or psychiatric issues, or someone with significant comorbidities, levodopa rather than a dopamine agonist would be the treatment of choice. In addition, in a younger patient currently employed and concerned with maintaining a high level of function, levodopa rather than a dopamine agonist may be initiated. It is not uncommon to use all three classes of medication in the same patient such that levodopa can initially be kept at a lower dose in an attempt to delay motor complications and so that dopamine agonists can be kept at a lower dose in an attempt to avoid adverse effects.

FIGURE 1.  Proposed treatment algorithm.

Declaration of Interest: Dr. Lyons has served as a consultant for St. Jude Medical and Teva Neuroscience. Dr. Pahwa has served as a consultant or received research support from Acadia, EMD Serono, Impax, Medtronic, Merck Schering, Novartis, St. Jude Medical, Teva Neuroscience, and Xenoport.