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Motor symptoms in Parkinson's disease (PD) are caused by a severe loss of pigmented dopamine-producing nigro-striatal neurons. Symptomatic therapies provide benefit for motor features by restoring dopamine receptor stimulation. Studies have demonstrated that delaying the introduction of dopaminergic medical therapy is associated with a rapid decline in quality of life. Nonmotor symptoms, such as depression, are common in early PD and also affect quality of life. Therefore, dopaminergic therapy should typically be initiated at, or shortly following, diagnosis. Monamine oxidase-B inhibitors provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-term outcomes, making them an important first-line treatment option. Dopamine agonists (DAs) provide moderate symptomatic benefit but are associated with more side effects than levodopa. However, they delay the development of motor complications by delaying the need for levodopa. Levodopa (LD) is the most efficacious medication, but its chronic use is associated with the development of motor complications that can be difficult to resolve. Younger patients are more likely to develop levodopa-induced motor complications and they are therefore often treated with a DA before levodopa is added. For older patients, levodopa provides good motor benefit with a relatively low-risk of motor complications. Using levodopa with a dopa-decarboxylase inhibitor lessens adverse effects, and further adding a catechol-O-methyl transferase inhibitor can improve symptom control.
Recent neuropathological [Braak and Del Tredici, 2008; Minguez-Castellanos et al. 2007; Langston, 2006] and epidemiological [Boeve et al. 2007; Stiasny—Kolster et al. 2005; Abbott et al. 2001] studies suggest that Parkinson's disease (PD) onset may predate, perhaps by decades, emergence of motor symptoms. Premotor symptoms may include anosmia, constipation, sleep disorders, anxiety, and depression. Encouraging work to identify these early nonmotor symptoms; blood, urine, and cerebrospinal fluid biomarkers [Berg, 2008; Miyamoto et al. 2008; Schwarzschild et al. 2008]; and positron emission tomography (PET), single photon emission computed tomography (SPECT), and novel neuroimaging [Mehta et al. 2008] is ongoing, and in the future, a diagnosis of PD prior to the emergence of motor signs may be possible. For now, the clinical diagnosis remains based on the presence of the cardinal motor features on examination: bradykinesia, cogwheel rigidity, and rest tremor.
Today it is still common for treatment to be delayed by 9–12 months following diagnosis. Medical therapy may be delayed as a patient awaits neurological consultation, ancillary assessments, or a confirmatory opinion. Even after functional impairment emerges, some patients and their physicians choose to delay beginning dopaminergic medication for fear of adverse effects, polypharmacy, or the stigma of requiring daily medication. Waiting to introduce medication until there was ‘functional impairment’ became a standard strategy in the past due to concern about possible neurotoxic effects of LD and the development of levodopa-induced dyskinesia. However, no convincing laboratory or clinical evidence of levodopa neurotoxicity has emerged. Nonetheless, it is clear that earlier introduction of LD is associated with earlier emergence of dyskinesia [Schrag and Quinn, 2000; Grandas et al. 1999], and this may be of particular concern in younger patients [Hauser et al. 2006; Kumar et al. 2005; Kostic et al. 1991]. Other dopaminergic medications such as monoamine oxidase-B (MAO-B) inhibitors and DAs are also available. There is no concern about neurotoxicity with these medications, and MAO-B inhibitors alone do not cause dyskinesia while DAs alone cause dyskinesia only rarely. Because of this, MAO-B inhibitors and DAs are commonly used to treat early PD in younger patients for as long as they are able to provide good control of motor symptoms. Identification and treatment of other, nonmotor symptoms is also important, including depression, anxiety, fatigue, sleep disorders, cognitive impairment, visual dysfunction, seborrhea, paresthesia/pain, constipation, and bladder dysfunction [Friedman et al. 2007; Chaudhuri et al. 2006; Langston, 2006; Hillen and Sage, 1996; Witjas et al. 2002; Bodis-Wollner et al. 1984].
Prior to the discovery of dopamine, the treatment of early PD relied on anticholinergic medications and, later, amantadine. LD is the most efficacious medication for the treatment of motor symptoms of PD but its chronic use is associated with the development of motor fluctuations and dyskinesia. When administered by itself, LD causes prominent nausea and vomiting due to peripheral decarboxylation todopamine. LD isnow administered with a dopa-decarboxylase inhibitor such as carbidopa (CD) to greatly reduce nausea and vomiting. DAs, medications that directly stimulate postsynaptic dopamine receptors, were later developed as possible alternatives to LD. MAO-B inhibitors reduce dopamine catabolism thereby increasing synaptic dopamine concentration.
