The diagnosis of Parkinson's disease is predominantly clinical, based on a combination of the cardinal features of tremor, bradykinesia and rigidity. The differential essentially lies between other conditions resulting in tremor, of which essential tremor is the commonest, and other akinetic-rigid syndromes. These include progressive supranuclear palsy, multiple system atrophy, toxins and other degenerative disorders, including diffuse Lewy body disease and corticobasal degeneration. The key clinical features of these disorders and a practical diagnostic approach are briefly reviewed in this article.

Controversy over the etiology and pathogenesis of Parkinson's disease (PD) has continued for many years and while the details have changed, the uncertainty persists. Although heritability was most emphatically refuted a decade ago by many investigators, recent progress firmly indicates that genetic factors at least play a role, although probably to a variable degree from one individual to another. Evidence for a variety of other etiological factors is amassed from epidemiological studies, animal models, molecular and cellular biology. Genetic factors, infectious and immunological abnormalities, the effects of ageing, toxins (endogenous as well as exogenous) and other environmental factors may all contribute to the development of PD. Loss of nigral dopaminergic neurons may be mediated by varying combinations of oxidative free radical toxicity, impaired mitochondrial function, “weak excitotoxicity” and abnormal handling of cytoskeletal proteins, all of which may shift the balance regulating apoptotic cell death.

Parkinson's disease is a readily recognized clinical syndrome, characterized by resting tremor, rigidity, bradykinesia and loss of postural reflexes. The introduction of levodopa transformed our management of this disease. As our experience has increased the long term side effects of levodopa have become more apparent. Levodopa complications comprise: wearing off, motor fluctuations, and psychiatric complications. The complexity of these clinical phenomena has been worked out with time and is now well-recognized. A number of management strategies can ameliorate these long-term complications. This article reviews the current management of late-stage Parkinson's disease.

While dopamine agonists are still traditionally used as adjunct medications to improve performance and smooth out motor response complications in advanced levodopa-treated Parkinson's disease, they are increasingly used in monotherapy or early in combination with levodopa particularly in patients under 65 years of age. Long-term studies using bromocriptine showed efficacy in lowering the cumulative levodopa dose and reducing the early incidence of levodopa-related motor response complications. New dopamine agonists have recently shown efficacy as adjunct medications in short-term trials. While we now have more options to fit our individual patients' needs and tolerance, it is important to view the new agonists in the light of the results obtained with ergot derivatives. In this article, the rationale for use and efficacy profile of the ergolines are briefly reviewed.

Ropinirole and pramipexole are non-ergoline dopamine agonists which are relatively specific for the D2 family of dopamine receptors. They have side-effect profiles linked to peripheral and central dopaminergic stimulation, amenable to tolerance through a slow titration or the addition of domperidone in sensitive patients. They do not have the uncommon but problematic ergot-related side effects of bromocriptine and pergolide. Ropinirole and pramipexole have both been shown to be efficacious when used as monotherapy in early Parkinson's disease (PD), and have been suggested as being less likely than levodopa to lead to the early development of motor fluctuations and dyskinesias in this clinical setting. They have also been shown to be useful as adjunctive therapy to levodopa in advanced PD and to have a levodopa-sparing effect in these patients. Dose equivalents amongst the available dopamine agonists is difficult to know with certainty but has been estimated as follows: 30 mg of bromocriptine, 15 mg of ropinirole, 4.5 mg of pramipexole, and 3.0 mg of pergolide

The COMT inhibitors, tolcapone and entacapone, are a new class of Parkinson's medications. By inhibiting the enzyme catechol-o-methyl-transferase (COMT), they prevent peripheral degradation of levodopa, allowing a higher concentration to cross the blood-brain barrier. Pharmacokinetic studies have shown that both tolcapone and entacapone significantly prolong the elimination half life, and increase the area under the curve of levodopa without increasing C max. Clinical studies with COMT inhibitors have shown benefit in both stable and fluctuating PD patients with improvement in motor function with lower levodopa doses. Fluctuating patients also had increased “on” time and reduced “wearing off”. Side effects were most commonly related to increased dopaminergic stimulation. Specific side effects included diarrhea and elevated liver enzymes. The recent reports of three cases of fulminant hepatitis with the use of tolcapone has led many countries to remove this compound from their market. Concerns about a possible class effect should impose close monitoring of liver function tests with the use of any of the nitrocatechols.

The early treatment of Parkinson's disease continues to be controversial as our understanding of the etiology of the disease remains incomplete. Ideally an intervention that reverses or protects against further damage to dopaminergic neurons would be initiated once the symptoms of the disease are recognized. Unfortunately, there are no currently available therapies that have been shown to have a major impact on the progression of the disease. However, delaying effective symptomatic therapy beyond a point of significant disability does result in increased mortality. Concerns have been raised regarding the potential toxicity of levodopa on remaining nigral neurons. Although there is little support for this concept, levodopa is associated with important complications. The development of new symptomatic treatments has made the management of early Parkinson's disease even more complex and requires that many different factors be considered prior to initiating therapy in an attempt to minimize current and future disability caused by the disease and its treatment.

Despite optimization of medical therapy, a large number of patients with Parkinson's disease continue to be disabled. For this group, alternate treatment strategies such as neurosurgical intervention can be considered. Recent advances in neurosurgical techniques and in understanding the pathophysiology of motor disturbances in PD have made surgery safer and more effective. Functional neurosurgical procedures to lesion or electrically modulate dysfunctional basal ganglia circuits or to protect or restore dopaminergic transmission are being increasingly used. These procedures are having a profound impact on the motor disturbances of PD and are producing important improvements in quality of life of patients.

Over the past decade, management of Parkinson's disease has changed significantly due to the expansion of medical and surgical treatment modalities. Neurologists now have the ability (and the challenge) of choosing from multiple medications to devise an individual management strategy for each patient depending on his/her clinical symptoms and needs. Several different surgical therapies are also available. The topics covered in this supplement have highlighted the new options that are now available, as well as the treatments that have been in clinical usage. This review attempts to synthesize the information that is currently available in an attempt to help clinical neurologists make the appropriate choice for their patients.