Dr. Mark is associate professor in the Department of Neurology at UMDNJ-Robert Wood Johnson Medical School in New Brunswick, NJ.
Disclosure: The author reports no affiliation with or financial interest in any organization that might pose a conflict of interest.
Please direct all correspondence to: Margery H. Mark, MD, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, 97 Paterson St, New Brunswick, NJ 08901; Tel: 732-235-7729; Fax: 732-235-7041; E-mail: email@example.com.
In the last decade, enormous strides have been made in understanding and treating Parkinson’s disease (PD). PD is now recognized as more than just a disorder of the nigrostriatal dopamine system, with significant involvement of cognition, behavior, and mood. Progress in understanding the disease process itself has been made possible by the identification of genes causing PD (such as mutations in α-synuclein and parkin) and the implications for α-synuclein aggregation and impairment of the ubiquitin/proteasome pathway in cell death. Ultimately, knowing why the cells degenerate will allow targeted drug therapy and interrupt the process. The neurologic syndrome of PD is charactrerized by bradykinesia, rigidity, tremor, and in later stages, postural instability. PD must be differentiated from the “Parkinson-plus” syndromes of dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Levodopa remains the most efficacious treatment for the cardinal neurologic features of PD, but recent trends have turned to initial therapy with direct-acting dopamine agonists in younger patients. Peripheral inhibition of catechol-O-methyltransferase inhibitors allowing prolongation of levodopa action is another therapeutic alternative added in the last decade. An old drug, amantadine, has found new life in reducing dyskinesias, possibly through its mechanism as an N-methyl-D-aspartate receptor antagonist. Despite the popularity of treatment algorithms, there is no single, correct answer for treating PD. Medication regimens need to be individualized for all PD patients, focusing on the motor as well as cognitive function and dysfunction of the patient.
Parkinson’s disesase (PD) is a chronic, progressive neurodegenerative disorder, classically affecting the nigrostriatal dopaminergic system. Its primary pathology is loss of dopamine-producing cells in the pars compacta of the substantia nigra. Prevalence rates vary, but it is estimated that about 1 million Americans have PD, with an annual incidence of 50,000–60,000. The average age of onset is about 60 years with a slight male predominance; however, between 5% and 10% of patients may begin to exhibit symptoms before 40 years of age—defined as young-onset PD. The majority of patients in the United States with PD are ≥65 years of age, making it the second most common neurodegenerative disease of the elderly (after Alzheimer’s disease), which has a significant impact on the financial resources of a progressively aging population.1
Etiology and Pathogenesis
Evidence for both genetic and environmental factors in the pathogenesis of PD accumulates daily. Age-dependent genetic factors with cumulative environmental influences are most likely responsible for the majority of cases. Oxidative stress, mitochondrial dysfunction, and apoptosis have been implicated in cell death via both exogenous (eg, toxic) and endogenous (eg, genetic) mechanisms.2
In the last decade, multiple genes for PD have been identified (Table 1). The first, and possibly the most significant, was a mutation in the α-synuclein gene, termed the PARK1 gene, found in a large Italian family with autosomal dominant PD called the Contursi kindred.3-5 Since its initial identification in 1997, there have been two further point mutations as well as both gene triplication and duplication.6 A central role for α-synuclein in all patients with PD is suggested by its biochemistry. α-synuclein aggregates, or more specifically oligomeric aggregates called protofibrils, have been demonstrated to cause cell membrane (including mitochondrial membrane) disruption and cell death. It is a major component of Lewy bodies, the pathognomonic feature of PD. Aggregation is enhanced in an oxidative milieu (both in the presence of toxins and in endogenous systems), and overexpression of α-synuclein yields a clinical picture of parkinsonism in transgenic animal models.7
More commonly occurring mutations exist in autosomal recessive genes with early-onset PD, those for parkin (PARK2)8, DJ-1 (PARK7)9, and PINK1 (PARK6).10,11 Parkin is an enzyme in the ubiqitin/proteasome system, DJ-1 has a putative role in a cell’s oxidative stress response, and PINK1 is a mitochondrial protein kinase. In recessive disorders, loss of function results in loss of protective mechanisms provided by these enzymes.
