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At the heart of general practice since 1960

Modern management of Parkinson's disease

Dr Richard Davenport explains recent advances in the management of this neurodegenerative disease

arkinson's disease (PD) is one of the commonest, and certainly most treatable, of all the neurodegenerative disorders. It is eminently newsworthy, and neurosurgical interventions are often particularly attractive to the media.

This year many patients have been asking for the 'Bristol brain surgery' treatment, referring to the use of glial derived neurotrophic factor (GDNF) via surgically implanted infusion devices. Although this was only an abstract at a US meeting reporting five patients with advanced PD1 with no substantial results yet available, it was widely reported in the UK press, together with a dramatic X-ray of the bilateral infusion pumps in one patient.

As important as these advances are, they rarely have immediate implications for most patients. Rather less media prominence was given to exciting new data regarding the use of the newer non-ergot dopamine agonists presented at the same meeting, yet these treatments are far more widely applicable2.

Diagnosing Parkinson's disease

Parkinsonism refers to a clinical syndrome comprising of tremor, rigidity, bradykinesia (slowness of movement) and postural instability.

Parkinson's disease is the commonest cause of parkinsonism, but the two are not synonymous. About 20 per cent of patients with parkinsonism will turn out to have a variety of other disorders such as drug-induced or vascular parkinsonism, or a Parkinson-plus disorder such as multiple system atrophy or progressive supranuclear palsy.

It is worth emphasising that PD remains a clinical diagnosis, and there are no routinely available diagnostic tests. For the expert, differentiating between parkinsonism and non-parkinsonism is usually (but not always) straightforward. It is much less easy (even for experts) to distinguish idiopathic PD from the other forms of parkinsonism.

Strictly speaking, the diagnosis of PD requires neuropathological confirmation, but this is scarcely helpful in clinical practice, and a pragmatic working definition of PD might be a levodopa responsive parkinsonian syndrome.

Ideally, most patients with possible parkinsonism should be referred to a physician with an interest in PD as soon as the diagnosis is considered and before any treatment is started3, 4, and that they be seen within three months of referral. It is regrettable that this ideal is difficult to achieve in many parts of the UK, but this should not stop us from attempting to improve the service. At the very least, I think it reasonable for GPs to discuss patients with a specialist, especially if they are considering treatment, even if the specialist is not able to see the patient immediately.

PD is a progressive illness, and it is useful to consider four evolutionary stages ­ diagnosis, maintenance, complex and palliative (not all patients will complete this cycle5,6). The first hurdle is the diagnostic stage.

Once a patient begins treatment, he or she will require treatment indefinitely, and therefore a crucial part of management is a careful explanation of the disease, its implications, and the aims of treatment and its potential complications (see box on page 46).

Specialist nurses and the Parkinson's Disease Society can play an invaluable role in this area, and I refer all newly diagnosed patients I see to both the PDS and my nurse specialist.

Neuroprotection

At present, there is no conclusive evidence that any of the current drugs are neuroprotective, but there are some encouraging data suggesting the newer non-ergot dopamine agonists may have neuroprotective properties. Two recent studies using functional imaging as a surrogate marker of disease progression have been reported, with similar results.

In the REAL-PET study, patients were randomised to receive ropinirole or levodopa (LD) once it was decided that treatment was required on symptomatic grounds7. All patients had a baseline positron emission tomogram, with repeat imaging at two years. Patients in the ropinirole group showed significantly less deterioration in their PET imaging than the LD group, suggesting that ropinirole may be neuroprotective compared with LD. Similar data using pramipexole and single photon emission computed tomography (SPECT) have also been reported8. These results have reassured me that many patients should ideally be treated with DA agonists initially (see below).

Symptomatic treatment

Diagnosis and maintenance stages

Although the neuroprotective data are encouraging, I rarely start medical therapy until the patients' symptoms are starting to impinge on their everyday life.

