Neurological Rehabilitation of Parkinson's Disease

Diane Playford

• Publisher: CRC Press
• Year: 2003
• Print ISBN:
  9781841842974
• eBook ISBN:
  9781135411404
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

The rehabilitation of Parkinson's disease patients comprises various forms of therapy: physical, speech and psychosocial therapy. Physical rehabilitation is used in conjunction with various anti-parkinsonian agents as a non-pharmacological treatment for Parkinson's disease. This book explores the long-term and short-term benefits of physical therap

1
The Pharmacological Management of Parkinson’s Disease

Maria Bozi and Kailash P Bhatia

Introduction

Parkinson’s disease (PD) is one of the commonest neurodegenerative diseases and amongst the commonest causes of disability in the elderly.

About 1% of the population over the age of 65 is affected by Parkinson’s disease. This ratio rises to 2% in the population over 80 years of age.¹

PD is characterised by a triad of motor symptoms, namely bradykinesia, rigidity, resting tremor. Pathologically, it is characterised by a progressive loss of the dopaminergic neurones in the substantia nigra that project into the striatum, resulting in a state of dopamine deficiency in the caudate and putamen. Lack of dopamine is the cause of the main motor symptoms of the disease, which classically involve tremor, rigidity and bradykinesia. It is widely accepted that the pathological process extends beyond the basal ganglia and affects other CNS neuronal populations that utilize other neurotransmitters such as serotonin (raphe nuclei), norepinephrine (locus ceruleus) and acetylcholine (pedunculopontine nucleus). The involvement of these non-dopaminergic pathways is believed to account for the non-motor symptoms of PD, as well as for symptoms that do not respond to dopaminergic medication. These symptoms include postural instability, freezing, alterations of mentation, behaviour and mood, sleep disorders and autonomic dysfunction. The cause of PD is uncertain but both genetic and environmental factors seem to contribute to its pathogenesis in the majority of cases.^1,2

The management of PD is complex since the clinician has to deal with a chronic and progressively disabling disease with a large spectrum of motor and non-motor symptoms. Superimposed on the symptoms of the disease are early and late side-effects of medication.

Four different clinical stages can be recognized throughout the course of the disease.³ The first stage of diagnosis is followed by the stage of maintenance during which a good control of the patient’s symptoms is achieved without complications. The complex stage is characterized by the presence of complications such as motor fluctuations, dyskinesias and other non-motor symptoms. The last is the palliative stage where therapeutic interventions no longer offer adequate symptomatic control and the patient is severely disabled.

The main goal of the palliative stage is to prevent the complications of immobility, to maintain the social integration of the patient and to reduce the psychological distress of the patient and carer. Medical interventions differ between the early (diagnostic and maintenance) and late (complex and palliative) stages of the disease.

Management of Early-stage Disease

At this stage patients are first informed about the diagnosis. Because of the chronic nature of the disease and the disability that it implies the communication of the diagnosis is stressful. Intervention at this stage aims to facilitate the acceptance of the diagnosis and to reduce stress as well as to relieve symptoms. Provision of accurate and sensitive education to patients and their families, support services and the introduction of patients to specialist nurses, when available, are very important to help patients understand the disease and reconcile themselves with their emerging needs and perspectives. Early education programmes, which include informing patients about services and rehabilitation therapies and their roles are essential. These topics are discussed in more detail in Chapters 3 and 4. Pharmacological treatment should ideally aim to prevent the progression of the disease, relieve symptoms and reduce the risk of motor complications.^4,5

Prevention of Disease Progression

Prevention in PD should slow down, stop or even reverse the process of neuronal death.

Many factors have been implicated in the pathogenesis of PD including oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium dysregulation and inflammation.⁶

Agents that interfere with any of these factors could potentially provide neuroprotection; several compounds have been tested but no definite conclusions could be drawn. One limitation is the lack of a method to measure neuronal death in vivo since it is uncertain how clinical symptoms correlate with the degree of neuronal loss. Moreover, it is difficult to separate symptomatic from neuroprotective effects clinically.⁷ Lately, imaging techniques, such as fluorodopa PET and β-CIT SPECT have been used as objective measures of the progression of the disease, but such endpoints are still exploratory.

Potential neuroprotective agents that have been or are being currently tested include:

• vitamin E (tocopherol) and selegiline because of their antioxidant effects;
• riluzole, an inhibitor of glutamine release and remacemide, a glutamine antagonist, both agents that block glutamatemediated toxicity;
• anti-inflammatory compounds such as cyclooxygenase-2 inhibitors;
• antiapoptotic drugs including the caspase inhibitor minocycline;
• co-enzyme Q, a compound that acts as a cofactor for mitochondrial complex I. Recently, a study has shown a delay in disease progression in early-stage patients who were treated with co-enzyme Q but further studies are required before any conclusions can be drawn.⁸

Selegiline was one of the first drugs to be tested because of its ability to inhibit the MAO-B-mediated metabolism of dopamine and the formation of free radicals. It is also thought to have antiapoptotic effects. The delay in the need for levodopa that was noticed in one study in the selegiline group (compared with placebo) was initially interpreted as neuroprotection. However, the current conclusion from the clinical trials with selegiline is that the drug has a mild symptomatic effect, enough to delay the need for levodopa.^9,10