The newest mutation to be reported, PARK8, is in the gene for the enzyme LRRK2 (leucine-rich repeat kinase 2) on chromosome 12p.12 LRRK2 encodes for a newly-described protein, dardarin, which appears to function as a tyrosine kinase. The reported mutations may have an activating effect on the kinase activity of LRRK2,13 thus expanding the pathogenetic possibilities to include phosphorylation of key proteins involved in PD. The clinical phenotype is fairly characteristic for typical PD, although the age of onset (35–78 years)14 and neuropathology15 are variable. This autosomal dominant mutation accounts for about 5% to 6% of familial and 1% to 2% of apparent sporadic cases, making it the most common known genetic cause of PD.16
Despite genetic heterogeneity, biochemical properties of the mutant genes suggest a common pathogenetic mechanism in PD. A likely scenario is that cell death results from common mechanisms (with or without mutations) involving either or both protein folding and degradation through the ubiquitin/ proteasome pathway as well as oxidative stress. Future drug therapy may be directed at these targets to slow down or even prevent cell death in both inherited and sporadic forms of PD.
Typical PD may begin with subtle, unilateral symptoms and signs such as unilateral hand tremor, decreased arm swing, micrographia, and loss of facial expression (hypomimia). Depression, anxiety, and sleep abnormalities may also be early complaints. The diagnostic criteria of PD (defined for research protocols to minimize inclusion of patients with atypical parkinsonisms) include the cardinal triad of rest tremor, akinesia or bradykinesia (lack of movement or slow movement), and rigidity, with two of the three required for diagnosis.17 Later in the disease, loss of postural reflexes may occur. PD typically begins unilaterally and usually remains asymmetric throughout the course of disease, often with the initially affected side showing greater severity of signs and symptoms. Course of disease is variable among patients, but is usually slowly progressive. While life-span is generally reduced, younger-onset patients may live for decades after the onset of symptoms with appropriate treatment.
The tremor of PD is most often seen when the body part is at rest, meaning it is not voluntarily activated and is completely supported against gravity. It is classically a 4-6 Hz rest tremor, but postural and simple kinetic tremor may also be seen. Tremor at rest is seen most easily when the patient’s hand is resting in his lap, or dangling freely while walking. It usually abates when the patient performs a purposeful movement. Rarely, some PD patients have a greater postural/kinetic tremor (and even rarer, only a posture/kinetic tremor). Tremor most often occurs in the hands, but may also affect the feet, lips, and jaw; it does not affect the head, neck, or voice as seen in essential tremor. Some patients may complain of the sensation of an internal tremor, even if it is not visible.18
The akinesia/bradykinesia is manifested by general slowing of movements, decreases in fine motor control and rapid alternating movements (eg, buttoning clothes, cutting meat), and hypomimia (mask-like faces), exempified by decreased blink rates. More problematic are the limitations in initiating movements (start hesitation). This includes getting out of a chair and walking. The gait is characterized by dragging a leg or short, shuffling steps. Pivoting while turning becomes difficult and they may need to take small, marching steps to complete a turn (turning en bloc).18
Rigidity, or “lead-pipe” rigidity, is a uniform increase in tone of a limb that is the same throughout the range of motion around a joint (eg, wrist, elbow, shoulder, knee). It should be differentiated from upper motor neuron spasticity in which there is a catch and release of tone. The term “cogwheeling” indicates tremor superimposed on tone and should be avoided.18
Postural instability gradually becomes a considerable problem in PD. Initially it may be manifested by minor retropulsion, in which the patient may stumble backwards or take multiple steps backward on pull test. Eventually, the patient will lose the righting reflex and be unable to prevent falling (usually backwards). In the latest stages, patients are unable to stand or walk without assistance and are unable to find their vertical position in space.18
Features Consistent With Parkinson’s Disease
Disorders of mood (depression, anxiety) and cognition, as well as psychosis (primarily visual hallucinations) are common in PD.18 Some patients with typical PD may have, either in the treated or untreated state, a secondary dystonia that is manifested generally by painful cramping of muscles. Curling of toes, especially upon rising in the morning (when the patient is at his lowest dopamine level), is typical, but cramping of calves, thighs, and the neck are also common. Non-motor features that are not inconsistent with PD include disorders of autonomic function manifested by orthostatic hypotension (usually asymptomatic in typical PD); sweating abnormalities; bladder dysfunction, such as urgency and frequency; impotence; and gastrointestinal complaints, such as abdominal bloating and constipation.18