Anticholinergics, such as trihexiphenidyl, typically have modest effects on motor symptom control [Doshay et al. 1954]. They are now mainly used to reduce tremor in patients whose tremor is not adequately controlled by dopaminergic medications. Their effect on tremor may sometimes be robust, especially in younger onset, tremor-predominant cases. Unfortunately, increasing dosages are associated with limiting adverse effects, especially in older patients, making this class of medication less-commonly used. These adverse effects include cognitive impairment, dry mouth, blurred vision, constipation, and bladder dysfunction.
The antiviral medication, amantadine, continues to be useful in the treatment of early PD [Fahn and Isgreen, 1975]. Amantadine has a mild antiparkinson effect. Its mechanism of action is unclear, and may involve both anticholinergic and glutamatergic effects as well as increasing dopamine release. Symptoms may be controlled with amantadine monotherapy for approximately 6–12 months. It is typically well tolerated when used at a dose of 100 mg at breakfast and lunch. It should be used cautiously in older individuals and those with cognitive dysfunction as it can induce hallucinations. Since amantadine is mainly cleared renally, reduced creatinine clearance with aging or in chronic renal insufficiency may increase adverse effects, and require a lower dose of 100 mg once daily. Adverse effects of amantadine include hallucinations, confusion, constipation, pedal edema, and livedo reticularis.
Since the discovery of dopamine and recognition of its depletion in PD [Hornykiewicz, 1962; Carlsson, 1964; 1959], dopaminergic therapies have been the foundation of early PD treatment. LD, the precursor of dopamine, is administered orally, enters the circulation through intestinal transport in the proximal small-bowel, and readily crosses the blood-brain barrier, where it is converted directly into dopamine within presynaptic neurons. With landmark studies demonstrating its robust efficacy in PD [Birkmayer and Hornykiewicz, 2001; Cotzias et al. 1967; Hoehn and Yahr, 1967], and its subsequent combination with CD orbenserazide (peripheral decarboxylase inhibitors that limit conversion of LD to dopamine outside the brain)[Schwartz et al. 1973], it rapidly became the drug of choice, the ‘gold standard’ to treat PD with consistent efficacy and tolerability. Even after 40 years, LD/CD still remains a viable option to treat early PD. Its robust clinical effects, lower cost, and favorable side effect profile support its potential use as initial therapy. The main drawback of LD as initial therapy is the earlier development of dyskinesia, especially in younger patients [Hauser et al. 2006]. A recent study suggests that combining LD/CD with the catechol-O-methyl transferase inhibitor entacapone (LD/CD/EC) improves symptom control when used as initial therapy compared with LD/CD, although with an increase in some adverse effects [Hauser et al. 2009a].
Following its introduction in the late 1960s, LD use rapidly became widespread in both early and advanced disease simultaneously. Recognition of motor complications, especially troublesome dyskinesia in many advanced patients treated with LD, raised concern over its potential toxicity, precipitating the search for other agents to augment the dopaminergic system. Attempts to directly stimulate dopamine receptors in the early 1970s led to the development of the dopamine agonist bromocriptine [Lieberman et al. 1976; Goldstein et al. 1975], the subsequent development of pergolide, and then the newer non-ergoline DAs pramipexole [Shannon et al. 1997], ropinirole [Adler et al. 1997], and rotigotine [Watts et al. 2007].
Extensive work has since been done to investigate the role of DAs as monotherapy in the treatment of early PD. Initially, these drugs were studied to evaluate their efficacy in relation to LD. In early disease, they can provide antiparkinson benefit that is similar to that initially provided by LD. Many patients can be maintained on a DA for 1–4 years and then LD must be added to maintain good control of motor symptoms. Possibly related to their distinct pattern of dopamine-receptor subtype affinities, DAs may have a particularly good effect on tremor [Pogarell et al. 2002], depression [Rektorova et al. 2008; Barone et al. 2006; Lemke et al. 2005; Rektorova et al. 2003], and perhaps other nonmotor symptoms [Isaacson et al. 2008a].
Initiation of a DA prior to beginning LD delays the emergence of both dyskinesia and end-of-dose wearing off [Parkinson Study Group, 2000; Rascol et al. 2000]. This apparent benefit appears to persist through 5–10 years [Hauseret al. 2007]. Once LD is added, motor complications accumulate at the same rate, whether the patient was first treated with a DA and LD was added, or LD was used without a DA [Katzenschlager et al. 2008; Weiner and Reich, 2008; Constantinescu et al. 2007; Rascol et al. 2006]. Thus the benefit of DAs in delaying motor complications seems related to their ability to delay the need for LD.