Lately there has been a growing interest in the putative neuroprotective properties of the dopamine agonists.¹¹ These agonists could provide protection through several mechanisms by inducing:

• levodopa-sparing effect;
• decreased dopamine synthesis, release and metabolism by the activation of dopamine autoreceptors;
• direct antioxidant effects;
• receptor-mediated anti-apoptotic effects;
• inhibition of excitotoxicity mediated by overactivity of the subthalamic nucleus.¹²

Several prospective clinical trials have been initiated to assess the putative effect of dopamine agonists on the rate of progression of PD using clinical and imaging endpoints. Both CALM-PD and REAL-PET studies have demonstrated a slower progression of the disease in patients receiving pramipexole or ropinirole, respectively, compared to levodopa.^13,14 However, as discussed above, the design of the trials to show neuroprotection in PD is controversial and the use of SPECT or PET as endpoints is still exploratory.

At present, despite the increasing interest and the growing body of information, there are insufficient data to recommend any specific regimen for neuroprotection.⁸

Initiation of Symptomatic Therapy

As long as no convincing neuroprotective agent is yet available, treatment is considered when symptoms of PD cause functional disability. Functional impairment should be defined on an individual basis because there are different functional implications for different patients depending on age, profession and lifestyle. Once the initiation of treatment has been agreed, the choice of drug becomes the main issue.¹⁵ The goal of the treatment should be to offer good symptomatic control with a reduced risk of late motor complications. Different options are available, as listed in Box 1.1.

Box 1.1 Drugs that could be used as initial therapy in Parkinson’s disease

• Dopamine agonists
• Anticholinergics
• Amantadine
• Selegiline
• Standard-release levodopa
• Controlled-release levodopa
• Standard- or controlled-release levodopa + COMT inhibitor

Amongst them, dopamine agonists and levodopa are the ones that give the best control over parkinsonian symptoms.

Levodopa

Levodopa remains the gold standard treatment for PD.¹⁶ Its dramatic clinical effect in PD was first demonstrated in 1967, when high doses were used by Cotzias.¹⁷

Levodopa is the immediate precursor of dopamine and its use replaces the endogenous deficient neurotransmitter.

It is absorbed from the duodenum and penetrates to a certain degree the brain through the blood–brain barrier. In the brain it is converted to dopamine by the enzyme dopa decarboxylase, which is located in the remaining dopaminergic terminals and in extradopaminergic glial and neuronal compartments. Levodopa is combined with the peripheral dopa decarboxylase inhibitors benserazide or carbidopa, which inhibit the conversion of levodopa to dopamine peripherally. Peripheral dopaminergic adverse effects, such as nausea, vomiting and postural hypotension, are thus reduced, central delivery is amplified and the dose of levodopa can be decreased. Levodopa has a short plasma half-life of about 60 to 90 minutes.

Levodopa improves, often dramatically, parkinsonian signs and symptoms, functional disability and perhaps even survival.^18,19 The drug is well tolerated with few side-effects, the commonest ones being nausea, postural hypotension and psychiatric symptoms. Following its initiation, there is a period of sustained uncomplicated response – the ‘levodopa honeymoon’ – although unfortunately the excellent response is not maintained.²⁰ After several years of treatment, patients begin to experience response fluctuations and dyskinesias, which are very disabling and difficult to treat.

Several presynaptic and postsynaptic mechanisms are believed to be involved in the pathogenesis of motor complications. The most important ones are the pulsatile non-physiological stimulation of the dopaminergic receptors and the subsequent modulation of many downstream neurotransmitter systems.^21,22 The continued loss of dopaminergic nerve-endings associated with the progression of the disease results in the loss of the storage sites of dopamine formed from levodopa. The formation and release of dopamine shifts to non-dopaminergic compartments that lack the vesicular storage apparatus. Thus, formation of dopamine and receptor stimulation oscillates in parallel with plasma and striatal levodopa levels and so the buffering effect is lost. The short plasma half-life of levodopa contributes to the oscillatory nonphysiological stimulation of the dopaminergic receptors. It has also been suggested that motor complications might even be primed by the first doses of levodopa.²³ It is postulated that continuous dopaminergic stimulation from the early phase of treatment will reduce the likelihood of developing motor complications. Therefore motor complications could be prevented or delayed by postponing the initiation of levodopa.

However, the role of levodopa for induction of motor complications remains a matter of controversy.²⁴ Several studies suggest that the degree of the nigrostriatal degeneration and the way dopaminergic agents are administered are t...

Table of contents

• Cover Page
• Title Page
• Copyright Page
• Contributors
• Series Preface
• Preface
• 1: The Pharmacological Management of Parkinson’s Disease
• 2: The Psychosocial Impact of Parkinson’s Disease and its Clinical Management
• 3: Non-Pharmacological Therapies
• 4: Developing and Delivering Services
• 5: Evaluating the Outcome of Rehabilitation Interventions
• 6: Future Directions: The Potential for Recovery and Repair