The diagnosis of PD is almost exclusively clinical, based on history and neurological examination. Approximately 15% to 25% of patients with a parkinsonism will have an atypical parkinsonian syndrome.19 Appropriate inquiry should be made as to the medications that the patient is taking or has taken, as drug-induced parkinsonism is largely reversible. Vascular parkinsonism may be non-progressive or progress in a step-wise fashion; vascular risk factors will be present and prevention of further cardio- and cerebrovascular events may prevent further insult. Most of the rest of these atypical patients will have a primary neurodegenerative disorder. There are currently no reliable, commercially available tests that can diagnose PD or differentiate from the atypical neurodegenerative parkinsonisms or Parkinson-plus syndromes. “Red flags” that suggest an alternate diagnosis include early postural instability, absence of rest tremor, early dementia, rapid progression of symptoms, early or severe dysautonomia, and involvement of other neurologic systems (corticospinal tract involvement, peripheral neuropathy, supranuclear gaze abnormalities, cerebellar features). The primary neurodegenerative parkinsonisms include dementia with Lewy bodies (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).20 Tables 2–5 list the major clinical features of each of these disorders. Although tremor may occur in all four disorders (most prevalent in DLB, next in MSA, less common in PSP, and rare in CBD), it is less common than in PD.20 Except for DLB, the parkinsonism is generally unresponsive to treatment with levodopa.21
It has been estimated that at least 50% of substantia nigra pars compacta neurons are lost by the time of onset of motor symptoms of PD. There is also cell loss in the locus ceruleus, dorsal raphe nuclei, nucleus basalis of Meynert, and dorsal motor nucleus of the vagus. The pathognomonic feature of PD (as well as DLB) is the Lewy body, a characteristic cytoplasmic inclusion body. In DLB and PD-dementia, Lewy bodies are found diffusely throughout the brain, including the cortex.22
Immunocytochemical studies originally were not particularly helpful in characterizing Lewy bodies. They contained ubiquitinated protein, and unlike the neurofibrillary tangles of Alzheimer’s disease, PSP, and CBD, they are tau-negative. But in the last few years, following the identification of the first gene for PD as a mutation in α-synuclein, antibodies to this protein demonstrated highly sensitive staining of Lewy bodies.23 It is also nearly specific, as only the glial cytoplasmic inclusions seen in MSA are also synuclein-positive. PD, DLB, and MSA are now identified as synucleinopathies and are distinguished from the parkinsonism tauopathies, PSP and CBD.20
Treatment of Parkinson’s Disease
Early Stages of the Disease
When a patient first presents with motor symptoms of PD, there are several treatment options. If symptoms extremely mild (eg, the patient has a subtle, non-bothersome rest tremor and little else symptomatically), one may choose to delay therapy until a proven neuroprotective agent is available. A medication for mild symptoms may be in order, such as selegiline, a centrally-acting monoamine oxidase type B (MAO-B) inhibitor. Anticholinergic drugs are only effective for tremor and come with a host of side effects; these agents should be used with care and reserved for younger patients with pronounced, bothersome rest tremor. Certainly, if depression or anxiety are prominent complaints early on, they should be treated symptomatically.
Once a patient develops functionally disabling symptoms, however, therapy should begin with either a dopamine agonist or levodopa.24,25 Polytherapy is not needed in early PD, and indeed starting more than one medication simultaneously may be confusing if side effects ensue. Which drug to begin treatment with is largely a matter of choice. As a rule, many experts employ dopamine agonists as initial monotherapy in mild, younger-onset patients, whereas older patients or those with baseline cognitive difficulties should be started on a levodopa preparation from the beginning. Nevertheless, using agonists as first-line treatment continues to generate controversy, and many experts recommend more critical examination of this approach.25
Dopamine agonists have less antiparkinson effect than levodopa, but are less likely to cause dyskinesias and have a longer duration of action.26 Two ergot-derivative dopamine agonists, bromocriptine and pergolide, and two non-ergot drugs, pramipexole and ropinrole, are currently marketed in the US. Bromocriptine is seldom used anymore as it is the least potent of the agonists.26 The two non-ergot agonists are approved for treatment of both early (as monotherapy) and advanced disease (with levodopa).27 Long-term studies with pramipexole28 and ropinirole29 have shown ongoing improvement, although in all studies, levodopa remained more effective at all time points. Over time, virtually all patients on agonists require the addition of levodopa.