Potential adverse effects of oral DAs have limited their use. While the early DAs (bromocriptine, pergolide) were ergolines with risk of ergot-induced fibrosis including cardiac valvulopathy, the newer DAs pramipexole, ropinirole, and rotigotine are non-ergot compounds, and presumably devoid of this potential risk [Zanettini et al. 2007]. Potential adverse effects of DAs include nausea, hypotension, pedal edema, somnolence, hallucinations, and impulse control disorders. Nausea and hypotension occur mainly during titration, and are minimized by starting at a low dose and slowly titrating upward. Doses used should not exceed those necessary to maintain good motor control. Despite adjustments in dosing, some patients cannot tolerate DAs. Edema, somnolence, hallucinations, and impulse control disorders may occur during introduction or after chronic treatment, even without a change in dose. These side effects are generally dose-related and may respond to lowering of the daily dose. Prior daytime somnolence or a history of a sleep disorder such as sleep apnea can predispose to intolerable excessive daytime somnolence. Orthostasis or low blood pressure can be exacerbated by DAs. Cognitive and memory impairment, when present, may be worsened. Impulse control disorders including pathologic gambling, shopping, sexual activity, and internet use may occur, and patients on DAs should be questioned about these behaviors. Newer once daily 24-hour preparations of DAs [Stocchi et al. 2008; Pahwa et al. 2007; Watts et al. 2007] with steadier plasma levels may have fewer peak adverse effects, and may be better tolerated even in the elderly [Isaacson et al. 2008b]. Thus, DAs provide significant antiparkinson benefit with fewer daily doses, but may have more side effects than LD. Their principal role in early PD is to delay the onset of motor complications, probably by delaying the use of LD.
The identification of selective MAO-B inhibitors that reduce the breakdown of dopamine in the brain, led to their use in PD treatment [Lees et al. 1977]. These medications enhance levels of dopamine in the synapse by inhibiting its clearance. There are presently three selective MAO-B inhibitors available: oral selegiline, orally disintegrating Zydis selegiline, and oral rasagiline. All three are approved as adjuncts to LD but only rasagiline is approved for use in early PD. However, studies also suggest some antiparkinson efficacy for oral selegiline in early PD. Rasagiline and oral selegiline provide mild symptomatic benefit in early PD, with patients returning to their baseline status in approximately 6–9 months [Parkinson Study Group, 2002; 1993]. When used as monotherapy in early disease, adverse effects are uncommon. The oral formulation of selegiline may cause insomnia, presumably related to its amphetamine metabolites.
There is great interest as to whether rasagiline and selegiline can provide a neuroprotective effect in PD or improve long-term outcomes. Both rasagiline and selegiline provide neuroprotective effects in cell culture and animal models [Youdim et al. 2001]. Several clinical trials now suggest the possibility of a neuroprotective effect in PD too. The DATATOP study found that compared with placebo, oral selegiline significantly delayed the need for LD therapy [Parkinson Study Group, 1993; 1989]. However, a modest symptomatic effect confounded assessment of potential neuroprotection. In patients who did not reach the need for LD therapy, once selegiline was added in patients who initially received placebo, there was a rapid ‘catch-up’ and the groups then progressed similarly [Parkinson Study Group, 1996]. More recently, a 7-year study of selegiline versus placebo as initial treatment was reported [Palhagen et al. 2006; 1998]. Patients could be treated with other medications as needed over time. Results demonstrated that patients receiving selegiline experienced statistically significantly less clinical decline and required less LD than patients receiving placebo.
