Parkinson's disease

Treatment

Despite intensive research, there is as yet no treatment that will reliably prevent the onset of Parkinson’s disease (PD), arrest its progression when clinically manifest or reverse the degenerative process. That said, the ongoing research effort does seem to illuminate promising possibilities in the near future.

Whilst management of PD has changed over the past years, it remains anchored in:

• pharmacological management of the symptoms of PD (see Table 6)
• pharmacological and, in refractory cases, surgical management of the complications of the symptomatic treatments
• pharmacological management of the non-motor complications and comorbidities of PD
• physical, psychological and social support for the victims of PD and their carers.

Whilst research to extend the effectiveness and to limit or abolish the adverse consequences of chronic treatment has had some success over recent years, the ideal agent to arrest or reverse the degenerative process of PD remains elusive. A recent review of the management of PD (Goetz et al, 2002) found no convincing evidence for neuroprotective properties of any current treatment (see Table 7).

Therefore, the objectives of treatment are – as far as possible – to limit the impact of the motor symptoms of PD and to avoid the complication of chronic symptomatic management. Overall, however, the main objective of treatment is to preserve for as long as possible the quality of life of the person with PD.

Achievement of these objectives involves a balancing act with some key decision points; in particular:

• when active management should begin
• what agent(s) to use at what stage of the disease
• if and when to take radical procedures.

In the clinical management of PD it is vital that the person with PD and their carers are actively involved in all key therapeutic decisions, to achieve optimal results. Consequently, the first priority is to establish trust, confidence and effective rapport with the patient, who will need to understand the importance of his or her evaluation of the effects of treatment and PD. Patient education will prove critical and it is up to the therapist to provide the necessary information or sources of information.

Initiation of Active Treatment

Starting active treatment is as critical as any other therapeutic decision that will be made during management of a patient with PD. Whether or not active treatment should begin will depend upon the individual patient’s circumstances, including age and employment. It is equally important both at this stage and throughout treatment that the patient is intimately involved in the decision and understands the pros and cons in addition to the degree of uncertainty of diagnosis and long-term prognosis.

Management of individuals often depends more heavily upon clinical judgement than on evidence from clinical trials. Whilst distinctions between age groups are often suggested, it is more important to consider the physiological rather than the chronological age of patients.

There is no convincing evidence that early treatment with any drug delays progression of PD and little evidence to suggest that treatment is beneficial before symptoms have a significant impact on the functioning and quality of life of the person with PD. In the absence of evidence to the contrary, early PD is probably best left untreated but regularly reviewed.

Inevitably, however, PD will begin to interfere with functioning and symptomatic treatment is necessary.

Pharmacological Treatment

Levodopa, which remains the mainstay for the management of PD in the longer term, is essentially a pro-drug; that is itself inactive, but after penetrating the blood-brain-barrier (BBB) is metabolised to dopamine. It is, however, readily metabolised in the periphery (first-pass metabolism), seriously reducing the amount of levodopa available to the central nervous system (see Figure 2). Coupled with a very short half-life of 60-90 minutes, it is very difficult to provide a relatively constant and physiological supply of dopamine to the striatum.

Three main approaches have been taken to try to even out the ‘lumps’ inherent in repeated dosing of levodopa:

1. Suppress one or other route of metabolism – peripheral or central metabolism.
2. Use a controlled-release form of levodopa.
3. Use many smaller, divided doses. This approach can result in sub-therapeutic doses unless the total daily dose is increased, and a dosing regimen that may invite non-compliance.

Levodopa crosses the gut wall via the aromatic and branched-chain ‘L’ amino acid transporter system whereupon most of it is decarboxylated in the periphery – leaving very little to reach the cerebral circulation. It has been estimated that as little as 1% actually crosses the BBB to reach the striatum. Consequently, levodopa is given together with a peripheral decarboxylase inhibitor such as benserazide or carbidopa that inhibits peripheral dopa decarboxylase, thus allowing much more levodopa to reach and cross the BBB.

Although a decarboxylase inhibitor helps place levodopa into the circulation, much of it still metabolised in the periphery (first-pass metabolism) via the catechol-O-methyltransferase (COMT) pathway (see Figure 2).

Whilst levodopa remains the most effective treatment for the management of the motor symptoms of PD, all patients are at risk for complications in the longer term. Consequently, patients with early onset PD (EOPD), who are at particular risk for response fluctuations (91% after 5 years, 100% after 10 years), should be started on a dopamine agonist with other possibilities noted more or less in order of preference (see Table 7). Treatment of young patients should not be started with levodopa.