Side effects of dopamine agonists include nausea, somnolence and postural hypotension, confusion and toxic psychosis, and potentiation of dyskinesias in patients on levodopa. Sudden sleep attacks are an infrequent but real adverse effect of all dopaminergic drugs, most commonly seen with dopamine agonists.30 All patients on dopaminergic therapy who drive should be made aware of sedation and sleep attacks as side effects of their treatment. A recently reported, uncommon but increasingly recognized and potentially serious side effect of dopamine agonist therapy is pathologic gambling31—reduction of the agonist is invariably effective in eliminating the problem. Of increasing concern are recent reports of several cases of heart valvular disease, some requiring surgery, in patients on high doses of pergolide.32 It is suggested that all patients on pergolide undergo baseline echocardiographic evaluation with yearly follow-up, and discontinuation of the drug in patients with indication of valve abnormalities.
The most effective drug in treating PD is levodopa, the immediate precursor of dopamine, which crosses the blood-brain barrier. It must be used in combination with carbidopa, a peripheral decarboxylase inhibitor.26 Levodopa is effective for most patients during at least the first 5 years of treatment.33 Later, as the disease progresses, the duration of benefit from each dose may shorten (the “wearing off” effect), and still later some patients develop sudden, unpredictable fluctuations between mobility and immobility (the “on-off” effect). After about 5–8 years of levodopa therapy, patients may have either dose-related clinical fluctuations, dose-related dyskinesias (chorea, dystonia), or inadequate response (Table 6). Carbidopa/levodopa is available in an immediate-release (IR) and controlled-release (CR) form; either one may be used initially, and they may be used together for a quick “kick-in” (IR) and for more sustained serum levels (CR).
Side-effects of levodopa include anorexia, nausea, and vomiting, as well as orthostatic hypotension, vivid dreams, hallucinations, delusions, confusion, and sleep disturbance.
Levodopa has been implicated as a source of oxidative stress, but there is no clear evidence that the drug causes neurotoxicity in humans.34 A recent National Institutes of Health sponsored, double-blind study of levodopa versus placebo in early, mild PD patients demonstrated clear superiority of levodopa in a dose-dependent manner over placebo, including after two weeks of washout, indicating no clinical acceleration of disease.35
Advanced Stages of the Disease
Early in the illness, patients with Parkinson’s disease will respond with a smooth, stable improvement in symptoms and signs. With time, however, the therapeutic window narrows. Those on dopamine agonists as monotherapy will require addition of a levodopa preparation. Those already on levodopa may develop response fluctuations, beginning with simple wearing off. Strategies for compensating for these problems center around the concept of continuous dopaminergic stimulation.36 The levodopa dosage may be increased or the dosage interval may be narrowed to compensate for the shorter duration of response. CR may be added to IR preparations or vice versa. As peripheral methylation of levodopa decreases the available drug for transport from the gut to the blood, inhibition of intestinal catechol-O-methyltransferase (COMT) with entacapone or tolcapone allows for more sustained levodopa levels, decreasing “off” time (Table 6).27 If patients are not yet on an agonist, the addition of one of these drugs may also result in improved “on” time. An old drug, apomorphine, a non-specific dopamine agonist, can be used parenterally, and has recently been approved and marketed in a subcutaneous injectable form for rescue therapy for “off” periods in advanced PD.37
If dyskinesias develop, levodopa may be reduced while dosages of adjunctive drugs may be adjusted up or down as needed for reduction in fluctuations. Another old drug, amantadine, originally developed as an antiviral agent, has been used to treat mild symptoms of PD. More recently, it has also been found to be effective in reducing dyskinesias,38 probably via its putative mechanism as an antagonist of striatal interneuronal N-methyl-D-aspartate (NMDA) receptors.
