Should advanced therapies be started earlier in the treatment of Parkinson’s disease?

Posted in Sponsored Feature on 28th May 2013

Highlights of a debate held at the World Congress on Controversies in Neurology (CONy), 12 April 2013, Istanbul, Turkey

This article was commissioned by Britannia Pharmaceuticals Ltd and was written by Helen Lawn & Associates. The debate was part of the Britannia sponsored CME accredited plenary session on Parkinson’s disease – held on 12 April during the recent CONy Congress in Istanbul.

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In deciding when to start advanced therapies in Parkinson’s disease (PD), the question arises as to how the advanced stage of the disease is defyned. The traditionally held view is that so-called advanced treatments – continuous subcutaneous apomorphine infusion, levodopa/carbidopa intestinal gel (LCIG) and deep brain stimulation – should be used at the end of the advanced stage of PD and not before. However opinions now differ as to when the advanced stage of PD starts and whether these advanced treatments could be effective if introduced much earlier, at the point where patients start to deteriorate despite optimal oral treatment and/or at the start of unpredictable response-fluctuations.

The spectrum of PD covers a potential 40-year span. Professor Okan Dogu, (Mersin University School of Medicine, Turkey) outlined that there is a premotor phase, where precursor symptoms such as hyposmia, constipation and REM sleep changes indicate the onset of neurodegeneration. These symptoms can occur 5–10 years before motor complications become evident and PD is actually diagnosed. Advanced PD is characterised by motor complications refractory to oral treatment, as well as non-motor symptoms. Advanced PD is not late-stage Parkinson’s disease, however, when symptoms are refractory to all conventional therapies.

Professor Dogu conceded that motor fluctuations and dyskinesia are poorly controlled by current oral medications and continuous delivery of dopaminergic drugs using non-oral therapy or deep brain stimulation (DBS) should be used whenever motor and non-motor complications fail to respond to conventional oral therapy. However for Dr Teus van Laar (Groningen University Medical Center, The Netherlands) advanced PD treatments are currently started too late (and sometimes neglected altogether), with a clear impact on social function and activities of daily living. In his view, the timing of these therapies is crucial, because the therapeutic window narrows as PD progresses.

Dr van Laar believes advanced PD is defined by the occurrence of unpredictable on-off fluctuations and/or severe hyperkinesia not responsive to oral treatment. Most patients show these symptoms within 10 years of diagnosis. However, he noted that in The Netherlands there are 45,000 patients with PD and one-third of these will have unpredictable random fluctuations, around 10% of which are really troublesome (i.e. 1500 patients), yet figures show that only 10% of these 1500 patients are receiving adequate therapy, indicating undertreatment.

If advanced treatments are started too late in the course of PD, the clinical outcome is not as positive as it might be with earlier use. Inclusion data from several studies on LCIG and continuous apomorphine infusion show that patients are included in these studies 7–8 years after the start of unpredictable fluctuations, with a huge impact on quality of life1,2. Dr van Laar also presented data from the recent EARLY STIM trial3 supporting this hypothesis, showing that early DBS offers benefits in terms of patient-rated measures of quality of life and motor function, even in patients already receiving best medical treatment. For Dr van Laar, the message from this study is that if advanced treatments are started while there is still room for improvement then there is longer-lasting benefitt. This means treating younger patients earlier in the course of their disease.

However, while Professor Dogu conceded that all three advanced therapies are powerful strategies for advanced PD, in his view their side effects, invasiveness and cost limit their use in clinical practice. Also important is the sustainability of both continuous apomorphine infusion and LCIG, with drop-out rates on account of adverse effects. Patients should therefore be carefully selected for these treatments.

For Professor Murat Emre (Istanbul University, Turkey), who summed up the debate, treatment decisions depend on patient, environment and context. For example, a PD patient still of working age living in a complex social environment may need advanced treatment earlier than an older, less active patient. For this reason, chronological age is not the best guide when considering advanced treatment.

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1.Garcia Ruiz PJ, Sesar Ignacio A, Ares Pensado B et al. Mov Disord 2008; 23(8): 1130-6.

2.Fasano A, Ricciardi L, Lena F et al Eur Rev Med Pharmacol Sci 2012; 16(1): 79-89.

3.Schuepbach WM, Rau J, Knudsen K et al. N Engl J Med 2013; 368: 610-22.

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