Other agents for the treatment of PD include:

• dopamine agonists
• monoamine oxidase-B (MAO-B) inhibitors
• amantidine
• anticholinergics (if tremor  is predominant)
• COMT inhibitors.

Dopamine Agonists
Dopamine agonists act directly at dopamine receptors in the striatum, thereby bypassing any need for metabolic conversion or storage. They are, after levodopa, the most effective treatment for PD and are probably preferred as the initial treatment in most cases. Six are currently available:

• bromocriptine
• cabergoline
• lisuride
• pergolide
• pramipexole
• ropinirole.

Evidence from studies of the newest of these, ropinirole, provides the strongest evidence in favour of the dopamine agonists as first-line therapy in people with PD. In a 3-year comparison of ropinirole with bromocriptine (Korczyn et al, 1999), 60% and 55%, respectively, of patients completed the trial period on the agonist alone with only 3% developing dyskinesias in either group. Motor and Activities of Daily Living scores were superior in the ropinirole group at the end of the study. These studies show that monotherapy with dopamine agonists during the early years of PD are practical, safe and efficacious and should be seriously considered as the treatment of choice.

The advantage of dopamine agonists may derive from their kinetic profiles, which typically show a half-life 4–5 times longer than levodopa; this should lead to less variable stimulation of striatal receptors. Dopamine agonists have also proved useful as adjunct therapy in late-stage PD, reducing the dose of levodopa needed, increasing ‘on’ time and reducing dyskinesias. Whether or not combination therapy with low-dose levodopa and a dopamine agonist could further delay the onset of treatment complications has not been determined.

Finally, it should be noted that apomorphine delivered subcutaneously or by infusion pump may be used, especially in late-stage disease to treat ‘sudden offs’. Apomorphine is not recommended for initial therapy.

Monoamine Oxidase-B inhibitors
These drugs improve dopamine supply by inhibiting the activity of this metabolic pathway. Among this class of drugs the most extensively studied and widely used is selegiline. Although there is some evidence to suggest that selegiline may have a neuroprotective effect, this has not been clinically confirmed.

Consequently, the use of selegiline as monotherapy is – like amantadine – limited to younger patients with early disease and without disabling symptoms. High doses (>30 mg/day) must be avoided as ensuing MAO-A inhibition may lead to dietary interaction and hypertensive crisis (the ‘cheese effect’). Normal doses of 5–10 mg/day, preferably given in the morning to avoid sleep disturbance should be used.

MAO-B inhibitors are useful as adjuncts to levodopa as they can effectively inhibit the extensive peripheral metabolism of levodopa, thereby allowing maintenance of therapeutic effects with reduced doses of levodopa.

Amantadine
Also indicated as an antiviral, the anti-PD mechanism of action of amantadine is unknown, although it has known anticholinergic properties and reports suggest that it may release dopamine from central neurons , delay dopamine uptake by neural cells, and block NMDA receptors.

In people with mild PD symptoms, amantadine alone can improve symptoms and is considered useful as an adjunct to levodopa in late-stage disease. The effect is modest, but can diminish all the cardinal features and can decrease dyskinesias.

Anticholinergics
PD leads to an acetylcholine–dopamine imbalance in the striatum due to the depleted supply of dopamine. Anticholinergics (commonly used before the advent of levodopa) can to a degree redress the balance and improve symptoms of PD – principally tremor. However, some individuals show highly variable responses to anticholinergic therapy. Anticholinergics should be avoided in elderly patients due to side effects – especially confusion and other cognitive symptoms.

Catechol-O-methyltransferase Inhibitors
The COMT inhibitors tolcapone (peripheral and central inhibition) and entacapone (peripheral inhibition) have been used to increase the half-life of levodopa. Tolcapone has now been withdrawn from most markets due to an association with hepatotoxicity, but is available in some countries on a ‘named patient’ basis. The COMT inhibitors have no effect as a monotherapy and should be used in combination with levodopa to decrease levodopa requirements, decrease ‘off’ time and improve motor symptoms.

The other main approach for improving the duration of levodopa effect is the development of a controlled-release (CR) formulation of the levodopa/dopa decarboxylase combination. The CR formulation has proved equally safe and effective in a 5-year comparison against the standard formulation (Koller et al, 1999) and Activities of Daily Living scores on the UPDRS favoured the CR formulation.

Continuing Treatment

After initiation of treatment, regular review is needed to optimise therapy. Many people with PD will be able to modify their regimens to best match their own situations and should be encouraged in this partnership whenever possible.