There is considerable controversy regarding the optimal initial treatment, and the decision will be based upon a number of factors including the patient's age, functional and cognitive status, predominant symptoms, and their own wishes. Dopaminergic therapies are most effective at alleviating bradykinesia and stiffness, and the two main choices are between LD and dopamine agonists; all patients will end up on LD sooner or later, and it remains the cheapest, most effective, and best-tolerated treatment for PD. There is no evidence to support the use of modified-release LD over standard preparations, although CR preparations may be useful symptomatically overnight9.

The concern regarding LD is the development of motor complications (see box, right) which occur in most, if not all, patients within a few years of LD treatment; the precise pathophysiological mechanisms of these complications remain uncertain, but they are a complex result of progressing PD and chronic LD treatment. There is now reliable evidence to show such complications are far less common with dopamine agonist monotherapy10, and many specialists favour this group of drugs as initial therapy ­ my own practice is to start either ropinirole or pramipexole in suitable patients.

In patients with cognitive impairment, I am more likely to favour LD and avoid agonists, as they do not tolerate agonists well. If the patient is unresponsive or unable to tolerate the agonist, I then substitute LD, although I try to keep the dose as low as possible. I also use agonists as adjunctive therapy in patients who have already been started on LD by others in an attempt to keep the dose low.

For those patients with tremor predominant disease, I often try non-dopaminergic therapies first, such as

?-blockers or anti-cholinergics. The response of tremor to dopaminergic therapies is unpredictable.

Complex and palliative stages

As motor complications intervene (usually after several years of LD treatment), management becomes much more difficult and complicated. Again, it is essential to be realistic with patients about what might be achievable, and I often refer to the 'therapeutic tightrope', which becomes narrower and narrower as time goes by [see box above].

Specialist help is usually appropriate, although no doctors find this stage of the disease straightforward.

In some situations, especially when the patient's quality of life is poor,

and there are no further therapeutic options available, simplifying their prescription by with drawing many drugs other than LD may be appropriate (palliative stage).

Non-motor symptoms

In addition to the motor symptoms of PD, there are a large number of non-motor symptoms including sleep disorders, anxiety and depression, cognitive changes, sexual and sphincter dysfunction, constipation, pain and fatigue, which are not helped (and in some instances may be exacerbated by) the treatments listed above.

Some of these symptoms are treatable, in particular depression, and it is vital not to forget these features which may impair the quality of life even more than the motor symptoms. There are also a number of motor symptoms, such as freezing and falling, which are common in PD, and usually refractory to medical treatment.

There are still no routinely available diagnostic tests

for Parkinson's~

Modern management

of Parkinson's disease

1. Medical treatments for motor symptoms of Parkinson's disease

Disadvantages

Associated with long-term motor complications

Not effective in all patients, less well tolerated, expensive, complicated titration regimes; ergot agonists rarely associated with serious side-effects such as pulmonary/pleural fibrosis

Suggestion in single study of increased mortality

Exacerbates adverse effects of LD

Anti-cholinergic side effects and may exacerbate cardiac failure

Often poorly tolerated, especially in elderly

1. Medical treatments for motor symptoms of Parkinson's disease

Symptom

Wearing off: individual doses of LD effective for shorter period of time. Timing initially predictable.

LD induced dyskinesias (LIDs): choreoathetoid (writhing) movements often affecting head, neck, upper limbs. Range from asymptomatic to utterly disabling.

On-off phenomena: wearing off and LIDs become increasingly unpredictable, and end-stage is patient who cycles randomly through the day either 'on' with marked dyskinesias (drugs working), to 'off' (rigid, drugs not working).

Therapeutic options

·Increase number of LD doses or

use CR preparation

·Add entacapone

·Add DA agonist

·Add selegeline

·Reduce total LD dosage

·Add DA agonist (to enable reduction

in LD dosage without losing anti-PD

effect)

·Add amantadine as anti-dyskinetic

agent

·All of above

·Apomorphine (subcutaneous

preparation only); either as prn

injections for 'off' or constant infusion

via pump

·Neurosurgery

2. Long-term motor complications of Parkinson's disease

in association with levodopa treatment

Key points

 · PD is a common, progressively disabling disease, with numerous motor and non-motor symptoms. Some of these are responsive to treatment, others not.

