Elsevier

The Lancet Neurology

Volume 3, Issue 8, August 2004, Pages 466-474
The Lancet Neurology

Review
Neuroprotection and pharmacotherapy for motor symptoms in Parkinson's disease

https://doi.org/10.1016/S1474-4422(04)00823-3Get rights and content

Summary

Parkinson's disease leads to major disability that impairs the quality of life of patients and leads to increased health-care costs. While there is no proven neuroprotective treatment, more basic-science research and clinical trials are needed to identify drugs that slow or halt the progression of the disorder. The mainstay of symptomatic treatment is levodopa. With long-term use, levodopa causes motor complications including involuntary movements and response fluctuations. These have lead to more cautious prescribing of levodopa. Dopamine agonists can be used as an alternative initial therapy to delay the onset of motor complications but at the expense of more dopaminergic adverse events, poorer control of motor symptoms, and increased cost. Once motor complications have developed, adjuvant therapy with dopamine agonists or entacapone can reduce off time and levodopa dose. Severe fluctuations that are not controlled by oral combination therapy can be controlled with subcutaneous apomorphine injections or infusions.

Section snippets

Differential diagnosis

Before treatment is started, it is of crucial importance to accurately differentiate idiopathic PD from disorders such as essential tremor, multiple cerebral infarct state, and drug-induced parkinsonism. Idiopathic PD must also be differentiated from Parkinson-plus syndromes such as progressive supranuclear palsy and multiple system atrophy;7, 8, 9 failure to do so can lead to a poor response to antiparkinsonian medication and inaccurate prognoses.

Poor differential diagnosis is a major problem

Definitions

The degeneration of dopaminergic neurons in PD leads to loss of the pathway from the substantia nigra to the corpus striatum. It is the deficiency of dopamine in the striatum that leads to most of the motor features of PD such as bradykinesia, hypokinesia, and rigidity. The aim of neuroprotective therapy is to prevent further dopaminergic cell death, thereby slowing or halting disease progression.18 “Neurorescue” is the salvage of dying neurons and may be part of the process of neuroprotection.

Symptomatic therapy

In the absence of neuroprotective therapy for PD, clinicians treat the motor and psychiatric symptoms of the disorder. At presentation, these symptoms are typically mild and include bradykinesia, rigidity, and unilateral rest tremor. In many patients disability does not significantly affect function, so symptomatic therapy can be avoided for 6–18 months.

Management algorithm

Providing a high quality evidence base for prescription in PD is a laudable goal but, in many cases, it has not helped the clinician. Many guidelines for PD management have been developed, few have used rigorous methodologies and many have been funded by the pharmaceutical industry.97, 98, 99, 100, 101, 102 The National Institute for Clinical Excellence is developing guidelines for the investigation and management of PD in England and Wales; these will be ready for consultation in July 2005 and

Future developments

The triple combination of levodopa, carbidopa and entacapone has recently been launched and rasagiline will probably be licensed for use in later PD in 2005. The non-ergot dopamine agonist rotigotine is highly lipophilic and has been formulated into a transdermal patch. This is the subject of phase III clinical trials after positive results in phase II studies.104, 105 By providing continuous 24 h dopaminergic stimulation, the rotigotine patch may be able to reduce motor complications but

Search strategy and selection criteria

Cochrane systematic reviews of PD therapy and reviews by a Movement Disorder, Society task force, published in Movement Disorders, formed the basis of this review. References were also obtained by searches of electronic databases, including MEDLINE and EMBASE, with the search terms “Parkinson's disease” and “Parkinson”. In most cases, only papers published in English since 1990 were reviewed.

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