Complications of Treatment

Given the relentless progression of PD, it is inevitabke that complications will arise. These include:

• fluctuations of response, including dose-related, ‘wearing-off’ and ‘on/off’ fluctuations
• orthostatic hypotension
• gastrointestinal problems
• dyskinesias
• drug failure
• freezing
• postural instability
• gait disturbances.

Fluctuations of Response
Dose-related. Various pharmacokinetic and pharmacodynamic effects can lead to fluctuations of response to levodopa. These include factors that affect gastric emptying such as acidity, anticholinergics and food. Treatment-related changes in the central nervous system may also affect the pharmacodynamics of levodopa. Such factors as reduced striatal storage of dopamine, damage to dopaminergic neurons by toxic byproducts of dopamine metabolism or altered dopamine receptors may be involved.

‘Wearing-off’. This is the most frequent fluctuation and is characterised by shorter periods of benefit following each dose of levodopa. ‘Wearing-off’ is a regular and predictable phenomenon linked with nigro-striatal system degeneration and reflects the extent of nigrostriatal dopamine system loss.

‘On/off’. With time and further neuronal degeneration, the relatively predictable ‘wearing-off’ fluctuations can give way to the abrupt and unpredictable ‘on/off’ phenomenon, which is characterised by sudden and unpredictable shifts between the ‘on’ and ‘off’ states, together with dyskinesias. During this phase, people with PD may show sensory, psychiatric and autonomic symptoms. They may complain of pain, parasthesias, sweating, constipation or shortness of breath, generally during the ‘off’ times. ‘On/off’ fluctuations appear to be associated with a lowered threshold for dyskinesias.

Management of motor fluctuations can involve delicate balancing of regimen, doses and drugs. The objective is to obtain maximum effect without over-shoot – achieving this is not simple.

When the problem appears to be related to half-life, adjunct dopamine agonists are likely to help smooth the fluctuations and adjusting the relative doses of agonist and levodopa should give optimal effect with acceptable tolerability. COMT inhibitors or selegiline may also prove useful for controlling ‘wearing-off’ phenomena.

Orthostatic Hypotension
Orthostatic hypotension is common in PD – arising from either the disease or its treatment, or both. Although most medications used in PD can cause or exacerbate the problem, the dopamine agonists are most likely to cause orthostatic hypotension. If the typical light-headedness upon arising or standing is mild, it may be managed by taking care to avoid sudden changes in posture from supine to erect, whilst also ensuring also some steadying support.

If the problem is severe, one of the pharmaceutical agents that raise blood pressure can be used, but these may cause problematic side-effect in elderly people with PD, such as oedema, symptoms of congestive heart failure or supine hypertension. The peripheral dopamine blocker domperidone has been reported to have positive effects on orthostatic hypotension in people with PD.

Gastrointestinal Problems
Constipation due to decreased gut motility secondary to autonomic dysfunction is a frequent complaint of people with PD. It can be exacerbated by most anti-PD medications as well as by low dietary fibre, inadequate fluids and lack of exercise. Correction of these should help alleviate the problem. Bulking agents, stool softeners (eg docusates) or, in severe cases, enemas can all be considered in addition to agents that hasten gastric emptying.

Nausea is an adverse effect of all the dopaminergic agents. Taking levodopa with food may help, but this approach can also lead to drug failures if absorption is overly diminished. Domperidone has also been found to be very effective in relieving nausea in people with PD.

Dyskinesias
Dyskinesias in PD may involve either involuntary movement (dystonia) or difficulty with voluntary movements. It is a common feature of PD and may be related to inadequate treatment or the disease itself. Dyskinesia is usually associated with peaks in the levodopa kinetic profile, but may occur sometimes between the ‘on’ and ‘off’ phases of fluctuating response.

Levodopa-induced dyskinesias can be divided into three main classes:

• ‘on’ dyskinesias: with dystonic movements, chorea
• ‘off’ dyskinesias: dystonic postures, especially of the feet
• diphasic dyskinesias: most often manifest as a pattern of dyskinesia, both at the beginning and end of the levodopa dosing interval.

Dyskinesias may be improved by small reductions in the levodopa dose and the addition of a dopamine agonist to help maintain motor control. Amantadine may also be helpful in reducing dyskinesias and motor fluctuations. Diphasic dyskinesias may respond to very small dosing intervals that in some cases will only be achieved using a (home-made) liquid levodopa preparation or infusion of levodopa or dopamine agonists, such as lisuride and apomorphine. Surgery (pallidum and subthalamic nucleus) can also be helpful.

Drug Failure
A phenomenon that usually appears in the afternoon or evening, levodopa failure may be related to delayed gastric emptying or inadequate absorption. Agents that improve gastric motility or dietary changes may help.