For appropriate candidates (relatively young and healthy, cognitively intact, on optimal medication treatment, with significant fluctuations and dyskinesias), bilateral deep brain stimulation (DBS) of the subthalamic nucleus appears to be at least as effective as thalamic stimulation in controlling parkinsonian tremor, and has been shown to be more than twice as effective as pallidotomy in treating all the symptoms of PD.39 Bilateral stimulation improves tremor, rigidity, and bradykinesia, and allows sustainable post-operative reduction in levodopa dosage.40 Despite a more complex process for programming the electrical stimulator, DBS of the subthalamic nucleus has proven long-term efficacy and has supplanted all other surgical procedures. It is generally the current surgical treatment of choice for PD.41
Unfortunately, not all motor complications of PD respond to dopaminergic therapy. These exceptions include freezing of gait, falling and balance problems, and speech abnormalities. Non-motor complications, including psychiatric disorders as well as autonomic dysfunction (orthostatic hypotension, bladder frequency and urgency, impotence, and constipation) should all be addressed and treated symptomatically.
Despite the popularity of treatment algorithms, there is no single, correct answer for treating PD; any of the multiple treatment choices may be the right one for an individual, and indeed medication regimens need to be individualized for all PD patients. The most important principle in medication adjustment is to “start low and go slow.” The chief complaint of patients (eg, too much “off” time, disabling dyskinesias, or hallucinations) should be addressed first, and one new medication should be added or adjusted at a time, focusing on the drug interval as well as the dose. Finally, one should be alert for “red flags,” such as advanced age, vivid dreams, hallucinations, and confusion. When these problems occur or threaten, drugs with an unfavorable risk-benefit ratio should be reduced or eliminated first. These include anticholinergics, followed by MAO-B inhibitors, amantadine, dopamine agonists, leaving levodopa as monotherapy if necessary.
PD is a chronic, progressive neurodegenerative disease. The main pathology targets the nigrostriatal dopamine system, with the clinical hallmarks being motor signs and symptoms of rest tremor, akinesia, rigidity, and postural instability. More recent evidence shows that PD is a much more diffuse condition, with involvement of cognitive processes being the rule rather than the exception. Treatment of the motor disorder is aimed at replacing the dopamine deficiency with levodopa, the immediate precursor of dopamine that crosses the blood-brain barrier, and other strategies such as direct acting dopamine agonists, central MAO-B inhibitors, peripheral COMT inhibitors, and NMDA-receptor antagonists. Appropriate candidates may benefit from DBS of the subthalamic nucleus. Finally, the cause of PD remains to be elucidated, but clues from the first cloned genes in familial PD cases suggest that cell death results from common mechanisms involving the ubiquitin/proteasome pathway and oxidative stress. Future drug therapy may be directed at these targets to slow down or even prevent cell death in both inherited and sporadic forms of PD. PP
1. Lang AE, Lozano AM. Parkinson’s disease. First of two parts. N Engl J Med. 1998;339:1044-1053.
2. Huang Z, de la Fuente-Fernandez R, Stoessl AJ. Etiology of Parkinson’s disease. Can J Neurol Sci. 2003;30(suppl):S10-S18.
3. Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A large kindred with autosomal dominant Parkinson’s disease. Ann Neurol. 1990;27:276-282.
4. Polymeropoulos MH, Higgins JJ, Golbe LI, et al. A gene for Parkinson’s disease maps to 4q21-q23. Science. 1996;274:1197-1199.
5. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in alpha synuclein identified in families with Parkinson’s disease. Science. 1997;276:2045-2047.
6. Golbe LI, Mouradian MM. Alpha-synuclein in Parkinson’s disease: Light from two new angles. Ann Neurol. 2004;55:153-156.
7. Mouradian MM. Recent advances in the genetics and pathogenesis of Parkinson disease. Neurology. 2002;58:179-185.
8. Lücking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson’s diesase and muations in the parkin gene. French Parkinson’s Disease Genetics Study Group. N Engl J Med. 2000;342:1560-1567.
9. Bonifati V, Rizzu P, Squtieri F, et al. DJ-1 (PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci. 2003;24:159-160.
10. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304:1158-1160.