 · Early referral is appropriate for most patients with a suspected diagnosis of PD, for confirmation of diagnosis and guidance on the initial therapy.

 · Currently, there is no cure. There are data to support the suggestion that the newer non-ergot dopamine agonists may be neuroprotective, but further work is required.

 · Effective symptomatic treatment is available, although long-term complications are common. Many patients may be best treated initially with dopamine agonists rather than levodopa.

Notes

Cure: reversal of the established pathological damage, and thereby return the patient to normal function. Not currently available.

Disease modifying treatment (neuroprotection): treatment which will halt/slow down the progressive degenerative changes, thus preventing further clinical deterioration. Still no convincing evidence that any treatment is definitely neuroprotective, but some intriguing evidence from recent studies with dopamine agonists (see text).

Symptomatic: treatment to alleviate symptoms, although no effect on disease progression.

Advantages

Most effective drug for treating motor PD symptoms

­ cheap, easy to use

Much lower frequency of motor complications as monotherapy, and some may be neuroprotective; may be used as adjunctive therapy to keep LD dose low

Initial reports of neuroprotection now discounted, but has a symptomatic effect

Used only in conjunction with LD, and may help smooth effect of LD

Mild symptomatic therapy, now re-emerging as

anti-dyskinetic therapy

Occasionally effective for tremor

Drugs available

Co-careldopa (Sinemet®)

Co-beneldopa (Madopar®)

Dispersible, standard and slow-release preparations available

Ropinirole (ReQuip®)

Pramipexole (Mirapexin®)

Cabergoline (Cabaser®)

Pergolide (Celance®)

Bromocriptine

Apomorphine (Britject®)

Selegeline (Eldepryl®

or Zelapar®)

Entacapone (Comtess®)

Amantadine

Benzhexol, orphenadrine

Class of drug

Levodopa: the most effective anti-PD drug available, cheap, but associated with subsequent motor complications

Dopamine agonists

MAOI type B inhibitors

COMT inhibitors

Anti-viral

Anti-cholinergics

References

01 Gill SS et al. Intraparenchymal putaminal administration of glial-derived neurotrophic factor in the treatment of advanced Parkinson's disease. Neurology 2002;58(suppl 3):A241.

02 Findley LJ, Baker MG. Treating neurodegenerative diseases. What patients want is not what doctors focus on. BMJ 2002;324:1466-7.

03 Working Together. Improving primary care for people with Parkinson's disease London: Parkinson's Disease Society, 2001.

04 The Parkinson's Disease Consensus Working Group. Updated Guidelines for the Management of Parkinson's Disease. Hospital Medicine 2001;62:456-70.

05 Clarke CE. Parkinson's Disease in Practice. London: Royal Society of Medicine Press Ltd, 2001.

06 Quinn NP (ed). Clinical Neurology: International Practice and Research: Parkinsonism. London: Bailliere Tindall, 1997.

07 Whone AL et al. The REAL-PET Study: Slower progression in early Parkinson's disease treated with ropinirole compared with L-dopa. Neurology 2002;58(suppl 3):A82-3.

08 Marek K and the Parkinson Study Group. Pramipexole versus levodopa: Effects on Parkinson's disease progression assessed by Dopamine transporter imaging. Neurology 2002;58(suppl 3):A82.

09 Clarke C, Moore AP. Modified release levo-dopa (v immediate-release LD) in people with early disease. Clinical Evidence. London: BMJ Books, 2002.

10 Rascol O et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with Ropinirole or Levodopa.

N Eng J Med 2000;342:1484-91.

Useful contact

Parkinson's Disease Society

Website: www.parkinsons.org.uk

Telephone: 0207 9831 8080

Email: inquiries@parkinsons.org.uk

or branch.info@parkinsons.org.uk

(for local branch contacts)

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