Freezing
This is a type of akinesia that can occur in the ‘on’ – but more often the ‘off’ state – which often involves difficulty in starting to walk or sudden immobility when actually walking or performing a task. The cause is enigmatic but is sometimes aided by visual cues, indicating a striatal loop dysfunction of the peripheral vision. Freezing appears to be exacerbated by stress. Apomorphine is helpful and there is some suggestion that amantadine may also be effective in relieving freezing in people with PD.

Postural Instability
Instability is one the common feature of advanced PD and is unresponsive to levodopa. In fact, levodopa may simply allow patients to walk and consequently risk falling. There is no effective treatment for postural instability; mobile patients at risk should be supplied with a walking frame or other such device that will minimise the risk.

Gait Disturbance
The slow, shuffling walk is a frequent feature of PD. The problem arises from the asymmetry of walking, with the person with PD regularly shifting his or her weight from side to side. There may also be problems with initiating walking (start hesitation) and, for those with postural instability, heightened risk of falling. Optimal medication is paramount, but physical therapy can help to minimise the problem by teaching the person with PD techniques which help control weight shift and starting problems.

Non-pharmacological Treatment

Non-pharmacological interventions can help minimise handicap and improve the quality of life of people with PD and their carers. They are best provided as part of an integrated treatment programme by a multi-disciplinary team that includes:

• physiotherapists: to maximise functional ability and minimise secondary complications through movement rehabilitation
• occupational therapists: to maintain optimal levels of self-care, work and leisure activity for as long as possible
• speech and language therapists: to help with speech disorders or dysarthria and dysphagia that result from disturbances in muscle control
• continence nurses: for bladder disturbances in advanced PD
• dieticians: to minimise weight loss that is often seen in PD
• psychologists: to assist in the evaluation of psychiatric symptoms that may be disease or medication related
• PD nurse specialists: to co-ordinate care and provide an important link between the patient and carer/relative and primary and secondary care.

Surgery
Manifest limitations of long-term pharmacological treatment of PD, together with advances in surgical techniques and an understanding of functional central nervous system anatomy, have led to the use of surgery when refractory symptoms are disabling. Some examples of such interventions include:

• pallidotomy – helpful with motor fluctuations and somewhat helpful in tremor, ‘on/off’ problems and dyskinesias, but has little effect on balance or gait disturbances. Bilateral pallidotomy may cause cognitive impairment and there is a risk of effects on the visual field
• thalamotomy – benefits tremor, although with bilateral thalamotomy there is a high risk of adverse effects on speech and swallowing that must be balanced against any possible benefits
• chronic deep brain stimulation (DBS) – has effects similar to thalamotomy, with the advantage that it is reversible if required and the effects can be modulated over time as well as allow for bilateral surgery. There are good long-term data on tremor reduction with DBS in the VIM region. DBS in the Gpi nucleus can reduce dyskinesias, akinesia and rigidity and has long lasting effects. DBS in the subthalamic nucleus is a relatively novel approach, but a 10-year follow-up of some people with PD who have had DBS has been made. Prominent anti-parkinsonian effects can be obtained, allowing for marked drug reductions (about 50%) over time (The Deep Brain Stimulation for Parkinson’s Disease Study Group, 2001; Volkman et al, 2002).

Future Possibilities

Whilst all of the interventions currently available are directed at symptomatic relief, intensive research is underway aimed at preventing, arresting or reversing the progression of PD.

New symptomatic treatments
These conventional drugs are aimed at differing targets that include:

• adenosine A2A antagonists
• opioid antagonists
• NMDA antagonists.

Neuroprotective Agents
These agents are aimed at arresting or slowing the processes of cell death, mainly using pharmacologic agents to inhibit apoptosis. It has been suggested that some existing PD medications may have such properties, but there is very little evidence to confirm this. Newer approaches include:

• cyclo-oxygenase 2 inhibitors
• neurotrophic factors
• non-immunosuppressive immunophilins.

Cell Implants
Replacement of neurons through transplantation of foetal cells and stem cells has been undertaken clinically with variable results, but with sufficient success in a few cases to encourage efforts to refine and control the process. Approaches under active investigation include immortalised cell lines and neuronal precursor cells.

Cell Regeneration
It is known that the growth factors involved in peri- and post-natal brain development remain in the adult brain, but are inhibited. Processes that could suspend such inhibition are under active research, as are methods to replace growth factors.

Gene Therapy
The genetic changes associated with central nervous system cell death provide another avenue to avert or arrest degenerative changes. Research efforts include ex-vivo methods using autologous cells and in vivo methods using viral vectors or direct plasmid DNA transfer.