11. Hatano Y, Li Y, Sato K, et al. Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol. 2004;56:424-427.
12. Paisan-Ruiz C, Saenz A, de Munain AL, et al. Familial Parkinson’s disease: clinical and genetic analysis of four Basque families. Ann Neurol. 2005;57(3):365-372.
13. Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet. 2005;76(4):672-680.
14. Di Fonzo A, Rohe CF, Ferreira J, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease.[see comment]. Lancet. 2005;365(9457):412-415.
15. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. [see comment]. Neuron. 2004;44(4):601-607.
16. Brice A. How much does dardarin contribute to Parkinson’s disease? Lancet. 2005;365:363-364.
17. Ward CD, Gibb WR. Research diagnostic criteria for Parkinson’s disease. Adv Neurol. 1990;53:245-249.
18. Paulson HL, Stern MB. Clinical manifestations of Parkinson’s disease. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. 2nd ed. New York: McGraw-Hill, 2004: 233-245.
19. Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-184.
20. Mark MH. Lumping and splitting the Parkinson plus syndromes. Neurol Clin. 2001;3:607-627.
21. Louis ED, Klatka LA, Liu Y, et al. Comparison of extrapyramidal features in 31 pathologically confirmed cases of diffuse Lewy body disease and 34 pathologically confirmed cases of Parkinson’s disease. Neuology. 1997;48:376-380.
22. Lowe J, Lennox G, Leigh PN. Disorders of movement and system degeneration. In: Graham DJ, Lantos P, eds. Greenfield’s Neuropathology. London: Arnold, 1997:285-290.
23. Spillantini MG, Schmidt ML, Lee VM, Troganowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839-840.
24. Miyasaki JM, Martin W, Suchowersky O, et al. Practice parameter: Initiation of treatment for Parkinson’s disease: An evidence-based review: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2002;58:11-17.
25. Wooten GF. Agonists vs levodopa in PD: the thrilla of whitha. Neurology. 2003;60:360-362.
26. Poewe W, Granat R, Geser F. Pharmacologic treatment of Parkinson’s disease. Disorders: Neurologic Principles and Practice. 2nd ed. New York: McGraw-Hill, 2004:247-271.
27. Lambert D, Waters CH. Comparative tolerability of the newer generation antiparkinsonian agents. Drugs Aging. 2000;16:55-65.
28. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. JAMA. 2000;284:1931-1938.
29. 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.
30. Paus S, Brecht HM, Koster J, Seeger G, Klockgether T, Wullner U. Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson’s disease. Mov Disord. 2003;18:659-667.
31. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology. 2003;61:422-423.
32. Van Camp G, Flamez A, Cosyns B, Goldstein J, Perdaens C, Schoors D. Heart valvular disease in patients with Parkinson’s disease treated with high-dose pergolide. Neurology. 2003;61:859-861.
33. Koller WC, Hutton JT, Tolosa E, Capildeo R, the Carbidopa/Levodopa Study Group. Immediate-release and controlled-release carbidopa/levdopa in PD. A 5-year randomized multicenter study. Neurology. 1999;53:1012-1019.
34. Agid Y, Chase T, Marsden D. Adverse reactions to levodopa: drug toxicity or progression of disease? Lancet. 1998;351:851-852.
35. Parkinson Study Group. Does levodopa slow or hasten the rate of progression of Parkinson disease? The results of the ELLDOPA trial. Neurology. 2003;60:A80-81.
36. Sage JI, Mark MH. The rationale for continuous dopaminergic stimulation in patients with advanced Parkinson’s disease. Neurology. 1192;42(Suppl 1):23-28.
37. Dewey RB, Jr, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol. 2001;58:1385-1392.
38. Verhagen Metman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology. 1998;50:1323-1326.
39. Esselink RA, de Bie RM, de Haan RJ, et al. Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial. Neurology. 2004;62:201-207.
40. Kleiner-Fisman G, Fisman DN, Sime E, Saint-Cyr JA, Lozano AM, Lang AE. Long-term follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease. J Neurosurg. 2003;99:489-495.
41. Rodriguez-Oroz MC, Zamarbid eI, Guridi J, Palmero MR, Obeso JA. Efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson’s disease 4 years after surgery: double blind and open label evaluation. J Neurol Neurosurg Psychiatry. 2004;75:1382-1385.