Rasagiline has now been studied in two ‘delayed start’ clinical trials. In the TEMPO study [Parkinson Study Group, 2004], patients treated with rasagiline 1 or 2 mg per day for 12 months did significantly better than patients treated with placebo for 6 months followed by rasagiline 2 mg per day for 6 months. Moreover, at 5.5–6 years, patients treated with rasagiline from the beginning of the trial were still doing significantly better than patients initially treated with placebo [Hauser et al. 2009b]. More recently, rasagiline was studied in a very large and rigorous ‘delayed-start’ study (ADAGIO). In this trial, patients with early PD treated with rasagiline 1 mg daily for 18 months had statistically significantly less clinical decline than patients who received placebo for 9 months followed by rasagiline for 9 months [O lanow et al. 2008]. Thus, in these ‘delayed-start’ studies, patients treated after an initial delay did not catch up to the early treatment group suggesting benefits beyond a simple symptomatic effect. In these studies, rasagiline displayed the characteristics that would be expected of a neuroprotective medication. Nonetheless, it remains possible that the earlier introduction of any symptomatic medication will provide benefits that are not captured with later introduction, perhaps through maintenance of beneficial compensatory mechanisms or avoidance of deleterious compensatory mechanisms. This possibility can only be evaluated as results of other ‘delayed-start’ studies become available.
The goal of early therapy is to achieve and maintain good control of PD symptoms, and to maintain optimal activities, experiences, and overall quality of daily life. Non-pharmacologic therapies are important to incorporate early in the treatment plan. Daily exercise may help optimize mobility, flexibility, and stability. Proper nutrition, stress management, and coping techniques may be needed throughout the course of this chronic disorder. A multi-disciplinary team approach can help coordinate wellness strategies. It is also important to identify nonmotor symptoms of PD and treat them appropriately. Screening for mood and cognitive disorders can help identify these nonmotor symptoms earlier, as well as serve as a baseline for future assessments. Referral to a psychiatrist may be needed if depression or anxiety are problematic and persist despite dopaminergic replacement. Assessment of nonmotor symptoms should also include the various body systems. Constipation may require intensive treatment, including consultation with gastroenterology. A (neuro)ophthalmologist can assist with visual complaints of difficulty focusing when reading and with blepharitis. Urological consultation may be useful to address bladder dysfunction. A dermatologist can offer periodic screening for melanoma, as well as treatment for seborrheic dermatitis. Constitutional symptoms may be significant, including fatigue.
With regard to medical treatment of motor symptoms of PD, there is no single correct approach. However, recent studies have demonstrated that patient quality of life deteriorates quickly if treatment is not instituted at, or shortly after, diagnosis [Grosset and Schapira, 2008; Grosset et al. 2007]. In addition, a common-sense approach might suggest that it is easier to maintain good function than to allow disability to accumulate and then try to reduce it.
There are several guiding principles that can help physicians develop a medical treatment strategy for each individual patient.
The treatment of early PD is optimized by careful attention to non-pharmacologic wellness strategies coupled with an individualized approach to pharmacologic therapies. Nonmotor symptoms such as depression should be identified and treated. Treatment of motor symptoms should be introduced at, or very shortly after, the diagnosis is made. MAO-B inhibitors provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-term outcomes. The addition of a DA provides moderate symptomatic benefit and may delay the emergence of motor complications by delaying the need for LD. Emerging once-daily DA formulations may provide more consistent dopaminergic stimulation and improved tolerability. The eventual addition of LD/CD or LD/CD/EC typically provides robust symptomatic benefit.
Dr Isaacson has received honoraria and/or research grant support from the following pharmaceutical companies: Acadia, Allergan, Boehringer Ingelheim, Chelsea, Eisai, GlaxoSmithKline, Ipsen, Medtronics, Merck, Merz, Neurogen, Novartis, Ortho-McNeil, Pfizer, Santhera, Schwarz Pharma, Serono, Schering Plough, Solstice, Solvay, Teva, UCB Pharma, Valeant, Vernalis.
Dr Hauser has received honoraria from the following pharmaceutical companies for consulting, advisory or speaking service: Allergan Neuroscience, AlphMedica, ApotheCom, Axis Health Care, Bayer-Shering, Boehringer Ingelheim, CNS Schering Plough, Centopharm, Embryon, Eisai, Genzyme, GlaxoSmithKline, Impax, Ipsen Pharmaceuticals (formerly Vernalis), Kyowa Pharmaceutical, Merck, Novartis, Ortho McNeil, Pfizer, Prestwick, Quintiles, Santhera, Schwarz Pharma, Schering Plough, Solvay, Teva Neuroscience, Valeant, Vernalis (now Ipsen Pharmaceuticals).
Stuart H. Isaacson, Voluntary Assistant Professor of Neurology, University of Miami School of Medicine, Miami, FL; Director, Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA ; Email: gro.retneCsnosnikraP@noscaasi.
Robert A. Hauser, Professor of Neurology, Pharmacology and Experimental Therapeutics, Director, Parkinson's Disease and Movement Disorders Center, University of South Florida, Tampa, FL, USA.